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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
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Study was performed similar to OECD 414 with acceptable deviations. Sufficient information on methods and results was provided to evaluate data.
Remarks:
none
Justification for type of information:
none

Data source

Reference
Reference Type:
publication
Title:
Unnamed
Year:
1979

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Deviations:
yes
Remarks:
: Limited or no information on environmental conditions and animals. Dams dosed from days 6-15 of gestation. Maternal mortality exceeded 10% at the highest dose. The dosing volume exceeded recommended volume. Limited information on clinical observations.
GLP compliance:
not specified
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): biphenyl
- Molecular formula (if other than submission substance): not applicable
- Molecular weight (if other than submission substance): not applicable
- Smiles notation (if other than submission substance): not applicable
- InChl (if other than submission substance): not applicable
- Structural formula attached as image file (if other than submission substance): see Fig. not applicable
- Substance type: no data
- Physical state: no data
- Analytical purity: no data
- Impurities (identity and concentrations): no data
- Composition of test material, percentage of components: no data
- Isomers composition: no data
- Purity test date: no data
- Lot/batch No.: no data
- Expiration date of the lot/batch: no data
- Stability under test conditions: no data
- Storage condition of test material: no data
- Other:no data

Test animals

Species:
rat
Strain:
Wistar
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Woodlyn Farms, Guelph, Ontario, Canada
- Age at study initiation: no data
- Weight at study initiation: 175-200 g (females)
- Housing: no data
- Diet (e.g. ad libitum): no data
- Water (e.g. ad libitum): no data
- Acclimation period: no data

ENVIRONMENTAL CONDITIONS: no data

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
corn oil
Details on exposure:
PREPARATION OF DOSING SOLUTIONS: no details

VEHICLE
- Justification for use and choice of vehicle (if other than water): corn oil
- Concentration in vehicle: 12.5, 25, 50 and 100 mg/ml
- Amount of vehicle (if gavage): 10 ml/kg bw
Analytical verification of doses or concentrations:
no
Details on analytical verification of doses or concentrations:
not applicable
Details on mating procedure:
- Impregnation procedure: cohoused
- If cohoused:
- M/F ratio per cage: not indicated
- Length of cohabitation: not indicated
- After ... days of unsuccessful pairing replacement of first male by another male with proven fertility. Not indicated
- Further matings after two unsuccessful attempts: not indicated
- Verification of same strain and source of both sexes: not indicated
- Proof of pregnancy: positive vaginal smear referred to as day 1 of pregnancy
- Any other deviations from standard protocol: administration of test substance from implantation (day 6) through day 15 of gestation (rather than to the day prior to scheduled caesarean section)
Duration of treatment / exposure:
Day 6 through day 15 of gestation
Frequency of treatment:
Once daily
Duration of test:
Until day 22 of gestation
No. of animals per sex per dose:
18 to 20 mated females
Control animals:
yes
Details on study design:
No further details

Examinations

Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes: mortality

DETAILED CLINICAL OBSERVATIONS: No data

BODY WEIGHT: Yes
- Time schedule for examinations: day 1, 6 through 15, and 22 of pregnancy

POST-MORTEM EXAMINATIONS: Yes : necropsy
- Sacrifice on gestation day 22
- Organs examined: no data
Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: Yes
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes
Fetal examinations:
- External examinations: Yes: all per litter
- Soft tissue examinations: Yes: one-thirds per litter
- Skeletal examinations: Yes: two-thirds per litter
- Head examinations: Yes: No data
Statistics:
Values of t for test group mean maternal body weight versus control group (Dunn's test)
Mean fetal parameters: proportion of a litter having a particular attribute calcuilated, mean and SE derived (Hald method)
Significant differences if p<0.05.
Indices:
Number of rats pregnant/number mated
Number of corpora lutea per pregnancy
Number of live fetuses per pregnancy
Dead and resorbed fetuses (%), i.e. (number of resorption sites + dead fetuses / total implants)x 100
Number of anomalous fetuses/number examined
Number of anomalous litters/number examined
Historical control data:
No data

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:
Maternal toxic effects:yes

Details on maternal toxic effects:
1000 mg/kg bw/day dose group:
- resorption occurred in one litter
- 5 animals were found not to be pregnant (may be due to interference with implantation)
- in 5 pregnant dams mortality occurred. Each death occurred during the dosing period and was preceded by a sharp reduction in body weight and diarrhea.
125, 250 and 500 mg/kg bw/day dose groups:
- no signs of toxicity occurred.

Effect levels (maternal animals)

open allclose all
Dose descriptor:
NOAEL
Effect level:
500 mg/kg bw/day (actual dose received)
Basis for effect level:
other: maternal toxicity
Dose descriptor:
LOAEL
Effect level:
1 000 mg/kg bw/day (actual dose received)
Basis for effect level:
other: maternal toxicity
Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day (actual dose received)
Basis for effect level:
other: developmental toxicity

Results (fetuses)

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

Details on embryotoxic / teratogenic effects:
Although 1000 mg/kg bw/day biphenyl was lethal for five dams, for the dams that survived, it did not affect the incidence of corpora lutea, live fetuses, or dead fetuses plus resorption sites, nor did it affect fetal weight. Although the latter was reduced, and the incidence of dead fetuses plus resorptions increased, these values were not statistically significant from the control animals. In both the 1000 and 500 mg/kg fetuses with missing and unossified sternebrae not statistically significant. The incidence and types of anomalies and ossifications in the biphenyl dosed groups and the control were also similar.
Results are presented for doses 0, 125, 250, 500 and 1000 mg/kg respectively:
- number of rats with live fetuses/number mated: 16/18, 20/20, 18/19, 18/20, 9/20
- number of corpora lutea per pregnancy (mean +/- SE): 12.6 +/-0.4, 12.9 +/-0.4, 13.7 +/-0.5, 13.3 +/-0.4, 12.5 +/-0.7
- number of live fetuses per pregnancy (mean +/- SE): 11.3 +/-0.7, 11.8 +/-0.6, 11.9 +/-0.6, 11.2 +/-0.5, 10.7 +/-1.3
- dead and resorbed fetuses (%): 4.8, 3.3, 6.1, 7.8, 13.7
- fetal weight (g mean +/- SE): 5.1 +/-0.1, 5.3 +/-0.1, 5.2 +/-0.1, 5.2 +/-0.1, 4.5 +/-0.3
- number of anomalous fetuses/number examined: 17/176, 22/236, 22/213, 35/199, 25/107
- number of anomalous litters/number examined: 8/16, 11/20, 13/18, 15/18, 6/9
Anomalies (number of fetuses affected):
- wavy ribs uni- and bilateral: 3, 7, 9, 8, 5
- extra ribs uni- and bilateral: 9, 12, 9, 15, 6
- 13th rib small sized: 1, 1, 2, 1, 0
- missing or unossified sternebrae: 4, 3, 4, 16, 17
- delayed ossification calvarium: 0, 2, 0, 0, 8

Effect levels (fetuses)

Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No changes at this dose level

Fetal abnormalities

Abnormalities:
not specified

Overall developmental toxicity

Developmental effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
Mortality occured during the dosing period in 10% of dams dosed with 1000 mg/kg bw. No statistically significant effects on fetotoxicity or teratogenicty occured at any of the doses evaluated.