Application for approval to import HFO- 1234yf for release · 2019. 4. 6. · Overall evaluation and recommendation ... We note that HFO-1234yf is expected by the applicant to have

EPA STAFF REPORT

www.epa.govt.nz

Application for approval to import HFO-1234yf for release

APP202547

November 2016

2

Application for approval to import HFO-1234yf for release (APP202547)

November 2016

Overview

Substance HFO-1234yf

Application code APP202547

Application type To import or manufacture for release any hazardous substance

under Section 28 of the Hazardous Substances and New Organisms

Act 1996 (“the Act”)

Applicant Honeywell International Inc.

Purpose of the application To import HFO-1234yf, a gas for use in refrigeration and air

conditioning

Date application received 5 July 2016

Submission period 18 July 2016 – 29 August 2016

Submissions Eleven submissions were received

Information requests and

time waivers

The timeframe for submissions was waived under section 59 of the

Act to allow a submission after submissions had closed.

Further information was requested under section 58 of the Act, and

consequently the timeframe for consideration of this application was

waived under section 59 of the Act.

3


November 2016

Table of Contents

Overview .................................................................................................................................................... 2

1. Executive summary ........................................................................................................................ 4

2. Background ..................................................................................................................................... 6

3. Process, consultation and notification ........................................................................................ 8

4. Hazardous properties .................................................................................................................. 10

5. Submissions ................................................................................................................................. 10

6. Risk, cost, and benefit assessment............................................................................................ 16

7. The effects of the substance being unavailable ....................................................................... 21

8. Controls ......................................................................................................................................... 21

9. Overall evaluation and recommendation ................................................................................... 23

Appendix A: Controls recommended for HFO-1234yf ........................................................................ 24

Appendix B: Hazard classifications ...................................................................................................... 30

Appendix C: Physico-chemical properties .......................................................................................... 32

Appendix D: Mammalian toxicology ..................................................................................................... 33

Appendix E: Ecotoxicology ................................................................................................................... 73

Appendix F: Confidential information .................................................................................................. 81

Appendix G: Standard terms and abbreviations ................................................................................. 82

4


November 2016

1. Executive summary

1.1. Honeywell International Inc. applied to import the substance 2,3,3,3-tetrafluoropropene, also known as

HFO-1234yf or R1234yf. This substance is a flammable gas and is intended for use as a heat transfer

agent in refrigeration systems and in air conditioning. This includes use in blends with other

refrigerants.

1.2. HFO-1234yf has a low global warming potential (GWP) compared to many existing refrigerants, and it

is not ozone depleting.

1.3. We recommend that the hazard classification that is applicable to HFO-1234yf based on product data,

the composition of the substance, and the properties of its components, is 2.1.1A.

Hazard Endpoint EPA staff classification

Flammable Gas 2.1.1A

1.4. The application was publicly notified and eleven submissions were received.

Submissions

1.5. There was strong support among submitters for the approval of HFO-1234yf.

1.6. Six of the submitters requested to speak at a hearing.

1.7. A significant issue raised by submitters is whether the current training system requirements will ensure

that users of HFO-1234yf and other flammable refrigerants are adequately trained in the safe handling

of these substances. Submitters expressed concern that without appropriate training, people could

attempt to retrofit existing air-conditioning systems that are not designed for flammable gases with

HFO-1234yf. Several submitters considered that Approved Filler Certificates should be required, and

that these certificates should be specific to flammable gases.

1.8. Several submitters noted the ASHRAE1 Standard 34 classification used in the refrigerant industry for

HFO-1234yf of A2L – ‘mildly flammable refrigerant’. Submitters noted that more flammable refrigerants

were likely to be used in future due to the low GWP refrigerants largely being flammable. They

expressed concern that the highly flammable but cheaper substances isobutane, propane and LPG

could be used in favour of the less flammable HFO-1234yf if they were considered by users of

refrigerants to have the same degree of flammability. One submitter noted that inappropriate use of

butane or other hydrocarbons has already been observed in Australia in automotive refrigeration.

1.9. A wide range of other concerns were also expressed, which are discussed in detail in this report.

1.10. WorkSafe provided information to the EPA regarding the submissions. They noted that existing

requirements under the Health and Safety at Work Act 2015 and associated regulations impose a duty

1 The American Society of Heating, Refrigerating and Air-Conditioning Engineers. Standard 34 relates to the Designation and

Safety Classification of Refrigerants

5


November 2016

on persons conducting a business or undertaking (PCBUs). PCBUs have a duty towards every person

carrying out work of any kind, using plant (equipment) of any kind, or dealing with a substance of any

kind that is capable of causing a risk in a workplace. They considered that this duty ensures that

anyone working with flammable gases is required to be trained in the safe use of refrigerant gases that

are flammable. There are also requirements for plant to be designed and manufactured so as not to

cause risks to the health and safety of persons.

1.11. WorkSafe noted that the Electricity (Safety) Regulations 2010 do not allow a flammable gas to be

refilled into a system that is not designed for the substance.

1.12. We acknowledge the release of two recent Australian/New Zealand Standards regarding refrigerants,

AS/NZS 817:2016 and AS/NZS 5149.1-4:2016 that incorporate differences in the requirements

between A2L refrigerants such as HFO-1234yf and more highly flammable refrigerants. We have

taken this and information provided by WorkSafe New Zealand into account in our risk assessment.

Risk assessment

1.13. We did not undertake a quantitative assessment of the risks to human health and the environment

because HFO-1234yf does not have human health or ecotoxicological hazard classifications and is not

expected to cause significant effects as a result of any toxicological or ecotoxicological hazards.

1.14. However, there are some potential risks associated with the physical properties of the substance,

including its flammability, the potential for cryogenic burns due to rapid evaporation of the liquefied

gas, and the potential for asphyxiation in enclosed spaces where there is poor ventilation.

1.15. We propose to apply the default controls for a 2.1.1A flammable gas. We propose additional label

information requirements to communicate the potential for cryogenic and asphyxiation effects on

people handling HFO-1234yf.

1.16. We consider that the potential risks to human health and aquatic and terrestrial environments are

negligible with the proposed controls in place.

1.17. We consider that the potential risks to Māori culture or traditional relationships with the environment

are negligible.

1.18. We note that the approval of HFO-1234yf could assist New Zealand in complying with its obligations

under the Montreal Protocol, New Zealand’s international climate change obligations, and related

agreements, as a result of its low global warming potential and zero ozone depleting potential.

1.19. We note that HFO-1234yf is expected by the applicant to have improved energy efficiency compared

with existing refrigerants it is intended to replace.

1.20. Overall, we consider that there are significant benefits associated with the approval of HFO-1234yf,

including financial benefits to the refrigerant industry, a reduction in harm to the environment

compared with existing refrigerants, and benefits with respect to New Zealand’s international

obligations.

6


November 2016

1.21. We consider that the risks of this substance are negligible, and that the significant benefits of the

substance outweigh any risks or costs. Accordingly we recommend that the application be approved

with controls.

2. Background

2.1. 2,3,3,3-tetrachloropropene, which is referred to as HFO-1234yf throughout this report, is a flammable

gas to be used as a heat transfer fluid for refrigeration and air conditioning systems, including those in

passenger cars. It will also be a component of gas mixtures for use in refrigeration and air conditioning

systems.

2.2. The applicant intends that the substance will be imported into New Zealand in 4.5 kg and 11.3 kg net

fill steel cylinders, and the cylinders will be transported within New Zealand by road and sea.

2.3. HFO-1234yf is intended to be disposed of by recycling or controlled destruction.

Global warming potential and ozone depletion potential

2.4. Global warming potential (GWP) is a relative measure of how much heat a greenhouse gas causes to

be trapped in the atmosphere. It is usually expressed by comparison of the warming potential with the

same mass of carbon dioxide, where the GWP of carbon dioxide is exactly 1. GWP values differ based

on the timeframe for comparison. GWP values given in this report are 100-year time horizon values.

Where possible, these values are taken from the International Panel on Climate Change (IPCC)

Fourth Assessment Report: Climate Change 20072, and these values are the values most frequently

used in international literature to compare GWP.

2.5. Ozone depletion potential (ODP) is a relative measure of how much degradation a substance can

cause to the ozone layer. It is usually expressed by comparison with the ODP of

trichlorofluoromethane (R-11), which is fixed at exactly 1. ODP values given in this report, with the

exception of the value for HFO-1234yf, are taken from New Zealand’s Ozone Layer Protection

Regulations 19963, Schedule 5, Annexes A-E.

2.6. HFO-1234yf has a GWP of 4 according to information provided by the applicant. It does not contain

bromine or chlorine atoms that are involved in the catalytic destruction of ozone in the stratosphere,

and therefore is effectively not ozone depleting (ODP = 0), based on information provided by the

applicant.

2 The table of direct GWP values and related information is on pages 212-213 of the report, available at:

http://www.ipcc.ch/pdf/assessment-report/ar4/wg1/ar4-wg1-chapter2.pdf

3 http://www.legislation.govt.nz/regulation/public/1996/0222/18.0/whole.html

http://www.ipcc.ch/pdf/assessment-report/ar4/wg1/ar4-wg1-chapter2.pdf

http://www.legislation.govt.nz/regulation/public/1996/0222/18.0/whole.html

7


November 2016

Other refrigerants mentioned in this report

2.7. Several other refrigerants and classes of refrigerants are mentioned in this report. These are

described briefly in this section, and names used in the rest of the report are given in bold.

2.8. Liquid carbon dioxide, or R-744, is able to be used as a refrigerant. It is non-toxic, non-ozone

depleting, non-flammable, and has a GWP of 1. While it is a highly efficient refrigerant, it needs to be

used at high pressures that require specially designed components to prevent equipment failure from

rapid gas expansion.

HCFCs

2.9. Hydrochlorofluorocarbons, or HCFCs are a family of refrigerants containing hydrogen, chlorine,

fluorine and carbon atoms. These substances are ozone depleting and their use has been phased out

under the Montreal Protocol. These substances also have significant global warming potential, with

GWP values ranging from 77 – 2310.

HFCs

2.10. Hydrofluorocarbons, or HFCs are a family of refrigerants containing hydrogen, fluorine, and carbon

atoms. Substances in this class of refrigerants have insignificant ozone depleting potential, but have

high global warming potential. These substances are subject to the Climate Change Response Act

2002.

2.11. Difluoromethane is an HFC known as R-32 or HFC-32. R-32 is not ozone depleting and has a GWP of

675. R-32 is flammable, and is classified as 2.1.1A in New Zealand.

2.12. Chlorodifluoromethane is an HFC known as R-22. R-22 has an ozone-depleting potential of 0.05 and

a GWP of 1810.

2.13. Pentafluoroethane is an HFC known as R-125. It is not ozone depleting and has a GWP of 3500.

2.14. 1,1,1,2-tetrafluoroethane is an HFC known as R-134a, HFC-134a or norflurane. R-134a is not ozone

depleting and has a GWP of 1430. It is non-flammable. HFO-1234yf, and blends containing HFO-

1234yf, are intended by the applicant to be a replacement for R-134a and blends containing R-134a.

2.15. 1,1,1-trifluoroethane is an HFC known as R-143a. It is not ozone depleting and has a GWP of 4470.

HFOs

2.16. Hydrofluoroolefins, or HFOs are a new family of refrigerants. Substances in this class of refrigerants

have insignificant ozone depleting potential, and have lower global warming potential than HFCs. This

application for HFO-1234yf is the first application under the HSNO Act 1996 for a hydrofluoroolefin

substance. These substances are not subject to the Climate Change Response Act 2002.

2.17. HFO-1234ze, or trans-1,3,3,3-tetrafluoroprop-1-ene is another HFO. It has a GWP < 1 and has a (Z)

and an (E) isomer, the latter of which is used in some blends with HFO-1234yf.

8


November 2016

Blends

2.18. A wide variety of blended refrigerants is available. The following blends are referred to in this

document.

2.19. R404A is a blend containing R-143a (52%), R-125 (44%), and R-134a (4%). It has a GWP of 3922.

2.20. R448A, also known as Solstice N40 is a blend containing the HFOs HFO-1234yf (20%) and HFO-

1234ze (E-isomer) (7%) as well as R-32 (26%), R-125 (26%), and R-134a (21%). It has a GWP of

1273.

International obligations

2.21. The United Nations Framework Convention on Climate Change (UNFCCC) is an international treaty

involving commitments to reduce greenhouse gas emissions. New Zealand has taken an emissions

reduction commitment for the period 2013-2020 under the UNFCCC. New Zealand implemented the

Emissions Trading Scheme through the Climate Change Response Act 2002 in recognition of its

commitments. HFCs are included in the UNFCCC and in the New Zealand Emissions Trading

Scheme.

2.22. The Montreal Protocol on Substances that Deplete the Ozone Layer is an international treaty

regarding the phasing out of production of substances that are responsible for ozone depletion. New

Zealand has implemented its obligations under the Montreal Protocol through the Ozone Layer

Protection Act 1996 (OLPA) and its associated regulations.

2.23. The Montreal Protocol and OLPA cover, among other substances, HCFCs.

2.24. In October 2016 the Kigali Amendment to the Montreal Protocol was adopted. The Kigali Amendment

is an agreement to also phase out the use of HFCs.

3. Process, consultation and notification

3.1. The application was formally received on 5 July 2016.

3.2. The Ministry for the Environment, WorkSafe New Zealand (“WorkSafe”), and the Agricultural

Compounds and Veterinary Medicines (ACVM) group of the Ministry for Primary Industries were

advised of the application and notified of the submission period. No comments were received.

3.3. The application was publicly notified and was open for submissions from 18 July to 29 August 2016.

3.4. The application was publicly notified because it was considered it would be of significant public

interest and because the EPA sought information from the refrigerant industry and other affected

parties regarding the management of the risks related to the flammability of HFO-1234yf.

3.5. Eleven submissions were received from:

Sythree Pty Ltd

9


November 2016

Climate Controls Companies Association and the Institute of Refrigeration Heating and Air

Conditioning Engineers (“CCCA” and “IRHACE” – joint submission)

Refrigerant License Trust Board (“RLTB”)

Refrigerant Recovery New Zealand Limited (“RRNZ”)

Chemiplas

Te Rūnanga o Ngāti Whātua

CoolCar Air-Conditioning Centres (“CoolCar”)

Tru-Test Ltd

Motor Industry Association (Inc) (“MIA”)

VASA Automotive Air Conditioning, Electrical and Cooling Technicians of Australasia (“VASA”)

Motor Trade Association Inc (“MTA”)

3.6. CCCA/IRHACE did not state support or opposition to the application. The remaining ten submitters

supported the application.

3.7. The timeframe for the close of submissions was waived under section 59 of the Act to allow the

submission of the Motor Trade Association to be accepted after submissions had closed.

3.8. Six submitters requested to speak at a hearing – CCCA/IRHACE, RLTB, RRNZ, CoolCar, Tru-Test

Ltd, and VASA.

3.9. During the evaluation of the application, the EPA determined that further information was required in

order to complete the evaluation and risk assessment. Further information was requested from

WorkSafe and the New Zealand Fire Service under section 58 of the Act and the timeframe for holding

a hearing for this application was waived under section 59 of the Act. Information was received from

WorkSafe on 20 October 2016.

3.10. In preparing this report, the following documents and information were taken into account:

the application form

confidential material submitted by the applicant with the application form, including:

toxicological and ecotoxicological studies on HFO-1234yf

physical properties and physical hazard information for HFO-1234yf

the submissions

information received from WorkSafe

other available information

10


November 2016

4. Hazardous properties

4.1. We determined the hazard profile of HFO-1234yf (Table 1) as described in Appendix B.

4.2. Physico-chemical, mammalian toxicology and ecotoxicology studies were provided for HFO-1234yf.

Information from these studies and mixture rules were used to classify the substance. Based on these

studies we determined that no human health or ecotoxicological classifications are appropriate for

HFO-1234yf.

4.3. HFO-1234yf is classified as a 2.1.1A flammable gas: high hazard because its range of flammability in

mixture with air (6.0 – 13.3%) satisfies one of the two criteria that result in classification as 2.1.1A –

specifically the criterion that the gas is ignitable in a mixture of 13% or less by volume with air.

Table 1 Hazard classifications of HFO-1234yf

Hazard Endpoint Applicant classification EPA Staff classification

Flammable Gas 2.1.1A 2.1.1A

5. Submissions

5.1. There was strong overall support for the application amongst the submissions, with no submitters

opposing the application. The submissions were particularly consistent in their support for the move to

refrigerants that are not ozone-depleting and that have much lower global warming potential than

currently used refrigerants such as HFCs.

5.2. We have used the information gained from submissions, where relevant, to inform our risk

assessment. Key issues raised in submissions are highlighted below.

Approved Filler Certificates and training requirements

Submissions

5.3. Several submitters noted the need for a robust training system for users of flammable refrigerants.

These submitters recommended that there be a requirement for appropriate trade qualifications for

handling flammable refrigerants, and a requirement for an Approved Filler Certificate. Chemiplas

noted that training was important so that HFO-1234yf is only used in systems designed for flammable

refrigerants.

