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

Identification and background data

Two CAS RNs listed in profile: 8016-31-7 and 84837-06-9Profile data mainly refers to the formerUse in cosmetics, tobacco and as a food flavouring, Environmental / occupational air concentrations- no dataEstimated US food flavouring intake is 0.0001129 mg/kg bw/dayEquates to 6.8 µg/day for a 60-kg personVery low

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Exposure example

Lovage oil (LO) intake = 0.036 mg/day[for systemic effects assessment] 600 puffs/day. Puff volume 55 mLTotal puff volume = 0.033 m3  Puff LO concentration = 1.1 mg/m3

[for local effects assessment]4

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

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 unnecessary6

Other toxicity data - Acute oral/dermal

HumanNo data Non-humanOral LD50 2-5 g/kg bw in rodentsNo dermal data Acute toxicity is low for the oral route 7

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

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Repeated dermal dose studies

No data were found

Lack of data not critical for current assessment

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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 TTC10

Reproductive anddevelopmental toxicity

Human - No dataNon-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 4Monitored clinical toxicity, survival, litter delivery and offspring weights

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Reproductive anddevelopmental toxicity

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

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Human - No data Non-humanUndiluted (500 mg; 24-hr contact] - moderate irritation of rabbit skinUndiluted – mild irritation in guinea pigs

Other relevant data – skin irritation

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Other relevant effects –sensitisation and intolerance

No data on respiratory sensitisation HumanSingle 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

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Additional useful informationregarding classification

LO and LOE – no harmonised EU CLPLO 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

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Expert Group Health Criteria Valuesor Occupational Exposure Levels

No inhalation HCVs/OELs or HCVs for other routes of exposure have been identified for LO

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