Registration Dossier

Administrative data

Description of key information

Low acute toxicity for oral route ( 2000 mg/kg bw).
Low acute toxicity dermal (5000 mg/kg bw) extrapolated to D-Menthol
It can be expected the same low acute toxicity for the inhalation route.

Key value for chemical safety assessment

Acute toxicity: via oral route

Endpoint conclusion
Dose descriptor:
LD50
2 000 mg/kg bw

Acute toxicity: via dermal route

Endpoint conclusion
Dose descriptor:
LD50
5 000 mg/kg bw

Additional information

Justification for Read-across:

Based on the identical 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 Acute toxicity studies :

Structure/activity relations and computer systems compiled under OECD-Toolbox don’t flag up any structural alerts and classified D-menthol and its isomers in Class I (i.e. Low hazard according to Cramer classification).

Considering the published toxicokinetic data on menthols in general, D-menthol isn’t considered as a toxic chemical likely to persist in the bloodstream.

Therefore, even if the acute oral toxicity studies were not performed according to guideline methods they may be accepted on a scientific point of view to evaluate this endpoint.

An oral acute toxicity study in rat were performed on D-menthol and D/L-menthol in the same laboratory and using the same protocol. The LD50 was > 2046mg/kg for D-menthol. Similar range of values has been founded on the isomers in several studies.

Another LD50 value of 3.4 g/kg in mice was found for L-Menthol.

There aren’t any dermal acute toxicity data in rat on D-menthol according to current guideline methods. However, based on the similarity of menthol isomers, one evaluates this end-point based on read-across with the isomers.

Ten rabbits received a single dermal application of L-menthol at the dose of 5g/kg/body weight. Observations were made for 14 days. No mortality or clinical signs were observed during the 14-day observation period. The LD50 was determined to be greater than 5g/kg based on 0/10 deaths at the dose.

Moreover, four healthy albino rabbits received a dermal application of neat menthol racemic. Prior to application, the backs of all animals were clipped free of hair and epidermal abrasionswere made, over the lipped area of exposure. Menthol racemic at 5 ml/kg (i.e 5g/kg) body weight was applied to the clipped intact and abraded skin areas. The test areas were covered with a rubber sleeve or dam which fit snugly around each animal. After the 24-hour exposure period, the rubber sleeves were removed and the reactions were recorded. The animals were observed for 14 days after dosing. No deaths occurred. The acute dermal LD50 was determined to exceed 5ml/kg body weight.

Taken together, it can be assumed that the acute oral and dermal toxicity of D-menthol are low. Although no experimental studies are available the low systemic toxicity of menthols (LD50 > 2000 mg/kg bw) that is documented for oral application and single dermal contact can be expected also for the inhalation route.

Justification for classification or non-classification

Test results from studies performed by oral and dermal exposure indicate LD50 values beyond the limits for classification and hence D-menthol does not meet the criteria for classification and labelling for these endpoints, as set out in Regulation (EC) NO. 1272/2008. Inhalative exposure is not expected to have significant toxic effects, given the experience from use over many decades of human exposure. This includes the absence of aspiration hazards, which would have been reported if present. However, animal data according to standard tests are not available.

Specific target organ toxicity: According to CLP classification criteria, the substance does not meet the criteria for classification and labelling for this endpoint (STOT single exposure) as set out in Regulation (EC) No. 1272/2008 as no indications were observed in acute animal studies.