Registration Dossier

Administrative data

Key value for chemical safety assessment

Toxic effect type:
dose-dependent

Effects on fertility

Description of key information

Reproductive toxicity study

Based on the data available from different studies, NOAEL for test material was considered to be in range of 30-51mg/kg /day for reproductive toxicity, when male and female rats were treated with test material orally. Thus, comparing this value with the criteria of CLP regulation test material is not likely to classify as reproductive toxicant.

Link to relevant study records
Reference
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
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
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:
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
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
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
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
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: oestrous cycle:
not specified
Reproductive function: sperm measures:
not specified
Reproductive performance:
not specified
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.
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
Critical effects observed:
not specified
System:
other: not specified
Organ:
not specified
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
Behaviour (functional findings):
not specified
Developmental immunotoxicity:
not specified
Dose descriptor:
other: not specified
Generation:
other: not specified
Based on:
not specified
Sex:
not specified
Remarks on result:
not measured/tested
Critical effects observed:
not specified
System:
other: not specified
Organ:
not specified
Reproductive effects observed:
not specified
Treatment related:
not specified
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.

 

Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
30 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Quality of whole database:
Data is Klimicsh 2 and from authoritative database
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

Reproductive toxicity study

Data available from different studies were reviewed to determine the reproductive toxicity of testchemical.The studies are as mentioned below:

Study 2

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.

 Study 3

A two-generation rat reproduction study was undertaken toevaluate the effects of test chemical . Four groups of 30 male and 30 female 6-week-old Fischer-344 rats (F0 generation) were exposed to diets adjusted weekly to provide dose levels of 0, 0.3, 3 and 30 mg /kg body weight per day for 100 days and were then allowed to mate to produce the F1 generation. The F1 weanlings were similarly dosed for 120 days prior tobreeding. The F1 adults were mated twice to produce F2a and F2b litters. At weaning of F1, F2a and F2b litters, 10 pups of eachsex at each dose level were sacrificed and selected organs were examined histologically. No signs of toxicity in any animals were found during the study. A significant decrease in food consumption and body weight of adult F1 males dosed with 30 mg/kg per day was found.No adverse effects in any of the treated groups over two generationswere noted with respect to gestation length, number of live pups delivered, neonatal survival, litter weight and sex ratio. Decreased pregnancy rates (fertility index) were observed in mid-dose (60%) and high-dose (63%) F1 females following the first mating (F2a litter), in comparison with 83% in the control rats. Test animals continued to be treated with propachlor and were remated to produce a second (F2b) litter. Pregnancy rates for the F2b litter were 83%for controls and 83, 83 and 80% for low-, mid- and high-dose groups, respectively. No treatment-related gross necropsy findings were noted. Slightincreases in absolute and/or relative liver weights were noted in high-dose F0 adults, mid- and high-dose F1 adults and high-dose F2a weanlings. Hypertrophy of the centrolobular hepatocytes was noted during microscopic examination of livers from the high-dose F0 and F1 adult females. There was no evidence of compound-related microscopic changes in the testes and ovaries of test animals for either generation.

 The no observed adverse effect level (NOAEL) relating to reproductive effects for the given test materialin Fischer-344 rats male/female was estimated to be  30 mg/kg/bw for the two generation.

Based on the data available from different studies, NOAEL for test material was considered to be in range of 30-51mg/kg /day for reproductive toxicity, when male and female rats were treated with test material orally. Thus, comparing this value with the criteria of CLP regulation test material is not likely to classify as reproductive toxicant.

Effects on developmental toxicity

Effect on developmental toxicity: via oral route
Endpoint conclusion:
no study available
Effect on developmental toxicity: via inhalation route
Endpoint conclusion:
no study available
Effect on developmental toxicity: via dermal route
Endpoint conclusion:
no study available

Justification for classification or non-classification

Thus, comparing this value with the criteria of CLP regulation test material is not likely to classify as reproductive toxicant.