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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:
17 July 1984 to 10 August 1984
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1984
Report Date:
1984

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Version / remarks:
12 May 1981
Deviations:
no
GLP compliance:
yes
Limit test:
yes

Test material

Reference
Name:
Unnamed
Type:
Constituent

Test animals

Species:
rat
Strain:
other: Sprague Dawley COBS CD rats
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Breeding laboratories, Inc., Portage, Michigan
- Age at study initiation: 13 wk
- Weight at study initiation: 225-297 g
- Housing: Individually housed in wire mesh cages suspended above cage board
- Diet: Purina certified rodent chow; ad libitum
- Water: Tap water; ad libitum
- Acclimation period: 14 d

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 0.16
- Humidity (%): 40
- Photoperiod (h dark / h light): 12 h / 12 h

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
corn oil
Details on exposure:
PREPARATION OF DOSING SOLUTIONS: A specified amount of the test material for each dose group was weighed (not adjusted for purity), and transferred to a volumetrie flask which was first coated with the Mazo1a4l' corn oil vehic1e, using aseries of vehicle rinses. Vehicle was then added in sufficient quantity to achieve the appropriate concentration for each group. The flasks were inverted and manually shaken several times prior to stirring. The mixtures were stirred continuously for 5 minutes until homogenous using a magnetic stir plate and bars. The mixtures were prepared fresh daily and stirred prior to dispensing. A magnetic stir plate and bars were also utilized during dose administration to ensure adequate mixture. A total volume of 100 ml per test group was prepared daily during the course of the study. The bulk chemical was stored at room temperature.

VEHICLE: CORN OIL
- Purity: 100 %
Analytical verification of doses or concentrations:
no
Details on mating procedure:
- Impregnation procedure: Cohoused
- If cohoused:
- M/F ratio per cage: 1:1
- Verification of same strain and source of both sexes: Yes
- Proof of pregnancy: Presence of vaginal plug referred to as Day 0 of pregnancy
Duration of treatment / exposure:
10 d, from Day 6 to 15 of gestation, inclusive
Frequency of treatment:
Once daily
Duration of test:
25 d
Doses / concentrations
Dose / conc.:
1 000 mg/kg bw/day (nominal)
No. of animals per sex per dose:
30 females/dose
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: Based on the results of a range-finding study, the test dosage (1000 mg/kg bw/d) was selected since it was anticipated to induce some degree of maternal toxicity but one which would not likely affect maternal survival.
- Rationale for animal assignment: On a given day, the first mated female and the appropriate gestation day 0 designation were entered on the form and the fe male was assigned to group 1, the second mated female was assigned to group 2, and the third to group 3, etc. This process was continued daily until 30 females had been placed into each group.

Examinations

Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Daily

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: From Day 0 through 20 of gestation

BODY WEIGHT: Yes
- Time schedule for examinations: Day 0, 6, 9, 12, 16 and 20
- Mean body weight changes were calculated for each corresponding interval of gestation additionally for Day 6-16, 16-20 and 0-20.

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation Day 20
Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes
Examinations included:
- 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: half per litter
- Skeletal examinations: Yes: half per litter
- Head examinations: Yes: all per litter
Statistics:
1. The fetal sex ratios were compared by the Chi-square test with Yates' correction factor.
2. The number of litters with malformations and developmental variations were compared by Fisher's Exact Test
3. The numbers of early and late resorptions, dead fetuses and postimplantation losses were compared by the Mann-Whitney U-test
4. Mean numbers of corpora lutea, total implantations, viable fetuses, mean fetal and maternal body weights, and maternal body weight gain at each interval were analyzed by a one-way ANOVA and Dunnett's test.
Indices:
- Fetal sex ratios, number of litters with malformations and developmental variations, numbers of early and late resorptions, dead fetuses and postimplantation losses
- Numbers of corpora lutea, total implantations and viable fetuses
Historical control data:
Yes

Results and discussion

Results: maternal animals

General toxicity (maternal animals)

Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
Clinical signs of toxicity, expressed by salivation prior to and following dosing, were observed in the test material groups onIy. Urogenital matting and hair loss from various body surfaces occurred at a higher incidence in the test material groups.
Dermal irritation (if dermal study):
not examined
Mortality:
mortality observed, non-treatment-related
Description (incidence):
Two rats died due to an intubation error.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
A slight decrease in mean body weight gain was observed in each treated group during the first three days of treatment, gestation days 6-9. A slight decrease in mean body weight gain was also observed during the last days of the treatment period, gestation days 12-16. Over the entire treatment period, gestation interval 6-16, mean body weight gains were significantly decreased in all test material 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):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
no effects observed
Description (incidence and severity):
There were no gross internal morphological changes among the dams at the terminal sacrifice which could be considered treatment induced.
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
not examined
Histopathological findings: neoplastic:
not examined
Other effects:
not examined

Maternal developmental toxicity

Number of abortions:
no effects observed
Pre- and post-implantation loss:
no effects observed
Description (incidence and severity):
There were no biologically meaningful or statistically significant differences concerning the mean numbers of viable fetuses, early or late resorptions, postimplantation loss, implantation sites or corpora lutea between the control and alI test material groups.
Total litter losses by resorption:
no effects observed
Early or late resorptions:
no effects observed
Description (incidence and severity):
There were no biologically meaningful or statistically significant differences concerning the mean numbers of viable fetuses, early or late resorptions, postimplantation loss, implantation sites or corpora lutea between the control and alI test material groups.
Dead fetuses:
no effects observed
Changes in pregnancy duration:
not examined
Changes in number of pregnant:
not examined
Other effects:
not examined
Details on maternal toxic effects:
Maternal toxic effects: yes

Effect levels (maternal animals)

Key result
Dose descriptor:
LOAEL
Effect level:
1 000 mg/kg bw/day (nominal)
Based on:
test mat.
Basis for effect level:
body weight and weight gain

Maternal abnormalities

Key result
Abnormalities:
no effects observed

Results (fetuses)

Fetal body weight changes:
no effects observed
Description (incidence and severity):
The mean fetal weights were not affected by treatment.
Reduction in number of live offspring:
no effects observed
Changes in sex ratio:
no effects observed
Description (incidence and severity):
The fetal sex ratios were not affected by treatment.
Changes in litter size and weights:
no effects observed
Changes in postnatal survival:
not examined
External malformations:
effects observed, non-treatment-related
Description (incidence and severity):
One malformed fetuses occurred. The malformation observed was of single incidence and dissimilar.
Skeletal malformations:
no effects observed
Visceral malformations:
effects observed, non-treatment-related
Description (incidence and severity):
One malformed fetuses occurred. The malformation observed was of single incidence and dissimilar.
Other effects:
not examined
Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects: no effects

Effect levels (fetuses)

Key result
Dose descriptor:
NOAEL
Effect level:
> 1 000 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Remarks on result:
not determinable due to absence of adverse toxic effects

Fetal abnormalities

Key result
Abnormalities:
no effects observed

Overall developmental toxicity

Key result
Developmental effects observed:
no

Applicant's summary and conclusion