Registration Dossier

Administrative data

Endpoint:
extended one-generation reproductive toxicity - basic test design (Cohorts 1A, and 1B without extension)
Type of information:
experimental study planned
Justification for type of information:
TESTING PROPOSAL ON VERTEBRATE ANIMALS

NON-CONFIDENTIAL NAME OF SUBSTANCE:
- Name of the substance on which testing is proposed to be carried out: (+/-)-Menthol CAS no. 89-78-1

CONSIDERATIONS THAT THE GENERAL ADAPTATION POSSIBILITIES OF ANNEX XI OF THE REACH REGULATION ARE NOT ADEQUATE TO GENERATE THE NECESSARY INFORMATION [please address all points below]:
- Available GLP studies: There are no fertility studies with menthol or its isomers available. No effects on reproductive organs (weight and/or histopathology) were reported in comprehensive chronic 2-years studies conducted with D/L-menthol in mice and rats (NTP 1979) and it can be concluded that there is no indication of toxicity to fertility based on the available repeated-dose toxicity studies.

- Available non-GLP studies: There are no fertility studies with menthol or its isomers available. No effects on reproductive organs (weight and/or histopathology) were reported in comprehensive chronic 2-years studies conducted with D/L-menthol in mice and rats (NTP 1979) and it can be concluded that there is no indication of toxicity to fertility based on the available repeated-dose toxicity studies.

- Historical human data: OECD “SIDS INITIAL ASSESSMENT PROFILE” menthols widely used “According to the About 13,600 tonnes of menthols were produced worldwide in 2001. About 75 % of the menthol output is of biotic and 25 % of synthetic origin L-Menthol, D/L-menthol and menthol liquid are widely used in oral care products, pharmaceuticals, flavors, tobacco and others.” (OECD SIDS 2003). Despite the wide use of D/L-menthol there is no information which indicates any menthol related observation on fertility in humans.

- (Q)SAR: no data: no data available

- In vitro methods: no data available

- Weight of evidence : No effects on reproductive organs (weight and/or histopathology) were reported in comprehensive chronic 2-years studies in mice and rats and no observation relevant for potential toxicity to fertility is reported in humans. Based on a WoE there is no indication of toxicity to fertility.
This conclusion is in agreement with the OECD “SIDS INITIAL ASSESSMENT PROFILE” on the menthols which discussed: “There is no fertility study available. Histopathological examinations of the reproduction organs of rats and mice showed no changes in repeated dose toxicity studies with D/L-menthol and also in carcinogenicity studies with D/Lmenthol. Hence there is no indication of a potential of D/L-menthol to interfere adversely with reproduction.” and concluded: “Human Health: The chemicals in the menthols category are currently of low priority for further work because of their low hazard potential. However, skin and eye irritation is noted.” (OECD SIDS 2003)

- Grouping and read-across: The OECD “SIDS INITIAL ASSESSMENT PROFILE” on the menthols established a menthol category with the following rational “Category Rationale: The menthols category is comprised of the isomers L-menthol, D-menthol, the racemate and menthol (unspecified isomers). The menthols can be considered as a category because of their similarity in physico-chemical, toxicological, ecotoxicological and environmental fate properties.”

- Substance-tailored exposure driven testing [if applicable]: not applicable

- Approaches in addition to above [if applicable]: not applicable

- Other reasons [if applicable]: Overall, taking into account the available database we concur with the conclusion by the OECD “SIDS INITIAL ASSESSMENT PROFILE” on the menthols: “Human Health: The chemicals in the menthols category are currently of low priority for further work because of their low hazard potential. However, skin and eye irritation is noted.” (OECD SIDS 2003). Any further testing on this substance should be of low priority and animal welfare should be taken into account.

