Registration Dossier

Administrative data

Description of key information

This endpoint is not required for the REACh registration purpose of D-Menthol. Nevertheless, we decided to use the chronic datas available on a mix of menthol isomers and on L-Menthol to derive some DNELs for Human health hazard assessment.
Data Summary:
No existence of intrinsic repeated dose study on L and DL-menthol.
No effect observed up to 7500ppm

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Dose descriptor:
NOAEL
375 mg/kg bw/day
Study duration:
chronic
Species:
rat

Mode of Action Analysis / Human Relevance Framework

Additional information

There is no data on D-menthol concerning the repeated dose toxicity endpoint and it is not a requirement anyway for this registration. Nevertheless, to develop a safer assessement the derivation of some DNELs was based on the L and DL-menthol chronic studies available following a read-across approach for this endpoint.

Justification for Read-across:

Based on the comparable profiles on OECD-Toolbox of the different menthols we can use them for read across studies. 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.

Details on the repeated dose studies :

Data from literature show no significant change in the body weight or in haematological or clinical chemistry parameters when L-menthol was administrated to rats (i.e. 200, 400 and 800mg/kg/day) by oral gavage for 28 days. At necropsy, a significant increase in absolute and relative liver weight at all doses in males and mid and high dose in female were observed.

Moreover two older tests performed on DL-menthol for 13-weeks respectively in rat (up to 937/998 mg/kg bw/d for males/females) and mice (up to 3913/4773 mg/kg bw/d for males/females). No toxicity was noted at the maximum dose tested in rat (i.e 1.5%), while in mice a slight body weight effect was observed at the higher dose without any gross and microscopic pathology related to the treatment. The NOAELs derived from these studies were 937 mg/kg bw/d for the male rat, 998 mg/kg bw/d for the female rat and 1956 mg/kg bw/d for the male mouse and 2386 mg/kg bw/d for the female mouse.

It does not exist an intrinsic long-term repeated dose study on L-menthol.

However, data from literature revealed no treatment related histopathological changes or increased incidences of tumours in a 103-weeks oral administration of 2% corn oil of dl-menthol in diet to rats. The NOAEL resulted from this study was 7500ppm (i.e. 375 mg/kg/day).



Repeated dose toxicity: via oral route - systemic effects (target organ) cardiovascular / hematological: heart; cardiovascular / hematological: spleen; cardiovascular / hematological: thymus; digestive: colon; digestive: esophagus; digestive: pancreas; digestive: stomach; glandular: mammary gland; glandular: parathyroids; glandular: thyroids; neurologic: brain (multiple sections); neurologic: eyes (retina, optic nerve); neurologic: pituitary; neurologic: spinal cord (3 levels); urogenital: kidneys; urogenital: ovaries; urogenital: prostate; urogenital: testes; urogenital: urinary bladder; urogenital: uterus

Justification for classification or non-classification

A 2 years feeding study on DL-Menthol in rats and mice shows no signs of toxicity or negative effects in a concentration relevant for classification. Also this study didn’t reveal any indication of tumor incidences with animals treated. Hence it can be concluded that the substance does not meet the criteria for classification and labeling for carcinogenicity or repeated dose toxicity (STOST), as set out in Regulation (EC) NO. 1272/2008. By read across approach we can extend the non classification justification to D-Menthol.