Vinyltoluene

Developmental toxicity / teratogenicity

Administrative data

Endpoint:

developmental toxicity

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Data source

Reference

Reference Type:

publication

Title:

Unnamed

Year:

2003

Report date:

2003

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

other: Not referenced

GLP compliance:

yes

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

4-methylstyrene

EC Number:

210-762-8

EC Name:

4-methylstyrene

Cas Number:

622-97-9

Molecular formula:

C9H10

IUPAC Name:

1-methyl-4-vinylbenzene

Details on test material:

SMILES:CC1=CC=C(C=C)C=C1

Test animals

Species:

rat

Strain:

CD-1

Details on test animals or test system and environmental conditions:

Sexually mature, virgin female Charles River COBS CD rats (approximately 12 weeks old).

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

olive oil

Remarks:

Dose volume of 5 mL/kg

Details on exposure:

Beginning on day 6 of gestation and continuing daily through day 19 of gestation, the test substance was suspended in corn oil and administered by oral gavage (volume, 5.0 ml/kg) to pregnant females at a single daily dose of 50, 300, and 600 mg/kg/day. A control group received the vehicle only on comparable regimen at a volume of 5 ml/kg.

Analytical verification of doses or concentrations:

not specified

Details on mating procedure:

Sexually mature, virgin female Charles River COBS CD rats (approximately 12 weeks old) were mated in 1:1 with males in sufficient numbers to assign a minimum of 25 pregnant animals per group.

Duration of treatment / exposure:

seven days/week

Frequency of treatment:

Once daily

Duration of test:

20 days after gestation

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

600 mg/kg bw/day (nominal)

Doses / concentrations 2

Dose / conc.:

300 mg/kg bw/day (nominal)

Doses / concentrations 3

Dose / conc.:

50 mg/kg bw/day (nominal)

No. of animals per sex per dose:

25 females

Control animals:

yes, concurrent vehicle

Details on study design:

Sexually mature, virgin female Charles River COBS CD rats (approximately 12 weeks old) were mated in 1:1 with males in sufficient numbers to assign a minimum of 25 pregnant animals per group. Beginning on day 6 of gestation and continuing daily through day 19 of gestation, the test substance was suspended in vehicle and administered by oral gavage (volume, 5.0 ml/kg) to pregnant females at a single daily dose of 50, 300, and 600 mg/kg/day. A control group received the vehicle only on a comparable regimen at a volume of 5 ml/kg.

Examinations

Maternal examinations:

mortality(Prior to treatment and GD 6 to 19)
appearance and behavior(Prior to treatment )
clinical signs (GD 6 to 19)
body weights (GD 0 to 20)

Ovaries and uterine content:

organ weight, the number and location of viable and nonviable fetuses, early and late resorptions, and the number of total implantations and corpora lutea

Fetal examinations:

weight, examined for external malformations and variations, including the palate and eyes. Each
fetus was externally sexed and individually numbered and tagged for identification. Approximately one-half of the fetuses were placed in Bouin’s fixative for subsequent visceral examination by razor-blade sectioning. The remaining one-half of the fetuses were fixed in alcohol, macerated in potassium hydroxide and stained with Alizarin Red S for subsequent skeletal examination.

Results and discussion

Results: maternal animals

General toxicity (maternal animals)

Clinical signs:

no effects observed

Mortality:

no mortality observed

Body weight and weight changes:

effects observed, non-treatment-related

Description (incidence and severity):

Compared to the control group there was a reduction in maternal weight gain in all treated groups.

Food consumption and compound intake (if feeding study):

not examined

Food efficiency:

not examined

Ophthalmological findings:

not examined

Haematological findings:

not examined

Clinical biochemistry findings:

not examined

Urinalysis findings:

not examined

Behaviour (functional findings):

no effects observed

Immunological findings:

not examined

Organ weight findings including organ / body weight ratios:

not examined

Gross pathological findings:

not examined

Neuropathological findings:

not examined

Histopathological findings: non-neoplastic:

not examined

Histopathological findings: neoplastic:

not examined

Maternal developmental toxicity

Number of abortions:

not specified

Pre- and post-implantation loss:

not specified

Total litter losses by resorption:

not specified

Early or late resorptions:

not specified

Dead fetuses:

not specified

Changes in pregnancy duration:

not specified

Changes in number of pregnant:

not specified

Effect levels (maternal animals)

Dose descriptor:

NOAEL

Effect level:

>= 600 mg/kg bw/day (nominal)

Basis for effect level:

behaviour (functional findings)

body weight and weight gain

mortality

Maternal abnormalities

Abnormalities:

no effects observed

Results (fetuses)

Fetal body weight changes:

effects observed, non-treatment-related

Reduction in number of live offspring:

no effects observed

Changes in sex ratio:

not specified

Changes in litter size and weights:

no effects observed

Changes in postnatal survival:

no effects observed

External malformations:

effects observed, non-treatment-related

Description (incidence and severity):

No malformations were observed in the control, 50 or 300 mg/kg/day groups. One malformation, meningocele, was observed in one fetus from one litter in the 600 mg/kg/day. The number of
fetuses and litters with genetic or developmental variations in all treated groups was comparable to the control group.

Skeletal malformations:

no effects observed

Visceral malformations:

no effects observed

Effect levels (fetuses)

Dose descriptor:

NOAEL

Effect level:

>= 600 mg/kg bw/day (nominal)

Basis for effect level:

reduction in number of live offspring

fetal/pup body weight changes

external malformations

skeletal malformations

visceral malformations

Fetal abnormalities

Abnormalities:

no effects observed

Overall developmental toxicity

Developmental effects observed:

no

Applicant's summary and conclusion

Conclusions:

Under the study conditions, the NOAEL for teratogenicity was established at 600 mg/kg bw/day.

Executive summary:

A study was conducted to determine the teratogenic potential of the read across substance, 4-methylstyrene. Groups of 25 pregnant Charles River COBS CD rats were given the test substance by oral gavage (volume, 5.0 ml/kg), from Gestation Day (GD) 6 to 19 at a single daily dose of 50, 300, and 600 mg/kg/day. A control group received the vehicle only, olive oil, at a dose volume of 5 mL/kg bw.

There were no mortalities or clinical signs in the maternal groups. Compared to controls, there was a reduction in maternal weight gain in all treated groups and this was considered not statistically significant. Fetal weights in all treated groups were also significantly lower than the controls. However, this may have been the results of an unusually high control value for fetal weight, above the normal background range of the laboratory. There were no biologically meaningful differences in the mean number of corpora lutea, total implantations, early or late resorptions, post implantation loss, viable fetuses, fetal sex distribution, mean fetal body weight or number of fetuses (and litters) with malformations. 

Under the study conditions, the NOAEL for teratogenicity was established at 600 mg/kg bw/day.