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. Identification and background data Two CAS RNs listed in profile: 8016-31-7 and 84837-06-9 Profile data mainly refers to the former Use in cosmetics, tobacco and as a food flavouring, Environmental / occupational air concentrations- no data Estimated US food flavouring intake is 0.0001129 mg/kg bw/day Equates to 6.8 µg/day for a 60-kg person Very low 3

4. Exposure example Lovage oil (LO) intake = 0.036 mg/day [for systemic effects assessment] 600 puffs/day. Puff volume 55 mL Total puff volume = 0.033 m 3 Puff LO concentration = 1.1 mg/m 3 [for local effects assessment] 4

5. ADME data No data. Normal procedure - obtain data on composition from supplier (perhaps beta- phellandrene, terpinyl acetate, cis-beta- ocimene, ligustilide and myrcene?) Then seek ADME data on components Exposure is very low (36 µg/day) Probably sufficient to assume 100% absorption from oral and inhalation exposure 5

6. Toxicity data: inhalation studies No inhalation data were found For acute or repeated dose studies The standard procedure would be to obtain data on composition from suppliers, and seek inhalation data on components Exposure is so low that this is probably unnecessary 6

7. Other toxicity data - Acute oral/dermal Human No data Non-human Oral LD50 2-5 g/kg bw in rodents No dermal data Acute toxicity is low for the oral route 7

8. Human - No data Non-human - Only a one-generation reproductive study (see later) The standard procedure (to seek data on components) is probably unnecessary as the exposure level is so low – 36 µg/day Repeated oral dose studies 8

9. Repeated dermal dose studies No data were found Lack of data not critical for current assessment 9

10. Genotoxicity & Carcinogenicity No data were found Normal procedure – ask suppliers for data on composition, seek mutagenicity and carcinogenicity data on these, and/or run QSAR models for these key endpoints Identify components down to those supplying 0.15-1.5 µg/day Below that – use TTC 10

11. Reproductive and developmental toxicity Human - No data Non-human – 1-generation study in female rats (10/group) 0, 100, 200 or 400 mg/kg bw/day by gavage from 7 days before mating, through mating and gestation, to postnatal day 4 Monitored clinical toxicity, survival, litter delivery and offspring weights 11

12. Reproductive and developmental toxicity LOAEL = 100 mg/kg bw/day - maternal toxicity (clinical signs, decreased food consumption and/or reduced growth) at all dose levels Reduced pup growth at 200 mg/kg bw/day and above. Increased stillborn pups and lower pup viability at top dose NOAEL for maternal toxicity was <100 mg/kg bw/day NOAEL for developmental toxicity was 100 mg/kg bw/day Critically the developmental NOAEL > maternal NOAEL 12

13. Human - No data Non-human Undiluted (500 mg; 24-hr contact] - moderate irritation of rabbit skin Undiluted – mild irritation in guinea pigs Other relevant data – skin irritation 13

14. Other relevant effects – sensitisation and intolerance No data on respiratory sensitisation Human Single case of allergic contact dermatitis from use of LO said to contain mainly beta- phellandrene, terpinyl acetate, cis-beta- ocimene, ligustilide and myrcene Non-human - No data 14

15. Additional useful information regarding classification LO and LOE – no harmonised EU CLP LO classified as a skin sensitiser by 34/57 notifiers, 24 for both skin and eye irritation, 1 for mutagenicity and 1 for carcinogenicity; none classified as a respiratory tract irritant LOE classified by >900/1002 notifiers as a skin sensitiser, skin and eye irritant, mutagen and carcinogen; none classified as a respiratory tract irritant 15

16. Expert Group Health Criteria Values or Occupational Exposure Levels No inhalation HCVs/OELs or HCVs for other routes of exposure have been identified for LO 16