2. 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

3. 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

4. Collect background exposure data Use in aerosol mists/smoke 1 ppm PG is equivalent to 3.11 mg/m 3 (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

5. 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 m 3 Puff PG concentration = 97 mg/m 3 [for local effects assessment] 5

6. 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

7. 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

8. Acute inhalation toxicity Humans (Wieslander et al.) 1 ‑ min exposure of 27 non-asthmatic volunteers to PG mist (concentration range 176 to 851 mg/m 3 ; geometric mean 309 mg/m 3 ), no symptoms indicative of systemic toxicity 8

9. Acute inhalation toxicity Laboratory animals (Werley et al.) 4-hr Rat LC 50 >44.9 g/m 3 No indication of multiple concentrations tested Nose-only exposure No mortality (7-day observation) 9

10. 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

11. 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/m 3 for 90 days (no further duration data given but assumed to be 6 hr/day, 5 days/wk) Repeated dose inhalation toxicity 11

12. SYSTEMIC EFFECTS – Females: decreased white blood cell (WBC) counts at 1000 mg/m 3 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/m 3 Repeated dose inhalation toxicity 12

13. LOCAL EFFECTS – Nasal haemorrhaging at LOAEC of 160 mg/m 3 ; 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

14. 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/m 3 for 13-18 months caused no adverse effects on the respiratory system Increased haemoglobin counts seen in monkeys 14

15. 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

16. 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 LD 50 >>2 g/kg bw in rats, mice, rabbits, guinea pigs and dogs Dermal toxicity is also very low in rabbits 16

17. 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

18. 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

19. 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

20. 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

21. 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

22. 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/m 3 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

23. Reproductive and developmental 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

24. 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

25. 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

26. 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/m 3 ; geometric mean 309 mg/m 3 ) induced reduced tear film stability and sensations of eye irritation 26

27. 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

28. 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

29. 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

30. 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

31. Additional useful information regarding 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

32. 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

33. Expert Group Health Criteria Values HCV (mg/m 3 ) Basis 50 The EU REACH registration dossier on PG includes long-term inhalation DNELs (derived no-effect levels) of 50 mg/m 3 for systemic effects and 10 mg/m 3 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/m 3. 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

34. Occupational Exposure Levels Inhalation HCVs HCV (mg/m 3 ) Basis UK HSE WEL (8-hr TWA) 10 (particulate s) No details available. 474 (total vapour and particulates ) Long-term DNEL (worker) 168 The derivation of the REACH DNELs is unclear. Apparently an AF of 3 was applied to an NOAEC (which would be about 500 mg/m 3 ) to generate the chronic systemic value for workers, and a factor of 9 was applied to an LOAEC (which would be about 90 mg/m 3 ) for local effects. 10 34

35. Key HCVs for other routes of exposure Other HCVs HCV (mg/kg bw/day) BasisReference Oral acceptabl e 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