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Registration Dossier
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EC number: 239-816-9 | CAS number: 15721-78-5
Toxicological information
Toxicity to reproduction
Currently viewing:
Administrative data
- Endpoint:
- screening for reproductive / developmental toxicity
- Type of information:
- read-across from supporting substance (structural analogue or surrogate)
- Adequacy of study:
- key study
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- comparable to guideline study with acceptable restrictions
- Justification for type of information:
- Weight of evidence based on the data of test chemicals.
Cross-referenceopen allclose all
- Reason / purpose for cross-reference:
- read-across source
Reference
- Endpoint:
- screening for reproductive / developmental 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 is from a HPVIS report.
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
- Principles of method if other than guideline:
- According to OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
- GLP compliance:
- not specified
- Limit test:
- no
- Justification for study design:
- No Data Available
- Species:
- rat
- Strain:
- Sprague-Dawley
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- No Data Available
- Route of administration:
- oral: gavage
- Type of inhalation exposure (if applicable):
- not specified
- Vehicle:
- corn oil
- Details on exposure:
- The test material was administered by gavage to three groups each of ten male and ten female Sprague-Dawley Crl:CD® (SD) IGS BR strain rats, for up to fifty-four consecutive days, at dose levels of 50, 250 and 600 mg/kg/day.A control group of ten males and ten females was dosed with vehicle alone (corn oil).
Exposure period: Males: 43 days; Females: up to 54 days - Details on mating procedure:
- - M/F ratio per cage:one male:one female
- Proof of pregnancy: [vaginal plug / sperm in vaginal smear] referred to as [day 0 / day 1] of pregnancy : The presence of sperm within the vaginal smear and/or vaginal plug in situ was taken as positive evidence of mating.
- After ... days of unsuccessful pairing replacement of first male by another male with proven fertility. : N/A
- Further matings after two unsuccessful attempts: [no / yes (explain)] : no - Analytical verification of doses or concentrations:
- not specified
- Details on analytical verification of doses or concentrations:
- No Data Available
- Duration of treatment / exposure:
- 14 days prior to mating, throughout mating and gestation and continuing through lactation day 3.
- Frequency of treatment:
- daily
- Details on study schedule:
- No Data Available
- Remarks:
- Doses / Concentrations:
0, 50, 250 and 600 mg/kg-bw/day
Basis:
no data - No. of animals per sex per dose:
- Number of Animals per Dose: 20
0 mg/kg/day (control) - 10 males and 10 females
50 mg/kg/day - 10 males and 10 females
250 mg/kg/day - 10 males and 10 females
600 mg/kg/day - 10 males and 10 females - Control animals:
- yes, concurrent vehicle
- Details on study design:
- No Data Available
- Positive control:
- No Data Available
- Parental animals: Observations and examinations:
- Pregnancy and parturition: The following was recorded for each female:
i) Date of mating
jj) Date and time of observed start of parturition
iii) Date and time of observed completion of parturition
iv) Duration of gestation - Oestrous cyclicity (parental animals):
- No Data Available
- Sperm parameters (parental animals):
- No Data Available
- Litter observations:
- Offspring Litter Size and Viability
- Postmortem examinations (parental animals):
- No Data Available
- Postmortem examinations (offspring):
- No Data Available
- Statistics:
- No Data Available
- Reproductive indices:
- No Data Available
- Offspring viability indices:
- No Data Available
- Clinical signs:
- not specified
- Dermal irritation (if dermal study):
- not specified
- Mortality:
- 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
- Behaviour (functional findings):
- not specified
- Immunological findings:
- not specified
- Organ weight findings including organ / body weight ratios:
- not specified
- Histopathological findings: non-neoplastic:
- not specified
- Histopathological findings: neoplastic:
- not specified
- Other effects:
- not specified
- Reproductive function: oestrous cycle:
- not specified
- Reproductive function: sperm measures:
- not specified
- Reproductive performance:
- no effects observed
- Dose descriptor:
- NOAEL
- Effect level:
- 250 mg/kg bw/day
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: No adverse effects on mating performance, fertility or gestation were observed.
- Remarks on result:
- other: Not Specified
- Dose descriptor:
- LOAEL
- Effect level:
- 600 mg/kg bw/day
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: Based on higher pre-implantation losses.
- Remarks on result:
- other: Not Specified
- Critical effects observed:
- not specified
- System:
- other: Not Specified
- Clinical signs:
- not specified
- Dermal irritation (if dermal study):
- not specified
- Mortality / viability:
- mortality observed, treatment-related
- Description (incidence and severity):
- Females treated with 600 mg/kg/day showed a higher percentage of pre-implantation losses in comparison to controls, resulting in the birth of less offspring per litter and lower total litter weights at this dose level.
- 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:
- LOAEL
- Generation:
- F1
- Effect level:
- 600 mg/kg bw/day
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- viability
- mortality
- other: not specified
- Remarks on result:
- other: not specified
- Dose descriptor:
- NOAEL
- Generation:
- F1
- Effect level:
- 250 mg/kg bw/day
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- viability
- mortality
- Remarks on result:
- other: Not Specified
- Critical effects observed:
- not specified
- System:
- other: Not Specified
- Reproductive effects observed:
- not specified
- Treatment related:
- not specified
- Conclusions:
- Based on all the observation and results, it was concluded that the NOAEL of the test chemical was 250 mg/kg bw after administration to the test animals.
