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Toxicological information

Developmental toxicity / teratogenicity

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Administrative data

Endpoint:
developmental toxicity
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
weight of evidence
Study period:
1994-02-09 to 1994-09-30
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: The study was conducted under the regulations of GLP and the respective guideline. A read-across approach was used. For justification please refer to IUCLID Section 13.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1995
Report Date:
1995

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to
Guideline:
other: U.S. Environmental Protection Agency Pesticide Assessment Guidelines Subdivision F, 83-3
Deviations:
no
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Deviations:
yes
Remarks:
treatment from GD 6 to GD 15
Qualifier:
equivalent or similar to
Guideline:
EU Method B.31 (Prenatal Developmental Toxicity Study)
Deviations:
yes
Remarks:
treatment from GD 6 to GD 15
GLP compliance:
yes
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
solid: particulate/powder
Remarks:
migrated information: powder

Test animals

Species:
rabbit
Strain:
New Zealand White
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: HRP, Inc., Denver, Pennsylvania
- Age at study initiation: 11 month
- Weight at study initiation: 2.8 to 5 kg
- Fasting period before study: no
- Housing: individual
- Diet: Certified Rabbit Diet #5322, ad libitum
- Water: R.O. water incl. chlorine, ad libitum

ENVIRONMENTAL CONDITIONS
- Temperature (°F): 61-72
- Humidity (%): 40-60
- Air changes (per hr): 10
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
other: Aqueous 0.5% methylcellulose
Details on exposure:
PREPARATION OF DOSING SOLUTIONS: Suspensions of the test substance were prepared daily

VEHICLE
- Justification for use and choice of vehicle: common vehicle
- Concentration in vehicle: 3, 10 and 30 mg/mL
- Amount of vehicle: 10 mL/kg
- Lot/batch no.: 922148
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Method: HPLC-UV
Column: Supelcosil LC-18, 5µm 15 cm x 4.6 mm or equivalent
Mobile phase: ACN / 0.05 M trifluoroacetic acid in water (1/1, v/v)
Detector Wavelength: 280 nm
Injection Volume: 5 µL
Flow rate: 0.6 mL/min

Results of analyses of suspensions of the test substance demonstrated that homogeneous suspensions could be achieved for the range of dosages administered for this study. Concentrations prepared for the first and last day of dosage for this study averaged within +/- 10 % of the target value.
Details on mating procedure:
Timed-pregnant female rabbits were used.
Duration of treatment / exposure:
GD 6 to GD 19
Frequency of treatment:
Once a day
Duration of test:
24 days (up to GD 29)
Doses / concentrations
Remarks:
Doses / Concentrations:
30,100, 300 mg/kg bw/day
Basis:
actual ingested
No. of animals per sex per dose:
20 females/dose
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: Dosages were selected on the basis of two dosage-range studies
- Rationale for animal assignment: random
- Route of administration rationale: The oral route (via gavage) was selected for use because- 1) in comparison with the dietary route, the exact dosage can be accurately administered and 2) it is one possible route of human exposure.

Examinations

Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice each day
- Cage side observations: viability.

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: immediately before and one hour after dosage from GD6 to GD19 and once from GD20 to GD29

BODY WEIGHT: Yes
- Time schedule for examinations: daily during dosage period and on GD20, GD24 and GD29

FOOD CONSUMPTION: Yes
- Time schedule for examinations: daily during dosage and post-dosage period

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 29
- Organs examined: tissues with gross lesions
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
- Head examinations: Yes
Fetal examinations:
- External examinations: Yes, all per litter
- Soft tissue examinations: Yes, all per litter
- Skeletal examinations: Yes, all per litter
Statistics:
I. Parametric:
Bartlett's Test - Analysis of Variance - Dunnet's Test

II: Nonparametric:
A: Kruskal-Wallis Test (<75% ties) - Dunn's Test
B: Fisher's Exact Test

III. Test for Proportion Data:
Variance Test for Homogeneity of the Binomial Distribution
Indices:
no data
Historical control data:
Historical control data from 105 studies are available.

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:
Details on maternal toxic effects:
The increase mortality and abortion incidences in Group IV were considered effects of the 300 mg/kg bw/day dosage of the test substance because these does generally had abnormal feces, persistent weight loss and reduced feed consumption from the beginning of the dosage period. Necropsy of five of these Group IV does that died or aborted revealed a gastric trichobezoar, an observation probably associated with altered gastric motality and emtying as the result of the high viscosity of the test substance suspension; a gastric trichobezoar also occurred in one Group IV doe that survived to scheduled sacrifice.