5.4. These submitters considered that there is a need to widen the current minimum requirement to obtain

an Approved Filler Certificate (required for transferring a gas into a compressed gas cylinder) so that it

is also required for transferring gas into and out of a refrigeration system or unit. This was considered

important with flammable refrigerants due to the potential for overcharging these systems to cause a

catastrophic failure and result in human injury. Submitters also expressed concern should attempts be

made to retrofit existing air-conditioning systems to use HFO-1234yf.

5.5. Some submitters also considered that Approved Filler Certificates that are specific to refrigerant gases

should be required, rather than the certificate being obtained from courses that focus on other gases.

11


November 2016

5.6. Submitters also recommended that there be more stringent requirements around moderation and

review of Approved Filler Certificates.

5.7. These submitters considered that a restriction should be placed on the sale of refrigerants to ensure

that sale of refrigerants is only to persons with an Approved Filler Certificate and appropriate training

to use the substances. Similarly, the submitters recommended that the current voluntary wholesaler

restriction of refrigerant sale to persons with an Approved Filler Certificate be made into an

enforceable requirement among all wholesalers and anyone who imports or sells refrigerants.

5.8. RLTB considered that it should be mandatory for people working with mildly flammable and highly

flammable refrigerants under the ASHRAE Standard 34 on the Designation and Safety Classification

of Refrigerants to have an Approved Filler Certificate.

5.9. RLTB noted that a unit standard for Flammable Refrigerant Safety Awareness has been developed

and considered that this or a similar training course should be made a requirement.

EPA response

5.10. We note the concerns of several submitters regarding training requirements and the potential for

untrained users to handle the substance or refill equipment inappropriately.

5.11. WorkSafe noted that an Approved Filler Certificate is required by the regulations when discharging

from a refrigeration system into a compressed gas cylinder. WorkSafe did not agree with submitters

that an Approved Filler Certificate is required for transferring gas to a refrigeration system. They noted

that Regulation 9 of the Health and Safety at Work (General Risk and Workplace Management)

Regulations 2016 requires PCBUs to ensure all persons are provided the information training,

instruction or supervision they need to protect them from health and safety risks arising from the

PCBUs work. They noted that PCBUs have a duty towards every person who carries out work of any

kind, uses plant of any kind, or deals with a substance of any kind that is capable of causing a risk in a

workplace. WorkSafe considered that this duty ensures that anybody working with flammable

refrigerant gases is required to be trained in the safe use of flammable refrigerant gases.

5.12. WorkSafe noted the potential for retrofitting of existing air-conditioning systems to use HFO-1234yf,

and the potential for over-filling to cause a catastrophic failure. WorkSafe noted that regulation 20 of

the Electricity (Safety) Regulations 2010 does not allow a flammable gas to be filled into a system that

is not designed for the substance.

5.13. WorkSafe also noted that regulations 39-41 of the Health and Safety At Work Act 2015 place duties on

upstream PCBUs to design, manufacture and supply plant that is without risks to the health and safety

of persons.

5.14. We therefore consider that existing regulation addresses these concerns.

Benefits of HFO-1234yf

5.15. Sythree Pty Ltd considered that there are significant environmental benefits.

12


November 2016

5.16. Sythree Pty Ltd considered that use of HFO-1234yf and blends containing it in refrigeration will

provide cost savings for end users as a result of increased energy efficiency.

5.17. We note the benefits described by submitters, including cost savings for end users from increased

energy efficiency, and environmental benefits from using a refrigerant with low GWP and no ODP. We

have taken these benefits into account in our risk assessment of HFO-1234yf.

Changes to the Compressed Gases Regulations4

Submissions

5.18. Several submitters recommended changes be made to the Compressed Gases Regulations. This

includes the above recommendations related to Approved Filler Certificates.

5.19. CCCA and IRHACE requested a change in the Compressed Gases Regulations to allow greater

enforcement by the EPA or WorkSafe of the requirements for access to and safe use of refrigerants.

5.20. CCCA and IRHACE consider that a system should be introduced similar to the EU F Gas classification

of types of work requiring specific types of training. RLTB supported CCCA and IRHACE’s proposal.

EPA response

5.21. The EPA notes that WorkSafe responded to this issue. In its response it referred to Regulation 9 of the

Health and Safety at Work (General Risk and Workplace Management) Regulations 2016 that

provided requirements as described above in 5.11. They noted that they have many means by which

they can secure the health and safety of workers and workplaces, including education, engagement,

and enforcement. They noted that when using the enforcement lever, their Enforcement Decision-

Making Model assists inspectors when they are considering what enforcement, if any, is suitable for

the situation. WorkSafe noted that breach of Regulation 9 above is an enforceable offence.

Classification of refrigerants under the HSNO Act and AS/NZS Standards

Submissions

5.22. Multiple submitters noted that any regulatory changes for refrigerants will need to align with the joint

classification system set out in the revised version of AS/NZS 1677.2:1998 Refrigerating Systems and

its replacements AS/NZS 817:2016 Refrigerants – Designation and Safety Classification and AS/NZS

5149.1-4:2016 Refrigerating Systems and Heat Pumps – Safety and Environmental Requirements.

5.23. Several submitters noted that in the refrigerant industry HFO-1234yf is an A2L mildly flammable

refrigerant and that this is a new classification for certain flammable refrigerants under ASHRAE

Standard 34. This classification distinguishes HFO-1234yf and other A2L or B2L mildly flammable

refrigerants from more highly flammable refrigerants (classes A2, A3, B2 and B3). These submitters

considered that because of this classification there will need to be amendments to the charge limit

4 Hazardous Substances (Compressed Gases) Regulations 2004

13


November 2016

information for the storage and transportation of flammable refrigerants. Further discussion is included

below under “Flammability”.

5.24. Several submitters noted that while HFO-1234yf is classified as highly flammable under the New

Zealand HSNO system (which is based on the range of flammability in air), HFO-1234yf is a mildly

flammable gas according to the classification system of the ASHRAE Standard 34.

EPA response

5.25. HFO-1234yf is classified as a 2.1.1A flammable gas – high hazard under the Hazardous Substances

(Classification) Regulations 2001. This classification triggers a number of default controls to be applied

to HFO-1234yf to manage the risk from flammability. These controls apply standard requirements to

flammable gases regardless of the degree of flammability of the 2.1.1A gas, and we consider it

appropriate to retain these requirements.

5.26. The EPA notes that the classification system adopted by Standards Australia / Standards New

Zealand is not within the scope of this application process.

Flammability of the substance

Submissions

5.27. RRNZ noted that the applicant stated in their application that “most of the better performing blends

containing HFO-1234yf are non-flammable”. RRNZ expressed concern with this statement as they

noted that many blends containing this refrigerant are flammable. RRNZ also noted that the blends

containing HFO-1234yf that have GWP under 500 and are most likely to be used as long term

refrigerants are all flammable.

5.28. RRNZ also considered the application to be misleading in stating that the risks in using HFO-1234yf

“do not vary markedly from the HFC and HCFC refrigerants it will replace,” because other than R-32,

the HFC and HCFC refrigerants in common use in New Zealand are non-flammable. RRNZ noted that

in the past, the refrigeration industry has not been trained to handle flammable hazards due to the use

of non-flammable refrigerants.

5.29. CoolCar Air-Conditioning Centres and VASA noted that due to the high price of HFO-1234yf and the

rising price of R134a, consumers would seek cheaper alternatives. They expressed concern that given

HFO-1234yf and cheaper isobutane/propane or LPG would each have a 2.1.1A highly flammable gas

classification consumers may be misled into believing that these gases present the same level of

flammability risk when HFO-1234yf presents a much lower flammability risk than isobutane, pentane

or LPG. They reported that Australia has seen this issue with hydrocarbon gases being inappropriately

used as automotive refrigerants.

5.30. In response to the above concern, several submitters recommended that changes in the marketplace

from approval of HFO-1234yf should not have the unintended consequence of encouraging greater

14


November 2016

use of highly flammable hydrocarbon gases as refrigerants in systems that are not designed for their

use, and noted that this was the case in the Tamahere cool store fire.

5.31. The Motor Industry Association noted that some of their members do not support the use of HFO-

1234yf due to concerns regarding flammability. This is because of in-house testing showing that a

serious head-on collision in which the refrigerant line is severed can result in ignition of HFO-1234yf in

a hot engine compartment, whereas currently used R-134a does not ignite.

5.32. In contrast to some of the other submitters, the Motor Trade Association noted that it was their

understanding that the potential for fire as the result of motor vehicle accidents was unrealistic, and

considered that they were satisfied that use of HFO-1234yf as a motor vehicle refrigerant did not pose

a danger to the industry or the public.

EPA response

5.33. WorkSafe proposed that in addition to the default controls for a 2.1.1A substance, variations to certain

controls be applied to ensure that the controls on HFO-1234yf are in line with those applied to LPG,

propane, butane and isobutene in refrigeration systems.

5.34. We have taken relevant information on this matter into account in our risk assessment and our

proposed controls for HFO-1234yf. We consider that the risks related to the flammability of HFO-

1234yf are managed by the proposed controls.

Disposal and recovery, and levies

Submissions

5.35. RRNZ noted that they had confirmed with the facility that destroys their recovered refrigerants that the

controlled incineration method of disposal used for other refrigerant gases is suitable for destruction of

HFOs such as HFO-1234yf.

5.36. They also noted that the cost of destruction of refrigerant gases is currently funded only by the

collection of a voluntary levy on the importation of bulk HFC refrigerants and through the NZ Units

(under the Emissions Trading Scheme) received from the export of HFC refrigerants exported for

destruction. Funding is not received from the equipment and vehicles arriving with HFCs in them, and

yet RRNZ noted that they still need to fund destruction of those refrigerants. For HFOs, RRNZ

considered that there needed to be an effective method to fund the destruction of HFOs, or less

funding would be available for HFC destruction. They noted that NZ Units collected for export or

disposal of HFOs would not be likely to cover the costs of their destruction.

5.37. While RRNZ noted that HFOs are not currently subject to requirements under the Climate Change

Response Act and that HFO-1234yf has a comparatively low Global Warming Potential (100 year

GWP = 4), they considered it important that industry ensures that all synthetic refrigerants are not

released to the atmosphere when no longer required.

5.38. As a result they considered that HFOs should be required to be collected and destroyed.

15


November 2016

5.39. CoolCar Air-Conditioning Centres and VASA noted that CFCs and HFCs were considered safe when

initially approved and later found to cause unacceptable ozone depletion (CFCs) and contribute to

global warming. For this reason they recommend that recovery of HFO-1234yf be mandatory, with

recycling and re-use where possible, lest there be unforeseen consequences from the release of the

substance.

5.40. There is currently a voluntary training and destruction levy for refrigerants. RLTB recommended that

all sellers of refrigerant should be required to collect this levy.

5.41. The Motor Trade Association recommended investigation of an import levy to support the destruction

of end-of-life refrigerants.

EPA response

5.42. We note the concerns raised by industry. However, the issue of industry levies is out of scope of the

EPA application process and has no bearing on our risk assesment.

5.43. We note that there is the potential for there to be costs incurred by organisations undertaking disposal

and recovery activities on refrigerant gases in order for those organisations to have suitable

equipment for handling HFO-1234yf. We have taken these costs into account in our assessment.

5.44. We consider that the proposed controls for HFO-1234yf adequately manage risks to people and the

environment from the disposal of this substance.

Emissions Trading Scheme

Submissions

5.45. CoolCar Air-Conditioning Centres expressed a number of concerns relating to the Emissions Trading

Scheme and enforcement of requirements under the Ozone Layer Protection Act 1996 and the

Climate Change Response Act 2002.

5.46. Submitters noted that costs have increased recently due to the rise in the price of emissions units.

This has increased the cost of importing HFCs. Submitters noted that this may create a perverse

incentive to use improper substitutes for HFCs.

EPA response

5.47. We note the concerns raised by industry, and that HFO-1234yf (along with all HFOs) is not currently

included within the ETS. However, enforcement of the Scheme, and differing costs of gases included

or not, are outside the scope of this risk assessment.

Existing market for the product

Submissions

5.48. Sythree Pty Ltd noted that there is a market for this refrigerant and blends containing the refrigerant.

16


November 2016

5.49. Several submitters noted that vehicle refrigeration systems containing HFO-1234yf are already

entering New Zealand. It was also noted that several vehicle manufacturers have adopted HFO-

1234yf as their refrigerant of choice, to replace R134a. The submitters stated that they have

encountered vehicles in New Zealand using HFO-1234yf for which replacement refrigerant has not

been available. This means those vehicles are unable to undergo service to the air-conditioning

system at this time. They also noted that HFO-1234yf systems [in automobiles] cannot be retrofitted to

use any other refrigerant.

5.50. The Motor Industry Association noted that the European Union has mandated5 that refrigerant

systems in all new approved motor vehicle models from 1 January 2013 must not be filled with a

refrigerant with a Global Warming Potential higher than 150, and at present HFO-1234yf is the only

permitted refrigerant that satisfies these requirements. They therefore expect the number of vehicles

containing HFO-1234yf imported to New Zealand to increase.

EPA response

5.51. We note these submissions acknowledging that HFO-1234yf will already be entering New Zealand in

vehicle air-conditioning systems. We have taken into account the expected market for the substance

in our benefits assessment.

Regulatory Process

5.52. We note Tru-Test Ltd’s comments regarding regulatory process and their recommendation for a new

group standard for HFO refrigerants.

5.53. We note that there are existing group standards for compressed gas mixtures that blends containing

HFO-1234yf will be able to use should HFO-1234yf be approved.

6. Risk, cost, and benefit assessment

6.1. HFO-1234yf is intended to be manufactured in the United States of America and imported fully

labelled and packaged in 4.5 kg and 11.3 steel pressure cylinders with refrigerant valves. The

applicant intends that the cylinders only be made available for industrial and commercial users.

6.2. HFO-1234yf will be used to make blends with other refrigerant gases. These blends will be

transported in 800 kg steel pressure cylinders. These mixtures are not covered by this application and

are instead expected to be assigned to one of the Compressed Gas Mixtures Group Standards.

6.3. HFO-1234yf will also be used (unblended) in motor vehicle air conditioning systems.

5 In Directive 2006/40/EC, entering into effect in the EU in 2011: http://eur-

lex.europa.eu/LexUriServ/LexUriServ.do?uri=OJ:L:2006:161:0012:0018:EN:PDF

http://eur-lex.europa.eu/LexUriServ/LexUriServ.do?uri=OJ:L:2006:161:0012:0018:EN:PDF

http://eur-lex.europa.eu/LexUriServ/LexUriServ.do?uri=OJ:L:2006:161:0012:0018:EN:PDF

17


November 2016

Effects from fire

6.4. HFO-1234yf is a flammable gas and therefore presents potential risks from fire, including harm to

human health, property damage, wider communities and surrounding environments.

6.5. We recommend that the default controls for 2.1.1A flammable gases be applied to HFO-1234yf.

WorkSafe New Zealand also recommended that variations to some of the default controls be applied

to align requirements with those for certain existing flammable gases. We consider that these controls

and requirements under other legislation will manage the risks associated with the flammability of

HFO-1234yf such that the resulting level of risk is negligible.

Human health effects

6.6. HFO-1234yf is intended for use in closed refrigeration and air-conditioning systems, and as such,

human exposure is expected to be very limited. Some exposure may occur in the event of leakage,

other types of equipment failures, or human error. Some installed systems will be vulnerable to

physical impact, in particular air conditioning systems in motor vehicles.

6.7. A qualitative assessment of the risks to human health was undertaken. We have also considered

information from other sources, including the NICNAS (National Industrial Chemicals Notification and

Assessment Scheme, Australia) risk assessment of the health significance of potential exposure to the

substance from a private motor vehicle.

6.8. We note that HFO-1234yf has no human health classifications and do not anticipate that there are

likely to be any significant adverse effects related to its human toxicological properties from intended

uses.

6.9. However, gases stored as liquids under pressure have the potential to cause some adverse effects

related to their physical properties. We note that there is the potential for skin or eye contact with the

liquid, and that such contact could cause cryogenic burns as a result of rapid evaporation of the

liquefied gas. We consider that this risk can be managed by ensuring that people handling the

substance are aware of this risk and have recommended a labelling control. With this control in place,

we consider that the risk is negligible.

6.10. HFO-1234yf is also more dense than air, and therefore has the potential to accumulate in enclosed

spaces if there is insufficient air movement or ventilation. This presents potential risks of fire and

asphyxiation. We consider that the risk of fire is managed by the controls applied to flammable gases.

We have recommended a labelling control to inform users of the potential for asphyxia in areas where

there is insufficient air movement or ventilation, and with this control in place we consider that the risk

is negligible.

18


November 2016

Environmental effects

Ecotoxicology

6.11. We did not undertake quantitative exposure modelling for environmental endpoints for HFO-1234yf,

because the use pattern of the substance and the gaseous form of the substance limits the potential

for a significant environmental exposure.

6.12. We have therefore qualitatively assessed the potential risks to aquatic and terrestrial ecosystems. We

note that liquefied gas released during an accidental spill will evaporate. We consider that it is highly

unlikely that there would be a significant environmental exposure other than atmospheric exposure.

Additionally HFO-1234yf is non-toxic to the aquatic environment and we consider it highly unlikely that

there would be a sufficiently large inhalation exposure to terrestrial vertebrates to cause adverse

effects. We therefore do not anticipate that there are likely to be any significant adverse effects related

to its ecotoxicological properties.

