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Toxicological information

Toxicity to reproduction

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Administrative data

Endpoint:
reproductive toxicity, other
Remarks:
reproductive organ toxicity
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
4 (not assignable)
Rationale for reliability incl. deficiencies:
secondary literature
Justification for type of information:
Data from NTRL report

Data source

Reference
Reference Type:
other: secondary source
Title:
Basic Toxicity of test material
Author:
NTRL report
Year:
1981
Bibliographic source:
NTRL report ,1981

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
other: As mentioned below
Principles of method if other than guideline:
Reproductive toxicity study of test material was performed on rats.
GLP compliance:
not specified
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
solid
Details on test material:
Name of test material (as cited in study report): 1-Phenyl-3-pyrazolidone
Molecular formula: C9H10NO
Molecular weight :162.191 g/mol
Smiles: c1ccc(cc1)N2CCC(=O)N2
InChl : 1S/C9H10N2O/c12-9-6-7-11(10-9)8-4-2-1-3-5-8/h1-5H,6-7H2,(H,10,12)
Substance Type: Organic
Physical State: Solid

Test animals

Species:
rat
Strain:
other: CRL: COBS 'CD '(SD)BR
Sex:
male/female
Details on test animals and environmental conditions:
Details on test animals and env. conditions
TEST ANIMALS
- Source: Charles River Breeding Laboratory, Wilmington, MA.
- Age at study initiation: 6 weeks
- Weight at study initiation: No data available
- Fasting period before study:No data available

- Housing: Animals were kept five per cage in stainless steel wire-mesh cages fitted with automatic watering nipples. Males and females were housed on separate racks. Cages containing rats of different 'dose levels were distributed randomly over the racks
- Use of restrainers for preventing ingestion (if dermal): yes/no
- Diet (e.g. ad libitum): Feed was Purina Laboratory Rodent Chow 5001, ground meal, and was available ad lib.
- Water (e.g. ad libitum): Water, ad libitum
- Acclimation period:

ENVIRONMENTAL CONDITIONS
- Temperature (°C):21.66-23.33°C
- Humidity (%):35-49%
- Air changes (per hr):No data available

- Photoperiod (hrs dark / hrs light): 12 hour light period (6 AM-6 PM).

IN-LIFE DATES: From: To:

Administration / exposure

Route of administration:
oral: feed
Vehicle:
corn oil
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:
The test material soluble in corn oil and the mixture was combined with laboratory rodent chow. The
Corn oil was added to all diets at a concentration of 1.0%.
DIET PREPARATION
- Rate of preparation of diet (frequency):No data available
- Mixing appropriate amounts with (Type of food)
- Storage temperature of food: No data available
VEHICLE
- Justification for use and choice of vehicle (if other than water):corn oil
- Concentration in vehicle:0, 0.02%, 0.08%, 0.32 %( 9, 46, or 214 mg/kg/day, 10, 51 or 239 mg/kg/day
- Amount of vehicle (if gavage): No data available
- Lot/batch no. (if required): No data available
- Purity: No data available
Details on mating procedure:
No data available
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
90 days
Frequency of treatment:
Daily
Doses / concentrations
Remarks:
0, 0.02%, 0.08%,0.32 %( 9, 46, or 214 mg/kg/day for male ,10,51 or 239 mg/kg/day for female )
No. of animals per sex per dose:
Total:240
For male
0 mg/kg bw/day:30
9mg/kg bw/day:30
46mg/kg bw/day:30
214mg/kg bw/day:30
For female
0 mg/kg bw/day: 30
10mg/kg bw/day: 30
51mg/kg bw/day: 30
239mg/kg bw/day: 30
Control animals:
yes
Details on study design:
The dose levels were selected on the basis of a 12 day feeding study in which rats were fed diets of 1.0, 0.1 or 0.0% of test material
Positive control:
No data available

Examinations

Parental animals: Observations and examinations:
Parental animals observation and examinations
CAGE SIDE OBSERVATIONS: yes

DETAILED CLINICAL OBSERVATIONS: Yes

Time schedule: daily
BODY WEIGHT: Yes
Time schedule for examinations: Body weights were determined on days 0, 4, 7, and weekly thereafter
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):YesFeedconsumption was determined on days 4, 7, and twice weekly thereafter.
Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes
Compound intake calculated as time-weighted averages from the consumption and body weight gain data: Yes / No / No data: No data available


WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No data
Time schedule for examinations
Oestrous cyclicity (parental animals):
No data available
Sperm parameters (parental animals):
No data available
Litter observations:
No data available
Postmortem examinations (parental animals):
Postmortem examinations (Parent Animal)
SACRIFICE : on day 90
GROSS NECROPSY: yes
HISTOPATHOLOGY / ORGAN WEIGHTS: yes
Postmortem examinations (offspring):
No data available
Statistics:
All numerical data were evaluated using the following computer generatedstatistical tests: one-way analysis of variance (ANOVA). Bartlett's test,and Duncan's multiple range test where appropriate. A significance level of p<0.05 was chosen to indicate a statistically significant difference
Reproductive indices:
No data available
Offspring viability indices:
No data available

