Approaches for establishing limits for different routes of ... for... · Approaches for establishing limits for different routes of administration Trish Parris. When to consider route

Approaches for establishing limits for different routes

of administration

Trish Parris

When to consider route specific exposure limit -

Only data available

• Volatile compounds

• Oral carcinogenicity data unavailable

• Bis(chloromethyl)ether (BCME)

Effect Summary

Human exposure Known carcinogen

Mutagenicity In vitro mutagen

Carcinogenic Effects ip injection (only 1 dose group TD50 of 182 μg/kg/day), inhalation and

dermal studies. Rat inhalation study most sensitive and robust (multiple

doses and >50 animals/group). Increase in olfactory epithelium tumours

(esthesioneuroepitheliomas). TD50 of 3.57 μg/kg/day.

M7 Addendum, 2015; Leong et al. (1981)

BCME

3

• Using the TD50 of 3.57μg/kg/day, linear extrapolation

o Acceptable intake (AI) = 4 ng/day

• Similar to published regulatory limit US EPA for drinking water

o 3.2 ng/day

• Highly conservative, applicable to all routes

Route specific toxicity/sensitivity

• Local or site of contact effects – irritation and/or cancer

• Dimethylcarbamyl Chloride (DMCC)

4

Effect Summary

Human exposure Probable carcinogen

Mutagenicity In vitro mutagen

Carcinogenic Effects ip, sc injection, dermal and inhalation carcinogenicity studies.

Only TD50s available for ip and inhalation.

Mouse ip injection malignant tumours at injection site, TD50 of

4.59 mg/kg/day. Hamster inhalation Squamous cell

carcinoma of nasal cavity, TD50 of 0.625 mg/kg/day.

M7 Addendum, 2015; Sellakumar et al. 1980; Van Duuren et al. 1974

DMCC

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TD50 AI Route

Mouse ip injection site tumours:

TD50 4.59 mg/kg/day

5 μg/day Parenteral and oral

Hamster inhalation nasal cavity

tumours: TD50 0.625 mg/kg/day

0.6 μg/day Inhalation

• Mutagenic AI = linear extrapolation from TD50

Chemical specific adjustment factor

• Reduce conservatism in route to route extrapolations

Renwick et al, 1991

6

AF Description

F1 Extrapolation between species, max value 10

TK TD

4 2.5

Poorly soluble - Titanium dioxide (not nano!)

• Metal catalyst, packaging leachable

• Minimal parenteral data, no chronic (EHC 24, 1982; OECD, 2013)

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Effect Summary

Human exposure Possible carcinogen

Mutagenicity Overall, not mutagenic or genotoxic (some +ve in vitro

genetox)

Non-Carcinogenic Effects

(oral,iv)

Not toxic

Carcinogenic Effects (oral) NOAEL: mice 6,500 mg/kg/day and rats 2,500 mg/kg/day.

Carcinogenic Effects

(inhalation)

Rats, bronchioloalveolar adenomas, squamous metaplasias,

pulmonary keratin cysts and squamous cell carcinomas

observed at 250 mg/m3, no compound-related lung tumors.

NOEAC 50 mg/m3

Titanium dioxide

• Non-genotoxic rodent carcinogen - PDE using ICH Q3C

• Oral – PDE not calculated

• Inhalation – NOEAC of 50 mg/m3 = 6.1 mg/kg/day

• PDE = 3.1 mg/day

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AF Description Value

F1 Extrapolation between species 1 (usually 5 but rat more sensitive

than human, ILSI, 2000)

F2 Variability between people 10

F3 Short-term to long term extrapolation 1 (carci study)

F4 Severe toxicity 10 (non-genotoxic carcinogen)

F5 NO(A)EL established 1

Titanium dioxide - Parenteral

• no chronic repeat-dose parenteral data available

• inhalation carcinogenicity considered most sensitive endpoint suitable to derive

parenteral PDE

o Using inhalation NOEAC of 50 mg/m3 = 6.1 mg/kg/day

o PDE = 1.2 mg/day

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F1 Extrapolation between

species

2.5 (as per ECHA guidance)


F3 Short-term to long term

extrapolation

1 (carci study)

F4 Severe toxicity 10 (non-genotoxic carcinogen)


OECD, 2013;