- Executive summary:
In the combined repeated-dose/reproductive/developmental toxicity screening study, the test material was administered by gavage to three groups each of ten male and ten female Sprague-Dawley Crl:CD® (SD) IGS BR strain rats, for up to fifty-four consecutive days, at dose levels of 50, 250 and 600 mg/kg/day. The following was recorded for each female: Date of mating, Date and time of observed start of parturition, Date and time of observed completion of parturitionand Duration of gestation. After dosing, it was observed that, Females treated with 600 mg/kg/day showed a higher percentage of pre-implantation losses in comparison to controls, resulting in the birth of less offspring per litter and lower total litter weights at this dose level. Thus, no adverse effects (NOAEL) on mating performance, fertility or gestation were observed at 250 mg/kg-bw/day of concentartion. Also, the same NOAEL was considered for fetal parameters. Thus, based on all the observation and results, it was concluded that the NOAEL of the test chemical was 250 mg/kg bw after administration to the test animals.
No adverse effects on mating performance, fertility or gestation were detected.
Offspring Litter Size and Viability: Females treated with 600 mg/kg/day showed a higher percentage of pre-implantation losses in comparison to controls, resulting in the birth of less offspring per litter and lower total litter weights at this dose level.
- Reason / purpose for cross-reference:
- read-across source
Reference
- Endpoint:
- screening for reproductive / developmental 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 is from the abstract of a study report.
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
- Principles of method if other than guideline:
- According to OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
- GLP compliance:
- not specified
- Species:
- rat
- Strain:
- other: Sprague-Dawley Crl:CD· (SD) IGS DR Strain Rat
- Details on species / strain selection:
- No Data Available
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River Limited. (UM) , Margate, kent .
- Age at study initiation: Approximately 8 weeks
- Weight at study initiation: Parental males weighed 185-230g and parental females weighed 150-187g.
- Housing: Animals were housed in groups of five in polypropylene cages with stainless steel grid floors and tops, suspended over polypropylene trays lined with absorbent paper. Mated females were housed individually during gestation and lactation, in polypropylene cages with
solid floors and stainless steel lids, furnished with softwood flakes.
- Diet (e.g. ad libitum): Rodent PMI 5002 pelleted diet, ad libitum
- Water (e.g. ad libitum): drinking water was supplied from polycarbonate bottles attached to the cage, Ad libitum
- Acclimation period: At least 13 days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 2 1±2°C
- Humidity (%): 55 ±15%
- Air changes (per hr): At least fifteen air changes per hour
- Photoperiod (hrs dark / hrs light): 12-hr dark/12-hr light
Other details :
The animals were allocated to dose groups using a randomization procedure based on stratified bodyweights and the group mean body weights were then determined to ensure similarity between the dose groups. The animals were uniquely identified within the study, by an ear punching system. - Route of administration:
- oral: gavage
- Type of inhalation exposure (if applicable):
- not specified
- Vehicle:
- corn oil
- Details on exposure:
- 48 consecutive days
- Details on mating procedure:
- - M/F ratio per cage: 1:1
- Length of cohabitation: A maximum of 14 days
- Proof of pregnancy: [vaginal plug / sperm in vaginal smear] referred to as [day 0 / day 1] of pregnancy : The presence of sperm within the vaginal smear and/or vaginal plug in situ was taken as positive evidence of mating (Day 0 of gestation)
- Further matings after two unsuccessful attempts: [no / yes (explain)] : no
- After successful mating each pregnant female was caged (how): Mated females were housed individually during gestation and lactation. - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Gas Chromatography (GC) using an external standard technique.
- Duration of treatment / exposure:
- 48 consecutive days
- Frequency of treatment:
- Daily
- Details on study schedule:
- No Data Available
- Remarks:
- Doses / Concentrations:
0, 50, 250 and 600 mg/kg/day
Basis:
analytical conc. - No. of animals per sex per dose:
- Control: 10 males and 10 females
50 mg/kg/day: 10 males and 10 females
250 mg/kg/day: 10 males and 10 females
600 mg/kg/day: 10 males and 10 females - Control animals:
- yes, concurrent vehicle
- Details on study design:
- No Data Available
- Positive control:
- No Data Available
- Parental animals: Observations and examinations:
- DETAILED CLINICAL OBSERVATIONS: Yes
All animals were examined for overt signs of toxicity, ill-health and behavioral change immediately before and after dosing, and one and 5 hours after dosing during the working week.
BODY WEIGHT: Yes
Individual body weights were recorded on Day 1 (prior to the start of treatment) and then weekly for males until termination. Females were weighed weekly until mating was evident. Body weights were recorded on Days 0, 7. 14 and 20 post coitumand on Days 1 and 4 post-parium.
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
During the maturation period, weekly food consumption was recorded for each cage of adults. Food consumption was recorded for the periods covering Days 1-7, 7-14 and 14-21. For females with live litters, food consumption was recorded on Days 1 and 4 post-partum.
WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): Yes
Water intake was observed daily by visual inspection of water bottles for any overt change.
OTHER:
reproductive function: corpora lutea and inplantation sites were examined.
Reproductive Indites:
Mating Index, pregnancy index and fertility index were examined.
organ weight:
Adrenals, Brain, Epididymides, Heart, Kidneys,, Liver, Ovaries, Spleen, Testes and Thymus were weighted.
Haematological and blood chemical observations :
Hematological and blood chemical investigations were performed on 5 males and 5 females selected from each test and control group on Day 14 (day prior to pairing).Blood samples were obtained from the lateral tail vein. Animals were not fasted prior to sampling.