Environmental fate

6.13. HFO-1234yf is unlikely to enter the waterways or contaminate soils for a prolonged period of time due

to the volatility and physical state of the substance.

6.14. The atmospheric lifetime of HFO-1234yf is relatively short compared with HFC and HCFC refrigerants,

and we note that the substance has a much smaller contribution to global warming effects than the

refrigerants it is intended to replace. We have taken this into account in our benefits assessment.

6.15. We also note that HFO-1234yf is considered not ozone depleting.

Relationship of Māori to the Environment

Kupu arataki (context)

6.16. The potential effects of HFO-1234yf on the relationship of Māori to the environment have been

assessed in accordance with sections 5(b), 6(d) and 8 of the Act. Under these sections all persons

exercising functions, powers and duties under this Act shall: recognise and provide for the

maintenance and enhancement of people and communities to provide for their cultural well-being,

and; take into account the relationship of Māori and their culture and traditions with their ancestral

lands, water, taonga and the principles of the Treaty of Waitangi (Te Tiriti o Waitangi).

6.17. We note that HFO-1234yf is a flammable gas, and that there is the potential for cultural risk from this

hazardous property. Cultural risk includes any negative impacts to treasured flora and fauna species,

the environment, and the general health and well-being of individuals and the community.

6.18. In general, the introduction and use of hazardous substances has the potential to inhibit the ability of

Māori to fulfil their role as kaitiaki.

19


November 2016

Mahinga kai (food resources)

6.19. HFO-1234yf is not expected to pose any significant risk to mahinga kai as mahinga kai species are not

expected to be adversely impacted in the event of a fire arising from the hazard properties of this

substance. We note that the expected environmental concentrations are below levels that would

cause harm to mahinga kai species.

Te Marae o Maru me Te Marae o Tāne (freshwater and terrestrial ecosystems)

6.20. HFO-1234yf is not expected to pose any significant risk or impacts in relation to Te Marae o Maru

(freshwater ecosystems) or Te Marae o Tāne (terrestrial ecosystems), including culturally significant

species associated with mahinga kai, rongoā (medicine), pūere (textiles), taputapu (tools and

equipment), mahi toi (arts and craft) and whakarākei (ornamentation).

6.21. No significant risk is anticipated in relation to:

Ngā wai koiora me ngā rauropi wai (aquatic habitats and aquatic organisms)

Te Aitanga Pepeke (insects and arthropods)

Ngā one me Te Aitanga a Punga (soils and soil dwelling organisms)

Ngā manu (birds)

Ngā ngāngara (reptiles)

Ngā otaota (plants)

Ngā rīroi (rodents)

Ngā mōkaikai me ngā kararehe (pets and quadrupeds).

Taha hauora (human health)

6.22. As HFO-1234yf is a flammable gas, HFO-1234yf poses a risk to taha hauora, in particular the

dimensions of taha wairua (spiritual health and well-being obtained through the maintainance of a

balance with nature and the protection of mauri) and taha tinana (physical health and wellbeing).

6.23. Fire caused by HFO-1234yf would have the potential to inhibit taha whānaunga – the responsibility to

belong, care for and share in the collective, includings relationships and social cohesion. Adverse

impacts on the ability of people to protect co-workers and others could impact on collective welfare,

well-being, and safety amongst those using HFO-1234yf and in wider communities.

6.24. We note that HFO-1234yf will generally be used on private premises or other areas where access to

systems or facilities using HFO-1234yf is controlled, or in closed refrigeration systems. We note that

persons responsible for these places will be obliged to advise others of the hazards associated with

use of HFO-1234yf. We note that there will be controls on the use of HFO-1234yf to mitigate these

risks to taha hauora from the flammability of HFO-1234yf.

20


November 2016

6.25. We therefore consider that the risks to taha hauora will be mitigated by users, operators, installers and

service people following the controls on this substance.

Ētahi atu mea (other matters)

6.26. The use of HFO-1234yf as a heat transfer fluid is expected to bring economic benefits for people who

own or work with refrigeration and air conditioning facilities – some of whom will be Māori.

Kupu whakatepe (conclusion)

6.27. Based on the information provided, including the use pattern and the controls proposed to be assigned

to HFO-1234yf, the potential risks to Māori culture or traditional relationships with the environment are

expected to be negligible.

6.28. If HFO-1234yf is used in the intended manner it is considered that it is not likely to breach the

principles of the Treaty of Waitangi, including the principle of active protection.

New Zealand’s international obligations

6.29. HFO-1234yf is not itself currently subject to any international obligations that affect this approval.

However, there are a number of international obligations that apply to other refrigerants, specifically

obligations related to the Kyoto Protocol and the Montreal Protocol. These protocols are described in

section 2 of this document and involve worldwide commitments to eliminate or reduce the use of

ozone-depleting substances and substances with global warming properties.

6.30. HFO-1234yf is an alternative refrigerant that has no ozone-depleting potential and a comparatively low

global warming potential. HFO-1234yf and blends containing HFO-1234yf will likely be used in place

of substances subject to the protocols. Approval of this application for HFO-1234yf would assist New

Zealand in meeting its obligations under these protocols by providing an alternative to HCFCs and

HFCs for the refrigerant industry. Approval of HFO-1234yf is expected to improve New Zealand’s

ability to meet its Montreal Protocol obligations and its emissions reduction commitment under the

UNFCCC.

Assessment of costs

6.31. We note that approval of HFO-1234yf could potentially lead to costs for organisations undertaking

recovery and disposal activities on refrigerants, should handling and recovery of HFO-1234yf be more

expensive due to the requirement for new or upgraded equipment. We consider that these potential

costs are likely to be not significant in terms of their overall impact.

21


November 2016

Assessment of benefits

Applicant

6.32. The applicant notes that HFO-1234yf is non-ozone depleting, and has a much lower global warming

potential than the substances it is intended to replace. They note that the blends containing HFO-

1234yf will also have a lower GWP than the gases or blends of gases they are intended to replace.

6.33. They also note that blends containing HFO-1234yf are showing performance improvements in energy

efficiency in refrigerant applications, referring to the blend R448A compared with the existing blend

R404A and with R22.

6.34. They also noted that HFO-1234yf degrades readily in the environment, with an 11 day lifetime in the

atmosphere.

Submissions

6.35. We note the benefits described by submitters, including cost savings for end users from increased

energy efficiency, and environmental benefits from using a refrigerant with low GWP and no ODP.

EPA assessment

6.36. We consider that HFO-1234yf provides a non-ozone depleting, low global warming potential

refrigerant gas alternative to existing refrigerants that are subject to international regulation.

Accordingly we consider that availability of HFO-1234yf would provide significant benefits to the

refrigeration industry, to the environment and to New Zealand’s ability to meet its international

obligations.

7. The effects of the substance being unavailable

7.1. We consider that if HFO-1234yf was not approved, the significant benefits described above to the

refrigeration industry, the environment, and to New Zealand’s international obligations, would not be

realised. We also note that the potential costs to the organisations undertaking recovery of refrigerants

would not be incurred.

8. Controls

8.1. A set of default controls are specified by regulations under the Act, based on the hazard classifications

determined for HFO-1234yf. The default controls form the basis of the controls proposed to be applied

to HFO-1234yf as set out in Appendix A. Based on the risk assessment, we recommend that the

following additions, variations and deletions are applicable to HFO-1234yf.

The setting of exposure limits

8.2. We note that HFO-1234yf does not trigger the controls that prescribe for Tolerable Exposure Limits

(TELs), Acceptable Daily Exposure (ADE), and Potential Daily Exposure (PDE) values to be set.

Nevertheless, we considered whether these values should be set for HFO-1234yf. We concluded that

22


November 2016

due to the low toxicity of the substance with no identified target organ effect following acute or chronic

exposures, these values should not be set for HFO-1234yf.

8.3. Environmental Exposure Limits (EELs) can be set to limit hazardous substances from entering the

environment in quantities sufficient to present a risk to it. No EEL values are proposed for HFO-1234yf

as the substance does not trigger any ecotoxic hazard classifcations.

Variation and deletion of controls

8.4. Approved handler requirements for flammable substances apply to this substance as a result of its

flammable gas classification. We consider it appropriate to apply approved handler requirements

through the lifecycle of this substance, but to apply a variation to the default control so that approved

handler requirements do not need to be met during transportation of HFO-1234yf. This is because the

Dangerous Goods Regulations provide sufficient measures to mitigate the potential risks of HFO-

1234yf during transport of the substance.

8.5. WorkSafe New Zealand proposed variations to some of the controls that are the same variations as

are currently applied to LPG, butane, propane, and isobutane. They consider that these variations will

ensure consistency in regulation of flammable gases, and we recommend these variations be applied.

Additional controls

8.6. HFO-1234yf presents a potential risk to people handling the substance if there is a significant release

of the substance, due to cryogenic effects from rapid evaporation of the liquefied gas. The default

controls for HFO-1234yf do not include identification requirements that would require this potential risk

be identified to users of the substance. We therefore recommend that an additional control be applied

to HFO-1234yf to require that information about the potential risk from cryogenic effects be included

on the label for the substance, along with information about the appropriate personal protective

equipment (PPE) to be worn to protect from cryogenic effects.

8.7. HFO-1234yf is heavier than air and therefore a leak of the substance presents the potential for pooling

of the substance in areas where there is poor ventilation and air flow. This leads to the potential for

asphyxiation where there is reduced oxygen available for breathing. We therefore recommend that an

additional control be applied to HFO-1234yf to require that information about this risk appear on the

label for the substance, to communicate this information to users of the substance.

Risks of the substance given the recommended controls

8.8. We consider that with the proposed controls in place, the level of risk to human health and the

environment will be negligible.

Review of controls for cost-effectiveness

8.9. We consider that the proposed controls are the most cost-effective means of managing the identified

potential risks and costs associated with this substance.

23


November 2016

9. Overall evaluation and recommendation

9.1. We consider that there are significant, non-negligible benefits associated with the approval of HFO-

1234yf.

9.2. The risk assessment indicates that there is a negligible level of risk to human health and the

environment, to Māori culture, and to society, community and the local economy, when using HFO-

1234yf with the proposed controls in place.

9.3. We consider that the controlled use of HFO-1234yf is consistent with the principles of the Treaty of

Waitangi. We also consider that the proposed controls (see Appendix A) will appropriately manage the

cultural impacts of this substance.

9.4. With the proposed controls in place, the benefits provided by HFO-1234yf will outweigh the risks and

any costs associated with the adoption of HFO-1234yf. Therefore, we recommend that the application

be approved with the controls documented in Appendix A, in accordance with clause 26 of the

Methodology.

24


November 2016

Appendix A: Controls recommended for HFO-1234yf

Please refer to the Hazardous Substances Regulations6 for the requirements prescribed for each control and

the modifications listed as set out in Section 6 of this document.

Hazardous Substances (Classes 1 to 5 Controls) Regulations 2001

Code Regulation Description Variation

F1 7 General test certification

requirements for hazardous

substance locations

F2 8 Restrictions on the carriage of

flammable substances on passenger

service vehicles

F3 55 General limits on flammable

substances

F4 56 Approved handler/security

requirements for certain flammable

substances

The following regulation is inserted

immediately after regulation 56:

56A Exception to approved handler

requirement for transportation of this

substance when packaged

(1) Regulation 56 is deemed to be

complied with if:

(a) when this substance is being

transported on land—

(i) by rail, the person who drives the

rail vehicle that is transporting the

substance is appropriately licensed

under the Railways Act 2005; and

(ii) other than by rail, the person who

drives, loads, and unloads the

vehicle that is transporting the

substance has a current dangerous

goods endorsement on his or her

driver licence; and

(iii) in all cases, Land Transport

Rule: Dangerous Goods 2005 (Rule

45001/1) is complied with; or

(b) when this substance is being

transported by sea, one of the

following is complied with:

6 The regulations can be found on the New Zealand Legislation website; http://www.legislation.co.nz

http://www.legislation.co.nz/

25


November 2016

(i) Maritime Rules: Part 24A –

Carriage of Cargoes – Dangerous

Goods (MR024A):

(ii) International Maritime Dangerous

Goods Code; or

(c) when this substance is being

transported by air, Part 92 of the Civil

Aviation Rules is complied with.

(2) Subclause (1)(a)—

(a) does not apply to a tank wagon or

a transportable container to which the

Hazardous Substances (Tank Wagons

and Transportable Containers)

Regulations 2004 applies; but

(b) despite paragraph (a), does apply

to an intermediate bulk container that

complies with chapter 6.5 of the UN

Model Regulations.

(3) Subclause (1)(c)—

(a) applies to pilots, aircrew, and

airline ground personnel loading and

managing this substance within an

aerodrome; but

(b) does not apply to—

(i) the handling of this substance in

any place that is not within an

aerodrome; or

(ii) the loading and managing of this

substance for the purpose of aerial

spraying or dropping.

(4) In this regulation, UN Model

Regulations means the 19th revised

edition of the Recommendation on the

Transport of Dangerous Goods Model

Regulations, published in 2015 by the

United Nations

F5 58, 59 Requirements regarding hazardous

atmosphere zones for class 2.1.1,

2.1.2 and 3.1 substances

F6 60 – 70 Requirements to prevent unintended

ignition of class 2.1.1, 2.1.2 and 3.1

substances

F11 76 Segregation of incompatible

substances

26


November 2016

F12 77 Requirement to establish a

hazardous substance locations if

flammable substances are present

F14 81 Test certification requirements for

facilities where class 2.1.1, 2.1.2 or

3.1 substances are present

F16 83 Controls on transit depots where

flammable substances are present

Hazardous Substances (Identification) Regulations 2001


I1 6, 7, 32 – 35,

36(1) – (7)

Identification requirements, duties of

persons in charge, accessibility,

comprehensibility, clarity and

durability

I5 11 Priority identifiers for flammable

substances

I9 18 Secondary identifiers for all

hazardous substances

I13 22 Secondary identifiers for flammable

substances

I19 29 – 31 Additional information requirements,

including situations where substances

are in multiple packaging

I21 37 – 39,

47 – 50

General documentation requirements

I25 43 Specific documentation requirements

for flammable substances

I29 51, 52 Signage requirements Regulation 51(1) of the Hazardous

Substances (Identification) Regulations

2001 applies to the substances as if the

words

“the quantities of any hazardous

substances of a hazard classification

specified in Schedule 3 exceed the

amount specified in that schedule for

hazardous substances of that

classification”

were omitted and the following

substituted:

“greater than 50 kg of the substances is

held within a building, or where any

quantity of the substances is held in an

27


November 2016


integral part of a refrigeration system and

the refrigeration system is contained in a

machinery room as defined in section

1.4.34 of AS/NZS 1677.2:1998

Refrigerating Systems Part 2: Safety

requirements for fixed applications, or

any other place where greater than 250

kg of the substance is present”

Hazardous Substances (Compressed Gases) Regulations 2004

Code Regulation/description Variation

CG The Hazardous Substance (Compressed Gases)

Regulations 2004 prescribe a number of controls

relating to compressed gases including aerosols and

gas cylinders

Hazardous Substances (Disposal) Regulations 2001


D2 6 Disposal requirements for flammable

substances

D6 10 Disposal requirements for packages

D7 11, 12 Information requirements for

manufacturers, importers and

suppliers, and persons in charge

D8 13, 14 Documentation requirements for

manufacturers, importers and

suppliers, and persons in charge

Hazardous Substances (Emergency Management) Regulations 2001


EM1 6, 7, 9 – 11 Level 1 information requirements for

suppliers and persons in charge

EM8 12 – 16, 18 –

20

Level 2 information requirements for

suppliers and persons in charge

EM9 17 Additional information requirements

for flammable and oxidising

substances and organic peroxides

EM10 21 – 24 Fire extinguisher requirements

28


November 2016


EM11 25 – 34 Level 3 emergency management

requirements: duties of person in

charge, emergency response plans

EM13 42 Level 3 emergency management

requirements: signage

Regulation 42(1) of the Hazardous

Substances (Emergency Management)

Regulations 2001 applies to the substances

as if the words:

“a quantity of a hazardous substance that is

equal to or greater than the quantity specified

for hazardous substances of that

classification in Schedule 5”

were omitted and the following substituted:

“greater than 50 kg of the substances is held

within a building, or where any quantity of the

substances is held in an integral part of a

refrigeration system and the refrigeration

system is contained in a machinery room as

defined in section 1.4.34 of AS/NZS

1677.2:1998 Refrigerating Systems Part 2:

Safety requirements for fixed applications, or

any other place where greater than 250 kg of

the substance is present”

Hazardous Substances and New Organisms (Personnel Qualifications) Regulations 2001


AH 17 4 – 6 Approved Handler requirements

(including test certificate and

qualification requirements)

Hazardous Substances (Tank Wagons and Transportable Containers) Regulations 2004


Tank

Wagon

4 – 43, as

applicable

Controls relating to tank wagons

and transportable containers

7 Refer to Control F4

29


November 2016

Additional controls

Code Section of

the Act Control

Use control 77A A restriction has been placed on refrigeration systems containing this substance.

(1) A person in charge of a refrigeration system that contains the substance

as an integral part of that refrigeration system must ensure that the quantity and

the means of containing the substances are in accordance with:

(a) AS/NZS 5419.1-4:2016; or

(b) a code of practice approved by the Authority under section 78(1) of the

Act that sets out the requirements for containing the substances in a refrigeration

system.