CONSIDERATIONS THAT THE SPECIFIC ADAPTATION POSSIBILITIES OF ANNEXES VI TO X (AND COLUMN 2 THEREOF) OF THE REACH REGULATION ARE NOT ADEQUATE TO GENERATE THE NECESSARY INFORMATION:
- [There are no fertility studies with menthol or its isomers available. No adverse effects on reproductive organs were observed in the available repeated dose (carcinogenicity) studies. The substance is not known to be a carcinogen or germ cell mutagen. Relevant human exposure cannot be excluded because menthol is used in consumer products. The substance is not known as a developmental toxicant. Therefore the specific adaption possibilities of Annexes VI to X and column 2 thereof doesn't apply]

FURTHER INFORMATION ON TESTING PROPOSAL IN ADDITION TO INFORMATION PROVIDED IN THE MATERIALS AND METHODS SECTION:
- Details on study design / methodology proposed [extended one-generation reproductive toxicity - basic test design (Cohorts 1A, and 1B without extension) - oral route is appropriate, as no adverse effects on fertility are known form the repeated dose studies and based on the whole database of studies to other endpoints]

Data source

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
OECD Guideline 443 (Extended One-Generation Reproductive Toxicity Study)
Justification for study design:
SPECIFICATION OF STUDY DESIGN FOR EXTENDED ONE-GENERATION REPRODUCTION TOXICITY STUDY WITH JUSTIFICATIONS [please address all points below]:

- Premating exposure duration for parental (P0) animals: 2 weeks before mating; based on the available toxicokinetic data rapid metabolism and excretion mainly as glucuronides is reported. Menthol glycuronic acid appeared in the urine of rabbits in less than an hour after gavage dosing menthol, and 90 per cent of the conjugated acid was found to be excreted in 6 hours when 2 g of menthol were feed. Even when larger doses were given over 90 per cent of the total amount excreted appeared in the urine during the first 24 hours. In another study after a single oral administration of 1 g/kg bw of menthol racemic to rabbits, 59 % of the applied test substance was excreted as glucuronide with the urine within 2d (see chapter Toxicokinetics).

Repeated dose sub-acute, sub-chronic and chronic toxicity studies are available in rats and mice. These studies indicate that toxicity to menthols are not time dependent (see chapter Repeated dose toxicity).

The default pre-mating period according to the ECHA guidance documents is 10 weeks, but compound specific data should be taken into account to define the pre-mating time. Overall, taking into account the available data on toxicokinetics and repeated dose toxicity studies a 2 week premating as indicated in the OECD TG 443 is considered to be appropriate and sufficient for this substance.

- Basis for dose level selection: Will be determined based on the available data and a pilot study conducted as a dose-range finding study.

- Inclusion/exclusion of extension of Cohort 1B: Not intended; there is no indication from the available studies that would justify an extension of cohort 1B. Histopathological examinations of the reproduction organs of rats and mice showed no changes in repeated dose toxicity studies with D/L-menthol and also in carcinogenicity studies with D/Lmenthol. Hence there is no indication of a potential of D/L-menthol to interfere adversely with reproduction.

- Termination time for F2: Not intended; there is no indication from the available studies that would justify an extension of cohort 1B. Histopathological examinations of the reproduction organs of rats and mice showed no changes in repeated dose toxicity studies with D/L-menthol and also in carcinogenicity studies with D/Lmenthol. Hence there is no indication of a potential of D/L-menthol to interfere adversely with reproduction.

- Inclusion/exclusion of developmental neurotoxicity Cohorts 2A and 2B: Not intended; Histopathological examinations of the developmental toxicity relevant organs (e.g. thyroid, brain) of rats and mice showed no changes in repeated dose toxicity studies with D/L-menthol and also in carcinogenicity studies with D/Lmenthol. Hence there is no trigger to include the developmental neurotoxicity cohorts.

- Inclusion/exclusion of developmental immunotoxicity Cohort 3: Not intended; Histopathological examinations of the immune-toxicity relevant organs (e.g. spleen) of rats and mice showed no changes in repeated dose toxicity studies with D/L-menthol and also in carcinogenicity studies with D/Lmenthol. Hence there is no trigger to include the immunotoxicity cohort.

- Route of administration: oral

- Other considerations, e.g. on choice of species, strain, vehicle and number of animals [Study will be performed in rats, the preferred species according to OECD TG 443.]

Test material

Reference
Name:
Unnamed
Type:
Constituent

Results and discussion

Applicant's summary and conclusion