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1. Collection of relevant data – toxicity and exposure
2. Selection of critical studies and/or HCVs
3. Health risk assessment – systemic
4. Health risk assessment – respiratory tract irritation
Presentation overview
Collect background exposure data
Can be helpful
Precursor to various polymers (especially polyesters)
Use in cosmetics, pharmaceuticals, tobacco, food and drink
Used in anti-freezing and cleaning agents, paints, resins and paper 3
Collect background exposure data
Use in aerosol mists/smoke
1 ppm PG is equivalent to 3.11 mg/m3 (based on MWt)
No measured environmental or occupational air concentration data
Estimated food flavouring intake is 14.01 mg/kg bw/day in the US
4
Exposure example
Propylene glycol (PG) intake = 3.2 mg/day [for systemic effects assessment]
600 puffs/day
Puff volume 55 mL
Total puff volume = 0.033 m3
Puff PG concentration = 97 mg/m3 [for local effects assessment]5
ADME data
Oral – rapidly and extensively absorbed from the GI tract
Inhaled – rapid pulmonary absorption; blood levels similar to those from oral administration
Likely to be 100% for both routes
Extensively metabolised to endogenous compounds (lactate, pyruvate, acetate, propionaldehyde)
6
Toxicity
If available, start with likely key studies – inhalation acute, inhalation repeated
Other route studies give additional insights into toxicity potential – oral, dermal
Mutagenicity, carcinogenicity, reproductive/developmental, sensitisation, etc
May use read-across data to fill gaps and/or enrich data set
7
Acute inhalation toxicity
Humans (Wieslander et al.)
1‑min exposure of 27 non-asthmatic volunteers to PG mist (concentration range 176 to 851 mg/m3; geometric mean 309 mg/m3), no symptoms indicative of systemic toxicity
8
Acute inhalation toxicity
Laboratory animals (Werley et al.)
4-hr Rat LC50 >44.9 g/m3
No indication of multiple concentrations tested
Nose-only exposure
No mortality (7-day observation)
9
Acute inhalation toxicity
Slight body weight decrease on day 1-3 though growth was normal by day 7
Mild irritation (localised bleeding around the eyes/nose) seen at day 7.
Acute inhalation toxicity is very low 10
Humans – No data
Laboratory animals - Study 1 (key study) by Suber et al.
Effects on blood parameters
Rats (group size unspecified) exposed to PG vapour
0, 160, 1000 and 2200 mg/m3 for 90 days (no further duration data given but assumed to be 6 hr/day, 5 days/wk)
Repeated dose inhalation toxicity
11
SYSTEMIC EFFECTS – Females: decreased white blood cell (WBC) counts at 1000 mg/m3 and above; decreased mean corpuscular haemoglobin concentrations at top concentration; no dose-related changes in RBCs were observed in males. NOAEC for systemic = 160 mg/m3
Repeated dose inhalation toxicity
12
LOCAL EFFECTS – Nasal haemorrhaging at LOAEC of 160 mg/m3; thickened respiratory epithelium with enlarged goblet cells at higher concs; no local NOAEC determined
No details given regarding examination. Study was reported by ATSDR (i.e. check to confirm details).
Repeated dose inhalation toxicity
13
Laboratory animals –Study 2 (supporting study)
Limited reporting of study details in profile
Rhesus monkeys and rats, continuous exposure to PG concs up to 350 mg/m3 for 13-18 months caused no adverse effects on the respiratory system
Increased haemoglobin counts seen in monkeys 14
Laboratory animals –Study 3 (supporting study)
Limited reporting of study details in profile
28-day inhalation studies in rats and dogs
Systemic NOELs of 20 and 6.05 mg/kg bw/day, respectively
15
Other toxicity data –Acute oral/dermal
Human
Unreliable TDLo values of 10 and 79 g/kg bw for children (oral)
Behavioural/brain/metabolic changes at very high doses
Non-human
Oral LD50 >>2 g/kg bw in rats, mice, rabbits, guinea pigs and dogs
Dermal toxicity is also very low in rabbits16
Repeated oral dose studies
Human - no data
Non-human - various studies are available.