Pregnancy and Parturition:
Each pregnant female was observed in the morning, around noon and in the afternoon and around the period of expected parturition. At weekends and public holidays, observations were carried out at in the morning and around noon. For each female date of mating, date and time of observed start of parturition, date and time of observed completion of parturition and duration of gestation was recorded. - Oestrous cyclicity (parental animals):
- No Data Available
- Sperm parameters (parental animals):
- No Data Available
- Litter observations:
- Number of offspring born, Number and sex of offspring alive recorded daily and reported on Day 1 and 4 post partum, Clinical condition, Individual offspring and litter weights and surface righting reflex on Day 1 and 4 were observed
- Postmortem examinations (parental animals):
- GROSS NECROPSY:All adult animals , including those dying during the study, were subjected to a full external and internal examination, and any macroscopic abnormalities were recorded.
- Postmortem examinations (offspring):
- GROSS NECROPSY: All offspring were subjected to a full external and internal examination, and any macroscopic abnormalities were recorded.
- Statistics:
- Methods used included Dunnetts test or a pair wise Students t-test or Kruskal-Wallis non parametric one way analysis of variance and Mann Whitney “U” test/Wilcoxon signed rank test.
- Reproductive indices:
- No Data Available
- Offspring viability indices:
- No Data Available
- Clinical signs:
- effects observed, treatment-related
- Description (incidence and severity):
- In 600 mg/kg/day, Increased salivation, pink staining was evident 00 cage tray liners from the male, red coloured urine, red brown staining around the snout and physical injury to the tail tip were observed pilo-erection, tiptoe gait, hunched posture, and skin pallor by day 11 and decrease respiratory rat on Day 12 the dose group terminated on Day 13.
in 250 mg/kg/day,Increased salivation and Hunched posture 'and tiptoe gait were observed in male and female rats as comarped to control. - Dermal irritation (if dermal study):
- not specified
- Mortality:
- mortality observed, treatment-related
- Description (incidence):
- When treated with 600 mg/kg/day, one male killed on day 13, on efemale dead on day 15, two on day 16 and all animals are sacrificed on day 17 of study. In 150 mg/kg/day dose group, significant decease in survival were observed and this dose level was terminated on Day 31
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- slight reduction body weight gain were observed in 250 and 600 mg/kg/day treated rats as compared to control. in 50 mg/kg/day, no statistical significance effect were observed in treated rats as compared to control.
- Food consumption and compound intake (if feeding study):
- effects observed, treatment-related
- Description (incidence and severity):
- slight reduction body weight gain were observed in 250 and 600 mg/kg/day treated rats as compared to control. in 50 mg/kg/day, no statistical significance effect were observed in treated rats as compared to control.
- Food efficiency:
- not specified
- Water consumption and compound intake (if drinking water study):
- not specified
- Ophthalmological findings:
- not specified
- Haematological findings:
- effects observed, non-treatment-related
- Description (incidence and severity):
- A significantly lower platelet count was apparent for males receiving 250 mg/kg/day compared to controls. For females treated with 250 mg/kg/day, platelet count at pre-mating assessment was only marginally lower than controls.
Males receiving 50 or 250 mg/kg/day showed a significant reduction in white blood cell count at pre-mating assessment, compared with control. No similar effects were observed for females. - 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, non-treatment-related
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Description (incidence and severity):
- When treated with 600 mg/kg/day, Higher grades of severity of trabecular bone formation in female , Centrilobular hepatocyte enlargement of liver, Hypertrophy of the collecting duct epithelium of the renal papilla and extramadullary haemopiesis of spleen were observed male and female rats.
when treated with 250 mg/kg/day, Higher grades of severity of trabecular bone formation in female , Centrilobular hepatocyte enlargement of liver in male and female, Hypertrophy of the collecting duct epithelium of the renal papilla and extramadullary haemopiesis of spleen were observed female rats as compared to control. - Histopathological findings: neoplastic:
- not specified
- Other effects:
- no effects observed
- Reproductive function: oestrous cycle:
- not specified
- Reproductive function: sperm measures:
- not specified
- Reproductive performance:
- effects observed, treatment-related
- Description (incidence and severity):
- No effect were observed on mating performance or fertility and corpora lutea and implantation of treated rats as compared to control.
- Dose descriptor:
- NOAEL
- Effect level:
- 50 mg/kg bw/day
- Based on:
- test mat.
- Sex:
- male
- Basis for effect level:
- other: no effect on survival, body weight, clinical sign, food consumption, water consumption, hematolgy, clinical chemistry, organ weight, gross pathology and histopathology
- Remarks on result:
- other: Not Specified
- Dose descriptor:
- LOAEL
- Effect level:
- 50 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- female
- Basis for effect level:
- other: effect on hematology, clinical chemistry and histopatholgy
- Remarks on result:
- other: Not Specified
- Critical effects observed:
- not specified
- System:
- other: Not Specified
- Clinical signs:
- effects observed, treatment-related
- Description (incidence and severity):
- No effect were observed on growth of 50 mg/kg/day treated offspring as compared to control.
- Dermal irritation (if dermal study):
- not specified
- Mortality / viability:
- mortality observed, non-treatment-related
- Description (incidence and severity):
- The number of interim offspring deaths at 50 mg/kg/day was considerably higher than observed for controls.
- Body weight and weight changes:
- effects observed, non-treatment-related
- Description (incidence and severity):
- Offspring weights on Day 1 and subsequent weight gain at lower dose levels were similar to control and unaffected by treatment. For offspring at 250 mg/kg/day, bodyweight on Day 1 of age was slightly lower than control; differences failed to attain statistical significance and may reflect the generally shorter gestation length for litters at this dose level.
- 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:
- effects observed, non-treatment-related
- Description (incidence and severity):
- Males treated with 250 mg/kg/day showed elevated liver weights in comparison to controls, however, statistical significance was not achieved. Females treated with 250 mg/kg/day showed a statistically significant reduction in spleen weights.