(2) Clause (1) does not apply to domestic refrigerators, domestic heat

pumps or room air conditioners.

Label 77A The label for the substance must include information about the following:

- The potential for skin or eye damage as a result of cryogenic effects following a

significant release of HFO-1234yf

- Appropriate personal protective equipment to protect from cryogenic effects

where significant release of HFO-1234yf may occur

- The following statement, or words to the same effect:

Vapours of this substance are heavier than air and can pool in enclosed areas

with low ventilation. This could cause suffocation by reducing oxygen available

for breathing. Ensure that there is adequate ventilation and air flow when using

this substance.

Unintended

ignition

Schedule 10 SCHEDULE 10 OF THE HAZARDOUS SUBSTANCES (DANGEROUS GOODS

AND SCHEDULED TOXIC SUBSTANCES) TRANSFER NOTICE 2004

This schedule prescribes the controls for unintended ignition of class 2 and 3.1

hazardous substances. The requirements of this schedule are detailed in the

consolidated version of the Hazardous Substances (Dangerous Goods and

Schedule Toxic Substances) Transfer Notice 2004, available from

http://www.epa.govt.nz/Publications/Transfer-Notice-35-2004.pdf

The following clause replaces Clause 1 of Schedule 10 of the Hazardous

Substances (Dangerous Goods and Scheduled Toxic Substances) Transfer

Notice 2004:

This Schedule applies to this substance.

http://www.epa.govt.nz/Publications/Transfer-Notice-35-2004.pdf

30


November 2016

Appendix B: Hazard classifications

We classified HFO-1234yf based on studies and other information provided by the applicant.

Unless otherwise noted, all studies relied upon to support a conclusion on classification were conducted

according to Good Laboratory Practice (GLP) and were fully compliant with all requirements of the standard

international test methods where these are available.

Classification of HFO-1234yf

Table 3 Application and EPA classifications of HFO-1234yf

Hazard Class/Subclass

Substance

classification

Method of

classification

Remarks

Ap

plican

t

EP

A

Su

bsta

nce

data

Read

acro

ss

Mix

ture

ru

les

Class 1 Explosiveness No No

Class 2, 3 & 4 Flammability 2.1.1A 2.1.1A The study report provided

identified the ignition range from

10% (small blue flame) - 14%

(medium blue flame) (Younis,

2006 – see appendix C).

We note that flammability range at

20°C and standard atmospheric

pressure reported in the SDS is

slightly higher, 6.0 – 13.3%. This

was also reported by NICNAS.

(NICNAS, 20158).

The gas meets the criteria (a) for

classification as a high hazard

flammable gas in Table 4.1 User

Guide to Threshold and

Classification, 2008, p4-2.

Class 5 Oxidisers/Organic Peroxides No No The molecule contains no

functional groups which would

give oxidising potential.

Subclass 8.1 Metallic corrosiveness ND ND

Subclass 6.1 Acute toxicity (oral) ND ND

Subclass 6.1 Acute toxicity (dermal) ND ND

8 NICNAS, 2015. Public Report: 1-Propene, 2,3,3,3-tetrafluoro- File No: STD/1556.

31


November 2016

Hazard Class/Subclass

Substance

classification

Method of

classification

Remarks

Ap

plican

t

EP

A

Su

bsta

nce

data

Read

acro

ss

Mix

ture

ru

les

Subclass 6.1 Acute toxicity (inhalation) No No

Subclass 6.1 Aspiration hazard ND ND

Subclass 6.3/8.2 Skin

irritancy/corrosion

ND ND

Subclass 6.4/8.3 Eye irritancy/corrosion ND ND

Subclass 6.5A Respiratory sensitisation ND ND

Subclass 6.5B Contact sensitisation ND ND

Subclass 6.6 Mutagenicity No No

Subclass 6.7 Carcinogenicity No No

Subclass 6.8 Reproductive/

developmental toxicity

No No

Subclass 6.8 Reproductive/

developmental toxicity (via lactation)

ND No

Subclass 6.9 Target organ systemic

toxicity (inhalation)

No No No classification for single or

repeat exposure by inhalation.

Subclass 9.1 Aquatic ecotoxicity No No

Subclass 9.2 Soil ecotoxicity ND ND

Subclass 9.3 Terrestrial vertebrate

ecotoxicity

ND ND We note the classification as ND

as no oral or dermal studies in

terrestrial vertebrates were

performed, and inhalation studies

are not relevant for class 9.3.

Subclass 9.4 Terrestrial invertebrate

ecotoxicity

No ND

NA: Not Applicable --> For instance when testing is technically not possible: testing for a specific endpoint may be omitted, if it is

technically not possible to conduct the study as a consequence of the properties of the substance: e.g. very volatile, highly reactive or

unstable substances cannot be used, mixing of the substance with water may cause danger of fire or explosion or the radio-labelling of

the substance required in certain studies may not be possible.

ND: No Data --> There is a lack of data for the substance.

No: Data are available for the substance and classification is not triggered.

32


November 2016

Appendix C: Physico-chemical properties

Physical and chemical properties of HFO-1234yf

Table C1 Physical and chemical properties of the mixture

Table 1 Physical and chemical properties of the substance, HFO-1234yf.

Property Results Test method Klimisch Score

(1-4) Reference

Colour Colourless 4 (no guideline but

mentioned in GLP

report)

Younis (2006). Flammable

and Explosive Properties of

HFO-1234yf (2,3,3,3-

tetrafluoroprop-1-ene).

Chilworth Technology Ltd.

Chilworth Science Park,

Southampton, UK. Report

Number

GLP15024A1R1V1/06

Physical state Gas

Odour ND

Flammability of

gases

Highly

flammable

EC-method-A11 1 Younis (2006). Flammable

and Explosive Properties of

HFO-1234yf (2,3,3,3-

tetrafluoroprop-1-ene).

Chilworth Technology Ltd.

Chilworth Science Park,

Southampton, UK. Report

Number

GLP15024A1R1V1/06

Auto-ignition 405ºC EC-method A15

Explosive

properties

The material

will not

possess

oxidising or

explosive

properties

EC-testing

method A14

Oxidising properties

Solubility 198.2 mg/L EC-method-A6,

with some

adaption to test

a gas

2 (statements not

signed)

Spruit, Mak, Schouten

(2006). Determination of

some physico-chemical

properties of HFO-1234yf.

TNO. Report No: TNO

Defence, Security and

Safety, Lange Kleiweg 137,

Rijswijk, The Netherlands.

DV2 2006-

031.10607/01.03-01

Log Kow 2.15 KOWWIN v1.66

(estimate)

33


November 2016

Appendix D: Mammalian toxicology

Robust study summaries for HFO-1234yf

Acute toxicity [6.1]

Acute Oral Toxicity [6.1 (oral)]

No oral studies were provided by the applicant. The substance is a gas at room temperature and under

pressure so we considered significant oral exposure is unlikely.

Acute Dermal Toxicity [6.1 (dermal)]

No dermal studies were provided by the applicant. The substance is a gas at room temperature and under

pressure so we considered significant dermal exposure is unlikely.

Acute Inhalation Toxicity [6.1 (inhalation)]

Type of study Acute (4 hour) inhalation range finding study in mice

Flag Supporting information

Test Substance HFO-1234yf

Endpoint Mortality, signs of toxicity

Value LC50 > 99,830 ppm

Reference

Hoffman, G.; 2004. HFO 1234yf: An acute (4-hour) inhalation range finding

study in the mouse via whole body exposure. Huntingdon Life Sciences,

100 Mettlers Road, East Millstone, NJ 08875-2360, USA. HLS Study No

03-5479C

Klimisch Score N/A

Amendments/Deviations N/A

GLP No information

Test Guideline/s No information

Species Mice

Strain No information

No/Sex/Group 2

Dose Levels Target (actual): 20,000ppm (23,480 ppm), (100,000 ppm) (99,830 ppm)

34


November 2016

Exposure Type Whole body inhalation for 4 hours

Study summary

Two groups of mice were exposed, consisting of 2 male and 2 female

animals per dose group. There were no deaths and all exposed mice

survived the 7 – day post-exposure period

Additional Comments None

Conclusion LC50 >99,830 ppm

Type of study Acute (4-hour) inhalation study in rats

Flag Key study


Endpoint Mortality, signs of toxicity

Value LC50 >405,800 ppm

Reference

Muijser, H.; 2006. Acute (4-hour) inhalation toxicity study with HFO-1234yf

in rats. TNO Quality of Life, Toxicology and Applied Pharmacology,

Utrechtseweg 48, P.O.Box 360, 3700 AJ Zeist, The Netherlands. TNO

Report V6201/06 Final

Klimisch Score 1

Amendments/Deviations None

GLP Yes

Test Guidelines OECD 403 (1997)

Species Rat

Strain Sprague Dawley

No/Sex/Group 5

Dose Levels 201,600 (±800) ppm and 405,800 (±1200) ppm. [There were no control

animals9.]

9 OECD 403 (2009) does not require the use of control animals.

35


November 2016

Exposure Type Inhalation (nose-only) for 4 hours

Study summary

During the exposure to 201,600 ppm a slightly decreased breathing rate

was seen in two male and two female animals at the last two hourly

observation and an additional male animal at the 4 hour observation point.

During exposure to 405,800 ppm a slightly decreased breathing rate and

slightly laboured breathing were seen in two male and three female

animals at the second hourly observation time point and in all animals at

the third and fourth observation time point. In both groups, abnormalities

shortly after exposure and, in particular, signs of narcosis were not seen.

In both groups the body weight gain was considered to be within normal

range.

At necropsy, grey discoloured lungs were seen in one male and one

female animal of the group exposed at 201,600 ppm and in three male and

one female animal of the group exposed to 405,800 ppm. A red

discoloured spot on one lung lobe was seen in one male animal and a

petechia on one lobe in one female animal in the 201,600 ppm group.

Study authors report these findings are often seen in Wistar rats and

assume that this applies to Sprague Dawley rats also, but no evidence in

support of this claim was provided.

Additional Comments

We consider the grey lung discolouration in some animals in both groups

to be exposure-related in the absence of controls for comparison.

We note a non-statistically significant reduction in body weight gain in the

female rats dosed with 405,800 ppm in comparison to those dosed at

201,600 ppm.

These observations do not invalidate the conclusion that no LC50 value has

been established.

Conclusion LC50 > 405,800 ppm

Skin Irritation [6.3/8.2]

No skin irritation/corrosion studies were provided by the applicant. The substance is a gas at room

temperature and under pressure, so we consider significant dermal exposure is unlikely.

36


November 2016

Eye Irritation [6.4/8.3]

No eye irritation/corrosion studies were provided by the applicant. The substance is a gas at room

temperature and under pressure, so we consider significant exposure of the eyes to the liquid is unlikely.

Sensitisation [6.5]

No respiratory or contact sensitisation studies were provided by the applicant. The substance is a gas at

room temperature and under pressure so we consider significant dermal exposure is unlikely. No animal

models are available for respiratory sensitisation. A respiratory sensitisation classification would be derived

from human exposure reports. No such reports were provided by the applicant.

General conclusion about acute toxicity classification

The substance is a gas at room temperature and under pressure so no tests for a range of endpoints were

required as those routes of exposure are not relevant. This applies to acute oral and dermal toxicity, skin and

eye irritancy/corrosivity, and contact sensitisation. Due to the storage of the substance as a liquefied gas, it

is possible that skin and/or eye damage could occur due to its cryogenic properties if exposure to the liquid

occurred. Since this is the result of the physical properties of the substance it does not trigger any

classification, but an identification control for these effects is proposed. Acute inhalation studies demonstrate

the substance is of very low acute toxicity by this route. No studies relevant to respiratory sensitisation were

presented. The substance is not classified for any acute toxicity endpoint.

Genotoxicity [6.6]

In Vitro Studies

Study type/Test Guideline Result Reference

Salmonella typhimurium strains TS

1535, TA 1537, TA 98, TA 100 and

Escherichia coli str WP2 uvrA

with/without S9 (OECD 471)

[NB Using incubator chambers suitable

for a gas.]

Positive

under the

conditions of

this test for

TA100 and

WP2 uvrA

indicative of

base-pair

substitutions

(in the

presence of

S9 metabolic

activation)

van den Wijngaard, M. J. M. et al.; 2009.

Bacterial reverse mutation test with HFO-

1234yf. TNO Quality of Life, Physiological

Sciences Location Zeist, Utrechtseweg 48,

P.O.Box 360, 3700 AJ Zeist, The Netherlands.

TNO Report V6205/09 Final

37


November 2016

In vitro chromosomal aberration assay

in cultured human lymphocytes (OECD

473)

Negative for

clastogenicity

with and

without

metabolic

activation

de Vogel, N.; 2005. Chromosomal aberration

test with HFO-1234yf in cultured human

lymphocytes. TNO Quality of Life,

Physiological Sciences Location Zeist,

Utrechtseweg 48, 3704 HE Zeist, The

Netherlands. TNO Report V6202/07 Final

Conclusion Positive for bacterial mutagenicity but not clastogenic in

mammalian cells in vitro

In Vivo Studies

Type of study In vivo micronucleus test in mice

Flag Key study


Endpoint Clastogenicity and effects on spindle apparatus

Value Negative

Reference

de Vogel, N. and Muijser, H.; 2005. Micronucleus test in bone marrow cells of

mice treated with HFO-1234yf, administered by inhalation. TNO Quality of Life,

Physiological Sciences Location Zeist, Utrechtseweg 48, P.O. Box 360, 3700

AJ Zeist, The Netherlands. TNO Report V6204/03 Final

Klimisch Score 1


GLP Yes

Test Guidelines OECD 474

Species Mice

Strain Charles River CD-1 albino

No/Sex/Group

Male mice were used. Twelve for the higher dose group (to allow two reserve

mice), 5 males for the mid- and low dose groups. A positive control group of 5

mice was exposed to mitomycin C (0.75 mg/kg bw by intraperitoneal injection).

A negative control group of 10 was exposed to clean air.

Dose Levels 0, 12,500, 50,000 and 200,000 ppm [The actual concentrations were 12,552,

50,021 and 199,046 ppm respectively.]

38


November 2016

Study Summary

Five of each group were killed at 24 hours, but for the high dose and negative

control groups an additional 5 animals were also sacrificed at 48 hours.

The bone marrow from both femurs of each mouse was collected into calf foetal

serum and two slide smears prepared and stained with May – Grunwald

Giemsa solution. One smear was analysed and the other kept in reserve.

No increase in micronucleated polychromatic erythrocytes was seen in the

exposed animals.

The study was considered valid by study authors because the positive controls

gave the anticipated response and the negative controls were within the

historical range.

The conclusion by study authors was that the substance is not clastogenic.

Additional Comments

The inhalation route was selected because this is the likely exposure route for

humans. We note the study did not demonstrate exposure of bone marrow in

the study, but due to the nature of the molecule, distribution to all body

compartments is anticipated. The high dose group was exposed at the same

time as the rats for the 4 hour inhalation study in rats TNO study plan P6201/06

(see report above).

Conclusion The substance is not clastogenic in vivo.

Type of study Unscheduled DNA synthesis in hepatocytes after inhalation exposure

Flag Key study


Endpoint Nuclear repair (mean grains/nucleus)

Value Negative

Reference

Muijser, H. and Wijnands, M. V. W.; 2006. Sub-acute (4-week) inhalation

toxicity study (including Unscheduled DNA Synthesis and Micronucleus test)

with 2-week recovery period, with HFO-1234yf in rats. TNO Quality of Life,

Toxicology and Applied Pharmacology, Utrechtseweg 48, P.O Box 360 3700 AJ

Zeist, The Netherlands. TNO Report V6872/02.

(Annex 7 (p81ff) of this report)

Klimisch Score 1

39


November 2016


GLP Yes

Test Guidelines OECD 486 (1997)

Species Rat

Strain Sprague-Dawley

No/Sex/Group 5 males (with 2 reserve animals). One reserve animal was used in the 50,000

ppm group

Dose Levels

The dose groups used in the UDS investigation were:

Clean air controls, 15,000 and 50,000 ppm (actual mean concentrations given

in the review of the 4-week acute inhalation study below). The test animals had

been exposed for 20 or 21 days and were sacrificed within 24h of the last

exposure period. A positive control using 2-acetylaminofluorene (2-AAF) was

used to validate the study

Study Summary

Both the test material exposed groups and the control air group analyses

yielded net nuclear grains (NNG) ≤ 0. The criteria for a positive finding is NNG ≥

5. Therefore the substance did not produce unscheduled DNA synthesis in rat

hepatocytes.

The positive control group produced the anticipated result NNG ≥ 5 with at least

20% of the cells in repair, demonstrating the validity of the test system.


Conclusion Negative

Type of study Micronucleus test in rats after inhalation exposure

Flag Key study


Endpoint Micronuclei

Value Negative

Reference


toxicity study (including Unscheduled DNA Synthesis and Micronucleus test)

with 2-week recovery period, with HFO-1234yf in rats. TNO Quality of Life,

40


November 2016

Toxicology and Applied Pharmacology. Utrechtseweg 48, P.O.Box 360, 3700

AJ Zeist, The Netherlands. TNO Report V6872/02.

