Registration Dossier

Toxicological information

Toxicity to reproduction

Currently viewing:

Administrative data

Endpoint:
toxicity to reproduction
Remarks:
other: carcinogenicity study with histopathologic examiniation of male and female reproduction organs
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: According to ECVAM ToxRTool reliability 1 (Study performed 1979 therefor without GLP) carcinogenicity study with histopathologic examiniation of male and female reproduction organs
Cross-reference
Reason / purpose for cross-reference:
reference to same study

Data source

Reference
Reference Type:
publication
Title:
Unnamed
Year:
1979

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
other: OECD Guiline 453 (Combined Chronic Toxicity / Carcinogenicity Study)
Principles of method if other than guideline:
A bioassay of dl-menthol for possible carcinogenicity was conducted by administrating the test chemical in feed to Fisher 344 rats.
Groups of 50 rats of each sex were administrated dl-menthol at one of the following doses, either 3750 or 7500 ppm for 103 weeks, then observed for 1 or 2 additional weeks. Matched controls consisted of 50 untreated rats of each sex. All surviving rats were killed at 105 weeks.
At the end all animals were killed and necropsied; gross and microscopic examination of: all major organs, including reproductive organs; in male rats prostate,testes, epididymis, scrotum; in female rats mammary gland, vagina, uterus, uterus/endometrium, ovary/panovarian, ovary.
GLP compliance:
not specified

Test material

Constituent 1
Reference substance name:
DL Menthol
IUPAC Name:
DL Menthol
Constituent 2
Reference substance name:
Menthol
EC Number:
201-939-0
EC Name:
Menthol
Cas Number:
89-78-1
IUPAC Name:
2-isopropyl-5-methylcyclohexanol
Details on test material:
- Name of test material (as cited in study report): USP-grade DL-Menthol
- Lot/batch No.: 4-HTP-6 (for the first 3 weeks only) and N11-26-74-2054 (for the rest of the study)
- Storage condition of test material: The test material was stored at 1°C in their original containers
- Obtained from Glidden Organics International, Jacksonville, Florida (Lot No 4-HTP-6)
and from Norda, Inc., New York (Lot No N11-26-74-2054)
The identity of the chemical in both cases was established on the basis of elemental analyses (C, H) and infrared, ultraviolet, and nuclear magnetic resonance spectra. Gas-liquid chromatography of Lot. No. 4-HTP-6 showed two impurities estimated at 0.3% each, which were very similar in volatility to the major component, and one less volatile impurity of about 1.3%. One minor impurity (0.2%) was detected in Lot No. N11-26-74-2054 by the same technique. No impurities were detected in either lot by thin-layer chromatography. Karl Fischer analysis showed 0.22 ± 0.02% water in Lot No. 4-HTP-6, and less than 0.1% water in Lot No. N11-26-74-2054. Infrared and nuclear magnetic resonance spectra were consistent with spectra in the literature

Test animals

Species:
rat
Strain:
Fischer 344
Sex:
male/female

Administration / exposure

Route of administration:
oral: feed
Vehicle:
corn oil
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:

DIET PREPARATION
- Rate of preparation of diet (frequency): prepared each week and used within 1 week of preparation.
- Storage temperature of food: The containers were stored at room temperature.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Duplicate 10g dosed feed sample were extracted with 20ml of carbon disulfide, and aliquots of the extract analyzed by gas chromatography (thermal conductivity detector).
(see attached illustration for values)
Duration of treatment / exposure:
The compound was administered in the diet seven days a week for 103 weeks at the indicated level.
During the 2 post-treatment weeks (recovery), the animals were supplied with standard diet.
Frequency of treatment:
daily for 103 weeks
Doses / concentrationsopen allclose all
Remarks:
Doses / Concentrations:
0.375 % (= ca. 188 mg/kg bw/d)
Basis:
nominal in diet
Remarks:
Doses / Concentrations:
0.75%
Basis:
nominal in diet
No. of animals per sex per dose:
50 rats of either sex/dose
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: Based on the results of 13-week study (see cross reference studies).
- Rationale for animal assignment (if not random): Animals were segregated by body weight so that a homogeneous distribution of mean weight ranges was obtained between groups.
Positive control:
No data

Results and discussion

Results: P0 (first parental generation)

Effect levels (P0)

Dose descriptor:
NOAEL
Effect level:
ca. 375 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female

Overall reproductive toxicity

Reproductive effects observed:
not specified

Applicant's summary and conclusion

Executive summary:

Groups of 50 rats of each sex were administrated dl-menthol at one of the following doses, either 3750 or 7500 ppm for 103 weeks, then observed for 1 or 2 additional weeks. Matched controls consisted of 50 untreated rats of each sex. All surviving rats were killed at 105 weeks. Body weights and clinical signs were recorded and pathological and histopathological examinations conducted. At the end all animals were killed and necropsied; gross and microscopic examination of: all major organs, including reproductive organs; in male rats prostate,testes, epididymis, scrotum; in female rats mammary gland, vagina, uterus, uterus/endometrium, ovary/panovarian, ovary.

Histopathological examinations of the reproduction organs of rats showed no changes in the repeated dose toxicity studies with D/L-menthol and also in carcinogenicity studies with D/Lmenthol. Hence there is no indication of a potential of D/L-menthol to interfere adversely with reproduction.