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Diss Factsheets

Toxicological information

Developmental toxicity / teratogenicity

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Administrative data

developmental toxicity
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions
Missing: purity of substance, information on housing conditions, sufficient details of the administration scheme, statistical details

Data source

Reference Type:

Materials and methods

Test guideline
equivalent or similar to guideline
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
food consumption not reported; uterine weights and corpora lutea not determined; one third used for visceral examination; test substance identification missing; administration only during periods of organogenesis, no statistics, no historical data
GLP compliance:
Limit test:

Test material

Constituent 1
Chemical structure
Reference substance name:
EC Number:
EC Name:
Cas Number:
Molecular formula:

Test animals


Administration / exposure

Route of administration:
oral: gavage
corn oil
Details on exposure:
Dose: 0; 2.18; 10.15; 47.05; 218 mg/kg bw/day
administered as a corn oil solution.
The controls were sham treated with the vehicle at a level equivalent to the group receiving the highest test dose. Beginning on day 6 after gestation and continuing daily through day 15 of gestation, the females were dosed with the indicated dosages by oral intubation.

Details on mating procedure:
Virgin adult were mated with young adult males (observation of the vaginal sperm plug was considered Day 0 of gestation)
Duration of treatment / exposure:
gestation days 6-15
Frequency of treatment:
Duration of test:
10 consecutive days
Doses / concentrationsopen allclose all
Dose / conc.:
2.18 mg/kg bw/day
Dose / conc.:
10.15 mg/kg bw/day
Dose / conc.:
47.05 mg/kg bw/day
Dose / conc.:
218 mg/kg bw/day
No. of animals per sex per dose:
25 females per dose
No of pregnant animals (0; 2.18; 10.15; 47.05; 218 mg/kg bw/day): 25, 22, 23, 23, 22
Control animals:
yes, concurrent vehicle
other: positive control: Aspirin 250 mg/kg bw/day


Maternal examinations:
Body weights were recorded on day 0, 6, 11, 15, and 20 of gestation. All animals were observed daily for appearance and behavior with particular attention to food consumption and weight, in order to rule out any abnormalities which may have occurred as a result of anorexic effects in the pregnant female animal
Ovaries and uterine content:
On day 20 all dams were subjected to Caesarian section under surgical anesthesia, and the numbers of implantation sites, resorption sites, and live and dead fetuses were recorded. The body weights of the live pubs were also recorded. The urogenital tract of each dam was examined in detail for anatomical normality.
Fetal examinations:
All fetuses were examined grossly for the presence of external congenital abnormalities. One-third of the fetuses of each litter underwent detailed visceral examinations employing 10x magnification. The remaining two-thirds were cleared in potassium hydroxide (KOH), stained with alizarin red S dye and examined for skeletal defects.

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:
Maternal toxic effects: no effects

Details on maternal toxic effects:
No clinical signs of maternal toxicity

Effect levels (maternal animals)

Dose descriptor:
Effect level:
> 218 mg/kg bw/day
Based on:
not specified
Basis for effect level:
other: maternal toxicity
Remarks on result:
not determinable due to absence of adverse toxic effects

Maternal abnormalities

no effects observed

Results (fetuses)

Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects: no effects

Effect levels (fetuses)

open allclose all
Dose descriptor:
Effect level:
> 218 mg/kg bw/day
Based on:
not specified
Basis for effect level:
other: teratogenicity
Remarks on result:
not determinable due to absence of adverse toxic effects
Dose descriptor:
Effect level:
> 218 mg/kg bw/day
Based on:
not specified
Basis for effect level:
other: fetotoxicity
Remarks on result:
not determinable due to absence of adverse toxic effects

Fetal abnormalities

no effects observed

Overall developmental toxicity

Developmental effects observed:

Any other information on results incl. tables


·        Death: no dead fetuses in dosage groups (3 deaths in positive control)

·        Average fetus weight: no change in treated groups compared to controls

·        Abnormalities/malfunctionsa)sham control; b)pos. control; c)2.18; d)10.15; e)47.05; f)218 mg/kg bw/day

o  Skeletal findingsNo. of fetuses/No. of litters affected:

§ sternebrae (incomplete oss.): a)80/22; b)94/18; c)92/20; d)93/22; e)101/19; f)92/19

§ sternebrae (missing): a)14/6; b)11/19; c)11/8; d)17/5; e)11/4; f)0/22

§ skull (incomplete closure): a)41/16; b)114/19; c)46/15; d)63/16; e)67/20; f)49/17

o  Soft tissue abnormalities:

§ pos. control: 7 pups with meningoencephalocele and spina bifida

§ 10.15 mg/kg: 1 pup: petechiae, 1 pup: anophthalmia

§ 47.05 mg/kg: 2 pups anophthalmia, 2 pups: gastroschisis,1 pup hydrocephalus

o  All other findings:

§ were completely in the range of spontaneous abnormalities found in negative controls.

Applicant's summary and conclusion

Menthol was not embryo- or fetotoxic and had no teratogenic properties in rat at non-maternally toxic doses (218 mg/kg bw/day).
Executive summary:

The administration of up to 218 mg/kg bw/day of L-menthol to pregnant rats for 10 consecutive days had no clearly discernible effects on nidation or on maternal or fetal survival. The number of abnormalities seen in either soft or skeletal tissues of the test groups did not differ from the number occurring spontaneously in the sham treated controls.