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Diss Factsheets

Administrative data

Endpoint:
two-generation reproductive 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

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

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to guideline
Guideline:
OECD Guideline 416 (Two-Generation Reproduction Toxicity Study)
Deviations:
no
Qualifier:
according to guideline
Guideline:
EPA OPP 83-4 (Reproduction and Fertility Effects)
Deviations:
no
Qualifier:
according to guideline
Guideline:
other: MAFF Testing Guidelines for Toxicology Studies NohSan59, No. 4200
Deviations:
no
GLP compliance:
yes

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 ID: DPX-JE874-221 Technical
Lot #: DPX-JE874-221
Purity: 97.4%

Test animals

Species:
rat
Strain:
other: Crl:CD®BR
Details on species / strain selection:
The Crl:CD®BR rat has been selected on the bases of extensive experience with this strain and its suitability with respect to longevity, hardiness, sensitivity, and low incidence of spontaneous diseases.
Sex:
male/female

Administration / exposure

Route of administration:
oral: feed
Vehicle:
acetone
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Samples (approximately 10 grams each) were collected from each concentration of diet prepared with the test substance on test days -1 and 62 of the P1 generation and days 65 and 121 of the F1 generation.
The measured concentrations of the test substance in the recovery samples that were prepared with each diet analysis were 105.6 to 111.5% of nominal at the low concentrations and 87.2 to 109.9% of nominal at the high concentrations. These data indicate that the method performed satisfactorily over the entire concentration range.
Measured concentrations of the test substance in samples of test day -1, were 19.7 to 19.9 ppm at the 20 ppm level (C.V. = 0.51% for top, middle, and bottom); from 194 to 214 ppm at the 200 ppm level (C.V. = 5.1%); and from 768 to 842 ppm at the 800 ppm level (C.V. = 5.4%). These data indicate that the test substance was distributed homogeneously in the diet. Test substance was not detected in control diet.
Concentrations of the test substance were from 92.4 to 101.1% of nominal for all storage conditions. These data indicated that test substance was stable in diets that were stored at room temperature for 7 or 14 days or refrigerated for 14 days.
Diet samples were prepared on test day 62, P1, test day 65, F1, and test day 121, F1. Measured concentrations of the test substance in these samples were from 97.0 to 107.0% of nominal, 97.5 to 109.9% of nominal, and 102.6 to 110.0% of nominal, respectively. The test substance was not detected in control diets for any of the submittals.
Duration of treatment / exposure:
For 2 generations (approximately 9 weeks of age (P1) to scheduled necropsy (F1))
Frequency of treatment:
Daily
Doses / concentrationsopen allclose all
Dose / conc.:
20 ppm
Dose / conc.:
200 ppm
Dose / conc.:
800 ppm
No. of animals per sex per dose:
30
Control animals:
yes, plain diet

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
Statistically significant increase in the incidence of diarrhea in P1 males in the rats fed 800 ppm. Statistically significant increase in the incidence of alopecia for P1 females during gestation in the rats fed 800 ppm.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Statistically significant reductions in mean body weight, and overall mean body weight gain for P1 males in the rats fed 800 ppm. Statistically significant reduction in mean body weight for P1 females during gestation and on lactation days 0, 7, and 14 in the rats fed 800 ppm.
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
Statistically significant reductions in overall mean food consumption for P1 males, for P1 males during premating and gestation in the rats fed 800 ppm.
Food efficiency:
effects observed, treatment-related
Description (incidence and severity):
Statistically significant reductions in overall mean food efficiency for P1 males during premating in the rats fed 800 ppm.
Clinical biochemistry findings:
effects observed, treatment-related
Description (incidence and severity):
Evidence for altered lipid metabolism; statistically significant decrease in mean triglyceride concentration for P1 males and females, and statistically significant increase in mean cholesterol concentration for P1 females in the rats fed 800 ppm.
Statistically significant increase in hepatic enzyme activities and serum bilirubin concentration indicating hepatocellular injury and cholestasis for P1 males in the rats fed 800 ppm.
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Other effects:
effects observed, treatment-related
Description (incidence and severity):
Statistically significant increase in hepatic peroxisomal ß-oxidation rate for P1 males and females in the rats fed 800 ppm.

Reproductive function / performance (P0)

Reproductive performance:
no effects observed
Description (incidence and severity):
There were no biologically or statistically significant dose-related differences in mating, fertility, or gestation indices, implantation efficiency, or gestation length in the P1 generation.

Effect levels (P0)

Key result
Dose descriptor:
NOAEL
Effect level:
200 ppm
Based on:
test mat.
Sex:
male/female
Basis for effect level:
clinical signs
body weight and weight gain
food consumption and compound intake
food efficiency
clinical biochemistry

Results: F1 generation

General toxicity (F1)

Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
Statistically significant increase in the incidence of alopecia for F1 females during the premating and gestation in the rats fed 800 ppm.
Mortality / viability:
mortality observed, non-treatment-related
Description (incidence and severity):
For F1 litters of 800 ppm females, 0-4 day viability was statistically significantly reduced, however, that reduction was considered not to be adverse since the value (98.8%) fell well within the range of control data.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Statistically significantly reduced mean pup weight throughout the 21-day lactation period for F1 litters in the rats fed 800 ppm.
Statistically significant reductions in mean body weight, and overall mean body weight gain for F1 males in the rats fed 800 ppm.
Statistically significant reduction in mean body weight for F1 females on lactation days 0, 7, and 14 in the rats fed 800 ppm.
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
Statistically significant reductions in overall mean food, consumption for F1 males during premating and gestation in the rats fed 800 ppm.
Clinical biochemistry findings:
effects observed, treatment-related
Description (incidence and severity):
Evidence for altered lipid metabolism; statistically significant decrease in mean triglyceride concentration for F1 males and females, and statistically significant increase in mean cholesterol concentration for F1 males and females in the rats fed 800 ppm.
Statistically significant increase in hepatic enzyme activities and serum bilirubin concentration indicating hepatocellular injury and cholestasis for F1 males in the rats fed 800 ppm.
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
Statistically significant increase in mean relative liver weight for F1 females in the rats fed 800 ppm. Statistically significant decreases in mean absolute liver weight for F1 males in the rats fed 800 ppm.
Other effects:
effects observed, treatment-related
Description (incidence and severity):
Statistically significant increase in hepatic peroxisomal ß-oxidation rate for F1 males and females in the rats fed 800 ppm.

Details on results (F1)

There were no biologically or statistically significant dose-related differences in mating, fertility, or gestation indices, implantation efficiency, or gestation length in the F1 generation.

Effect levels (F1)

Key result
Dose descriptor:
NOAEL
Generation:
F1
Effect level:
200 ppm
Based on:
test mat.
Sex:
male/female
Basis for effect level:
body weight and weight gain

Results: F2 generation

General toxicity (F2)

Clinical signs:
no effects observed
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Statistically significantly reduced mean pup weight from postpartum day 4 through the end of lactation period for F2 litters in the rats fed 800 ppm.

Effect levels (F2)

Key result
Dose descriptor:
NOAEL
Generation:
F2
Effect level:
200 ppm
Based on:
test mat.
Sex:
male/female
Basis for effect level:
body weight and weight gain

Overall reproductive toxicity

Key result
Reproductive effects observed:
no

Applicant's summary and conclusion

Conclusions:
Rat NOAEL (Parental and offspring): 200 ppm
Executive summary:

A two-generation reproduction study was conducted with the test substance involving the production of one set of litters in each generation according to the guidelines OECD 416 and EPA 83-4. Throughout this study, rats (30/sex/concentration) were fed diets containing concentrations of 0, 20, 200, or 800 ppm. Following at least 70 days of diet administration, the animals were bred within their respective treatment groups, and allowed to deliver and rear their offspring until weaning (postpartum day 21). At weaning, 30 F1 rats/sex/group were randomly selected to produce the next generation. At least 105 days after weaning, the F1 rats were bred within their respective treatment groups to produce F2 litters. Barring F1 weanlings selected for propagation of the next generation, twenty F1 and F2 weanlings/ sex/concentration were designated for gross postmortem examination. The remaining unselected weanlings were sacrificed without pathological examination.


Prior to mating, clinical chemistry evaluations were performed on selected adult animals (10/sex/concentration) in both generations. After litter production, all parental rats were given a gross pathological examination. Testes (weighed), epididymides, prostate, seminal vesicles, coagulating gland, and pituitary were collected from each male. Ovaries, uterus, cervix, vagina, and pituitary were collected from each female. Livers of all adult animals were weighed and peroxisomal ß-oxidation assays were performed on liver samples of selected adult animals (5/sex/concentration) in both generations that had undergone clinical chemistry evaluations. The loss of liver samples resulted in ß-oxidation-evaluation of only 4 rats/group in the 200 ppm P1 male and F1 male and female groups. Tissues from rats in the control and 800 ppm groups of both generations were examined microscopically. In addition, gross lesions and target organs from adult rats in all dose groups were microscopically examined.


At the 800 ppm level, adverse effects considered to be related to the treatment include:



  • Statistically significant reductions in mean body weight, and overall mean body weight gain for P1 and F1 males.

  • Statistically significant reductions in overall mean food, consumption for P1 and F1 males, and overall mean food efficiency for P1 males during premating.

  • Statistically significant increase in the incidence of diarrhea in P1 males.

  • Statistically significant reductions in mean body weight, overall mean body weight gain, and overall mean food consumption for P1 and F1 females, and overall mean food efficiency for P1 females during the premating period.

  • Statistically significant reductions in mean body weight and overall mean food consumption for P1 and F1 females during gestation.

  • Statistically significant reduction in mean body weight for P1 and F1 females on lactation days 0, 7, and 14.

  • Statistically significant increase in the incidence of alopecia for F1 females during the premating period and for P1 and F1 females during gestation.

  • Statistically significantly reduced mean pup weight throughout the 21-day lactation period for F1 litters and from postpartum day 4 through the end of lactation period for F2 litters.

  • Statistically significant increase in hepatic peroxisomal ß-oxidation rate for P1 and F1 males and females.

  • Statistically significant increase in mean relative liver weight for P1 and F1 females.

  • Evidence for altered lipid metabolism; statistically significant decrease in mean triglyceride concentration for P1 and F1 males and females, and statistically significant increase in mean cholesterol concentration for P1 and F1 females and F1 males.

  • Statistically significant decreases in mean absolute liver weight for P1 and F1 males, and mean relative liver weight for P1 males.

  • Statistically significant increase in hepatic enzyme activities and serum bilirubin concentration indicating hepatocellular injury and cholestasis for P1 and F1 males.


No adverse compound-related effects were observed at dose levels of 200 ppm and below. Therefore, the no-observed-effect level (NOEL) for adult rats and their offspring was 200 ppm.