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Diss Factsheets

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:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Referenceopen allclose all

Reference Type:
study report
Title:
Unnamed
Year:
1999
Report date:
1999
Reference Type:
study report
Title:
Unnamed
Year:
1994
Report date:
1994

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to guideline
Guideline:
other: MAFF Testing Guidelines for Toxicology Studies NohSan 59, No. 4200
Deviations:
no
Qualifier:
according to guideline
Guideline:
EPA OPP 83-3 (Prenatal Developmental Toxicity Study)
Deviations:
no
Qualifier:
according to guideline
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Deviations:
no
GLP compliance:
yes
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
5-methyl-5-(4-phenoxyphenyl)-3-(phenylamino)-1,3-oxazolidine-2,4-dione
EC Number:
603-520-1
Cas Number:
131807-57-3
Molecular formula:
C22H18N2O4
IUPAC Name:
5-methyl-5-(4-phenoxyphenyl)-3-(phenylamino)-1,3-oxazolidine-2,4-dione
Test material form:
solid
Specific details on test material used for the study:
Substance name: DPX-JE874
Lot #: DPX-JE874-221
Purity: 97.4%

Test animals

Species:
rat
Strain:
other: Crl:CD®BR

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
other: water containing 0.5% Tween 80
Analytical verification of doses or concentrations:
yes
Duration of treatment / exposure:
on days 7-16 of gestation
Frequency of treatment:
Once daily
Duration of test:
10 days
Doses / concentrationsopen allclose all
Dose / conc.:
125 mg/kg bw/day
Dose / conc.:
250 mg/kg bw/day
Dose / conc.:
500 mg/kg bw/day
Dose / conc.:
1 000 mg/kg bw/day
No. of animals per sex per dose:
25
Control animals:
yes, concurrent vehicle

Results and discussion

Results: maternal animals

General toxicity (maternal animals)

Clinical signs:
effects observed, non-treatment-related
Description (incidence and severity):
No compound-related effects on the incidence or type of clinical observations were seen at any dose level.
Mortality:
mortality observed, non-treatment-related
Description (incidence):
Two rats died prior to scheduled sacrifice but neither death was related to administration of the compound. One rat in the control group sacrificed in extremis on Day 15G after clinical observations suggestive of gavage trauma were recorded. Postmortem observations confirmed that the animal had been misdosed. One rat in the 125 mg/kg/day group was found dead was Day 5G. The urinary bladder obstructed with a calculus, causing hydronephrosis. Since this animal died before dosing started, another animal was assigned to the 125 mg/kg/day group.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Maternal body weight gains were significantly reduced at 500 and 1000 mg/kg/day over 7-9G. No other effects on maternal weights, weight gains, or adjusted weights were seen.
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
Maternal food consumption was significantly reduced at 500 and 1000 mg/kg/day over 7-9G. For the 1000 mg/kg/day group, a rebound in food consumption was observed as the mean food consumed over days 17-22G was significantly increased. No other effects on maternal food consumption were seen.
Gross pathological findings:
no effects observed
Description (incidence and severity):
No compound-related effects were detected during the gross postmortem examinations.

Maternal developmental toxicity

Dead fetuses:
effects observed, non-treatment-related
Description (incidence and severity):
No compound-related effects on fetal mortality were observed. The incidence of early, late, or total resorptions was comparable across dose groups. At the high dose level, there was on litter that consisted of two dead fetuses. However, at necropsy, the maternal uterus was observed to be twisted and distended with red fluid. This finding is not believed to be compound related.
Other effects:
no effects observed
Description (incidence and severity):
No compound-related effects on any reproductive parameter (pregnancy rate, incidence of dams with total resorptions, mean corpora lutea, mean number of implantations, mean number of live and dead fetuses per litter, and mean sex ratio) were detected.

Effect levels (maternal animals)

Key result
Dose descriptor:
NOAEL
Effect level:
250 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
body weight and weight gain
food consumption and compound intake

Results (fetuses)

Fetal body weight changes:
no effects observed
Description (incidence and severity):
Mean fetal weight was unaffected by exposure to the test substance
Other effects:
no effects observed
Description (incidence and severity):
No compound-related effect on the incidence of any fetal malformation was detected.
No compound-related effect on the incidence of any fetal variation was detected.

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:
other: highest dose tested

Overall developmental toxicity

Key result
Developmental effects observed:
no

Applicant's summary and conclusion

Conclusions:
Rat NOAEL: 250 mg/kg/day (maternal toxicity); 1000 mg/kg/day (developmental toxicity, highest dose tested)
Executive summary:

This study was conduted following OECD guideling 414 and US EPA 83-3. The test substance was administered by gavage to groups of 25 Crl:CD®BR female rats on days 7-16 of gestation at dose levels of 0, 125, 250, 500, or 1000 mg/kg/day. Maternal toxicity was evident at 500 and 1000 mg/kg/day as significant dose-related decreases in maternal body weight gain and food consumption. No evidence of maternal toxicity was detected at 250 or 125 mg/kg/day. Therefore, under the conditions of this study, the maternal NOAEL was 250 mg/kg/day. Developmental toxicity was not detected at any dose level. The NOAEL for developmental toxicity was 1000 mg/kg/day. The test substance is not considered to be uniquely toxic to the conceptus.