1.Collection of relevant data – toxicity and exposure 2.Selection of critical studies and/or HCVs...

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

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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)

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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

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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

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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)

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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

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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

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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

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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

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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

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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)

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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

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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

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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]

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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

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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”

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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

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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

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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

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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

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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

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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)

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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

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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

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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

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