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Description of key information

No studies are available with (±)-neomenthol. Reliable data are available with the read across menthol (CAS 89 -78 -1).

No effects were observed in life-time (103 weeks) studies in rats and mice by using menthol up to the highest tested dose corresponding to 375 mg/kg bw/day for the rat and 667 mg/kg bw/day for the mouse. In a 90-day feeding study with menthol the NOAEL was 937 mg/kg bw/day for rats (highest dose tested). In a 90-day feeding study the NOAEL was 1250 mg/kg bw/day for mice based on slightly reduced body weight gain.
As no sytemic effects were seen in both 103 weeks repeated dose toxicity studies applied by oral route, repeated dose studies via dermal or inhalative route do not appear to be scientifically justified.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records
Reference
Endpoint:
repeated dose toxicity: oral, other
Remarks:
combined repeated dose and carcinogenicity, and subchronic
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:
read-across source
Related information:
Composition 1
Reason / purpose:
read-across source
Related information:
Composition 1
Reason / purpose:
read-across source
Related information:
Composition 1
Reason / purpose:
read-across source
Related information:
Composition 1
Test material information:
Composition 1
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 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, lacrimation, 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 DL-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 a 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.
Key result
Dose descriptor:
NOAEL
Remarks:
chronic, rat
Effect level:
> 375 mg/kg bw/day (nominal)
Based on:
act. ingr.
Sex:
male/female
Basis for effect level:
other: No effects were observed; recalculated from 7500 ppm in diet
Remarks on result:
not determinable due to absence of adverse toxic effects
Remarks:
rats: 103 weeks diet
Dose descriptor:
NOAEL
Remarks:
chronic, mice
Effect level:
> 667 mg/kg bw/day (nominal)
Based on:
act. ingr.
Sex:
male/female
Basis for effect level:
other: no adverse effects observed at highest dose; recalculated from 4000 ppm in diet
Remarks on result:
not determinable due to absence of adverse toxic effects
Remarks:
mice: 103 week study
Dose descriptor:
NOAEL
Remarks:
subchronic, rat
Effect level:
> 937 mg/kg bw/day (nominal)
Based on:
act. ingr.
Sex:
male/female
Basis for effect level:
other: no adverse effects observed at highest dose; recalculated from 15000 ppm in diet
Remarks on result:
not determinable due to absence of adverse toxic effects
Remarks:
rat: 13 week diet
Dose descriptor:
NOAEL
Remarks:
subchronic, mice
Effect level:
1 250 mg/kg bw/day (nominal)
Based on:
act. ingr.
Sex:
male/female
Basis for effect level:
body weight and weight gain
Remarks on result:
other:
Remarks:
mice: 13 week diet
Critical effects observed:
not specified
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:

A carcinogenicity study in mice and rats is available from structural analogue menthol (CAS 89-78-1). It is concluded that (±)-neomenthol is not toxic after chronic exposure. 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 the repeated dose toxicity.

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 a reference substance with similar 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 VIII/IX, 8.6, in accordance with Annex XI, 1.5, of Regulation (EC) No. 1907/2006.

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Mode of Action Analysis / Human Relevance Framework

Additional information

There is no reliable repeated dose 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.

Details on the repeated dose studies :

- Two tests were performed with menthol in rats for 13-weeks (males up to 998 mg/kg bw/day and females up to 937 mg/kg bw/day) and in mice (males up to 1956 mg/kg bw/d and females up to 2386 mg/kg bw/day) respectively. No toxicity was noted at the maximum dose tested in rat, while in mice a slight body weight effect was observed at the highest dose without any gross and microscopic pathological findings related to the treatment. The NOAELs derived from these studies were 937 mg/kg bw/day for rat and 1250 mg/kg bw/day for mouse.

- After 103 weeks oral administration of menthol the 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 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.

The NOAEL resulted from this study was 7500 ppm (i.e. 375 mg/kg bw/day).

- After 103 weeks oral administration of menthol the mean body weights of the dosed male and female mice were slightly lower than those of the corresponding controls throughout the bioassay. The appearance and behaviour of the dosed and control groups of animals were generally similar, and clinical signs usually associated with aging were noted at comparable rates in the control and dosed groups.

The NOAEL resulted from this study was 4000 ppm (i.e. 667 mg/kg bw/day).



Justification for classification or non-classification

(±)-neomenthol does not meet the criteria for classification and labeling for repeated dose toxicity (STOT), as set out in Regulation (EC) NO. 1272/2008 as indicated by study results on menthol used for read across.