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Toxicological information

Developmental toxicity / teratogenicity

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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

Constituent 1
Chemical structure
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
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 / concentrationsopen allclose all
Dose / conc.:
50 other: mg/kg/day nominal
Dose / conc.:
300 other: mg/kg/day nominal
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).