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Administrative data

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
Feb-Jul 2012
Reliability:
1 (reliable without restriction)

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2012
Report date:
2012

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
GLP compliance:
yes (incl. QA statement)

Test material

Constituent 1
Chemical structure
Reference substance name:
Mono- and/or di- and/or tri(1-phenylethyl)-m-cresol and p-cresol
EC Number:
700-427-9
Molecular formula:
CnHn+1O; n=15, 23 and 31
IUPAC Name:
Mono- and/or di- and/or tri(1-phenylethyl)-m-cresol and p-cresol

Test animals

Species:
rat
Strain:
Wistar

Administration / exposure

Route of administration:
other: oral: metal stomach tube
Vehicle:
olive oil
Remarks:
administered to control group
Analytical verification of doses or concentrations:
not specified
Details on mating procedure:
1 male per 4 females (1 male per 2 females in added animals) were used in mating. The females were placed overnight with the same male. Each morning during the mating procedure, the females were examined for the presence of sperms or vaginal plugs. If pregnancy was not determined, the females were returned to the orginal cage and back to overnight co-housing until pregnancy occurred ot two weeks have elapsed.Day 0 pregnancy was defined as the day a vaginal plug or sperms were found. Pregnant females were kept individually. In case of pairing was unsuccessful, re-mating of females with the successful males was introduced.
Duration of treatment / exposure:
15 days
Frequency of treatment:
once a day
Duration of test:
20 days, females were treated with the tested substance from day 5 to 19, day 20 was gestation
Doses / concentrations
Remarks:
Doses / Concentrations:
300, 550, 1000 mg/kg
Basis:
nominal in diet
No. of animals per sex per dose:
24 females in each of dose level and in control group, due to higher number of females with false gravidity, additional females were included, in total:
- control group: 30 females
- 300 mg/kg dose: 38 females
- 550 mg/kg dose: 24 females
- 1000 mg/kg dose: 34 females
Control animals:
yes, concurrent vehicle

Results and discussion

Results: maternal animals

Effect levels (maternal animals)

open allclose all
Dose descriptor:
NOAEL
Effect level:
550 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: other:
Dose descriptor:
LOAEL
Effect level:
1 000 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: other:
Dose descriptor:
NOAEL
Effect level:
550 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: maternal toxicity
Dose descriptor:
LOAEL
Effect level:
1 000 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: maternal toxicity

Results (fetuses)

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

Effect levels (fetuses)

Dose descriptor:
NOAEL
Effect level:
>= 1 000 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: teratogenicity

Fetal abnormalities

Abnormalities:
not specified

Overall developmental toxicity

Developmental effects observed:
not specified

Any other information on results incl. tables

Atlen SK at dose 300 mg/kg treatment orally did not cause mortality or adverse effects on maternal and embryo-foetal parameters in this study. Atlen SK caused the mortality of 4 pregnant females in the high dose group treated at 1000 mg/kg.

Body weights, food intake, and clinical conditions in low and mid dose groups (300 and 550 mg/kg) were comparable versus controls. At 1000 mg/kg, body weight gains and food intake were decreased, and adverse clinical signs were noted (lethargy, soft stool, lower feed and water intake).

Treatment with Atlen SK in all dose groups did not affect the placental weight.

At 1000 mg/kg, statistically significant increase of number corpora lutea, implantations and live foetuses were recorded. These changes were not considered as the signs of toxicity or adverse effect. The test item was administered fram day 5 of gestation, when the number corpora lutea and implantation sites were already formed.

At 550 and 1000 mg/kg, significantly increased incidence of undilatation of lateral and 3rd cerebral ventricles and moderate degree of internal hydrocephalus against other doses were noted. These finding could be caused by treatment. Other observed changes in the foetuses were considered to be incidental and not caused by treatment with Atlen SK.

Applicant's summary and conclusion

Conclusions:
Results of Prenatal Developmental Toxicity study of Atlen SK indicate that lowest dose od 550 mg/kg bw/day can be considered a NOAEL for this endpoint.
Executive summary:

Presented results originate from a guideline study conducted in accordance with the requirements of the GLP. Hence, this information can be considered reliable and suitable for use as the key study for this endpoint