Results and discussion

Results: P0 (first parental animals)

General toxicity (P0)

Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
Red and blue discoloration of the urine under the cages of all male and female rats fed the 0.32% diets. The abnormality was seen as distinct patches of red or blue urine stained paper under the cages.
Dermal irritation (if dermal study):
not specified
Mortality:
no mortality observed
Description (incidence):
There were no premature deaths during the study.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
All groups of animals gained weight although the 0.08% and 0.32% diets clearly retarded weight gain for both males and females. The 0.02% diet had no effect on body weight gain
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
The 0.08% and 0.32% diets reduced (p <0.05) feed consumption for both male and female rats, although not for every time period. Feed consumption was reduced the most at the introduction of the testdiets as reflected in the data for day 4. Reduction of feed consumption wasalso greater for males than for females. Diets of 0.02% dose group generally did not alter feed consumption with fewexceptions. These exceptions (p<0.05) included decreased feed consumptionmeasured on day 73 for males and increased feed consumption for females ondays 35, 39 (90-day group), 59, 63, and 87.
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not specified
Haematological findings:
not specified
Clinical biochemistry findings:
not specified
Urinalysis findings:
not specified
Behaviour (functional findings):
not specified
Immunological findings:
not specified
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
The growth of all of the weighed organs except the ovaries was affected by exposure to the 0.08 and 0.32% test diets.The only target organ effects which are apparent involve enlargement of the spleen (0.08% and 0.32% diets) and atrophy of the testes (0.32% diets). The only statistically significant effects in rats given diets of 0.02% were organ to body weight ratios for the liver (90 day), brain (42 day), and adrenal gland (42 day) for females. None of the differences in rats given the 0.02% diets were of sufficient magnitude or consistency to be considered toxicologically significant
Gross pathological findings:
effects observed, treatment-related
Description (incidence and severity):
Red blood cell toxicity wascharacterized as a macrocytic, very slightly hyperchromatic anemia with Heinzand Howell-Jolly bodies and secondary lesions in the spleen, liver, and kidneydue to increased hemoglobin catabolism and increased hematopoiesis. Theseverity of red blood cell damage was dose related and was detectable at thelowest dose 9-10 mg/kg/day for 90 days (0.02% diet).
Neuropathological findings:
not specified
Histopathological findings: non-neoplastic:
no effects observed
Description (incidence and severity):
No histopathology lesions in the spleen, liver, kidneys. Testes, epididymides and adipose tissue.
Histopathological findings: neoplastic:
not specified
Other effects:
not specified

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:
not specified
Reproductive function: sperm measures:
not specified
Reproductive performance:
not specified

Details on results (P0)

The growth of the testes was depressed .Males given the 0.32% diets for 90 days had lower absolute, testes/body weight ratio, and testes/brain weight ratio. Males given the 0.32% diets for 42 days had lower absolute and testes/brain weight ratio but comparable testes/body weight ratio. Degeneration of epididymal spermatozoa indicates a higher incidence of spermatogenic effects in the 0.32% dose group (8 of 10 rats after 42 days and 13 of 20 rats after 90 days). The mid dose group (1 of 10 ratsafter 42 days) and the control group (1 of 20 rats after 90 days) had single rats with testicular atrophy and degenerative epididymal spermatozoa. The 0.02% dose group had no animals with spermatogenic lesions.
Ovarian growth was not affected by exposure to any of the test diets.

Effect levels (P0)

open allclose all
Dose descriptor:
NOAEL
Effect level:
46 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male
Basis for effect level:
clinical signs
mortality
body weight and weight gain
food consumption and compound intake
organ weights and organ / body weight ratios
gross pathology
histopathology: non-neoplastic
Remarks on result:
other: No toxic effects were observed
Dose descriptor:
NOAEL
Effect level:
51 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
female
Basis for effect level:
clinical signs
mortality
body weight and weight gain
food consumption and compound intake
organ weights and organ / body weight ratios
gross pathology
histopathology: non-neoplastic
Remarks on result:
other: No toxic effects were observed

Target system / organ toxicity (P0)

Critical effects observed:
not specified
System:
other: not specified
Organ:
not specified

Results: F1 generation

General toxicity (F1)

Clinical signs:
not specified
Dermal irritation (if dermal study):
not specified
Mortality / viability:
not specified
Body weight and weight changes:
not specified
Food consumption and compound intake (if feeding study):
not specified
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not specified
Haematological findings:
not specified
Clinical biochemistry findings:
not specified
Urinalysis findings:
not specified
Sexual maturation:
not specified
Organ weight findings including organ / body weight ratios:
not specified
Gross pathological findings:
not specified
Histopathological findings:
not specified
Other effects:
not specified