(Annex 8 (p129ff) of the report)

Klimisch Score 1


GLP Yes

Test Guideline/s OECD 474 (1997)

Species Rat


No/Sex/Group 5

Dose Levels

0 (Air control), 5,000, 15,000, and 50,000 ppm. (Actual mean concentrations

given in the review of the 4-week acute inhalation study below). The test

animals had been exposed for 20 or 21 days.

A positive control group exposed to mitomycin C was used to validate the study.

Study Summary

The exposure groups did not demonstrate a statistically significant increase in

micronucleated polychromatic erythrocytes (MPE).

The proportion of polychromatic erythrocytes (PE)/erythrocytes (E) in the

exposed animals was not different from the negative controls, demonstrating

that no cytotoxicity in the bone marrow could be demonstrated up to the

maximum dose concentration of 50,000 ppm.

The report noted that the maximum concentration (50,000 ppm) corresponds to

a dose of approximately 17,000 mg/rat/day when the minute ventilation rate of

200 ml/min and a 6 hour exposure period is considered (assuming 100%

absorption of the substance via the inhalation route). This is far above the limit

dose required for studies of this type, 1000 mg/kg bw.

The number of MPEs in the positive control group was statistically significantly

different from the negative control, demonstrating the validity of the study.

The mean number of PE per E in the positive controls was statistically

significantly lower than in controls, demonstrating the cytotoxicity of the positive

control agent.


41


November 2016

Conclusion Negative

General conclusion about genotoxicity classification

The substance demonstrated mutagenic activity (base pair substitution) in in vitro bacterial test systems. It

was not clastogenic to mammalian cells in vitro. Unscheduled DNA synthesis and a micronucleus assay in

vivo following inhalation exposure for 20 or 21 days in rats were negative. We therefore consider that the

substance is not genotoxic. We recommend that no classification for genotoxicity is applied to HFO-1234yf.

Carcinogenicity [6.7]

No carcinogenicity studies (life-time bioassays in rodents) have been provided by the applicant.

A toxicogenomic study to assess the potential of the substance to cause tumours in the liver of mice and the

kidney of rats was provided by the applicant and is summarised below. Two supplementary reports were also

provided and the key points from these are included.

Toxicogenomic studies

Type of study Toxicogenomic study to predict potential human carcinogenicity in comparison

selected test chemicals following a 90 day exposure in rats

Flag Key study


Endpoint

Lowest Observable Adverse Effect Concentration (LOAEC): >50,000 ppm (No

adverse effects including histopathology findings reported after 90 days)

No Observable Adverse Effect Concentration (NOAEC): 50,000 ppm

Reference

Thomas R. S.; 2007. Toxicogenomic Assessment of the Carcinogenic Potential of

2,3,3,3-tetrafluoropropene. The Hamner Institutes for Health Sciences, 6 Davis

Drive, P. O. Box 12137, Research Triangle Park, NC 27709, USA. Laboratory

Protocol ID 06014.

Klimisch Score 1

Amendments/Deviation

s None

GLP Yes

Test Guidelines No guidelines apply for a study of this type

Species Mice and rats

42


November 2016

Strain Female B6C3F1/Crl mice and male F344/CrlBR rats.

No/Sex/Group 6/dose level

Dose Levels

For the test substance HFO-1234yf the target dose levels were 10,000 and 50,000

ppm. The actual daily mean concentrations were 10,054 and 49,728 ppm

respectively. The dosing for the gases was 6 hours/day, 5 days/week for 13 weeks.

Study Summary

The test set of chemicals were:

trichlorofluoromethane (TCFM, CAS 75-69-4)

N-(1-naphthyl)ethylenediamine dihydrochloride (NEDD, CAS 1465-25-4)

Iodoform (IODO, CAS 75-47-8)

1-amino-2,4-dibromoanthraquinone (ADBQ, CAS 81-49-2) [Carc]

Tris (2,3-dibromopropyl)phosphate (TDPP, CAS 126-72-7 [Carc]

tetrafluoroethylene, (TFEL, CAS 116-14-3) [Carc]

tetrafluoroethane (TFEA, CAS 811-97-2)

Three of the substances in the test set are identified as the positive (carcinogenic)

compounds for female mouse liver and male rat kidney cancers in US National

Toxicology Programme (NTP) bioassays as indicated [Carc]. The other four

substances were negative for these tumours.

Solutions were prepared for gavage administration for the solids, while the gas

exposures regime matched that for the target chemical, HFO-1234yf.

Dose regimes for the groups

Chemical No of

animals Route

Dose

(males)

Dose

(females)

TCFM 12 Gavage 977 mg/kg

bw/day

3925 mg/kg

bw/day

IODO 12 Gavage 142 mg/kg

bw/day

93 mg/kg

bw/day

Corn oil

(control) 12 Gavage N/A N/A

43


November 2016

ADBQ 10 Feed# 10,000

mg/kg 20,000 mg/kg

TDPP 10 Feed# 100 mg/kg 1000 mg/kg

NEDD 10 Feed# 1,000 mg/kg N/A

Feed

(control) 10 Feed# N/A N/A

TFEL 10 Inhalation 625 ppm 1250 ppm

TFEA 10 Inhalation 50,000 ppm 50,000 ppm

HFO 1234yf

(L) 10 Inhalation 10,000 ppm 10,000 ppm

HFO 1234yf

(H) 10 Inhalation 50,000 ppm 50,000 ppm

Air control 10 Inhalation N/A N/A

# We assumed that for the dietary studies this is the feed concentration not the

dose.

The dosing was 6 hour/day, 5 days/week for inhalation, 5 days/week for gavage and

7 days/week for feed, all for 13 weeks.

Gene expression changes following a sub-chronic exposure were used to assess

the carcinogenic potential of 2,3,3,3-tetrafluoropropene (HFO-1234yf) in the female

mouse liver and male rat kidney. No treatment-related histopathological lesions

were observed following a 90 day (6 hour/day, 5 days/week) exposure to HFO-

1234yf at 10,000 and 50,000 ppm.

We consider this indicates that the NOAEC for HFO-1234yf in mice and rats after

treatment for 13 weeks is 50,000 ppm.

Statistical classification analysis predicted HFO-1234yf to be non-carcinogenic in

both female mouse liver and male rat kidney.

In both the male rat kidney and female mouse liver, the test chemical HFO-1234yf

was predicted to be non-carcinogenic. In the female mouse liver, the statistical

classification analysis was able to accurately discriminate between the carcinogenic

44


November 2016

and non-carcinogenic control chemicals providing confidence in the carcinogenic

predictions for the three test chemicals.

However, study authors reported that the statistical classification analysis was more

problematic in the male rat kidney, thereby demanding more caution in interpreting

the results. Due to the consistent misclassification of TFEL as non-carcinogenic (in

this study), the chemical was removed from the analysis in the male rat kidney and

the number of known carcinogenic chemicals used to build the classification model

was limited to two.

This represents a relatively small set of chemicals from which to derive predictive

gene sets and make broad predictions about the carcinogenic potential in the rat

kidney. TFEL was chosen as a positive control due to its similarity to the untested

chemicals in containing fluorine. The remaining positive control chemicals (TDPP

and ADBQ) are not fluorinated and are not as chemically similar to the untested

chemicals, making any predictions more tenuous. However, despite the problems

associated with TFEL in the classification analysis, there were few gene expression

changes that were conserved between TFEL and HFO-1234yf suggesting that they

behave quite differently on a gene expression basis.

Despite the non-carcinogenic prediction, gene expression changes in the male rat

kidney following treatment with HFO-1234yf suggested potential endocrine-related

effects and were consistent with a reduction in circulating androgens. In addition,

HFO-1234yf showed a significant upregulation of the SA rat hypertension-

associated gene (Sah) in the male rat kidney. Increased expression of the human

homolog of this gene has been linked to increases in body mass index, triglyceride

levels, cholesterol, and blood pressure status.

There are two supplemental reports to this investigation.

Additional comments from the supplemental report Number 1.

(Thomas R. S.; 2009. Report Supplement on the Toxicogenomic Assessment of the

Carcinogenic Potential of 2,3,3,3,-tetrafluoropropene (HFO-1234yf). The Hamner

Institutes for Health Sciences, 6 Davis Drive, P. O. Box 12137, Research Triangle

Park, NC 27709, USA. Laboratory Protocol ID 06014)

In relation the TFEL findings there was discussion of the possible genetic difference

in between rat colonies used for the work the NTP carcinogenicity finding being with

F344/N rats, and an observation that the NTP F344/N rat colony has been retired

due to declining fertility, sporadic seizure activity and chylothorax. Researchers

argue that the negative genomic predictions are not present in isolation and note the

lack of genotoxicity in mammalian systems in vitro and in vivo, the lack of

histopathological changes in a 13-week study and assessment of the metabolism of

45


November 2016

HFO-1234yf. The study concludes: “Taken together, the results from the genomic

study when interpreted together with the other studies suggest that HFO-1234yf is

non-carcinogenic in the tissues studied”.

In relation to the endocrine effects we note that as with all genomic studies,

interpretation of the biological significance of the observed gene expression

changes is difficult. The study comments: “In many cases it is not known what a two-

fold, three-fold or even statistically-significant change in mRNA levels means in

respect to protein changes or, more importantly, on a functional level. In any case,

reproductive changes consistent with alterations in circulating androgens were not

evident in subsequent follow-up [developmental and reproductive toxicity] studies.”

Additional comments from the supplemental report Number 2.

(Thomas R. S.; 2009. Toxicogenomic Assessment of the Carcinogenic Potential of

2,3,3,3,-tetrafluoropropene (HFO-1234yf) in the Female Mouse Lung. The Hamner

Institutes for Health Sciences, 6 Davis Drive, P. O. Box 12137, Research Triangle

Park, NC 27709, USA. Laboratory Protocol ID 06014 Supplement Number 2.)

The B6C3F1 female mice were exposed for 13 weeks to a selection of 26

chemicals, of which approximately half produced an increased incidence of lung

tumours in a two year rodent cancer bioassay. The conclusion was that: “Based on

the results of this study, HFO-1234yf was predicted to be similar to other substances

found to be carcinogenic in the female mouse lung”. The report noted that there is

evidence both to support and oppose the positive prediction.

Expert opinion

An expert opinion10 was presented by the applicant to assess the extent to which

the prediction that HFO-1234yf is similar to other substances which cause lung

tumours in female mice is of relevance for human risk assessment.

Additional Comments

The EPA has not been provided with a report of the 90 day study used to generated

the NOAEC/LOAEC values referred to in this report. This is not considered a

significant deficiency in the data set as the purpose of the study is to present the

toxicogenomic findings.

10 Dekant W, 2009. “Expert report on the potential of HFO-1234-yf and HFO-1234ze to induce lung tumours in mice after

inhalation exposure and the relevance of this information for hazard assessment.” Institut fur Toxikologie, Universitat Wurzburg,

Versbacher Str. 9, 97078, Wurzburg, Germany.

46


November 2016

Conclusion

The toxicogenomic model indicates that the substance is unlikely to be carcinogenic

in mouse liver or rat kidney, but identifies a possible endocrine-related effect and

possible potential for carcinogenicity in the lung.

EPA staff conclusion on carcinogenicity classification

No life-time bioassays for carcinogenicity have been performed in mice or rats. The applicant has provided

an assessment of the likelihood that the substance presents a carcinogenicity hazard in relation to specific

target organs using toxicogenomics, specifically for mouse liver and lung and rat kidneys. The strains of

mouse and rat used are selected for their sensitivity based on the US National Toxicology Program database

(http://ntp-server.niehs.nih.gov/). While the analysis suggested the possibility that the substance has a

potential cause of lung tumours in mice, we conclude that its metabolic profile and a comparison of the

metabolic activity of mouse, rat and human lung means this conclusion is unlikely to be of relevance to

human exposure levels.

The overall conclusion is that there are sufficient data to conclude no classification of the substance for

carcinogenicity should be assigned. The results of the toxicogenomic study together with the negative

findings for genotoxicity and absence of histopathologic effects in subacute and subchronic toxicity studies

provide support for the conclusion that the substance is not likely to be carcinogenic. We therefore

recommend no classification for carcinogenicity.

Reproductive/Developmental Toxicity [6.8]

Developmental Toxicity

Type of study Pre-natal developmental toxicity in the rat

Flag Key study


Endpoints

Maternal Toxicity

LOAEC: >50,315 ppm

NOAEC: 50,315 ppm

Foetal Toxicity

LOAEC: >50,315 ppm

NOAEC: 50,315 ppm

Reference

Tegelenbosch-Schouten M. M.; 2007. Prenatal developmental inhalation toxicity

study with HFO-1234yf in rats. TNO Quality of Life, Toxicology and Applied

Pharmacology, Utrechtseweg 48, P.O. Box 360, 3700 AJ Zeist, The

Netherlands. TNO Report V6986 Final.

Klimisch Score 1

http://ntp-server.niehs.nih.gov/

47


November 2016


GLP Yes

Test Guidelines

OECD 414

EU Commission Directive 2004/73/EC, B31, Annex 2F.

Species Rat

Strain Wistar outbred (Crl: WI (WU)BR)

No/ Group 25 (females)

Dose Levels 0, 5000. 15,000, and 50,000pm. The actual mean concentrations were: 5,000 (±

20), 15,106 (± 290) and 50,315 (± 935) ppm.

Exposure Type Animals were only dosed during the period Gestation Day (GD) 6 – 19, using a

nose-only exposure equipment, for 6 h/day.

Study Summary

There were no mortalities and no findings in condition or behaviour related to

the test substance.

There was no effect on body weight attributed to the test substance, but the

body weights of all groups (including control animals) reduced during the GD 6 -

9 which was attributed by the study authors to reduced access to feed and

changes in animal husbandry.

Food consumption data showed reduced feed consumption in all groups for the

period GD 6-9.

Of the 25 females in each group 24, 21, 24 and 25 were pregnant and had live

foetuses at Caesarean section in the control, 5,000, 15,000, and 50,000 ppm

group respectively. Female 59 of the low-dose group had an early delivery.

No statistically significant differences were observed in female fecundity index

and gestation index between the groups. The number of corpora lutea was

statistically significantly increased in the mid dose group. No differences were

observed in the number of implantation sites, pre and post-implantation loss,

live and dead foetuses, resorptions or the sex ratio between groups. Variations

in body weight of dams were not test-substance-related.

Findings in the foetuses

A filiform tail was seen in one fetus of a low dose dam and one fetus of a high

dose dam. The incidence of this finding was 0.0, 0.4, 0.0 and 0.4% in the

control, low, mid and high dose groups respectively.

48


November 2016

The incidence of small foetus (<75% of the mean body weight in the control

group) was statistically significantly higher in mid and high dose groups both in

relation to litters and foetuses. The incidence of large foetuses (>125 % of the

mean body weight in the control group) was statistically increased in the low

dose group.

An increase in the placental weight for male and females and combined

foetuses was clearly statistically significant (P <000.1) in comparison to

controls. However, no dose-response was established and in the absence of

other findings (including foetal weight), this was not considered adverse

(although study protocol meant that investigation into the placentas was limited

to gross pathology).

The incidence of visceral anomalies were comparable between test and control

groups.

No dose response relationship applied in relation to visceral variations so the

findings were considered unrelated to exposure.

An increase in skeletal variants (two or more wavy ribs/ separated sternebrae)

and retarded ossification was seen in low, mid, and high dose groups, but this

was not dose related and such findings are considered reversible variations not

malformations.

The NICNAS report (date) stated: “The cases of wavy ribs seen in some

developing foetuses were considered to be of some concern by US EPA (US

EPA 2011). The US EPA also pointed out that the reversibility of the effect was

unclear and that the interim results from a two generation reproductive study

(TNO 2011) did not find an association between exposure to the notified

chemical and skeletal effects (US EPA 2011).”

We concluded that exposure to up to 50,315 ppm of the substance during

organogenesis is not associated with any test-substance adverse effect on

maternal animals or any pre-natal developmental effects on pups.


Conclusion Negative for pre-natal developmental toxicity in rats

Type of study Pre-natal toxicity in the rabbit

Flag Supporting study

49


November 2016

Test Substance

HFO-1234yf (Two separate commercial sources of the substance were used for

the mid-dose testing. The substance provided by the study sponsor [Honeywell

International Inc.] and the substance available from Du Pont.)

Endpoints

Parental Toxicity

LOAEC: 5,500 ppm based on mortality, moribundity,

abortions, premature delivery, lower mean body weight

gain, mean body weight loss and/or lower food

consumption observed at 5,500 and 7,500 ppm

NOAEC: 4,000 ppm

Foetal Toxicity

LOAEC: 5,500 ppm for visceral malformations (cardiac

and large vessel malformations)

NOAEC: 4,000 ppm for visceral malformations

Reference

Fleeman, T. L.; 2008. An Inhalation Prenatal Developmental Toxicity Study of

HFO-1234yf (2,3,3,3-tetrafluoropropene) in rabbits. WIL Research Laboratories,

LLC, 1407 George Road, Ashland, OH 44805-8946. USA. Study number: WIL-

447022.

Klimisch Score 1


GLP Yes

Test Guidelines OECD No 414, US EPA OPPTS 870.3700

Species Rabbit

Strain New Zealand White

No/ Group 12

Dose Levels

0, 2,500, 4,000, 4,000 [Du Pont source], and 7,500 ppm in Phase I.

