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Key value for chemical safety assessment

Effects on fertility

Description of key information

Reproductive toxicity study

Data available for the read across chemicals was reviewed to determine the reproductive toxicity of (+)-neomenthol. NOAEL was considered to be 800 mg/kg bw for male and in range of 405.0- 671 mg/kg bw for female, when male and female rats or hamster were treated with test material orally by gavage. Thus, comparing this value with the criteria of CLP regulation(+)-neomenthol is likely to be not classify as reproductive toxicant.

Link to relevant study records
Reference
Endpoint:
screening for reproductive / developmental toxicity
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
data from handbook or collection of data
Remarks:
Experimental data of read across substances
Justification for type of information:
Weight of evidence approach based on structurally similar chemicals
Reason / purpose:
read-across source
Related information:
Composition 1
Reason / purpose:
read-across source
Related information:
Composition 1
Reference:
Composition 0
Qualifier:
equivalent or similar to
Guideline:
other: As mrentioned below
Principles of method if other than guideline:
WoE report is based on two reproductive toxicity studies on rats 1.Reproductive toxicity of test material in hamsters2.Subacute toxicity study of Menthone in Rats to evaluate its reprotoxic nature.
GLP compliance:
not specified
Limit test:
no
Justification for study design:
No data available
Test material information:
Composition 1
Species:
other: 1.hamster 2.rat
Strain:
other: 1.Syrian 2.SPF
Details on species / strain selection:
No data available
Sex:
male/female
Details on test animals and environmental conditions:
Study 2.- Source: Mollegaards Breeding Centre Ltd., Ejby (DK-4623 L. Skensved).- Age at study initiation: 4 weeks old- Weight at study initiation:- Fasting period before study: not specified - Housing: The animals were kept in stainless steel wire cages (2 per cage)- Diet (e.g. ad libitum): The rats were fed a pelleted diet (Chow 101, Institute of Toxicology, and National Food Agency). ad libitum- Water (e.g. ad libitum): acidified water (citric acid, pH 3.5) was given ad lib.- Acclimation period:ENVIRONMENTAL CONDITIONS- Temperature (°C): 23’C ± 1°C,- Humidity (%): 60 % ± 5%- Air changes (per hr): air change 6-8 times/h,- Photoperiod (hrs): electric light from 21.00 to 09.00 hours
Route of administration:
oral: gavage
Type of inhalation exposure (if applicable):
not specified
Vehicle:
soya oil
Details on exposure:
Study 2.- Justification for use and choice of vehicle (if other than water): test material soluble in Soya oil - Concentration in vehicle: 0,200,400 and 800 mg/kgbw/ day
Details on mating procedure:
No data available
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
Study 15 days Study 2.28 days
Frequency of treatment:
Daily
Details on study schedule:
No data available
Remarks:
Study 1.4.05,21.15,98.2,405.0 mg/kg bw /dayStudy 2.0.0, 200.0,400.0 and 800.0mg/kg bw /day
No. of animals per sex per dose:
Study 2.Total: 800 (vehicle) mg/kg/day: 10 male, 10 female 200 mg/kg/day: 10 male, 10 female400 mg/kg/day: 10 male, 10 female800 mg/kg/day: 10 male, 10 female
Control animals:
yes, concurrent vehicle
Details on study design:
Not specified
Positive control:
Not specified
Parental animals: Observations and examinations:
Study 1&2Survival, Clinical sign, hematological examinations,Body weight and weight gain and clinical chemistry were examined.
Estrous cyclicity (parental animals):
Not specified
Sperm parameters (parental animals):
Not specified
Litter observations:
Not specified
Postmortem examinations (parental animals):
Study 2.Organ weight and histopathology was examined.
Postmortem examinations (offspring):
Not specified
Statistics:
Study 2.Body weights, food and water consumption were compared by means of Student’s t-test. Analysis of variance was performed on haematoiogical parameters, clinical chemical parameters and absolute and relative organ weights. The mean values were compared by the method of Tukey.
Reproductive indices:
Not specified
Offspring viability indices:
Not specified
Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
Study 2.When treated wtih 800 mg/kg bw, after 19 days of dosing female rats showed signs of toxic effects. They had pale mucous membranes and showed signs of pain prevent deaths in this group, the dose was reduced to 400 mg/kg.
Dermal irritation (if dermal study):
not specified
Mortality:
mortality observed, treatment-related
Description (incidence):
Study 1.No effect on survival of treated female hamsters were observed. Study 2.When treated wtih 800 mg/kg bw, 4 animals died during the study due to accidental intratracheal dosing.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Study 2.Decreased in body weight gain was observed in treated male and female rats at 200, 400 and 800 mg/kg bw as compared to control.