- Gross pathological findings:
- effects observed, non-treatment-related
- Description (incidence and severity):
- Necropsy
Interim death and terminal kill offspring did not show any abnormalities considered to be related to treatment. Two males treated with 250 mg/kg/day displayed liver pallor at terminal kill. - Histopathological findings:
- effects observed, non-treatment-related
- Description (incidence and severity):
- Minimal centrilobular hepatocyte enlargement 'was observed in relation to treatment for animals of either sex treated with 125 mg/kg/day. Females treated with 25 mg/kg/day were similarly affected.
- Other effects:
- not specified
- Behaviour (functional findings):
- not specified
- Developmental immunotoxicity:
- not specified
- Dose descriptor:
- NOAEL
- Generation:
- F1
- Effect level:
- 50 mg/kg bw/day
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- viability
- mortality
- body weight and weight gain
- organ weights and organ / body weight ratios
- gross pathology
- histopathology: non-neoplastic
- Remarks on result:
- other: Not Specified
- Critical effects observed:
- not specified
- System:
- other: Not Specified
- Reproductive effects observed:
- not specified
- Treatment related:
- not specified
- Conclusions:
- NOAEL was considered to be 50 mg/kg/day for male and LOAEL for female F0 generation and NOAEL F1 ganaration when Sprague-Dawley Crl: CD (SD) IGS BR male and female rats treated with the test chemical.
- Executive summary:
In a combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test, Sprague-DawleyCrl: CD (SD) IGS BR male and female rats treated with the test chemical in the concentration of 0, 50, 250 and 500 mg/kg/day orally by gavage. one male killed on day 13, on efemale dead on day 15, two on day 16 and all animals are sacrificed on day 17 of study at 600 mg/kg/day dose group and significant decease in survival were observed and this dose level was terminated on Day 31 at 250 ma/kg/day dose group. Increased salivation, pink staining was evident 00 cage tray liners from the male, red coloured urine, red brown staining around the snout and physical injury to the tail tip were observed. pilo-erection, tiptoe gait, hunched posture, and skin pallor by day 11 and decrease respiratory rat on Day 12 the dose group terminated on Day 13 in 600 mg/kg/day and Increased salivation and Hunched posture 'and tiptoe gait were observed in male and female rats as compared to control in 250 mg/kg/day dose group. slight reduction body weight gain were observed in 250 and 600 mg/kg/day treated rats as compared to control. in addition, skin pallor, pillo-erection, and staining around the snout, and pallor of lings, spleen, stomach, liver, small intestine and dark enlarge liver, thymus, kidney, left testis and prostate of treated male and female rats at 600 mg/kg/day and pallor of the extremities and vaginal bleeding and all tissues was pale and dark contents evident in gastro intestinal and uterus with red fluid. Liver pallor was prevalent for animals of either sex treated at this dose level at 250 mg/kg/day dose group. Higher grades of severity of trabecular bone formation in female , Centrilobular hepatocyte enlargement of liver, Hypertrophy of the collecting duct epithelium of the renal papilla and extramadullary haemopiesis of spleen in 600 mg/kg/day dose group and Higher grades of severity of trabecular bone formation in female , Centrilobular hepatocyte enlargement of liver in male and female, Hypertrophy of the collecting duct epithelium of the renal papilla and extramadullary haemopiesis of spleen were observed female rats as compared to control at 250 mg/kg/day dose group. no effect were observed on mating performance or fertility and corpora lutea and implantation of 50 mg/kg/day treated rats as compared to control. no effect were observed on offspring Viability, clinical sign and body weight of offsprings as compared to control. therefore NOAEL was considered to be 50 mg/kg/day for male and NOAEL for female F0 generation and NOAEL F1 ganaration when Sprague-DawleyCrl: CD (SD) IGS BR male and female rats were treated with the test chemical orally by gavage.
Clinical toxicity:
mortality:
when treated with 600 mg/kg/day, one male killed on day 13, on efemale dead on day 15, two on day 16 and all animals are sacrificed on day 17 of study. In 150 ma/kg/day dose group, significant decease in survival were observed and this dose level was terminated on Day 31
Clinical signs:
in 600 mg/kg/day, Increased salivation, pink staining was evident 00 cage tray liners from the male, red coloured urine, red brown staining around the snout and physical injury to the tail tip were observed pilo-erection, tiptoe gait, hunched posture, and skin pallor by day 11 and decrease respiratory rat on Day 12 the dose group terminated on Day 13.
in 250 mg/kg/day,Increased salivation and Hunched posture 'and tiptoe gait were observed in male and female rats as comarped to control.
BODY WEIGHT AND FOOD CONSUMPTION (PARENTAL ANIMALS)
No adverse effect was detected for males throughout the treatment period or for females during maturation or gestation. However, a slight reduction in body weight gain was observed for females treated with 125 mg/kg/day during lactation.
TEST SUBSTANCE INTAKE (PARENTAL ANIMALS)
No adverse effect was detected for males. There were no adverse effects on dietary intake or food efficiency for females throughout the maturation or gestation phases of the study. However, during lactation reduced dietary intake was detected for females receiving 125 mg/kg/day compared with controls.
REPRODUCTIVE PERFORMANCE (PARENTAL ANIMALS)
There was no effect on mating or fertility, however, a shorter gestation length was observed in females treated with 25 and 125 mg/kg/day.
OTHER FINDINGS (PARENTAL ANIMALS) :
Haematology
A significantly lower platelet count was apparent for males receiving 250 mg/kg/day compared to controls. For females treated with 250 mg/kg/day, platelet count at pre-mating assessment was only marginally lower than controls.
Males receiving 50 or 250 mg/kg/day showed a significant reduction in white blood cell count at pre-mating assessment, compared with control. No similar effects were observed for females.