In Phase II, the mid dose level was increased from 4,000 to 5,500 ppm.

The measured concentrations were: 2,504, 3,982, 4,013 (Du Pont) and 7512

ppm respectively for the 2500, 4000, 4000 (Du Pont), and 7,500 ppm groups

respectively in Phase I and 2,479, 5,408, 5,479 (Du Pont) and 7,441 ppm for

the 2500, 5,500, 5,500 (Du Pont), and 7,500 ppm groups respectively Phase II.

Exposure Type Whole body exposure for Day 6 – Day 28 of gestation (6h/day).

50


November 2016

Study Summary

The dosing was done in two phases.

Four and seven of the animals were found dead or euthanised in extremis in the

5,500 and 7,500 ppm group respectively. The signs of toxicity seen prior to

death or euthanasia were laboured and/or decreased respiration and/or

hypoactivity for 2 and 3 females in the 5,500 and 7,500 ppm groups

respectively. One and 3 of the females in these respective groups aborted on

day 26, 28 or 29 and one female in the 7500 ppm group delivered on Gestation

Day 29.

The mortality, morbidity, abortions and premature deliver in these groups were

attributed to exposure to the test substance. No test substance-related

macroscopic findings were found in these animals. All other animals survived to

the scheduled necropsy.

No test substance-related findings were noted at the daily examination or the

mid-point of, or 1 hour following, the exposure at any concentration.

Lower mean body weight gain was noted in the 7,500 ppm group during

Gestation Days 12 -20, with occasional corresponding reductions in mean feed

consumption. Since the most affected animals died or were euthanised prior to

the schedule necropsy the mean net body weight and net body weight change

in this group were not significantly different from the control group.

Pups: Heart and great vessel malformations (bulbus aorta, stenotic pulmonary

trunk, interventricular septal defects [absent septa], absent tricuspid valve

and/or interrupted aortic arch) were noted in 2 and 3 foetuses in the 5,500 and

7,500 ppm groups respectively. The mean litter proportions for these findings

exceed the maximum mean value in the laboratories historical control data for

these findings. Because of the increase in comparison to historical control data

and the similarity of the findings, the malformations in the cardiovascular

system of foetuses in these groups was considered test substance-related. The

malformations were noted in the presence of maternal toxicity. No test

substance-related effects on intrauterine groups and survival were noted at any

exposure level.

The conclusions of the researchers were that based on mortality, moribundity,

abortions, premature delivery, lower mean body weight gain, mean body weight

loss and/or lower food consumption observed at 5,500 and 7,500 ppm, an

exposure concentration of 4,000 ppm was considered to be the NOAEC for

maternal toxicity.

Substance-related visceral malformations in the heart, and/or great vessels

were observed in the 5,500 and 7.500 ppm groups in the presence of maternal

51


November 2016

toxicity, and an exposure concentration of 4,000 ppm was considered a NOAEC

for embryo/foetal development in the rabbit.


Conclusion The study did not identify any visceral malformations in rabbits at non-

maternally toxic dose concentrations by inhalation.

Reproductive toxicity

Type of study Two generation reproductive toxicity test in rats by inhalation

Flag Key study


Endpoints

Parental Toxicity

LOAEC: > 49,958 ppm (No systemic toxicity seen in

parental animals)

NOAEC: 49,958 ppm

Reproductive Toxicity

LOAEC: >49,958 ppm (No adverse reproductive or

developmental effects seen)

NOAEC: 49,958 ppm

Reference

Waalkens-Berendsen, D. H.; 2011. Inhalatory Two-generation Reproduction

Toxicity Study with HFO-1234yf in Wistar Rats. TNO Quality of Life,

Utrechtseweg 48, P.O.Box 360, 3700 AJ Zeist, The Netherlands. TNO Report

V7931/Final.

Klimisch Score 1

Amendments/Deviations

A relatively long list of protocol deviations are documented in this study,

although these are claimed by study authors not to have impacted on its

validity.

GLP Yes

Test Guidelines OECD 416 (2001) and US EPA OPPTS 870.3800 (1998)

Species Rat

Strain Wistar (Crl: WI (WU))

No/Sex/Group 28

52


November 2016

Dose Levels 0, 5,000, 15,000, 50,000 ppm. The average actual measured concentrations for

exposure were: 0, 4,995, 15,013, and 49,958 ppm

Exposure Type

Inhalation 6 hours/day 5 days/week during pre-mating, mating, gestation and

weaning using nose-only exposure, except during lactation during which whole

body exposure was used.

Study Summary

Males were exposed for at least 10 weeks prior to mating 6 hours/day, 5

days/week, and 6 hours/day during mating.

Female animals were exposed for at least 10 weeks prior to mating 6

hours/day, 5 days/week then during mating and up to gestation day 19 (nose-

only). From day 5 of lactation onwards females were exposed daily to 6

hours/day, to the test system by whole body exposure until the end of the

lactation period (Day 21).

Dams were allowed to raise one litter.

At the end of lactation the pups were weaned and selected for the next

generation or sacrificed. F0 females were sacrificed at or shortly after weaning.

F0 males were sacrificed after at least 11 weeks of exposure (for sperm

analyses and necropsy). F1 were then exposed at the same concentration as

their parents from weaning until maturity and through mating, gestation and

lactation to weaning of the F2 generation.

Clinical signs and mortalities did not reveal any treatment-related effects.

No dose-related changes in the oestrus cycles were observed in the HFO-

1234yf exposed animals.

Reproduction and fertility parameters were not affected by exposure to HFO-

1234yf by inhalation.

In both generations, the number of live and dead pups at delivery, the viability

of the pups, the sex ratio, pup body weights and body weight changes were not

affected by exposure to HFO-1234yf.

In the F1-male animals, no statistically significant difference was observed

between the day of achievement of preputial separation between the HFO-

1234yf-exposed groups and the control group. In F1-females, there was an

apparent delay in the onset of puberty evident as a delay in days to

achievement of vaginal opening, but we consider that this is likely to be be

related to food consumption parameters and not exposure to the test

substance.

53


November 2016

Sperm analysis did not reveal a treatment-related effects.

Macroscopic observation of the F0- and F1-pups selected for necropsy did not

indicate any treatment-related effect. No differences were observed between

pup brain and spleen weights. Microscopic observation of the thymus of the

control and high-concentration groups of the F1-generation, F2-pups, did not

reveal any treatment-related effects. For that reason the decrease detected in

absolute and relative thymus weight of the F2-pups, F1-generation, of the high-

concentration group was not considered to be a relevant effect. In addition, the

decrease in absolute and relative thymus weight (F1-pups, F0-generation) and

in relative thymus weight (F2-pups, F1-generation) of the low concentration

group were not considered to be treatment-related.

No relation to the concentration of the test substance was observed on the

effects on organ weights. The decrease in absolute organ weights and the

decrease and increase in relative organ weights were considered by

researchers to be related to the decreased terminal body weights of the HFO-

1234yf -exposed groups.

No treatment-related effects on the ribs of the F1 pups were observed.

The macroscopic and microscopic changes observed in the intercurrent death

and at scheduled sacrifice are common findings in rats of this strain and age or

occurred as individual fortuitous findings according to researchers. Furthermore,

they were equally distributed amongst the different treatment groups or

occurred in only one or a few animals. Therefore, they were not considered by

researchers to be related to treatment.

Two dams of the high-concentration group gave birth to three pups with

malformations. One pup showed acauda and anal atresia and another pup of

the same dam showed polypodia of the right hind limb. A pup of another dam

showed acauda. As no malformations were observed in the prenatal

developmental toxicity study with HFO-1234yf (TNO report V6986) [see above],

this finding was not considered by researchers to be a treatment-related effect.

Vaginal opening of the F1-female animals was statistically significantly delayed

in the mid- and high-concentration groups when compared to the control group.

When vaginal opening was statistically analysed using ANCOVA with pup

weight on PN 21 as the covariate, the delay was significant in the high-

concentration group.

54


November 2016

In conclusion, based on the data from this two-generation reproductive toxicity

study in rats, the high-concentration (50,000 ppm) is considered to be NOAEC

for systemic toxicity and reproductive toxicity.

Additional Comments

We note that in the original report of this study an NOAEC of 15,000ppm was

proposed due to the delayed vaginal opening in the female rats of the F1

generation at 50,000ppm. In the revised report this is seen as a reversible,

secondary effect of reduced body weight in the pups. We note that the higher

NOAEC was accepted in the NICNAS review.

Conclusion

No direct reproductive or developmental effects of the substance were identified

up to the highest concentration tested (49,958 ppm) included exposure via

lactation.

EPA staff conclusion on reproductive/developmental toxicity classification

Our overall conclusion is that the substance does not cause developmental or reproductive toxicity, directly

or via exposure during lactation.

The pre-natal (developmental) studies in rabbits demonstrate that the rabbit heart and skeletal muscle may

be more sensitive to the substance than in other species that have been studied, and lead to investigation of

the effects of inhalation in minipigs. This finding in rabbits is possibly reflected in the visceral findings in the

heart and large vessels in pups, but these only occurred at maternally toxic doses. We assume this is the

reason for the ND rather than No classification proposed by the applicant. We consider the rabbit appears

particularly sensitive in this respect and did not apply a classification based on this finding.

We note also the findings in the toxicogenomics report (discussed above) suggesting the substance may

have endocrine disruption potential. We concur with the conclusion that the significance of this in the

absence of any carcinogenicity or reproductive/developmental toxicity is unclear. We therefore recommend

no classification for reproductive/developmental toxicity is applied to HFO-1234yf.

Target Organ Systemic Toxicity [6.9]

Type of study 28 day inhalation study in rabbits

Flag Key study


Endpoint

LOAEC: 1000 ppm (males), 1500 ppm (females) based on anatomic

pathology findings in heart and skeletal muscle

NOAEC: 500 ppm (males), 1000 ppm (females)

55


November 2016

Reference

Hoffman, G. M.; 2013. A 28-day Inhalation (Whole-Body Exposure) study

in Rabbits with a 28 Day Recovery Period. Huntingdon Life Sciences, 100

Mettlers Road, East Millstone, New Jersey 08875-2360, USA. Study

Number 11-6387

Klimisch Score 1


GLP Yes


Species Rabbits


No/Sex/Group 25

Dose Levels

0, 500, 1500, 5500/4500 ppm daily for 6 hours for 6 or 13 days (Phase 1)

or 0, 500, 1000, 4500 ppm for 28 days (Phase 2). [Note the different dose

values for mid and top dose animals.] The top dose animals were exposed

to 5500 ppm for Days 1 - 6) and 4500 ppm for Days 7 – 15 in Phase 1. The

top dose group for the Phase 2 (28 day exposure) was also 4500 ppm,

while the mid dose was 1000 ppm.

The actual measure concentrations (in brackets) were 0 (0), 500 (497),

1500 (1508) 5500 (5533), 4500 (4338) ppm for phase 1, and 0 (0), 500

(478), 1000 (1010), and 4500 (4378) ppm respectively for Phase 2. The

size characterisation identified that exposure to the substance was

essentially a gas.

The modification of the dose regime was the result of findings in the interim

sacrifice animals (see below).

Note that this study used 6 hours/day, 7 days/week exposures, whereas

repeat dose studies typically use 6 hours/day, 5 days/week exposures.

This was done to reflect the previous rabbit developmental study. The

exposure type was whole body.

Study Summary

Five animals/sex/group were euthanised and necropsied at the end of up

to 7 or 13 days ((interim sacrificed 1 and 2, respectively), and 10

animals/sex/group were euthanised and necropsied at the end of 28 days

of treatment (terminal sacrifice). Recovery animals, 5/sex/group, were

euthanised and necropsied at the end of 28 days of recovery.

56


November 2016

Based on the results from the interim sacrifices at Day 7 and Day 14,

(elevation of creatinine kinase with corresponding effects on the hearts),

during Phase 1, the exposure levels for the 28 day Group 3 were lowered

from 1500 to 1000 ppm for Phase II.

Based on unscheduled deaths in Group 4 of Phase 1, the Group 4 animals

were not exposed on Day 7 and were sacrificed as scheduled on Day 8

after 6 exposures. When resuming exposure for the animals scheduled for

sacrifice on Day 14, the dose was reduced from 5500 to 4500 ppm (from

Day 8 onwards). These animals had only 13 days of exposure before

sacrifice on Day 14.

There were unscheduled deaths/sacrifices at 4500 ppm (1 female) and

5500 ppm (1 male and 1 female) in Phase 1). Exposure to the substance

was associated with microscopic findings in the heart and skeletal muscle

at ≥1000 ppm with males more frequently affected than females.

Subacute/chronic [sic] myocardial inflammation was observed in one 1000

ppm male and 1 male/3 females at 1500 ppm, and 6 males/4 females at

45000 ppm, 2 males at 5500/4500 ppm and 5 males/2 females at 5500

ppm on Days 8, 15 and/or 29. Lesions were minimal to slight, did not

progress over time and recovery animals were clear after 28 days without

exposure.

There was minimal to moderate skeletal muscle necrosis in both sexes at ≥

1500 ppm on Day 15, and on Day 29 in males at ≥ 1000 ppm and females

at 4500 ppm.

Significant serum enzyme changes were found related to the effect on the

muscle tissue. Elevated myoglobin, total creatinine kinase (total CK),

isoenzyme CK-MM11, heart fatty acid-binding protein (H-FABP12),

isoenzyme CK-MB13, aspartate aminotransferase (AST), and/or alanine

aminotransferase (ALT) in males at ≥1000 ppm and females at ≥500 ppm.

11 CK-MM is a CK isoenzyme found in the heart and skeletal muscle

12 H-FABP is identified as a specific marker of myocardial infarction.

13 CK-MB is a CK isoenzyme found in the heart.

57


November 2016

The greatest elevations were noted for total CK and CK-MM which were

consistent with an effect on skeletal muscle and were only observed in

treated animals.

At no time in the study were H-FABP or CK-MB elevated in an animal

without concurrent pronounced elevations in total CK, CK-MM and or

myoglobin, suggesting (to researchers) that elevations in H-FABP and CK-

MB were secondary to skeletal muscle injury rather than cardiotoxicity.

Test substance-related increases in liver weight occurred in the 1500 and

5500 ppm males on Day 8 only, which had no associated

micropathological findings, so were considered a non-adverse adaptive

response.

The anatomic and clinical pathology changes fully resolved following the 28

day recovery period.

NOAEC was reported as 500 ppm in males and 1000 ppm in females,

based on anatomic pathology findings at higher dose levels. [We note that

the pathological findings were considered by the researchers to drive the

NOAEC assignments rather than the clinical pathology findings.]

Additional Comments

The researchers (and the NICNAS report) suggest that the rabbit is more

sensitive to these findings, which is why studies in minipigs were

undertaken. This suggested greater scrutiny should be attributed to the

findings in minipigs.

Conclusion

Repeated exposure to the substance for 28 days by inhalation in the rabbit

produced pathological changes in heart and skeletal muscle which were

rapidly reversible. As a result of this finding studies were done in minipigs

which are considered a more suitable animal model for assessment of

cardiovascular effects.

Type of study Sub-acute (2-week) inhalation toxicity study in rats



Endpoint

LOAEC: >51,960 ppm no adverse effects established

NOAEC: 51,960 ppm

58


November 2016

Reference

Mommers, C.; 2005. Sub-acute (2-week) inhalation toxicity study with HFO-

1234yf in rats. TNO Quality of Life, Toxicology and Applied Pharmacology.

Utrechtseweg 48, P.O. Box 360, 3700 AJ Zeist, The Netherlands. TNO Report

V6394/Final

Klimisch Score 1


GLP Yes


Species Rat

Strain Sprague Dawley (Crl:CD[SD])

No/Sex/Group 5

Dose Levels 0, 5,000, 20,000, and 50,000 ppm, 6 h/day, 5 days/week. The measured mean

concentrations were 4,990 (±36), 19,599 (±99) and 51,690 (±620) ppm.

Study Summary

Daily observation of the animals did not reveal any clinical abnormalities.

No treatment-related change in red blood cell variables, coagulation variables,

total white blood cell counts and differential white blood cell counts were

observed.

Clinical chemistry showed a statistically significant increase in calcium levels in

the plasma of the mid- and high-dose males, but these finding were not

considered by the researchers to represent adverse effects of the test material

because the differences were slight, not concentration-related, within the range

of historical control values and not accompanied by changes in any of the other

endpoints examined in the study.

No treatment-related changes in absolute or relative organ weights were

recorded.

Macroscopic examination at necropsy did not reveal treatment-related gross

changes.

Microscopic examination did not reveal treatment-related histopathological

changes in any of the organs/tissues examined (which included the complete

respiratory tract and nasal passages).

59


November 2016

The conclusion was that exposure did cause any adverse effects at any dose

levels, so the NOAEC proposed by researchers was 51,960 ppm.


Conclusion No adverse effects identified in the study up to 51,960 ppm over 2 weeks.

