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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:
1979
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: No international guideline mentioned. However, study is described in acceptable detail.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1979
Report Date:
1979

Materials and methods

Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
Pregnant Charles River CD rats were used to evaluate the teratogenic potential of DBPP in this study. The compound was administered orally by gavage as a single daily dose from days 6 through 15 of gestation. The test substance was administered at dosage levels of 3, 30 and 300 mg/kg/d at a constant volume of 10 ml/kg/d. Two control groups received the vehicle, corn oil, on a comparable regimen.

During gestation, the females were observed for mortality, body weight changes and clinical signs of toxicity. Cesarean sections were performed on day 20 of gestation. The number and location of viable fetuses, early and late resorptions, total implantations and corpora lutea were recorded. The fetuses were individually sexed, weighed and examined for external, soft tissue and skeletal malformations and variations.
GLP compliance:
not specified
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
other: Liquid
Details on test material:
- Name of test material (as cited in study report): DBPP
- Physical state: colorless liquid
- Label information: CP-850

Test animals

Species:
rat
Strain:
other: CD
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Breeding Laboratories, Inc. Portage, Michigan.
- Age at study initiation: approx. 3 months at time of mating
- Weight at study initiation: no data
- Fasting period before study: no data
- Housing: individually (except during mating), in hanging wire-mesh cages
- Diet (e.g. ad libitum):Purina Laboratory Chow, ad libitum
- Water (e.g. ad libitum): tap water, ad libitum
- Acclimation period: minimum 4 weeks prior to mating

ENVIRONMENTAL CONDITIONS
- Temperature (°C): controlled (no data on actual temperature)
- Humidity (%): controlled (no data on actual humidityà
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): controlled (no data on actual photocycle)

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
corn oil
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:
Mixing appropriate amounts with corn oil at concentrations to permit the administration of applicable dosage levels.
Individual dosages were based on individual body weights recorded on days 6, 9 and 12 of gestation.

DIET PREPARATION
- Rate of preparation of diet (frequency): daily
- Storage temperature of food: no data

VEHICLE
- Concentration in vehicle: depending on individual body weight
- Amount of vehicle (if gavage): 10 mL/kg/d
- Lot/batch no. (if required): "Mazola"
Analytical verification of doses or concentrations:
not specified
Details on mating procedure:
One female and one male rat of the same strain were placed together for mating. The day of mating was determined by daily inspection for copulatory plug or by a vaginal smear for sperm. The day that evidence of mating was detected was designated day 0 of gestation and the female was returned to an individual cage.
Duration of treatment / exposure:
From day 6 through day 15 of gestation.
Frequency of treatment:
SIngle daily dose.
Duration of test:
Until day 20 of gestation.
No. of animals per sex per dose:
25 female rats per test group
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: based on pilot study
- Rationale for animal assignment (if not random): no data

Examinations

Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily
- Cage side observations: mortality and clinical signs of toxicity

BODY WEIGHT: Yes
- Time schedule for examinations: gestation days 0, 6, 9, 12, 16 and 20

POST-MORTEM EXAMINATIONS: No data
Ovaries and uterine content:
The uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: No
- 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 fetuses
- Soft tissue examinations: Yes: approx. 1/3 of the fetuses
- Skeletal examinations: Yes: apporx. 2/3 of the fetuses
- Head examinations: Yes: all fetuses
Statistics:
All statistical analyses compared the treatment groups with the control groups, with the level of significance at p<0.05.

Male to female fetal sex ratio and the number of litters with anomalies were compared using the Chi-square test criterion with Yates correction for 2 x 2 contingency tables and/or Fisher's exact probability test as described by Siegel to judge significance of differences.

The proportion of early resorptions, late resorptions and post-implantation losses were compared by the Mann-Whitney U-test as described by Siegel and Weil to judge significance of differences.

The mean number of corpora lutea, implantation sites and live fetuses were compared by analysis of variance (one-way classification), Bartlett's test for homogeneity of variances and the appropriate t-test (for equal or unequal variances) as described by Steel and Torrie using Dunnett's multiple comparison tables to judge significance of differences.

Fetal body weights were compared by analysis of variance (hierarchal classification) and t-test as described by Stell and Torrie using Dunnett's multiple comparison tables to judge significance of differences.