Blood Chemistry
Clear reductions in total protein, albumin. and albumin:globulin ratio, compared to control levels were apparent for both sexes at 250 mg/kg/day, with similar changes also being observed, to a lesser degree, for both sexes at 50 mg/kg/day. Alkaline phosphatase levels during pre-mating and terminal assessments were elevated, in comparison to control for both sexes at 250 rug/kg/day and for males at 5 mg/kg/day.
Gross Pathalogy:
In 600 mg/kg/day dose group, skin pallor, pillo-erection, and staining around the snout, and pallor of lings, spleen, stomach, liver, small intestine and dark enlarge liver, thymus, kidney, left testis and prostate of treated male and female rats.
in 250 mg/kg/day dose group, pallor of the extremities and vaginal bleeding and all tissues was pale and dark contents evident in gastro intestinal and uterus with red fluid. Liver pallor was prevalent for animals of either sex treated at this dose level.
no effect were observed in 50 mg/kg/day dose group as comapred to control.
Histopathology:
When treated with 600 mg/kg/day, Higher grades of severity of trabecular bone formation in female , Centrilobular hepatocyte enlargement of liver, Hypertrophy of the collecting duct epithelium of the renal papilla and extramadullary haemopiesis of spleen were observed male and female rats.
when treated with 250 mg/kg/day, Higher grades of severity of trabecular bone formation in female , Centrilobular hepatocyte enlargement of liver in male and female, Hypertrophy of the collecting duct epithelium of the renal papilla and extramadullary haemopiesis of spleen were observed female rats as compared to control.
mortality:
when treated with 600 mg/kg/day, one male killed on day 13, on efemale dead on day 15, two on day 16 and all animals are sacrificed on day 17 of study. In 150 ma/kg/day dose group, significant decease in survival were observed and this dose level was terminated on Day 31
Clinical signs:
in 600 mg/kg/day, Increased salivation, pink staining was evident 00 cage tray liners from the male, red coloured urine, red brown staining around the snout and physical injury to the tail tip were observed pilo-erection, tiptoe gait, hunched posture, and skin pallor by day 11 and decrease respiratory rat on Day 12 the dose group terminated on Day 13.
in 250 mg/kg/day,Increased salivation and Hunched posture 'and tiptoe gait were observed in male and female rats as comarped to control.
BODY WEIGHT AND FOOD CONSUMPTION (PARENTAL ANIMALS)
No adverse effect was detected for males throughout the treatment period or for females during maturation or gestation. However, a slight reduction in body weight gain was observed for females treated with 125 mg/kg/day during lactation.
TEST SUBSTANCE INTAKE (PARENTAL ANIMALS)
No adverse effect was detected for males. There were no adverse effects on dietary intake or food efficiency for females throughout the maturation or gestation phases of the study. However, during lactation reduced dietary intake was detected for females receiving 125 mg/kg/day compared with controls.
REPRODUCTIVE PERFORMANCE (PARENTAL ANIMALS)
There was no effect on mating or fertility, however, a shorter gestation length was observed in females treated with 25 and 125 mg/kg/day.
OTHER FINDINGS (PARENTAL ANIMALS) :
Haematology
A significantly lower platelet count was apparent for males receiving 250 mg/kg/day compared to controls. For females treated with 250 mg/kg/day, platelet count at pre-mating assessment was only marginally lower than controls.
Males receiving 50 or 250 mg/kg/day showed a significant reduction in white blood cell count at pre-mating assessment, compared with control. No similar effects were observed for females.
Blood Chemistry
Clear reductions in total protein, albumin. and albumin:globulin ratio, compared to control levels were apparent for both sexes at 250 mg/kg/day, with similar changes also being observed, to a lesser degree, for both sexes at 50 mg/kg/day. Alkaline phosphatase levels during pre-mating and terminal assessments were elevated, in comparison to control for both sexes at 250 rug/kg/day and for males at 5 mg/kg/day.
Gross Pathalogy:
In 600 mg/kg/day dose group, skin pallor, pillo-erection, and staining around the snout, and pallor of lings, spleen, stomach, liver, small intestine and dark enlarge liver, thymus, kidney, left testis and prostate of treated male and female rats.
in 250 mg/kg/day dose group, pallor of the extremities and vaginal bleeding and all tissues was pale and dark contents evident in gastro intestinal and uterus with red fluid. Liver pallor was prevalent for animals of either sex treated at this dose level.
no effect were observed in 50 mg/kg/day dose group as comapred to control.
Histopathology:
When treated with 600 mg/kg/day, Higher grades of severity of trabecular bone formation in female , Centrilobular hepatocyte enlargement of liver, Hypertrophy of the collecting duct epithelium of the renal papilla and extramadullary haemopiesis of spleen were observed male and female rats.
when treated with 250 mg/kg/day, Higher grades of severity of trabecular bone formation in female , Centrilobular hepatocyte enlargement of liver in male and female, Hypertrophy of the collecting duct epithelium of the renal papilla and extramadullary haemopiesis of spleen were observed female rats as compared to control.
BODY WEIGHT (OFFSPRING):
Offspring weights on Day 1 and subsequent weight gain at lower dose levels were similar to control and unaffected by treatment. For offspring at 125 mg/kg/day, bodyweight on Day 1 of age was slightly lower than control; differences failed to attain statistical significance and may reflect the generally shorter gestation length for litters at this dose level.
ORGAN WEIGHTS (OFFSPRING)
Males treated with 125 mg/kg/day showed elevated liver weights in comparison to controls, however, statistical significance was not achieved. Females treated with 125 mg/kg/day showed a statistically significant reduction in spleen weights.