All other deaths and abortions were considered unrelated to the test substance because they were sequelae of intubation accidents, there were no observations indicative of effects of the test substance and the incidences were not dosage-dependent.
One death in each Group I, II, III and IV appeared to be sequelae of an intubation accident. One Group II doe that died did not have adverse clinical or necropsy observations or remarkable weight losses or reductions in feed consumption.

The premature delivery of a litter by one Group I doe on GD 29 was a spontaneous event unrelated to the vehicle.

One doe died on GD 28 during abortion of a litter of four late resorptions. Necropsy of the doe revealed a gastric trichobezoar interrelated with clinical observations, no weight gain and essentially absent feed consumption on GD 8 to 27.
One doe was found dead in GD 13. The litter consisted of nine embryos and two early resorptions. Although no adverse clinical or necropsy observation occurred in this doe, other characteristic effects of the test substance, weight loss and reduced feed consumption an GD 6 to 12 were present.
One doe was found dead on GD 28. The litter sonsisted of 11 apparently normal fetuses. Necropsy of the doe revealed a gestric trichobezoar interrelated with abnormal feaces, persistent weight loss after GD 13 and reduced feed consumption on GD 6 to 27.

Abnormal feces were characteristic effects of the test substance in Groups III and IV. Increased numbers of Group III and IV dies had soft or liquid feces or dried feces; significant (p<0.01) numbers of Group IV does had absent feces or mocoid feces.
All other clinical observations were considered unrelated to the test substance.

Significant numbers (p< 0.01) of Group IV does had a gastric trichobezoar, an observation presumed to be related to effects on feed consumption and gastric motility associated with the thick consistency of the high dosage suspension. All does that had a gastric trichobezoar, regardless of dosage group, had an interval of severly reduced feed consumption.

Group III and IV lost weight for the entire dosage period (GD 6 to 20). Average maternal body weights were comparable among the four doseage groups throughout the study.

Group IV absolute and relative feed consumption values for the entire dosage period (GD 6 to 20) were reduced to 78.8% and 76.5% of the Group I values, respectively. The severity of these effects tended to increase during the dosage period.
After completion of the dosage period, absolute feed consumption values tended to increase in all groups given the test substance (rel. feed consumption values were unaffected), observations interrelated with the weight gains that also occurred in these groups after completion of the dosage period.

Effect levels (maternal animals)

open allclose all
Dose descriptor:
NOAEL
Effect level:
30 mg/kg bw/day (actual dose received)
Based on:
test mat.
Basis for effect level:
other: maternal toxicity
Dose descriptor:
NOAEL
Effect level:
100 mg/kg bw/day (actual dose received)
Based on:
test mat.
Basis for effect level:
other: developmental toxicity

Results (fetuses)

Details on embryotoxic / teratogenic effects:
Details on embryotoxic / teratogenic effects:
Pregnancy occurred in 19, 16, 19 and 17 of the 20 naturally bred does in Group I through Group IV, respectively. 17, 15, 17 and 9 pregnant does in Groups I to IV, erspectively, were Caesarean-sectioned on GD 29. Caesarean-sectioning and litter parameters were unaffected by the test substance. The litter average for corpora lutea, implantations, litter sizes, live and dead fetuses, early and late resoptions, fetal body weight, percent male fetuses and percent dead or resorbed conceptuses were comparable among the four dosage groups.
Totals of 130, 111, 105 and 63 live, GD29 Caesarean-delivered fetuses in Group I through Group IV, respectively, were examined for gross external, soft tissue and skeletal alterations and average numbers of fetal ossification.
Combination of malformations and variations resulted in the following incidences for fetal alterations. In Groups I through IV, respectively, 14 (82.4%), 13 (92.8%), 12 (70.6%) and 8 (88.9%) litters had fetuses with any alterations observed. In these same respective dosage groups, the total numbers of fetuses with identified alterations were 45 (34.6%), 29 (26.1%) , 29 (27.6%) and 15 (23.8%).

Group IV had significant increases (P≤0.01) in the incidence of supernumerary thoracic ribs. This reversible fetal alteration is common at maternally toxic dosages, was evident as significant increases (P≤0.01) in the average numbers of pairs of ribs per fetus and related significant changes (P≤0.05) in the average numbers of thoracic and lumbar vertebrae (increases and decreases, respectively).
No other gross external, soft tissue or skeletal malformations or variations in the fetuses were considered effects of the test substance because: 1) the observations are frequent inthis strain of rabbit; 2) the incidences were within the ranges observed historically and/or 3) in the incidences were not dosage-dependent.

Fetal abnormalities

Abnormalities:
not specified

Overall developmental toxicity

Developmental effects observed:
not specified

Applicant's summary and conclusion