Registration Dossier

Toxicological information

Carcinogenicity

Currently viewing:

Administrative data

Description of key information

In a combined repeated dose/carcinogenicity study (NCI, 1979), in both dose groups (0.375% and 0.75% DL Menthol in diet of rats and 0.2 and 0.4% in the diet of mice), neither toxicity nor carcinogenicity in Fischer 344 rats or B6C3F1 mice was found after 103 weeks exposure. The mean body weights of the dosed rats and mice were slightly lower than those of corresponding controls. This could be explained by less palatability of the Menthol containing food combined with a smaller feed uptake.

Key value for chemical safety assessment

Carcinogenicity: via oral route

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
375 mg/kg bw/day
Study duration:
chronic
Species:
rat

Justification for classification or non-classification

L Menthol does not meet the criteria for classification and labelling for carcinogenicity, as set out in Regulation (EC) NO. 1272/2008 and Directive 67/548/EEC.

Additional information

Justification for Read-across:

Based on the identical profiles of the different Menthols we can use them for read across studies as laid out in detail 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-, 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 was manifested in LD50 values generally greater than 2000 mg/kg bw 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  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 and or results of the D Menthol isomer respectively.

Due to above discussion, to this endpoint, carcinogenic properties of L Menthol can be thought equivalent to the tested substance DL Menthol.

Key study:

In a combined repeated dose/carcinogenicity study (NCI, 1979), in both dose groups (0.375% or 0.75% DL Menthol in diet of rats and 0.2 or 0.4% in the diet of mice), neither toxicity nor carcinogenicity in Fischer 344 rats or B6C3F1 mice was found after 103 weeks exposure.

In male rats, no tumors occurred at incidences which were considered to be associated with the administration of DL Menthol.

In female rats, no tumors occurred at higher incidences in dosed groups than in control groups. Fibroadenomas of the mammary gland occurred at lower incidences in the low-dose (10/49) and high-dose (7/49) groups than in the control group (20/50), and alveaolar/bronchiolar adenomas or carcinomas of the lung occurred only in the controls (3/50).

In mice of either sex, no tumors occurred in dosed groups at incidences that were significantly different from those for corresponding control groups.

(highest tested dose levels in rats approx. 375 mg/kg bw/day, in mice approx. 667 mg/kg bw/day). Since DL Menthol contains the two isomers in a 50:50 ratio it can be assumed that neither L- nor D Menthol had carcinogenic properties.


Justification for selection of carcinogenicity via oral route endpoint:
The mean body weights of the dosed rats and mice were slightly lower than those of corresponding controls. This could be explaied by less palatability of the Menthol containing food combined with a smaller feed uptake. No other clinical signs related to administration of DL Menthol were noted in any dosed groups of rats and mice.