GROSS PATHOLOGY (OFFSPRING)
Necropsy
Interim death and terminal kill offspring did not show any abnormalities considered to be related to treatment. Two males treated with 125 mg/kg/day displayed liver pallor at terminal kill.
HISTOPATHOLOGY (OFFSPRING)
Minimal centrilobular hepatocyte enlargement 'was observed in relation to treatment for animals of either sex treated with 125 mg/kg/day. Females treated with 25 mg/kg/day were similarly affected.
OTHER FINDINGS (OFFSPRING)
Mortality :The number of interim offspring deaths at 25 and 125 mg/kg/day was considerably higher than observed for controls.
Offspring weights on Day 1 and subsequent weight gain at lower dose levels were similar to control and unaffected by treatment. For offspring at 125 mg/kg/day, bodyweight on Day 1 of age was slightly lower than control; differences failed to attain statistical significance and may reflect the generally shorter gestation length for litters at this dose level.
ORGAN WEIGHTS (OFFSPRING)
Males treated with 125 mg/kg/day showed elevated liver weights in comparison to controls, however, statistical significance was not achieved. Females treated with 125 mg/kg/day showed a statistically significant reduction in spleen weights.
GROSS PATHOLOGY (OFFSPRING)
Necropsy
Interim death and terminal kill offspring did not show any abnormalities considered to be related to treatment. Two males treated with 125 mg/kg/day displayed liver pallor at terminal kill.
HISTOPATHOLOGY (OFFSPRING)
Minimal centrilobular hepatocyte enlargement 'was observed in relation to treatment for animals of either sex treated with 125 mg/kg/day. Females treated with 25 mg/kg/day were similarly affected.
OTHER FINDINGS (OFFSPRING)
Mortality :The number of interim offspring deaths at 25 and 125 mg/kg/day was considerably higher than observed for controls.
- Reason / purpose for cross-reference:
- read-across source
Reference
- Endpoint:
- two-generation reproductive toxicity
- Type of information:
- experimental study
- Adequacy of study:
- weight of evidence
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- guideline study with acceptable restrictions
- Justification for type of information:
- Data is from a publication.
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- OECD Guideline 416 (Two-Generation Reproduction Toxicity Study)
- Principles of method if other than guideline:
- Chronic toxicity, reproductive effects of the test chemical to Albino Rats were assessed in 2 generation of rats overall estimation period of 734 days.
- GLP compliance:
- not specified
- Limit test:
- no
- Species:
- rat
- Strain:
- other: Slonaker-Addis
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- - Age : 5 weeks old
-Diet (e.g. ad libitum) : The Addis diet,ad libitum
-Water (e.g. ad libitum): Ad libitum - Route of administration:
- oral: feed
- Vehicle:
- other: Basal diet
- Details on exposure:
- The test chemical was mixed into the basal diet of commercial laboratory chow at concentrations of 0.0 (vehicle), 67 mg/kg bw/d (0.1%),167 mg/kg bw/d (0.25%)or 333 mg/kg bw/d (0.50%) over a period of 734 days.
- Details on mating procedure:
- - M/F ratio per cage: 1:4
- Length of cohabitation: once a week for 3 weeks
- After successful mating each pregnant female was caged (how): Females were placed in individual cages. - Analytical verification of doses or concentrations:
- not specified
- Details on analytical verification of doses or concentrations:
- No Data Available
- Duration of treatment / exposure:
- 734 days
- Frequency of treatment:
- Daily
- Details on study schedule:
- No Data Available
- Remarks:
- Doses / Concentrations:
0.0 (vehicle), 67 mg/kg bw/d (0.1%),167 mg/kg bw/d (0.25%) and 333 mg/kg bw/d (0.50%)
Basis: - No. of animals per sex per dose:
- PART I
Control: 3 males and 12 females
67 mg/kg bw /d (0.1%) : 3 males and 12 females
167 mg/kg bw/d (0.25%) : 3 males and 12 females
333 mg/kg bw/d (0.50%) :3 males and 12 females
PART II
Control: 3 males and 12 females
67 mg/kg bw/d (0.1%) : 3 males and 12 females
167 mg/kg bw /d (0.25%) : 3 males and 12 females
333 mg/kg bw/d (0.50%) :3 males and 12 females
PART III
Control: 3 males and 12 females
67 mg/kg bw/d (0.1%) : 3 males and 12 females
167 mg/kg bw/d (0.25%) : 3 males and 12 females
333 mg/kg bw/d (0.50%) :3 males and 12 females - Control animals:
- yes, concurrent vehicle
- Details on study design:
- No Data Available
- Positive control:
- No Data Available
- Parental animals: Observations and examinations:
- Following parameters were examined:
-Body weight and food consumption
-Live pups per litter
-Pup body weights
-Pup survival
-Histopathology
-Urine examination
-Gross Pathology : The 2-year ingestion of the test chemical caused lesions only in the urinary tract, namely, cystic dilatation of renal tubules with interstitial inflammation. Glomeruli were never altered. Lower tubules were sometimes filled with a proteinaceous fluid, and at other times with a blood-derived pigment. These accumulations were in some cases found in the renal pelvis or bladder, accompanied by mild epithelial hyperplasia or squamous metaplasia. The break-point for the occurrence of cystic change lies in the region of the 0.1% dietary concentration; and that for chronic nephritis, between 0.1 and 0.5%. The incidence of tumors was due to the senility of the rats at autopsy, not to treatment. - Oestrous cyclicity (parental animals):
- No Data Available
- Sperm parameters (parental animals):
- No Data Available
- Litter observations:
- -Live pups per litter
-Pup body weights
-Pup survival
-Histopathology - Postmortem examinations (parental animals):
- - Gross Pathology : The 2-year ingestion of the test chemical caused lesions only in the urinary tract, namely, cystic dilatation of renal tubules with interstitial inflammation. Glomeruli were never altered. Lower tubules were sometimes filled with a proteinaceous fluid, and at other times with a blood-derived pigment. These accumulations were in some cases found in the renal pelvis or bladder, accompanied by mild epithelial hyperplasia or squamous metaplasia. The break-point for the occurrence of cystic change lies in the region of the 0.1% dietary concentration; and that for chronic nephritis, between 0.1 and 0.5%. The incidence of tumors was due to the senility of the rats at autopsy, not to treatment.