Rats (30/sex/dose) given PG in diet at 0, 0.625, 1.25, 2.5 and 5% (nominal doses of 310, 630, 1300 or 2500 mg/kg bw/day) for 2 yr. No treatment-related adverse effects on growth, haematology, urine, clinical chemistry, or organ weights. No details on the effects (evidently not considered adverse) seen at the high dose. The NOEL was 1300 mg/kg bw per day (though expert groups have said the top-dose was the NOAEL, and cited this as providing 1700 or 2500 mg/kg bw/day)17
Repeated oral dose studies
Rats exposed in drinking water for 140 days at calculated doses of 1.6, 3.7, 7.7 or 13.2 g/kg bw/day i.e. well above limit dose of 1000 mg/kg/day established (by EPA) for an oral subchronic toxicity study in rats (CNS effects at top dose, see later). No histopathological abnormalities [no details of gross examination]
Dogs dosed at 2 or 5 g/kg in the diet for 2 years; minor blood effects at higher dose
Conclusion: PG is well-tolerated by the oral route
18
Repeated dermal dose studies
Female mice (group size unknown)
2.1, 10 or 21 mg/day over a lifetime
Extent of examination was not specified in the profile (study listed as “chronic exposure/carcinogenicity”)
No adverse effects reported (but poor reporting in abstract)
19
Genotoxicity
Expect to assess all studies for quality and reliability
Overview:
Inactive in Ames bacterial reverse mutation tests
Inactive in mammalian cell assays for chromosome aberration
Inactive in mammalian cell assays for sister chromatid exchange
20
Genotoxicity
Inactive mammalian cell assay for mutation
Induced DNA damage in mouse oocytes but only at very high concs
Inactive for in vivo micronucleus induction
Inactive in dominant lethal assay in vivo
Conclusion: PG is not mutagenic
21
Carcinogenicity
No human data
Non-human
Overview: Limited details only on study and extent of examination
Rhesus monkeys and rats (unspecified group sizes) continuous exposure to PG concs up to 350 mg/m3 for 13-18 months, no increase in tumour incidence
No evidence of carcinogenicity in a 2-yr dietary rat study at up to a nominal dose of 2500 mg/kg bw/day
Unchanged tumour incidences in dogs at up to 5 g/kg bw/day in diet for 2 yr [short study for dogs]
22
Reproductive anddevelopmental toxicity
Human - no data
Non-human
No repro/developmental toxicity in various NTP studies (rats, mice, hamsters and rabbits) at oral doses of >1000 mg/kg bw/day (during pregnancy)
Conclusion: Repro/developmental toxicity is not a critical endpoint for PG
23
Other relevant data –skin irritation
Human
Many studies so focus on Expert Groups
CIR refs: 138 irritant reactions upon patch testing (48-hr closed /covered) of 866 patients with neat PG; 190 irritant reactions when 1556 patients patch tested with neat PG )duration not specified)
OECD report of patch testing studies (n>300) demonstrates PG is “not irritating to skin”
24
Other relevant data –skin irritation
Non-human
Undiluted PG was at most a mild dermal irritant in a Draize test using rabbits with intact and abraded skin
Conclusion: skin irritation – mild 25
Other relevant data –eye irritation
Human
Again note Expert Groups
1 min exposure of volunteers to a PG mist (concentration range 176 to 851 mg/m3; geometric mean 309 mg/m3) induced reduced tear film stability and sensations of eye irritation
26
Other relevant data –eye irritation
OECD report of patch testing studies (n>300) demonstrates PG is “not irritating to eye”
Non-human
0.1-0.5 mL PG [presumably 100%] was non-irritating in rabbits
Conclusion: vapour may cause mild eye irritation
27
Other relevant effects –neurotoxicity
Some evidence of neurotoxicity (e.g. CNS depression) has been seen in humans and laboratory animals exposed to high levels of PG.
In rats, such effects are seen following subchronic oral (drinking water) treatment with doses exceeding 13,200 mg/kg bw/day
28
Other relevant effects –sensitisation and intolerance
No data on respiratory sensitisation
Human
OECD report of patch testing studies (n>300) - PG is “does not cause sensitisation upon skin contact”
CIR reports note a very small number of allergic reactions in large-scale patch tests
29
Other relevant effects –sensitisation and intolerance
Non-human
Series of skin sensitisation tests, 70% solutions do not sensitise guinea pigs
Conclusion: PG lacks significant sensitising potential
NB. PG is actually a vehicle control for the LLNA
30
Additional useful informationregarding classification
C&L inventory – no harmonised classification
Most notifiers (4551/4862) did not classify PG as hazardous
Classified as a respiratory tract, skin and eye irritant by 0, 9 and 52 suppliers, respectively
Classified for sensitisation by 0 suppliers (skin or respiratory tract)
31
Expert Group Health Criteria Values
No inhalation HCVs (applicable to the general population) for PG were identified in the profile. However, the REACH dossier includes a DNEL for systemic effects in the general population exposed long-term by inhalation. While this is not an HCV as such, it does nevertheless provide the submitter’s view of a tolerable level: 32
Expert Group Health Criteria Values
HCV (mg/m3)
Basis
50
The EU REACH registration dossier on PG includes long-term inhalation DNELs (derived no-effect levels) of 50 mg/m3 for systemic effects and 10 mg/m3 for local effects in the general population.
Detail on the ECHA website is insufficient for easy or independent verification.
An assessment factor (AF) of 5 (for intraspecies differences alone) was applied to an NOAEC of 250 mg/m3. As an interspecies AF of 1 was applied the data used for the derivation is likely to have been human rather than experimental animal, though there was no further information provided in the dossier.
10
33
Occupational Exposure Levels
Inhalation HCVs
HCV (mg/m3)
Basis
UK HSE WEL
(8-hr TWA)
10 (particulat
es)
No details available.474 (total
vapour and
particulates)
Long-term DNEL (worker)
168The derivation of the REACH DNELs is unclear. Apparently an AF of 3 was applied to an NOAEC (which would be about 500 mg/m3) to generate the chronic systemic value for workers, and a factor of 9 was applied to an LOAEC (which would be about 90 mg/m3) for local effects.
10
34
Key HCVs for other routes of exposure
Other HCVs
HCV (mg/kg bw/day)
Basis Reference
Oral acceptable daily intake (ADI)
0-25
Presumably from application of a total UF of 100 to the NOAEL of 2500 mg/kg bw/day observed in the 2-year rat study
JECFA, 2002
35