(±)-neomenthol

Carcinogenicity

Description of key information

No data is available for (±)-neomenthol. Reliable data are available from menthol (CAS 89 -78 -1).

Menthol and thus (±)-neomenthol do not show carcinogenic potential.

Key value for chemical safety assessment

Carcinogenicity: via oral route

Link to relevant study records

Reference

Endpoint:

carcinogenicity: oral

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Justification for type of information:

Please refer to IUCLID section 13 for a detailed justification of the category approach.

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across source

Details on results:

A. Body Weights and Clinical Signs (Rats)
Mean body weights of the dosed male and female rats were slightly lower than those of the corresponding controls throughout the bioassay. No other clinical signs related to administration of the DL Menthol were noted. Clinical signs commonly observed among rats of this strain were noted at comparable rates in the control and dosed groups, particularly during the second year of the bioassay, and increased in incidence as the animals aged. These signs included eye changes (redness, paleness, cloudiness, lacrimination, a red discharge or bloody crust, and an enlarged or protruding eye), a hunched and/or thin appearance, urine stains on the abdominal fur, and occasionally, nasal discharge, sores on the body or the extremities, soft feces, and enlarged testes.
The incidence of palpable nodules and tissue masses in the dosed males was generally comparable to that in the control males, but was lower in the dosed females than in the control females.

B. Survival (Rats)
The Kaplan and Meier curves estimates the probabilities of survival for male and female rats administered menthol in the diet at the doses of this bioassay, together with those of the matched controls. The results of the Tarone test for dose-related trend in mortality and the results of the Cox test comparing the survival of the control group with each dosed group are not significant in either sex.
In male rats, 34/50 (68%) of the high-dose group, 33/50 (66%) of the low-dose group, and 31/50 (62%) of the controls were alive at week 105. In females, 38/50 (76%) of the high-dose group, 35/50 (70%) of the low-dose group, and 36/50 (72%) of the controls were alive at week 105. Sufficient numbers of rats of each sex were at risk for the development of late-appearing tumors.

C. Pathology (Rats)
Each of the tumor types observed has been encountered previously as spontaneous lesion, and occurred with no appreciable differences in frequency between control and dosed rats with a few exceptions. In female rats, chromophobe adenomas of the pituitary gland and fibroadenomas of the mammary gland were observed with greater frequency in female control rats. Chromophobe adenomas occurred in 28/48 controls, 25/47 low—dose, and 19/43 high—dose female rats. Mammary gland fibroadenomas were diagnosed in 20/50 female controls, 10/49 low—dose, and 7/49 high—dose rats. Mammary adenocarcinomas were seen in 1/50 controls, 3/49 low—dose, and 0/49 high—dose rats.
Chronic inflammation of the kidney was observed with greater frequency in the dosed males than in the control males (29/49 controls, 41/50 low—dose, 41/50 high—dose); however, this finding is of questionable importance, since such lesions are often found in aged male Fischer 344 rats.
All other inflammatory, degenerative, and hyperplastic lesions that occurred were similar in incidence and kind to those naturally occurring lesions found in aged Fischer 344 rats.

Relevance of carcinogenic effects / potential:

Not found

Dose descriptor:

NOAEL

Remarks:

rat

Effect level:

> 375 mg/kg bw/day

Based on:

act. ingr.

Sex:

male/female

Basis for effect level:

gross pathology

histopathology: neoplastic

histopathology: non-neoplastic

Remarks on result:

not determinable due to absence of adverse toxic effects

Remarks:

7500 ppm in diet applied to mice were converted to 375 mg/kg/day calculated for rat with a mean body weight of 400 g and 20 g/day of food consumption

Dose descriptor:

NOAEL

Remarks:

mouse

Effect level:

> 667 mg/kg bw/day

Based on:

act. ingr.

Sex:

male/female

Basis for effect level:

gross pathology

histopathology: neoplastic

histopathology: non-neoplastic

Remarks on result:

not determinable due to absence of adverse toxic effects

Remarks:

4000 ppm in diet applied to mice were converted to 667 mg/kg/day calculated for Mice with a mean body weight of 30 g and 5 g/day of food consumption

Conclusions:

Based on the histopathologic examination, menthol was neither toxic nor carcinogenic to Fischer 344 rats and B6C3F1 mice under the conditions of this bioassay.

Executive summary:

Carcinogenicity tests are available from structural analogue menthol (CAS 89-78-1) in rats and mice. It is concluded that (±)-neomenthol does not have a carcinogenic potential. As explained in the justification for type of information, the differences in molecular structure between the target and the source are unlikely to lead to differences in carcinogenicity.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

375 mg/kg bw/day

Study duration:

chronic

Species:

rat

Quality of whole database:

The available information comprises adequate and reliable studies from read across based on grouping of substances (category approach) similar in structure and intrinsic properties. Read-across is justified based on structural similarities of menthols in PC/ECO/TOX properties (refer to category justification for further details). The selected study is thus sufficient to fulfil the standard information requirements set out in Annex VII, 8.5, in accordance with Annex XI, 1.5, of Regulation (EC) No. 1907/2006.

Carcinogenicity: via inhalation route

Endpoint conclusion

Endpoint conclusion:

no study available

Carcinogenicity: via dermal route

Endpoint conclusion

Endpoint conclusion:

no study available

Justification for classification or non-classification

(±)-neomenthol does not meet the criteria for classification and labelling for carcinogenicity, as set out in Regulation (EC) NO. 1272/2008.

Additional information

There is no reliable carcinogenicity study on (±)-neomenthol available.

Justification for Read-across:

Based on the identical profiles of the different menthols and supported by the Read-Across Justification for menthols (IUCLID chapter 13) all studies on stereoisomers of (±)-neomenthol are used for read across. These isomers are L-menthol (CAS 2216-51-5), (+)-menthol (CAS 15356-60-2), D/L-menthol (CAS 1490 -04 -6) and 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 Pow between 3.12 and 3.45 at 25°C), vapour pressure (from 3.6 to 21 Pa at 25°C) and water solubility (moderately soluble from 231 to 456 mg/L at 25°C). The read across is consistent based on these physico-chemical parameters.

Key study:

In a carcinogenicity study (NCI, 1979), in both dose groups (0.375% or 0.75% 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 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. The highest tested dose levels in rats correspond to approx. 375 mg/kg bw/da and in mice to approx. 667 mg/kg bw/day. Thus a carcinogenic potential for menthol was not observed in these studies.

In conclusion, menthol and thus (±)-neomenthol do not have carcinogenic potential.