- Postmortem examinations (offspring):
- -Live pups per litter
-Pup body weights
-Pup survival
-Histopathology - Statistics:
- No Data Available
- Reproductive indices:
- No Data Available
- Offspring viability indices:
- No Data Available
- Clinical signs:
- not specified
- Dermal irritation (if dermal study):
- not specified
- Mortality:
- mortality observed, non-treatment-related
- Description (incidence):
- Respiratory infections were responsible for the few mortalities. The animals that were visibly ill between that time and the 2-year period were sacrificed and were autopsied.
- Body weight and weight changes:
- no effects observed
- Description (incidence and severity):
- Mean weights of males were found to be deviated at 0.1% dose group while, no changes in weights were observed in females from all the dose groups.
- Food consumption and compound intake (if feeding study):
- no effects observed
- Description (incidence and severity):
- No effects were seen on food consumption
- 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:
- no effects observed
- Description (incidence and severity):
- At 333 mg/kg bw/d (0.50%) :Prolonged test chemical ingestion did not increase protein excretion by rats fed as much as 0.50%
- Behaviour (functional findings):
- not specified
- Immunological findings:
- not specified
- Organ weight findings including organ / body weight ratios:
- not specified
- Histopathological findings: non-neoplastic:
- not specified
- Histopathological findings: neoplastic:
- not specified
- Other effects:
- not specified
- Reproductive function: oestrous cycle:
- not specified
- Reproductive function: sperm measures:
- not specified
- Reproductive performance:
- no effects observed
- Dose descriptor:
- NOAEL
- Effect level:
- 67 mg/kg bw/day
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- mortality
- body weight and weight gain
- urinalysis
- gross pathology
- reproductive performance
- Remarks on result:
- other: not specified
- Critical effects observed:
- not specified
- System:
- other: Not Specified
- Clinical signs:
- not specified
- Dermal irritation (if dermal study):
- not specified
- Mortality / viability:
- no mortality observed
- Description (incidence and severity):
- No test chemical related mortality was observed.
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- Decreased weights of the pups was observed probably due to inadequate food intakes by their gestating and lactating mothers fed with test chemical through diet.
- 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:
- effects observed, treatment-related
- Description (incidence and severity):
- Litter observations :-
-There was no effect on the number of litters born nor on mortality of the offspring.
-The average size of the litters decreased as the concentration of dietary intake of the test chemical increased,with the anomalous exception of the numbers of pups born and weaned in the second generation whose mothers were fed the 67 mg/kg bw/d (0.1%) diet.
-At 333 mg/kg bw/d (0.50%) :
Reduced litter size and the weight of the youngs at 21 days was observed.
Survival:-
At 67 mg/kg bw/d (0.1%) and 333 mg/kg bw/d (0.50%) :There was good survival in all groups, with no significant reduction in the number of survivors at any level of the test chemical. - Behaviour (functional findings):
- not specified
- Developmental immunotoxicity:
- not specified
- Dose descriptor:
- NOAEL
- Generation:
- F1
- Effect level:
- 67 mg/kg bw/day
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- viability
- mortality
- body weight and weight gain
- food consumption and compound intake
- Remarks on result:
- other: Not Specified
- Critical effects observed:
- not specified
- System:
- other: Not Specified
- Dose descriptor:
- LOAEL
- Generation:
- F2
- Effect level:
- 67 mg/kg bw/day
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: see 'Remark'
- Remarks on result:
- other: not specified
- Dose descriptor:
- LOAEL
- Generation:
- F2
- Effect level:
- 333 mg/kg bw/day
- Based on:
- test mat.
- Sex:
- female
- Basis for effect level:
- other: see 'Remark'
- Remarks on result:
- other: not specified
- Reproductive effects observed:
- not specified
- Treatment related:
- not specified
- Conclusions:
- Based on all the observations and results, it was concluded that the NOAEL for the test chemical is found to be 67 mg/kg bw (0.1%).
- Executive summary:
Two-year feeding of 0.5 and 1.0% dietary levels of the test chemical to male and female albino rats caused growth arrests which were partly due to lowered food intakes. The females’ growth was slightly arrested at 0.1%, an effect apparently due to the test chemical itself. Any such effect at 0.1% on the males could have been obscured by the greater deviations of their weights from their mean weights than the deviations of the females’ weights. Moderate degrees of anemia resulted from prolonged ingestion of 0.5 and 1.0% concentrations of the test chemical, but prompt recoveries of hemoglobin followed feeding of the control diet. Leukocyte numbers and percentages remained within normal ranges. The test chemical did not increase proteinuria or cause glycosuria. It is highly probable that apparent decreases in litter sizes and numbers of pups weaned were largely due to inadequate food intakes by their gestating and lactating mothers fed with the test chemical. The significantly decreased weights of the pups, at weaning, in but one of the nine experimental dietary categories was probably due to the same cause. The 2-year ingestion of the test chemical caused lesions only in the urinary tract, namely, cystic dilatation of renal tubules with interstitial inflammation. Glomeruli were never altered. Lower tubules were sometimes filled with a proteinaceous fluid, and at other times with a blood-derived pigment. These accumulations were in some cases found in the renal pelvis or bladder, accompanied by mild epithelial hyperplasia or squamous metaplasia. The break-point for the occurrence of cystic change lies in the region of the 0.1% dietary concentration; and that for chronic nephritis, between 0.1 and 0.5%. Thus, based on all the observations and results, it was concluded that the NOAEL for the test chemical is found to be 67 mg/kg bw (0.1%).