Type of study 28 day inhalation study in rats with Unscheduled DNA Synthesis (UDS)

and micronucleus test

Flag Key study


Endpoint

LOAEC: >50,031 ppm (no adverse effects identified)

NOAEC: 50,031 ppm

Reference


toxicity study (including Unscheduled DNA Synthesis and Micronucleus

test) with 2-week recovery period, with HFO-1234yf in rats. TNO Quality of

Life, Toxicology and Applied Pharmacology. Utrechtseweg 48, P.O. Box

360, 3700 AJ Zeist, The Netherlands. TNO Report V6872/02

Klimisch Score 1


GLP Yes


Species Rat


No/Sex/Group 5

Dose Levels

0, 5,000, 15,000 and 50,000 ppm. The measured mean concentrations

were 4,997 (±7), 15,167 (±459) and 50,031 (±83) ppm. The mean

concentrations were equivalent to 23.5, 71.4 and 235.6 g/m3 for the low,

med and high concentrations respectively. Exposure was 6 hours/day, 5

days/week for 4 weeks (20 -21 exposure days in total)

60


November 2016

Study Summary

Daily observation of the animals did not reveal any treatment-related

clinical abnormalities.

Differences in body weight between treated and control groups were not

seen except on Day 14 on which the body weight of the female mid dose

group was decreased compared to control. At the next weighing the body

weights had recovered. Treatment-related differences in body weight gain,

food consumption and food conversion efficiency were not seen. There

was a slight reduction and subsequent increase in food consumption and

food conversion efficiency in weeks 1 – 3 related to the mid dose female

animal’s body weight variations.

No treatment–related differences in haematology were seen.

There was an increase in urea concentration in low and high dose females

and an increase in creatinine in the high dose females. The increases

were small and the increase in urea was not concentration related. No

difference in the female animals was seen after the 14 day recovery

period. In contrast, male animals showed increased urea concentration at

the end of the 14 day recovery period [there was only a top dose group in

the recovery phase], but not at the end of the exposure period. In male

animals potassium plasma concentrations in all treatment groups were

increased in animals at the end of the exposure period, but a clear

concentration-response relationship was absent. No such change was

seen at the end of the recovery period (meaning the values had returned

to normal).

Changes in absolute or relative organ weight were not detected at the end

of the exposure period. At the end of the 14-day recovery period absolute

liver weights and liver weights relative to body weight were increased for

the male groups. Due to UDS test in male animals no liver weights for the

main male study groups were available for comparison. The differences

were unrelated to treatment as there were no histopathological or other

hepatic changes at the end of the exposure period, nor were there effects

in the female animals at the end of the exposure or recovery periods.

Macroscopic examination at necropsy did not reveal any treatment-related

findings.

Microscopic examination of selected organs including the respiratory tract

did not reveal any exposure-related findings.

61


November 2016

Unscheduled DNA synthesis (UDS) in liver cells of the male rats at the

terminal sacrifice in this study was not observed.

No damage to chromosomes and/or mitotic spindle apparatus

(micronuclei) in the bone marrow target cells of rats were induced in the

males investigated at the terminal sacrifice in this study.

Exposure of the rats to up to 50,000 ppm of the substance did not result in

adverse effects in any of the exposure groups. In the sub-acute inhalation

toxicity study, the NOAEC was therefore the top dose of 50,000ppm for

both males and female rats.


Conclusion No adverse effects were seen up to the maximum concentration tested,

50,031 ppm for 4 weeks.

Type of study 14 Day Inhalation Study in Minipigs



Endpoint

LOAEC: >10,300 ppm

NOAEC: 10,300 ppm

Reference

Hoffman, G. M.; 2013. HFO-1234yf: A 14 Day Inhalation (Whole Body

Exposure) Investigative Study in Minipigs. Huntingdon Life Sciences 100

Mettlers Road, East Millstone, New Jersey 08875-2360, USA. Study

Number 13-6432.

Klimisch Score 1

Amendments/Deviations

Some protocol deviations are documented in the report, the most

significant of which was that the Group 2 males were only exposed for 3

hours on Day 1 due to a high relative humidity in the exposure chamber.

GLP Not certified as GLP compliant, but the investigation was performed at a

GLP facility.

Test Guidelines

OECD 412 Sub-acute inhalation toxicity (28 days).

(Procedures modified as appropriate for use of minipigs in place of rats for

this preliminary investigation.)

62


November 2016

Species Minipigs

Strain Gottingen

No/Sex/Group 3 males/group, 3 females/group for Groups 1 and 3, and 2 females/group

for Group 2.

Dose Levels

0, 5500, 10,000 ppm by whole body inhalation, 6h/day, 7 days/week. The

measured concentrations were 5490 and 10300 ppm (the average of the

male and female chambers.

Study Summary

The study focused on findings on cardiac or skeletal muscle specifically as

a follow up investigation in minipigs of the findings in the 28 day inhalation

study in rabbits, as minipigs are considered a better model to the human

cardiovascular system.

All animals survived to their scheduled termination.

There were no substance-related clinical signs.

There were no substance-related effects on body weight in comparison to

air control animals.

There were no substance-related effects on food consumption in

comparison to air control animals.

In relation to haematology, there were no substance-related effects. All

differences from controls, whether statistically significant or not, were not

considered substance-related. The effects were small in magnitude, not

dose-related, and/or individual values were comparable to pre-test findings

or consistent with normal biological variability.

In relation to clinical chemistry, there were no substance-related effects on

myoglobin, cardiac troponin, creatinine kinase (total CK, or isoenzymes

CK-MM and CK-MB), aspartate aminotransferase or alanine

aminotransferase.

There were no statistically significant changes in any organ weights.

All macroscopic findings occurred at a similar incidence in control and test

substance treated groups.

There were no substance-related microscopic findings involving the heart

(left ventricle, right ventricle and septum), or skeletal muscle (rectus

femoris, psoas, and soleus muscles as well as the diaphragm).

63


November 2016

The cardiac and skeletal muscle changes that were observed were

incidental. The findings were lymphocyte and macrophage aggregation.

At Day 15 there were no substance-related microscopic findings involving

the heart or skeletal muscle. Thus there was no evidence of cardiac or

skeletal muscle toxicity following exposure at up to 10,000ppm in this

study.

Additional Comments We note the limited nature of this study as a preliminary investigation to

establish dose concentration for the 28 day study (below).

Conclusion No adverse effects were seen at the maximum concentration used (10,000

ppm.

Type of study 28 Day Inhalation Study in Minipigs

Flag Key study


Endpoint

LOAEC: .>10,200 ppm

NOAEC: 10,200 ppm

Reference

Hoffman, G. M.; 2014. HFO-1234yf: A 28 Day Inhalation (Whole Body

Exposures) Toxicity Study in Minipigs. Huntingdon Life Sciences 100 Mettlers

Road, East Millstone, New Jersey 08875-2360, USA. Study Number 13-6434

Klimisch Score 1


GLP Yes

Test Guidelines

OECD 412 Sub-acute inhalation toxicity (28 days).

(Modified as necessary to be appropriate for use of minipigs and to specifically

investigate cardiac and skeletal muscle toxicity.)

Species Minipigs

Strain Gottingen

No/Sex/Group 8

64


November 2016

Dose Levels

Exposure was by whole body inhalation. The target exposure concentrations

were: 0, 5,000, 10,000 ppm (which are equivalent to 0, 26 and 50 mg/L) for 6

hours/day, 7 days/week for up to 28 consecutive days. The measured mean

gas concentrations were: 0, 5145, 10,200 ppm.

Study Summary

There were no substance-related deaths or sacrifices.

There were no substance-related effects on clinical signs.

There were no substance-related effects on body weight.

There were no substance-related effects on food consumption.

There were no substance-related effects on haematological parameters.

There were no test substance-related effects on clinical chemistry parameters.

Minimal increase in total creatinine kinase (CK) and CK-MM isoenzyme noted in

3/8 females on Study Day 21 at 10,000 ppm were not considered substance-

related because they were transient and the values were within normal

biological variability.

An increase in absolute and relative liver weights (in comparison to body weight

and brain weights) were seen at exposure levels of 5000 ppm and higher in

females. Potential correlation to histopathological findings was not possible as

the protocol did provide for examination of the livers using histopathology.

At termination there were no microscopic findings involving the heart (left

ventricle, right ventricle and septum) and skeletal muscle (rectus femoris, psoas

and soleus muscles as well as the diaphragm). There was no microscopic

evidence of cardiotoxicity, or skeletal muscle toxicity following whole body

inhalation of the test substance at up to 10,000 ppm for 28 consecutive days.

The researchers report the NOEL was the average maximum exposure

concentration of 10,200 ppm, based on the lack of findings in cardiac and

skeletal muscle. We note this assumes the changes in absolute and relative

liver weight are not an adverse finding. This cannot be verified due to the

limitations in the protocol (which did not require any histopathological

examination of all tissues). This NOAEC value is reported by NICNAS as being

specific to cardiac and skeletal muscle effects, rather than a general NOAEC.

Additional Comments

The study authors note that there is a very limited database for repeat

inhalation toxicity studies in minipigs. This study was intended to clarify the

relevance of the effects of the substance on cardiac and skeletal muscle in the

rabbit studies discussed above. As a result limited investigations were

65


November 2016

undertaken in this study. The study demonstrates that minipigs respond very

differently to the substance than rabbits.

Conclusion

No adverse findings were identified so the NOAEC is the highest dose tested

10,200 ppm, although the investigations undertaken were more limited than in

standard sub-acute investigations. Note that the NOAEC value is reported by

NICNAS as being specific to cardiac and skeletal muscle effects, rather than a

general NOAEC.

Special studies: Cardiac sensitisation in dogs

Type of study Toxicology study to detect cardiac sensitisation potential in dogs

Flag Key study


Endpoint

LOAEC: >120,000 ppm (12%)

NOAEC: 120,000 ppm (12%)

Reference

Weinberg, J. T.; 2006. Acute Cardiac Sensitisation Study of HFO 1234ze and

HFO 1234yf in Dogs. WIL Research Laboratories, LLC, 1407 George Road,

Ashland, OH 44805-9281, USA. Study Report No. WIL-447008

Klimisch Score 1


GLP Yes

Test Guidelines No guidelines apply for a study of this type

Species Dog

Strain Beagle

No/Sex/Group 6 (males)/dose level

Dose Levels

2, 6 and 12% (20,000, 60,000 or 120,000 ppm) of HFO1234yf via inhalation via

muzzle-only exposure for approximately 10 minutes. There were no controls as

each dog served as its own control. There was a minimum of 48 hours between

exposure of the animals to the different test substance concentrations.

Study Summary Dogs were administered a pre-exposure dose of epinephrine as a bolus

injection via a cephalic vein approximately 5 minutes prior to the exposure to

66


November 2016

the test article. The dose was started at 2 μg/kg bw, but increased to 3, 4, 6, or

8 μg/kg bw if necessary. The dose used in the post exposure challenge was

determined for each dog and was the highest dose level tested during the pre-

study evaluation that did not elicit a significant ECG finding (e.g. a premature

ventricular contraction).

Five minutes after exposure to the test substance the animals were

administered a challenge dose of epinephrine. Electrocardiographic data were

recorded continuously throughout the pre-exposure epinephrine dosing,

exposure to the test gas and for 5 minutes following administration of the

challenge epinephrine dose (a total of approximately 17 minutes).

The criteria for a sensitisation response included (but were not limited to) the

following criteria:

Eleven or more premature ventricular contractions (PVCs) in 10

seconds, with episodes of confluency

Ventricular tachycardia

Fibrillation

Results

All animals survived to study termination. No test article related clinical

observations were seen and body weights were unaffected by test article

administration.

There was no evidence of cardiac sensitisation following exposure to HFO-

1234yf at any of the concentrations tested, so the NOAEC for cardiac

sensitisation was 120,000 ppm.


Conclusion There was no evidence of cardiac sensitisation following exposure to HFO-

1234yf at any of the concentrations tested.

Discussion of classification for target organ systemic toxicity by the inhalation route

We note that the single dose toxicity data do not support classification as an single exposure target organ

systemic toxicant in comparison to the cut off thresholds of 5,000 ppm (EPA, User Guide, Table 17-1, p17-7).

In relation to repeat dose studies, none of the repeat dose inhalation tests from repeat exposures

6 hours/day for 14 days or more, identify adverse systemic target organ effects. All the studies in rats and

minipigs for the 14 – 28 day duration have an LOAEC >10,000 ppm. The 90 day repeat inhalation study in

rats also gives an LOAEC >50,000 ppm based on the NICNAS review (although that study was not available

to the EPA for review).

67


November 2016

The only species studied which appeared to suffer target organ effects was the rabbit, in which the cardiac

and skeletal muscle appear to be more sensitive than in other species. The LOAEC of 500 ppm in the male

rabbit in a 28 day study is the only LOAEC which could support any classification in comparison to the repeat

dose classification criterion cut off of 250 ppm for a 90 day study (EPA, User Guide, Table 17-2, p17-9).

Nevertheless, we consider that no classification is appropriate taking into account the negative data for the

rat and, in particular, the minipig, which is seen as a more appropriate model comparison for assessing

cardiovascular toxicity in the human.

We therefore recommend no classification for target organ systemic toxicity via the inhalation route for either

single or repeat exposure.

General conclusion about mammalian toxicology of active ingredient(s) and metabolite(s)

Table 2 Summary of studies with NOAEC and LOAEC values and key effects.

Study type NOAEC LOAEC Key effect

28 day inhalation study

in rabbits

500 ppm (males

1000 ppm (females)

1000 ppm (males

1500 ppm (females)

Anatomic pathology

findings in heart and

skeletal muscle

2 week inhalation study

in rats 51,690 ppm >51,690 ppm

No adverse effects

identified


in rats 50,031 ppm >50,031 ppm

No adverse effects

identified


in minipigs (by

inhalation)

10,300 ppm >10,300 ppm

No adverse effect, but

investigation focused

on cardiac and skeletal

muscle


in minipigs (by

inhalation)

10,200 ppm >10,200 ppm

No adverse effect, but

investigation focused

on cardiac and skeletal

muscle

Cardiac sensitisation in

dogs (by inhalation) 120,000 ppm (12%) >120,000 ppm (12%)

No evidence of cardiac

sensitisation caused by

the substance with

epinephrine challenge

Pre-natal toxicity in the

rat (by inhalation)

50,315 ppm for both

maternal and foetal toxicity

>50,315 ppm for both

maternal and foetal toxicity

No adverse effects in

maternal or foetal

animals

Pre-natal toxicity in the

rabbit (by inhalation)

4000 ppm for maternal

animals

4000 ppm for visceral

malformations in pups

5,500 in maternal animals

5500 ppm for visceral

malformations in pups

Mortality, moribundity,

abortions, premature

delivery, lower mean

body weight gain,

mean body weight loss

and/or lower food

consumption observed

68


November 2016

at 5,5000 and 7,500

ppm (maternal

animals).

Adverse effects

visceral malformations

in pups only seen in

the presence of

maternal toxicity

Two generation

reproductive toxicity

study in rats (by

inhalation)

49,958 ppm in parental

animals

49,958 ppm for

reproductive/developmental

toxicity

>49,958 ppm in parental

animals

>49,958 ppm for

reproductive/developmental

toxicity

No systemic toxicity

seen in parental

animals

No adverse

reproductive or

developmental effects

seen


in rat (not submitted to

EPA by applicant).

[NICNAS review data

summarised.]

NICNAS reported >50,116

ppm. This is confirmed in

the toxicogenomic report

for both rats and mice.

EPA would assign NOAEC

= 50,116 ppm.

>50,116 ppm

No systemic toxicity

seen in parental

animals

(No study report

available to the EPA

for review for the 90

day inhalation study).

Toxicokinetics

The toxicokinetic assessment from the NICNAS report made the following key concluding remarks on

toxicokinetics, metabolism and distribution of the substance:

“The major metabolic pathway of the notified chemical is likely to be cytochrome P450 2E1-mediated

epoxide formation at low rates, followed by glutathione conjugation.”

“The results of the study suggested a low extent of biotransformation of the notified chemical and the same

major metabolic pathway as that in rats and mice. Most of major metabolites (95%) were excreted within 12

hours after the end of exposure (t1/2 = approx. 9.5 h).”

Further comments on epoxidation are discussed below under Conclusion on Toxicokinetics and Metabolic

Pathway.

Special study relating to metabolism in pregnant rabbits

Type of study Special 1 hour inhalation study in rabbits including analysis of urinary

metabolites

Flag Supporting information


69


November 2016

Endpoint

LOAEC: N/A

NOAEC: N/A

Reference

Hoffman, G. M.; 2011. HFO-1234yf: A 2-phase Inhalation Screening Study

and Single Exposure Study in Rabbits via Whole-body Inhalation Exposure

(GLP). Huntingdon Life Sciences, 100 Mettlers Road, East Millstone, New

Jersey 08875-2360, USA. HLS Study No; 10-2226.

Including: Appendix I. Rabbit urine analysis. Dekant, W., et al.; 2011.

Biotransformation and toxicokinetics of 2,3,3,3-tetrafluoropropene (HFO-

1234yf) in male, pregnant and non-pregnant female rabbits. Institute of

Toxicology, University of Wurzburg, Versbacher Str. 9, 97078 Wurzburg,

Germany

Klimisch Score 1


GLP Yes

Test Guidelines Not based on a test guideline but generally in accordance with US EPA

OPPTS 870.1300

Species Rabbit


No/Sex/Group

5 males/group, and 6 presumed pregnant females/group and 5 non

pregnant females (for control and top dose only). The exposure in the

presumed pregnant females being from Gestation Day 12 followed by a 14

day post exposure period.