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:
Maternal toxic effects:no effects

Details on maternal toxic effects:
There were no biologically meaningful differences in appearance or behaviour attributable to treatment with the test substance between any of the treated groups and the control groups.
Hairloss and matting of the haircoat were observed in all of the control and treatment groups. One rat in the second control group delivered prior to its scheduled sacrifice date due to an inaccurate determination of copulation. One rat in the 300 mg/kg/d dosage group died on gestation day 11. A sligh amount of dried red matter round the nose, accentuated lobulation of the liver, slight lung congestion and blood in the thoracic cavity were noted at necropsy. The cause of death was not determined. Survival was 100% in all other groups.
Maternal body weight gains in the 3 and 30 mg/kg/d dosage groups were comparable to the control groups. A very slight reduction in maternal body weight gains over the gestation period was noted in the 300 mg/kg/d dosage group when compared to the control groups.

Effect levels (maternal animals)

Remarks on result:
not determinable due to absence of adverse toxic effects

Results (fetuses)

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

Details on embryotoxic / teratogenic effects:
CESARIAN SECTION OBSERVATIONS:
There were no statistically significant or biologically meaningful differences in the mean number of viable fetuses, late resorptions, implantations or corpora lutea between any of the treated groups and the control groups. A slight, though not statistically significant increase in early resorptions and post-implantation losses was noted in all of the treatment groups when compared to control groups. However, this increase did not occur in a dose-related pattern.
There were no biologically meaningful differences in mean fetal body weights or in the male to female fetal sex ratios between any of the treated groups and the control groups. A statistically significant increase in mean fetal body weight was noted in the
300 mg/kg/d dosage group when compared to control group I. This difference was not statistically significant to control group II, and therefore is not considered to be biologically meaningful. A statistically significant difference in the male to female fetal sex ratio was noted in the 3 mg/kg/d dosage group when compared to control group II. However, this is not considered to be a compound-related effect as the fetal sex ratios in the 30 and 300 mg/kg/d dosage groups were comparable to the control groups, and this difference was not statistically significant when compared to control group I.

FETAL MORPHOLOGICAL OBSERVATIONS:
There were no statistically significant or biologically meaningful differences in the number of litters with malformations between any of the treated gropus and the control groups. An increase in the number of litters and fetuses with malformations was noted in the 30 mg/kg/d dosage group when compared to the control groups. However, these malformations did not occur in a syndrome-type pattern and no malformations were observed in the 300 mg/kg/d dosage group. Variations were comparable for all groups.

Effect levels (fetuses)

Dose descriptor:
NOAEL
Effect level:
300 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: teratogenicity

Fetal abnormalities

Abnormalities:
not specified

Overall developmental toxicity

Developmental effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
The test substance did not produce a teratogenic effect when administered to rats orally at dosage levels of 300 mg/kg/d or less.
Executive summary:

Pregnant Charles River CD rats were used to evaluate the teratogenic potential of DBPP in this study. The compound was administered orally by gavage as a single daily dose from days 6 through 15 of gestation. The test substance was administered at dosage levels of 3, 30 and 300 mg/kg/d at a constant volume of 10 ml/kg/d. Two control groups received the vehicle, corn oil, on a comparable regimen.

During gestation, the females were observed for mortality, body weight changes and clinical signs of toxicity. Cesarean sections were performed on day 20 of gestation. The number and location of viable fetuses, early and late resorptions, total implantations and corpora lutea were recorded. The fetuses were individually sexed, weighed and examined for external, soft tissue and skeletal malformations and variations.

There were no biologically meaningful differences in appearance or behavior between any of the treated groups and the control groups. Mean maternal body weight gains in the 3 and 30 mg/kg/d dosage groups were comparable to the control groups. A very slight reduction in mean maternal body weight gains was noted in the 300 mg/kg/d dosage group when compared to the control groups.

There were no biologically meaningful differences in the mean number of viable fetuses, implantations, corpora lutea, mean fatal body weights or in the male or female fetal sex ratios between any of the treated groups and the control groups. A slight increase of post-implantation losses was noted in all of the treatment groups when compared to the control groups. However, this increase did not occur in a dose-related pattern.

There were no biologically meaningful differences in the number of litters with malformations and variations in the DBPP treated groups when compared to the control groups.

The test substance did not produce a teratogenic effect when administered to rats orally at dosage levels of 300 mg/kg/d or less.