IPCS 2005

Bioavailability adjustment factor - Parenteral

• Often lack of chronic data

• Extrapolation from oral studies

ICH Q3D, 2014

10

Oral bioavailability AF

< 1% Divide by 100

< 50% Divide by 10

50-90% Divide by 2

> 90% Divide by 1

Discussion

• 2 compounds ~ 3 tables/compound

• Acrolein and Methyl bromide (Bercu et al., 2018)

• High level summary of available genotoxicity and carcinogenicity data

(pre-read)

• 2 questions to discuss and answer with poll everywhere (10 mins)

• Feedback to group (10 mins)

11

Acrolein - 1

• Mutagenicity/Genotoxicity

o Highly reactive and cytotoxic

o Ames +ve

o Genotoxic in some in vitro systems – intrinsic reactivity may explain –ve results

• Non-Carcinogenic Effects

o Severe dermal, nasal and ocular irritant

➢ Nasal irritation most sensitive respiratory effect

o Chronic oral exposure with dogs, mice and rats results in irritation of GI mucosa

o 13-week studies with rats and mice mortality and stomach lesions

predominant effects12

Compound Structure In vitro

Mutagen

Rodent

Carcinogen

Limit (AI or PDE)

Acrolein

(CAS# 107-02-8)Yes No ???

Acrolein - 2

• Carcinogenic Effects

o IARC Group 3 - not classifiable as to carcinogenicity in humans; US EPA -

inadequate data

o 2 of 3 oral carci studies –ve and 1 questionable

➢ Critical effect is NOAEL of 0.05 mg/kg/day for decreased survival in

male and female rats treated by oral gavage for 2 years. Deaths were

attributed to localized effects (i.e. gastric irritation) with a clear dose-

dependant increase

o 2 inhalation studies –ve (although exposure only 1 yr, with a single

exposure concentration, and limited no. of animals)

➢ Critical effect is LOAEL of 0.1 mg/kg/day for nasal lesions in male and

female rats exposed to acrolein 6 hours/day, 5 days/week for 13

weeks

o Weight of evidence indicates that acrolein is not a rodent carcinogen13

Poll Question 1

While mutagenic, the weight of evidence indicates that

acrolein is not carcinogenic and therefore, which

methodology should be used to calculate exposure limits?

A. Linear extrapolation from TD50

B. Benchmark Dose approach

C. ICH Q3C PDE methodology

Answer: PDE

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Poll Question 2

Based on the summary information, which data would you use

to calculate route specific exposure limits for acrolein?

A. Mutagenicity/genotoxicity data

B. Dermal, nasal and ocular irritation study data

C. Chronic oral study data

D. Carcinogenicity study data

Answer: D

Local irritation driving most sensitive endpoint via oral and

inhalation exposure. Use oral and inhalation carci studies to

derive route specific exposure limits 15

Acrolein Oral PDE

• Oral carci study in rats, NOAEL of 0.05 mg/kg/day

• Lifetime PDE = 50 μg/day

• US EPA oral RfD = 25 µg/day, based on the same 2-year rat study

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species

5 (rat to human)



extrapolation

1 (carci study)

F4 Severity of effect 1 (gastric irritation has a clear

threshold)


Acrolein Inhalation PDE

• Inhalation carci study in rats, LOAEL of 0.1 mg/kg/day

• Lifetime PDE = 7 μg/day

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species

5 (rat to human)



extrapolation

5 (3-month study duration)

F4 Severity of effect 1 (effects not severe at the

LOAEL)

F5 LO(A)EL established 3

Methyl bromide - 1

18

Compound Structure In vitro

Mutagen

Rodent

Carcinogen

Limit (AI or PDE)

Methyl bromide

(CAS# 74-83-9)Yes No ???

• Mutagenicity/Genotoxicity

o Ames +ve (gas sealed dessicators)

o UDS –ve and chrom abs –ve in vivo rat bone marrow

o SCE +ve bone marrow and MN +ve blood in mouse 14-day inhalation study

• Non-Carcinogenic Effects

o Moderate acute toxicity via oral and inhalation

o 5 developmental inhalation studies. 4/5 No abnormalities observed

o 1/5 abnormalities observed in rabbit pups at 80 ppm due to significant maternal

toxicity. NOAEC 40 ppm (14 mg/kg/day)

Methyl bromide - 2

• Carcinogenic Effects

• IARC Group 3 - not classifiable as to carcinogenicity in humans; US

EPA Group D - not likely to be a human carcinogen

• Oral chronic studies in rats (2 years). Lowest NOAEL from 2 rat

dietary studies 2.2 mg/kg/day, BW changes at high doses.