Dose Levels

0, 50,000, and 100,000 ppm. The analytical concentrations were in Phase I

110,000 ppm and in Phase II 0, 45,000 (males), 47,000 (females), 100,000

(males) and 102,000 ppm (females)

Study Summary

This study was carried out due to earlier studies suggesting pregnant and

non-pregnant rabbits may be more sensitive to the substance than

expected in comparison to rats (see the pre-natal developmental study in

rabbits above).

The study was in two phases: Exposure in Phase 1 was to 100,000 ppm

only. In Phase 2 exposure was to 0, 50,000 or 100,000 ppm.

70


November 2016

The summary does not discuss the two phases, but we identified the

following:

Phase 1

This was a screening phase in which one non-pregnant and one presumed

pregnant group of female rabbits were given a whole body, 1-hour,

exposure of 100,000 ppm to HFO-1234yf.

Aside from confirming pregnancy status the animals were not examined.

Phase II

There were three dose levels and groups of presumed pregnant females,

non-pregnant females and males [PPF,NPF,M], as follows:

Air control/0 ppm: 6,5,5

50,000 ppm 6, 0, 5

100,000 ppm 6, 5, 5

The exposure was for 1 hour, whole body exposure. The animals were

euthanised 14 days after exposure and a complete post-mortem

undertaken (including determination of pregnancy status).

No key difference was seen between pregnant and non-pregnant rabbits,

but in relation to an unidentified metabolite there was a slight difference

between female and male rabbits.

All the animals survived until their scheduled sacrifice. There were no test

substance-related clinical signs in any of the test animals. There were not

test substance-related effects on body weights in any of the test groups of

animals.

Macroscopic pathology: In Phase I, all the presumed pregnant females

were pregnant. In Phase II all were presumed pregnant females were

pregnant except one control animal and one animal in the top dose.

In phase II there were no test substance-related macroscopic findings at

terminal sacrifice.

In phase II there were no test substance-related microscopic findings (in

the heart, kidney, liver or lungs) at terminal sacrifice.

In conclusion, no lethality and no clinical signs were observed in the

exposed animals. No substantial differences in urinary metabolite pattern

or quantity of metabolites excreted were observed between the different

groups, apart from the difference for the as yet unidentified metabolite

71


November 2016

found at 12-17% in female rabbits and >7% in male rabbits of the sex main

metabolites.


Conclusion

No significant metabolic differences were identified between pregnant

female rabbits, non-pregnant female rabbits or male rabbits which could

explain the previous findings of mortality in pregnant female rabbits in the

pre-natal toxicity test (above).

EPA Staff Conclusion on Toxicokinetic and Metabolic Pathway

We consider that the oxidation of the alkene group via an epoxide could potentially be a toxicologically

significant activation pathway based on comparison to other chemicals, particularly halogenated alkenes.

The total amount of metabolised HFO-1234yf was calculated to be less than 0.1% of the received dose in all

groups. We consider the small proportion of metabolic conversion is important when considering the

significance of the difference in proportion of the unidentified metabolite produced in males and females and

also in the broader context of a risk assessment for HFO-1234yf. We consider that while epoxidation is

referred to as the “major” pathway by the researchers, this is in relation to the other metabolic pathways. The

total extent of biotransformation of the test substance via this pathway is very low (calculated to be less than

0.1%), so the quantity undergoing epoxide formation is also very low and therefore unlikely to be of concern.

Human health risk assessment

Due to the proposed use pattern, human exposure to HFO-1234yf during the use stage of its lifecycle is

expected to be very limited. Nevertheless some human exposure is possible due to leakage. Some

installations will be vulnerable to impact, in particular, when used in motor vehicles. A quantitative human

health risk assessment has not been performed for all uses, but we have considered the NICNAS14 risk

assessment of the potential exposure from a private motor vehicle.

No human exposure and risk assessment was undertaken for industrial users due to the contained use

systems in which the substance will be used, either in pure form or as part of a refrigerant mixture and the

expectation that personal protective equipment will be used.

We considered the assessment NICNAS carried out associated with a worst case scenario and concluded

the risk to members of the public is low. In the NICNAS assessment a worst case scenario was examined in

which a pregnant individual was trapped in a motor vehicle and exposed to the entire refrigerant change

(within an unventilated car cabin) for 5 minutes.

NICNAS used a physiologically-based pharmacokinetic model the exposure was compared to the NOAEC

concentration for developmental toxicity in the rabbit pups. We note this rabbit value was used despite no

developmental effect being seen in the study at non-maternally toxic doses, so we consider it precautionary.

14 NICNAS, 2015. Public Report: 1-Propene, 2,3,3,3-tetrafluoro- File No: STD/1556.

72


November 2016

The total exposure in to the individual was estimated to be 1.2 mg/L.hr in comparison to the exposure for the

pregnant female rabbit (at the NOAEC concentration for the foetus) 225.6 mg/L.hr. So this represent a

margin of over 100. The conclusion is that the risks from the private use in motor vehicles is acceptable.

Based on this being a worst-case scenario, we also concluded the risks from other uses as in blend

(mixtures) are acceptable.

As discussed above, a special study was done to assess the potential of the substance to cause cardiac

sensitisation in dogs, which demonstrated that there was no evidence of this occurring up to a very high

concentration (120,000 ppm, 12% in air). We consider it noteworthy that this demonstrates that HFO-1234yf

has a much lower potential for cardiac sensitisation than other similar substances15. This is important due to

the possibility of deliberate inhalation of the substance.

Due to the relatively high gas density of HFO-1234yf (4 relative to air =1) there is a potential for asphyxiation

of person present in enclosed spaces where there is poor ventilation or lower bodies of air.

15 Mullin, L., Reinhardt, C. and Hemingway R. Cardiac arrhythmias and blood levels associated with inhalation of halon 1301.

American Industrial Hygiene Association Journal, 1979; pp 40, 653-358

73


November 2016

Appendix E: Ecotoxicology

Ecotoxicity - Robust study summaries for HFO-1234yf

Aquatic ecotoxicity – fish

Study type Acute toxicity study in Cyprinus carpio (Carp)

Flag Key Study


Endpoint LC50 96 hours

Value >197 mg/l

Reference

M. Bogers (2006). Acute toxicity study in carp with HFO-1234yf (static). Notox

B.V. Hambaken wetering 7, Den Bosch, The Netherlands. Report Number

V6472/04

Klimisch Score 1

Amendments/Deviations None that impacted the study

GLP Yes

Test Guideline/s OECD 203, ISO 7346-1:1996, EU C1

Dose Levels

Nominal: 30 and 60 minutes flow at approximately 100 ml/min

Measured: 197 mg/l (geometric mean) highest concentration

Analytical measurements GC-FID

Study Summary

Static toxicity with carp.

The tested substance was a gas which was bubbled for different time periods

through the medium.

Two tests were performed, one with solutions bubbled for 30 and 60 minutes at

approximately 100 l/min and one test with solutions bubbled for 60 minutes with

a flow of at approximately 100 ml/min.

In the first test average concentrations were below 100 mg/l. In the second test

the initial concentration was 114 mg/l and the geometric mean was 197 mg/l/.

Seven fish per concentration and the control were exposed.

74


November 2016

No fish died during the test and therefore the 96h-LC50 is determined to be

>197 mg/l. One fish in the second study showed slight signs of stress.

Conclusion LC50 > 197 mg/l (based on the geometric mean of the measured

concentrations)

Aquatic ecotoxicity - crustacea

Study type Acute toxicity study in Daphnia magna (waterflea)

Flag Key Study


Endpoint EC50 Immobility, 48 hours

Value >83 mg/l

Reference

M. Bogers (2006). Acute toxicity study in Daphnia magna with HFO-1234yf.

Notox B.V. Hambaken wetering 7, Den Bosch, The Netherlands. Report

Number V6472/03

Klimisch Score 1


GLP yes

Test Guideline/s OECD 202; ISO 6341:1996; EU

Dose Levels

Nominal: 4, 7.5, 15, 30 and 60 minutes flow at approximately 20 ml/min

Measured: 83 mg/l (geometric mean) highest concentration.


Study Summary

Static toxicity with Daphnia magna.

The tested substance was a gas which was bubbled for different time periods

through the medium.

After a range-finding test a final test was performed consisting of four replicates

per concentration containing 5 daphnids each.

The initial concentration was the concentration reached at 60 minutes flow at

approximately 20 ml/min. This was 102 mg/l at the start of the test and

decreased to 68 mg/l at the end of the test. The geometric mean was calculated

to be 83 mg/l.

75


November 2016

Not more than 5% of the daphnids were immobilised and therefore the 48h-

EC50 is determined to be >83 mg/l.

Conclusion EC50 > 83 mg/l (based on the geometric mean of the measured concentrations)

Aquatic ecotoxicity - algae

Study type Acute toxicity study in Selenastrum capricornutum

Flag Key Study


Endpoint ErC50 72- hours

Value >75 mg/l

Reference

M. Bogers (2006). Freshwater algal growth inhibition test with HFO-1234yf.

Notox B.V. Hambaken wetering 7, Den Bosch, The Netherlands. Report

Number V6472/02

Klimisch Score 1


GLP Yes

Test Guideline/s OECD 201; ISO 8692:2004; EU C3

Dose Levels

Nominal: 4, 7.5, 15, 30 and 60 minutes flow at approximately 20 ml/min

Measured: 83 mg/l (geometric mean) of the highest nominal concentration


Study Summary

A limit test with a saturated solution of HFO-1234yf was performed. The media

was purged for a 3-hour period. The initial concentration was 170 mg/l and this

decreased to 17-76 mg/l at the end of the exposure period. The overall average

exposure concentration was 75 mg/l.

Cell growth inhibition was <10%.

Although the maximum average concentration is 114 mg/l it is considered not to

be the ErC50 since the mean average concentration at this loading rate is lower.

The 114 mg/l was measured in one replicate at the highest loading rate,

however the average exposure concentration is considered more reliable.

76


November 2016

Conclusion 72-hour ErC50 > 75 mg/l (based on average exposure concentrations)

Summary of aquatic toxicity

An average exposure concentration at 100 mg/l was not reached for the Daphnia magna acute toxicity test and in the

algal growth inhibition test this concentration was almost achieved. Based on the results it is unlikely that the EC50 will be

below 100 mg/l. Therefore, no 9.1 classification is assigned.

Summary of other ecotoxicity classifications

No studies have been provided to determine the 9.2, 9.3 and 9.4 classification of the substance. Inhalation studies are

not used for the classification of terrestrial vertebrates.

Environmental fate - Robust study summaries

Biodegradability

Study type Readily biodegradability

Flag Key Study


Endpoint % of Theoretical Oxygen Demand (ThOD)

Value <5%

Reference

Daniel (2008). HFO-1234yf: Determination of 28 day ready biodegradability.

Brixham Environmental Laboratory, AstraZeneca UK Limited, Brixham, Devon,

UK. Report Number: BL8606/B

Klimisch Score 1


GLP Yes

Test Guideline/s OECD 301F

Dose Levels 117 mg/l

Analytical measurements Oxitop respirometers

Study Summary The aerobic biodegradation was determined using the Manometric

Respirometric method (OECD 301F). Oxitop respirometers were attached to

77


November 2016

500 mL dark glass bottles with magnetic stirrers to ensure optimal contact of

the substance with the test organisms.

Sewage sludge was used as an inoculum. The inoculum was collected, washed

and re-suspended seven days prior to the start of the exposure.

It should be noted that the Biological Oxygen Demand (BOD) of the control was

low, indicating that the sludge was not very active.

The ThOD of the substance was 0.98 g O2/g substance. Less than 0.05 gram

O2 per gram of substance was consumed. Therefore, no significant

biodegradation was observed (<5% of ThOD).

Conclusion The substance is not readily biodegradable.

Study type Ready Biodegradability

Flag Key Study


Endpoint % of ThOD translated to % of substance biodegraded

Value 0% for both

Reference

Kayashima (2008). Biodegradation study on HFO-1234yf by microorganisms.

Kurume Laboratory and Research Institute Japan 2-7, 3-chome, Miyanojin,

Kurume-shi, Fukuoka, Japan. Study Number 15157

Klimisch Score 1


GLP Yes

Test Guideline/s OECD 301D

Dose Levels 8.22 mg/l

Analytical measurements Oxygen meter and Gas Chromatography.

Study Summary

The aerobic biodegradation was determined using the closed bottle test (OECD

301D).

Closed bottles with a volume of 100 ml were cultivated “sealed and standing”

for 28 days. Sewage sludge was used as an inoculum. The inoculum was

78


November 2016

collected, washed and resuspended seven days prior to the start of the

exposure. 1 drop was added per litre of medium. Dissolved oxygen was

measured using a probe, the substance was measured using GC.

The percentage biodegradation based on BOD and substance concentration

was 0%

Conclusion The substance is not readily biodegradable.

Koc estimation

Study type Estimation of Koc



Endpoint Log Koc

Value 1.7-2.1 L/kg

Reference Not provided (printout from programme supplied)

Klimisch Score 3 (no GLP or method specified)

Amendments/Deviations NA

GLP NA

Test Guideline/s Not specified programme KOCWIN v2.00

Dose Levels Calculation

Analytical measurements NA

Study Summary

The Koc was estimated using KOCWIN v 2.00, no guidance or method

description was provided by the applicant.

The calculated log Koc was 2.1342 or Koc 136.2 L/kg

When the log Kow is used for the estimation, the log Koc is 1.7354 and Koc

54.38 L/kg

Conclusion Log Koc 1.7-2.1 L/kg

79


November 2016

Hydrolysis

Study type Expert statement on hydrolysis and biodegradation



Endpoint Hydrolysis and biodegradation

Value Both processes are unlikely to have a significant impact on the fate of the

substance

Reference C. Hamwijk (2006). Expert statement on hydrolysis and biodegradation of HFO-

1234yf

Klimisch Score 3 (no study)

Amendments/Deviations NA

GLP NA

Test Guideline/s No guideline calculations are performed in BIOWIN v 4.02 and HYDROWIN

v1.67

Dose Levels NA

Analytical measurements NA

Study Summary

Calculations based on the molecular structure are claimed to indicate that

hydrolysis and biodegradation are likely to be negligible.

The structure of the substance was adjusted to allow the programme to

calculate the degradation rate (i.e. carbon double bond removal). This is

expected not to have a significant influence on the hydrolysis rate. DT50 for

hydrolysis was calculated to be 106-107 years. The substance was predicted to

be not ready biodegradable.

Conclusion Negligible

Summary of the Environmental Fate

The substance is not readily biodegradable and hydrolysis seems a non-significant degradation pathway. According to

the estimation of the Koc the substance is moderately mobile to mobile according to FAO criteria. Based on the estimated

log Kow bioaccumulation is unlikely. Based on the physical state of the substance (gas at room temperature) vertical

movement (leaching into groundwater) in the soil is unlikely.

80


November 2016

Qualitative ecological risk assessment

The substance is used in closed systems and is not expected to be released in significant concentrations.

During an accident or leakage some of the substance might be released. The physical state of the substance

will be a gas, therefore limiting the exposure.

Exposure in the aquatic environment (pelagic and sediment) is considered unlikely because the substance is

highly volatile and is likely to quickly evaporate from the water if a spillage occurs. Furthermore the

substance is considered non-hazardous for the aquatic environment based on the data on Daphnia, fish and

algae. Although the substance is non-biodegradable, accumulation of the substance in the aquatic

environment is considered unlikely due to the use pattern and volatility of the substance. Inhalation might be

a relevant pathway for birds but due to the limited release of the gas expected exposure the risk is

considered negligible.

The atmospheric life is relatively short (DT100=11 days, Nielsen et al. 200716) and a reaction with ozone is not

expected to be the most dominant degradation pathway in the atmosphere. Because of the short

atmospheric life the substance is not expected to mix on a global scale. The global warming potential is 4.4

for the 100 year time horizon which is considered to represent a low climatic impact. The ozone-depletion

potential is considered to be nearly zero (Papadimitriou et al. 2007)17.

16 Nielsen et al (2007). Atmospheric chemistry CF3CF=CH2: Kinetics and mechanisms of gas-phase

reactions with Cl atoms, OH radicals and O3. Chemical Physics Letters, Vol 439, p 18-22.

17 Papadimitriou et al (2007). CF3CF=CH2 and (Z)-CF3CF=CHF: Temperature dependent OH ate coefficients

in global warming potentials. Physical Chemistry Chemical Physics, Vol 10, p 808-820.

81


November 2016

Appendix F: Confidential information

This appendix contains the confidential information provided by the applicant and is not publicly

available.

82


November 2016

Appendix G: Standard terms and abbreviations

Definitions

Unless defined below, terms used in the controls have the same meaning as defined in the Act or

regulations made under the Act.

Term Definition

DTx Time required to degrade x% of the substance

ECx Concentration which affects x% of the population

GC-FID Gas chromatography - flame ionisation detector

Kd Distribution coefficient

Koc Kd * 100 / % organic carbon

Kow Partitioning coefficient octanol - water

LCx Concentration which kills x% of the population

LOAEC Lowest observable adverse effect concentration

NOAEC No observed adverse effect concentration

ThOD Theoretical oxygen demand

Documents

Application for approval to import HFO- 1234yf for release · 2019. 4. 6. · Overall evaluation and recommendation ... We note that HFO-1234yf is expected by the applicant to have