(+)-neomenthol

Endpoint summary

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 for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across source

Qualifier:

equivalent or similar to guideline

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

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 or test system 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.

Oestrous 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

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: oestrous 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.