• Oral chronic study in dogs (12 months duration). No effect up to top

dose 0.28 mg/kg/day

• Inhalation chronic study in rats. 3 ppm (1.4 mg/kg/day) inflammation

/ hyperplasia of nasal epithelium NOAEC not defined.

• Inhalation chronic study in mice, LOAEC of 10 ppm (10.7

mg/kg/day) with hyperplasia of the nasal epithelium at all doses.

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Poll Question 1

While mutagenic, the weight of evidence indicates that methyl

bromide is not carcinogenic and therefore, Which

methodology should be used to calculate exposure limits?

A. Linear extrapolation from TD50

B. Benchmark Dose approach

C. ICH Q3C PDE methodology

Answer: PDE

20

Poll Question 2

Based on the summary information, which data should be used to calculate

the route specific exposure limits?

A. Oral rat carcinogenicity study data

B. Oral dog chronic study data

C. Inhalation rat carcinogenicity data

D. Inhalation mouse carcinogenicity data

Answer: A and C

Separate PDEs calculated for oral (A) and inhalation (C)

• Chronic inhalation studies more sensitive than oral

– effects in nasal region, site of contact 21

Methyl bromide Oral PDE

• NOAEL 2.2 mg/kg/day in rats, with BW changes observed at higher doses

• Lifetime PDE = 2.2 mg/day

• Oral PDE appropriate for parenteral

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species

5 (rat to human)



extrapolation

1 (chronic, study at least half a

lifetime)

F4 Severity of effect 1 (bodyweight changes)


Methyl bromide inhalation PDE

• Inhalation carcinogenicity study in rats, LOAEC 3 ppm (1.4 mg/kg/day)

• Main adverse effects of at low doses are localized at the site of contact

• Lifetime PDE for = 467 µg/day

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species

5 (rat to human)



extrapolation

1 (chronic, study at least half a

lifetime)

F4 Severity of effect 1 (inflammation and hyperplasia

of nasal region)

F5 LOAEC established 3

Take home message

• Generally, compound specific exposure limits are applicable

to all routes of administration

• Careful review of all data

• Calculate route specific exposure limit if you can!

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References - 1

• ICH M7(R2), 2015. Assessment and Control of DNA Reactive (Mutagenic)

Impurities in Pharmaceuticals to Limit Potential Carcinogenic Risk.

• Leong BKJ, Kociba RI, Jersey GC. A lifetime study of rats and mice

exposed to vapors of bis(chloromethy1) ether. Toxicol Appl Pharmacol

1981; 58:269-81.

• Sellakumar AR, Laskin S, Kuschner M, Rush G, Katz GV, Snyder CA, et

al. Inhalation carcinogenesis by dimethylcarbamoyl chloride in Syrian

golden hamsters, J Environ Pathol Toxicol 1980; 4:107-15.

• Van Duuren BL, Goldschmidt BM, Katz C, Seidman 1770 I, Paul JS.

Carcinogenic activity of 1771 alkylating agents, J Natl Cancer Inst 1974;

53:695-700.

• Renwick, A.G., 1991. Safety factors and establishment of acceptable daily

intakes. Food Addit. Contam. 8, 135-149.

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References - 2

• Organization for Economic Cooperation and Development (OECD) 2013. SIDS

Initial Assessment Profile (SIAP) on Titanium dioxide (CAS No. 13463-67-7)

• Environmental Health Criteria (EHC) 24 Titanium. World Health Organization

Geneva, 1982.

• ILSI, 2000. Technical Report 122. Relevance of lung overload for humans.

Accessed Feb 2018

• ICH Q3C(R6). Impurities: Guideline for Residual Solvents

• IPCS 2005. Chemical-specific adjustment factors for Interspecies differences and

human variability: Guidance document for use of data in dose/concentration-

response assessment

• ICH Q3D. Guideline for Elemental Impurities

• Bercu et al., 2018. Potential impurities in drug substances: Compound-specific

toxicology limits for 20 synthetic reagents and by-products, and a class-specific

toxicology limit for alkyl bromides. Regul Toxicol Pharmacol. 2018 Apr;94:172-

182.26

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Approaches for establishing limits for different routes of ... for... · Approaches for establishing limits for different routes of administration Trish Parris. When to consider route