4-methylstyrene

Developmental toxicity / teratogenicity

Administrative data

Endpoint:

developmental toxicity

Type of information:

experimental study

Adequacy of study:

key study

Study period:

From May 27, 1980 to June 20, 1980

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

comparable to guideline study with acceptable restrictions

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1981

Report date:

1982

Materials and methods

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 414 (Prenatal Developmental Toxicity Study)

Deviations:

yes

Remarks:

Choice of dose levels higher than current practice and methodology lacks detail

GLP compliance:

yes

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-ethenyl-4-methylbenzene

Test material form:

liquid

Details on test material:

- Batch/lot no.: 01188001

Test animals

Species:

rat

Strain:

CD-1

Details on test animals or test system and environmental conditions:

Virgin Charles River COBS CD rats were obtained from The Charles River Breeding Laboratory Inc, Michigan, and were 12 weeks of age and weighed between on GD 0. There were acclimatized in the laboratory for 14 days. Rats were house singly in suspended wire cages. Temperature and humidity were controlled (actual ranges not given) and light cycle was 12 hours dark/12 hours light. Purina certified rodent chow no 5002 and tap water were available ad libitum.

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

olive oil

Remarks:

Dose volume of 5 mL/kg

Details on exposure:

The test substance was administrated orally by gavage as a single daily dose on Days 6 through 19 of gestation. The test substance was prepared at concentrations to permit administration at dosage levels of 50, 300 and 600 mg/kg bw/day at constant volume of 5 ml/kg.

Analytical verification of doses or concentrations:

no

Details on mating procedure:

Rats were mated with a single male until a copulatory plug was observed: this was then deemed GD 0.

Duration of treatment / exposure:

GD 6 to 19

Frequency of treatment:

once daily

Duration of test:

Caesarean sections were conducted on GD 20.

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

50 other: mg/kg/day nominal

Doses / concentrations 2

Dose / conc.:

300 other: mg/kg/day nominal

Doses / concentrations 3

Dose / conc.:

600 other: mg/kg/day nominal

No. of animals per sex per dose:

25 females

Control animals:

yes, concurrent vehicle

Details on study design:

One male and one female rat of the same strain and source were placed together for mating. The day that evidence of mating was detected was designated day 0 of gestation and the female was returned to an individual cage.

Examinations

Maternal examinations:

Maternal observations:
Clinical observations: daily
Body weights: GD 0, 6, 9, 12, 16 and 20
Appearance and behavior
Cesarean section observations
Fetus: morphological observations

Ovaries and uterine content:

Necropsy GD 20: uterus weight, number and location of viable and non-viable fetuses, early and late resorptions, number of total implantations and corpora lutea.

Fetal examinations:

Fetal observations: weight, external abnormalities (incl. palate and eye), sexed. Approximately 50% placed in Bouins fixative for visceral examinations and sectioning as described by Wilson. Remaining 50 % fixed in alcohol, macerated in potassium hydroxide and stained with Alizarin Red S for skeletal examination.

Results and discussion

Results: maternal animals

General toxicity (maternal animals)

Clinical signs:

no effects observed

Dermal irritation (if dermal study):

not examined

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

Water consumption and compound intake (if drinking water study):

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

Other effects:

effects observed, treatment-related

Description (incidence and severity):

Occasional instances of hair loss on the limbs were observed in all test groups and control. Dry or oily haircoat, black or brown matter around the nose, red matter around the eyes, swollen limbs, and soft stool occurred occasionally in the control and treated groups.

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

Description (incidence and severity):

Migrated Data from removed field(s)
Field "Effects on pregnancy duration" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsMaternalAnimals.MaternalDevelopmentalToxicity.EffectsOnPregnancyDuration): not specified

Changes in number of pregnant:

not specified

Other effects:

not specified

Details on maternal toxic effects:

Maternal toxic effects:yes
Details on maternal toxic effects: Compared to the control group there was a reduction in maternal weight gain in all treated groups, this was considered to be test substance related.

Effect levels (maternal animals)

Key result

Dose descriptor:

NOEL

Basis for effect level:

other: maternal toxicity

Remarks on result:

not determinable

Remarks:

no NOAEL identified

Maternal abnormalities

Key result

Abnormalities:

no effects observed

Results (fetuses)

Fetal body weight changes:

effects observed, treatment-related

Description (incidence and severity):

Migrated Data from removed field(s)
Field "Fetal/pup body weight changes" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.FetalPupBodyWeightChanges): not examined

Reduction in number of live offspring:

no effects observed

Changes in sex ratio:

no effects observed

Changes in litter size and weights:

not examined

Changes in postnatal survival:

not examined

External malformations:

no effects observed

Skeletal malformations:

not examined

Visceral malformations:

not examined

Other effects:

not specified

Details on embryotoxic / teratogenic effects:

Embryotoxic / teratogenic effects:no effects
Details on embryotoxic / teratogenic effects: Fetal weights in all treated groups were also statistically significantly lower than the controls. However, it was considered that this may have been the results of an unusually high control value for fetal weight, above the normal background range in this laboratory.

Effect levels (fetuses)

Key result

Dose descriptor:

NOEL

Effect level:

600 mg/kg bw/day (nominal)

Based on:

test mat.

Basis for effect level:

other: teratogenicity

Fetal abnormalities

Key result

Abnormalities:

no effects observed

Overall developmental toxicity

Key result

Developmental effects observed:

no

Any other information on results incl. tables

 

Observation	Control	test substance (mg/kg/day)
		50	300	600
Number pregnant	25	23	22	25
Bwt gain GD 0 – 6 (g)	28	27	25	25
Bwt gain GD 6 – 9 (g)	7	7	2	0
Bwt gain GD 0 – 20 (adjusted) (g)	67	60	56	50
Bwt GD 20 (adjusted) (g)	316	305	296	291
Mean fetal bwt (g)	4.2+0.53	3.9 *+0.24	3.9 *+0.32	3.8 **+0.25

 

* = statistically different from control p < 0.05

** = statistically different from control p < 0.01

Applicant's summary and conclusion

Conclusions:

Under the study conditions, the NOAEL for teratogenicity was established at 600 mg/kg bw/day. The NOAEL for maternal toxicity was not identified, but the LOAEL was 50 mg/kg bw/day (transient bodyweight changes).

Executive summary:

A study was conducted to determine the teratogenic potential of the test substance in rats according to a method similar to OECD Guideline 414. Groups of 25 pregnant Charles River COBS CD rats were given the test substance by oral gavage, from Gestation Day (GD) 6 to 19 at dose levels of 50, 300 and 600 mg/kg bw/day at a constant volume rate of 5 mL/kg bw. A control group received the vehicle only, olive oil, at a dose volume of 5 mL/kg bw. Caesarean sections were conducted on GD 20. 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 to be substance-related. 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. The NOAEL for maternal toxicity was not identified, but the LOAEL was 50 mg/kg bw/day (transient bodyweight changes) (Spicer, 1981).