Developmental neurotoxicity (F1)

Behaviour (functional findings):
not specified

Developmental immunotoxicity (F1)

Developmental immunotoxicity:
not specified

Effect levels (F1)

Dose descriptor:
other: not specified
Generation:
other: not specified
Based on:
not specified
Sex:
not specified
Remarks on result:
not measured/tested

Target system / organ toxicity (F1)

Critical effects observed:
not specified
System:
other: not specified
Organ:
not specified

Overall reproductive toxicity

Reproductive effects observed:
not specified
Treatment related:
not specified

Applicant's summary and conclusion

Conclusions:
No Observed Adverse Effect Level (NOAEL) for maternal toxicity was considered to be 46 mg/kg/day for male and 51mg/kg/day were considered to be the NOAEL for female. Whenmale and female rats were treated with test material orally.
Executive summary:

The reproductive toxicity study of test material was performed on male and femaleCRL: COBS 'CD '(SD)BR rats. The test material soluble in corn oil and themixture was combined with laboratory rodent chow. The Corn oil was added to all diets at a concentration of 1.0%.Estimated consumption was0, 0.02%, 0.08%,0.32 %( 9, 46, or 214 mg/kg/day for male , 10,51 or 239 mg/kg/day for female ) for 90 day. The dose levels were selected on the basis of a 12 day feeding study in which rats were fed diets of 1.0, 0.1 or 0.0% test material .Thirty males and thirty females were exposed to each dietary concentration. Ten rats of each sex at each concentration were killed approximately half-way through' the study (42 days interim groups) and twenty rats of each sex were killed after approximately 90 days. Body weights were determined on days 0, 4, 7, and weekly thereafter. Feed consumption was determined on days 4, 7, and twice weekly thereafter. Necropsies were conducted according to pathology SOP TP 180. liver, kidneys, spleen, heart, adrenal glands, ovaries, testes, and brain. Paired organs were weighed together. Organ/body weight and organ/brain weight ratios were calculated. No mortality was observed.Red and blue discoloration of the urine under the cages of all male and female rats fed the 0.32% diets. The abnormality was seen as distinct patches of red or blue urine stained paper under the cages.All groups of animals gained weight although the 0.08% and 0.32% diets clearly retarded weight gain for both males and females. The 0.02% diet had no effect on body weight gain.The 0.08% and 0.32% diets reduced (p <0.05) feed consumption for both male and female rats, although not for every timeperiod. Feed consumption was reduced the most at the introduction of the testdiets as reflected in the data for day 4. Reduction of feed consumption wasalso greater for males than for females. Diets of 0.02%dose group generallydid not alter feed consumption with fewexceptions. These exceptions(p<0.05)included decreased feed consumptionmeasured on day 73 for males and increased feed consumption for females ondays 35, 39 (90-day group), 59, 63, and 87. Ovarian growth was not affected by exposure to any of the test diets.The only target organ effects which are apparent involve enlargement of the spleen (0.08% and 0.32% diets) and atrophy of the testes (0.32% diets). The only statistically significant effects in rats given diets of 0.02% were organ to body weight ratios for the liver (90 day), brain (42 day), and adrenal gland (42 day) for females. None of the differences in rats given the 0.02% diets were of sufficient magnitude or consistency to be considered toxicologically significant.Red blood cell toxicity wascharacterized as a macrocytic, very slightly hyperchromatic anemia with Heinzand Howell-Jolly bodies and secondary lesions in the spleen, liver, and kidneydue to increased hemoglobin catabolism and increased hematopoiesis. Theseverity of red blood cell damage was dose related and was detectable at thelowest dose 9-10 mg/kg/day for 90 days (0.02% diet).Nohistopathologic lesions in the spleen, liver, kidneys. Testes, epididymides and adipose tissue.

The growth of the testes was depressed .Males given the 0.32% diets for 90 days had lower absolute, testes/body weight ratio, and testes/brain weight ratio. Degeneration of epididymal spermatozoa indicates a higher incidence of spermatogenic effects in the 0.32% dose group (8 of 10 rats after 42 days and 13 of 20 rats after 90 days). The mid dose group (1 of 10 rats after 42 days) and the control group (1 of 20 rats after 90 days) had single rats with testicular atrophy and degenerative epididymal spermatozoa. The 0.02% dose group had no animals with spermatogenic lesions. HenceNo Observed Adverse Effect Level (NOAEL) for male was considered to be 46 mg/kg/day and for female NOAEL was considered to be the 51mg/kg/day on the bases of effects observed on reproductive organ .When male and femalerats were treated withtest materialorally.