Registration Dossier

Toxicological information

Developmental toxicity / teratogenicity

Currently viewing:

Administrative data

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1973
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: According to ECVAM ToxRTool reliability 2 (Study performed 1973 therefor without GLP) Missing: purity of substance, information on housing conditions, sufficient details of the administration scheme, statistical details

Data source

Reference
Reference Type:
publication
Title:
Unnamed
Year:
1973

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
other: unspecified
GLP compliance:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent

Test animals

Species:
rat
Strain:
Wistar

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
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:
daily
Duration of test:
10 consecutive days
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

Examinations

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:
NOEL
Effect level:
218 mg/kg bw/day
Based on:
no data
Basis for effect level:
other: maternal toxicity

Results (fetuses)

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

Effect levels (fetuses)

open allclose all
Dose descriptor:
NOEL
Effect level:
218 mg/kg bw/day
Based on:
no data
Basis for effect level:
other: teratogenicity
Dose descriptor:
NOEL
Effect level:
218 mg/kg bw/day
Based on:
no data
Basis for effect level:
other: fetotoxicity

Fetal abnormalities

Abnormalities:
not specified

Overall developmental toxicity

Developmental effects observed:
not specified

Any other information on results incl. tables

Fetotoxicity:

·        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

Conclusions:
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 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.