Registration Dossier

Diss Factsheets

Administrative data

Key value for chemical safety assessment

Effects on fertility

Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
375 mg/kg bw/day
Study duration:
chronic
Species:
rat
Additional information

There is no reproductive toxicity data on L Menthol.

Justification for Read-across:

Based on the identical profiles of the different Menthols we can use them for read across studies as described in the Read-Across Justification for Menthols (see file MentholsReadAcrossFinal.pdf in section 13). These isomers are L Menthol (CAS 2216-51-5), D Menthol (CAS 15356-60-2) and DL Menthol (CAS 89-78-1).

Moreover, a comparative physico-chemical profile of these isomers reinforces this similarity. As structural isomers, the members of the Menthol category share the same molecular weight. Of particular importance to environmental effects and human effects are the values for partition coefficient (log Kow around 3), vapour pressure (from 17 Pa at 25 °C for the DL Menthol to 21 Pa 25 °C for the natural L Menthol ) and water solubility (moderately soluble from 410 mg/l at 25 °C for the natural L Menthol to 470 mg/l at 25 °C for the DL Menthol). The read across is consistent based on these physico-chemical parameters.

In OECD SIDS, L Menthol (CAS 2216-51-5), D Menthol (CAS 15356-60-2) and DL Menthol (CAS 89-78-1) were recognized as a category group. Investigations on toxicokinetics show that L-, D-, DL- and the unspecified Menthol are well absorbed via the oral route. For all of the isomers, elimination is rapid and mainly occurs as glucuronic acid conjugates via urine, minor amounts via faeces. Significant differences in toxicokinetic properties of Menthol isomers were not reported.

The available toxicity data indicate very similar toxicity profiles for D-, L-, DL Menthol and the unspecified Menthol isomer mixture. In mammalian species the low toxicity is manifested in LD50 values generally greater than 2000 mg/kg bw/day in acute studies, limited toxicity in repeated dose studies, and no effects in teratology evaluations. Irritation to skin and eyes was slight to moderate. DL-Menthol is a racemic mixture of the D- and L- isomers and contains both isomers in equal proportion. Data gaps for L Menthol can therefore be filled by the respective results with the racemic mixture or the D Menthol isomer.

Due to above discussion, to this endpoint, reproductive properties of L Menthol can be thought equivalent to the tested substance DL Menthol (The NOAEL in this study on rats was determined at 375 mg/kg bw/day).

Detail for the waiving approach:

Since histopathological examinations of the reproduction organs of rats and mice did not show any changes in repeated dose toxicity studies of DL Menthol and also in carcinogenicity studies of DL Menthol, we can anticipate the same conclusion for L Menthol.


Short description of key information:
No changes were observed during the histopathological examinations of the reproductive organs of rats and mice in repeated dose toxicity studies and in carcinogenicity studies following the exposure to the Menthol isomer mixture: DL Menthol.
Toxicity to reproduction does not need to be conducted.

Effects on developmental toxicity

Description of key information
L Menthol is not considered to be embryo-or  fetotoxic or teratogenic. 
Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Study duration:
subacute
Species:
rat
Additional information
Teratogenicity studies with L Menthol were conducted in rats, mice, hamsters and rabbits (FDA,1973). In all four developmental toxicity studies, maternally toxic dose levels were not used. For Wistar rats the doses of 2.18, 10.15, 47.05 and 218.0 mg/kg bw/day were administered by gavage from gestation day 6 to 15. There was no maternal toxicity and fetotoxicity determined . Therefore the NOEL derived for maternal and fetal toxicity and teratogenicity in rats can be determined as 218.0 mg/kg bw/day. For CD-1 Mice the doses of 1.85, 8.59, 39.9 and 185.0 mg/kg bw/day were administered from gestation day 6 to 15. There was no maternal toxicity and fetotoxicity determined. The NOEL derived for maternal and fetal toxicity and teratogenicity was 185.0 mg/kg bw/day. For Dutch belted Rabbits the doses of 4.25, 19.75, 91.7 and 425.0 mg/kg bw/day were administered from gestation day 6 to 18. Few of the rabbits died or aborted before day 29 ( at 4.25 mg/kg bw/day 2 animals died on day 13 , at 19.75 mg/kg bw/d 3 animals died on day 13, at 91.7 mg/kg bw/d 1 animals died on day 11, at 425.0 mg/kg bw/day 4 animals died on day 14), however, these effects were not dose related and are not considered to be a consequence of test substance toxicity, but due to administration errors. There was no maternal toxicity and fetotoxicity determined. The NOEL derived for maternal and fetal toxicity and teratogenicity was therefore 425.0 mg/kg bw/day. For Syrian hamsters the doses of 4.05, 21.15, 98.2 and 405.0 mg/kg bw/day were administered during gestation days 6-10. There was no maternal toxicity and fetotoxicity. The NOEL for maternal and fetal toxicity and teratogenicity was therefore 405.0 mg/kg bw/day. Since only a NOEL for these 4 species could be derived and no developmental or fetotoxic effects were observed we can consider that L Menthol has no developmental toxicity and no teratogenic properties.

Justification for classification or non-classification

No changes were observed during the histopathological examinations of the reproductive organs of rats and mice in the combined repeated dose and 2 years carcinogenicity toxicity studies following exposure to the Menthol isomer mixture: DL Menthol.

The L Menthol has no developmental toxicity and no teratogenicty properties in well performed gavage studies in various species (rat, mouse, rabbit, hamster) at the highest dose of 185 (for mice) to 425 (for rabbits) mg/kg bw. Since we could only derived a NOEL for these 4 species we can consider that the L Menthol has no developmental or teratogenicity hazard.

The L Menthol should therefore not be classified either on reproduction toxicity or teratogenicity.

Additional information