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
Study 2.When treated wtih 800 mg/kg bw, Decreased in food consumption was observed in treated male rat, and in female rats from 3rd week as compared to control. When treated with 200 and 400 mg/kg bw, Decreased in food consumption was observed in female rat within the first 2 weeks as compared to control.
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not specified
Haematological findings:
not specified
Clinical biochemistry findings:
effects observed, treatment-related
Description (incidence and severity):
Study 2.When treated with 800 mg/kg bw, dose-dependent decrease of creatinine concentration and a dose dependent increase of both alkaline phosphatase activity and bilirubin content were observed in treated male and female rats as compared to control.
Urinalysis findings:
not specified
Behaviour (functional findings):
not specified
Immunological findings:
not specified
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
Study 2.When treated wtih 800 mg/kg bw, statistically significant dose-related increase of the relative weight of the spleen, liver and brain of the male and kidneys, spleen, liver and brain of female rats were observed as compare to control.
Gross pathological findings:
not specified
Neuropathological findings:
not specified
Histopathological findings: non-neoplastic:
no effects observed
Description (incidence and severity):
Study 2.Cyst-like spaces appeared scattered in the white matter of the cerebellum at 800 mg/kg bw.The findings resembled the changes found in rats dosed with peppermint oil. No histopathological changes were observed in reproductive organ of testis and ovary of treated rats as compared to control.
Histopathological findings: neoplastic:
not specified
Other effects:
not specified
Reproductive function: estrous cycle:
not specified
Reproductive function: sperm measures:
not specified
Reproductive performance:
no effects observed
Description (incidence and severity):
Study 1.No effect on Reproductive performance of treated female hamsters was observed.
Dose descriptor:
NOAEL
Effect level:
800 mg/kg bw/day
Based on:
test mat.
Sex:
male
Basis for effect level:
histopathology: non-neoplastic
Remarks on result:
other: No effect on histopathology of reproductive organs
Dose descriptor:
NOAEL
Effect level:
>= 405 - <= 671 mg/kg bw/day
Based on:
test mat.
Sex:
female
Basis for effect level:
clinical signs
mortality
body weight and weight gain
food consumption and compound intake
organ weights and organ / body weight ratios
gross pathology
histopathology: non-neoplastic
reproductive performance
Remarks on result:
other: No effect on histopathology of reproductive organs and reproductive performance
Critical effects observed:
not specified
System:
other: not specified
Organ:
not specified
Treatment related:
not specified
Dose response relationship:
not specified
Relevant for humans:
not specified
Clinical signs:
not specified
Dermal irritation (if dermal study):
not specified
Mortality / viability:
no mortality observed
Description (incidence and severity):
No effect on fetal survival of treated female hamsters were observed.
Body weight and weight changes:
not specified
Food consumption and compound intake (if feeding study):
not specified
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not specified
Haematological findings:
not specified
Clinical biochemistry findings:
not specified
Urinalysis findings:
not specified
Sexual maturation:
not specified
Organ weight findings including organ / body weight ratios:
not specified
Gross pathological findings:
no effects observed
Description (incidence and severity):
No dose-related number of abnormalities in soft or skeletal tissues were observed in fetus of treated hamsters were observed.
Histopathological findings:
not specified
Other effects:
not specified
Behaviour (functional findings):
not specified
Developmental immunotoxicity:
not specified
Dose descriptor:
NOAEL
Generation:
F1
Effect level:
405 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
not specified
Basis for effect level:
viability
mortality
gross pathology
other: not specified
Remarks on result:
other: No effects on developmental parameters was observed
Critical effects observed:
not specified
System:
other: not specified
Organ:
not specified
Treatment related:
not specified
Dose response relationship:
not specified
Relevant for humans:
not specified
Reproductive effects observed:
not specified
Treatment related:
not specified
Relation to other toxic effects:
not specified
Dose response relationship:
not specified
Relevant for humans:
not specified
Conclusions:
NOAEL was considered to be 800 mg/kg bw for male and in range of 405.0- 671 mg/kg bw for female when male and female rats or hamster were treated with test material orally by gavage .
Executive summary:

Study 1

In a Reproductive Toxicity study,Syrian female hamsters were treated with test material in the concentration of 4.05, 21.15, 98.2 and 405.0 mg/kg bw/day orally by gavage during gestation days 6-10. No effect on survival of treated female hamsters and fetus were observed. Similarly, No effect on Reproductive performance of treated female hamsters was observed.In addition, No dose-related number of abnormalities in soft or skeletal tissues were observed in fetus of treated hamsters were observed.Therefore, NOAEL was considered to be 405.0 mg/kg bw for P and F1 generation when Syrian female hamsters were treated with test material orally by gavage during gestation days 6-10.

Study 2.

In a repeated dose toxicity study,SPF male and female rats were treated with test material in the concentration of 0, 200, 400 and 800 mg/kg bw/ day orally by gavage for 28 days .At 800 mg/kg bw,after 19 days of dosing female rats showed signs of toxic effects. They had pale mucous membranes and showed signs of pain prevent deaths in this group, the dose was reduced to 400 mg/kg.4 animals died during the study due to accidental intratracheal dosing.Decreased in body weight gain was observed in treated male and female rats at 200, 400 and 800 mg/kg bw as compared to control. Decreased in food consumption was observed in treated male rat at 800 mg/kg bw, and in female rats from 3rd week at400 mg/kg bwas compared to control. Decreased in food consumption was observed in female rat within the first 2 weeks at 200 and 400mg/kg bwas compared to control. Dose-dependent decrease in creatinine concentration and a dose dependent increase of both alkaline phosphatase activity and bilirubin content were observed in treated male and female rats at 800 mg/kg bw as compared to control. Similarly,statistically significant dose-related increase in relative weight of the spleen, liver and brain of the male rat at 800 mg/kg bw and kidneys, spleen, liver and brain of female rats at 400 mg/kg bw were observed as compare to control. In addition, Cyst-like spaces appeared scattered in the white matter of the cerebellum at 800 mg/kg bw. The findings resembled the changes found in rats dosed with peppermint oil. No histopathological changes were observed in reproductive organ of testis and ovary of treated rats as compared to control. Therefore, NOAEL was considered to be 800 mg/kg bw for male and 671 mg/kg bw for female when SPF male and female rats were treated with test material orally by gavage for 28 days.

Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
405 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Quality of whole database:
Data is Klimicsh 2 and from authoritative database
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

Reproductive toxicity study

Data available from different studies were reviewed to determine the reproductive toxicity of(+)-neomenthol.The studies are as mentioned below:

Study 1

In a Reproductive Toxicity study, Syrian female hamsters were treated with test material in the concentration of 4.05, 21.15, 98.2 and 405.0 mg/kg bw/day orally by gavage during gestation days 6-10. No effect on survival of treated female hamsters and fetus were observed. Similarly, No effect on Reproductive performance of treated female hamsters was observed. In addition, No dose-related number of abnormalities in soft or skeletal tissues were observed in fetus of treated hamsters were observed. Therefore, NOAEL was considered to be 405.0 mg/kg bw for P and F1 generation when Syrian female hamsters were treated with test material orally by gavage during gestation days 6-10.

 

Study 2.

In a repeated dose toxicity study, SPF male and female rats were treated with test material in the concentration of 0, 200, 400 and 800 mg/kg bw/ day orally by gavage for 28 days .At 800 mg/kg bw, after 19 days of dosing female rats showed signs of toxic effects. They had pale mucous membranes and showed signs of pain prevent deaths in this group, the dose was reduced to 400 mg/kg.4 animals died during the study due to accidental intratracheal dosing. Decreased in body weight gain was observed in treated male and female rats at 200, 400 and 800 mg/kg bw as compared to control. Decreased in food consumption was observed in treated male rat at 800 mg/kg bw, and in female rats from 3rd week at400 mg/kg bwas compared to control. Decreased in food consumption was observed in female rat within the first 2 weeks at 200 and 400mg/kg bwas compared to control. Dose-dependent decrease in creatinine concentration and a dose dependent increase of both alkaline phosphatase activity and bilirubin content were observed in treated male and female rats at 800 mg/kg bw as compared to control. Similarly, statistically significant dose-related increase in relative weight of the spleen, liver and brain of the male rat at 800 mg/kg bw and kidneys, spleen, liver and brain of female rats at 400 mg/kg bw were observed as compare to control. In addition, Cyst-like spaces appeared scattered in the white matter of the cerebellum at 800 mg/kg bw. The findings resembled the changes found in rats dosed with peppermint oil. No histopathological changes were observed in reproductive organ of testis and ovary of treated rats as compared to control. Therefore, NOAEL was considered to be 800 mg/kg bw for male and 671 mg/kg bw for female when SPF male and female rats were treated with test material orally by gavage for 28 days

.

Based on the data available for the read across chemical, NOAEL was considered to be 800 mg/kg bw for male and in range of 405.0- 671 mg/kg bw for female when male and female rats or hamster were treated with(+)-neomentholorally by gavage. Thus, comparing this value with the criteria of CLP regulation(+)-neomentholis likely to be not classify as reproductive toxicant.

Effects on developmental toxicity

Effect on developmental toxicity: via oral route
Endpoint conclusion:
no study available
Effect on developmental toxicity: via inhalation route
Endpoint conclusion:
no study available
Effect on developmental toxicity: via dermal route
Endpoint conclusion:
no study available

Justification for classification or non-classification

Thus, comparing this value with the criteria of CLP regulation (+)-neomenthol is likely to be not classify as reproductive toxicant.