FOOD CONSUMPTION (PARENTAL ANIMALS):-No effects were seen on food consumption
GROSS PATHOLOGY (PARENTAL ANIMALS) :-At 67 mg/kg bw/d (0.1%) and 333 mg/kg bw/d (0.50%) :A lesion characteristically seen in the kidneys of untreated old rats becomes greatly exaggerated in degree.
At dietary levels of 0.01% and below : the renal lesions present were indistinguishable from those of the control group.
URINE EXAMINATION:At 333 mg/kg bw/d (0.50%) :Prolonged test chemical ingestion did not increase protein excretion by rats fed as much as 0.50%
EFFECT ON GROWTH: At 333 mg/kg bw/d (0.50%) - caused growth arrests which were partly due to lowered food intakes.
At 67 mg/kg bw/d (0.1%) :Caused no growth inhibition in either sex.
At 333 mg/kg bw/d (0.50%) : Distinct growth inhibition observed.
GROSS PATHOLOGY (PARENTAL ANIMALS) :-At 67 mg/kg bw/d (0.1%) and 333 mg/kg bw/d (0.50%) :A lesion characteristically seen in the kidneys of untreated old rats becomes greatly exaggerated in degree.
At dietary levels of 0.01% and below : the renal lesions present were indistinguishable from those of the control group.
URINE EXAMINATION:At 333 mg/kg bw/d (0.50%) :Prolonged test chemical ingestion did not increase protein excretion by rats fed as much as 0.50%
EFFECT ON GROWTH: At 333 mg/kg bw/d (0.50%) - caused growth arrests which were partly due to lowered food intakes.
At 67 mg/kg bw/d (0.1%) :Caused no growth inhibition in either sex.
At 333 mg/kg bw/d (0.50%) : Distinct growth inhibition observed.
Body weight :- At weaning: Decreased weights of the pups was observed probably due to inadequate food intakes by their gestating and lactating mothers with dietary intake of the test chemical.
Litter observations :-
-There was no effect on the number of litters born nor on mortality of the offspring.
-The average size of the litters decreased as the concentration of dietary intake of the test chemical increased,with the anomalous exception of the numbers of pups born and weaned in the second generation whose mothers were fed the 67 mg/kg bw/d (0.1%) diet.
-At 333 mg/kg bw/d (0.50%) :
Reduced litter size and the weight of the youngs at 21 days was observed.
Survival:-
At 67 mg/kg bw/d (0.1%) and 333 mg/kg bw/d (0.50%) :There was good survival in all groups, with no significant reduction in the number of survivors at any level of the test chemical.
Litter observations :-
-There was no effect on the number of litters born nor on mortality of the offspring.
-The average size of the litters decreased as the concentration of dietary intake of the test chemical increased,with the anomalous exception of the numbers of pups born and weaned in the second generation whose mothers were fed the 67 mg/kg bw/d (0.1%) diet.
-At 333 mg/kg bw/d (0.50%) :
Reduced litter size and the weight of the youngs at 21 days was observed.
Survival:-
At 67 mg/kg bw/d (0.1%) and 333 mg/kg bw/d (0.50%) :There was good survival in all groups, with no significant reduction in the number of survivors at any level of the test chemical.
- Reason / purpose for cross-reference:
- read-across source
Reference
- Endpoint:
- screening for reproductive / developmental toxicity
- Type of information:
- experimental study
- Adequacy of study:
- weight of evidence
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- guideline study with acceptable restrictions
- Justification for type of information:
- Data is from a MHLW report.
- Qualifier:
- according to guideline
- Guideline:
- other: OECD 422 (Combined Repeated and Reproduction/Developmental Toxicity Screening Test)
- Principles of method if other than guideline:
- According to OECD 422 (Combined Repeated and Reproduction/Developmental Toxicity Screening Test).
- GLP compliance:
- not specified
- Limit test:
- no
- Species:
- rat
- Strain:
- Crj: CD(SD)
- Details on species / strain selection:
- No Data Available
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- Details on test animal
TEST ANIMALS
- Source: No data available
- Age at study initiation: (P) x wks; (F1) x wks: P- 9 weeks old
- Weight at study initiation: (P) Males: x-x g; Females: x-x g; (F1) Males: x-x g; Females: x-x g: No data available
- Fasting period before study: No data available
- Housing: No data available
- Diet (e.g. ad libitum): No data available
- Water (e.g. ad libitum): No data available
- Acclimation period: No data available
ENVIRONMENTAL CONDITIONS
- Temperature (°C): No data available
- Humidity (%):No data available
- Air changes (per hr): No data available
- Photoperiod (hrs dark / hrs light): No data available - Route of administration:
- oral: gavage
- Type of inhalation exposure (if applicable):
- not specified
- Vehicle:
- olive oil
- Details on exposure:
- No data available
- Details on mating procedure:
- No data available
- Analytical verification of doses or concentrations:
- not specified
- Details on analytical verification of doses or concentrations:
- No data available
- Duration of treatment / exposure:
- Male: 42 days
Female: 41 - 55 days (from 14 days before mating to day 4 of lactation) - Frequency of treatment:
- daily
- Details on study schedule:
- No Data Available
- Remarks:
- Doses / Concentrations:
0, 25, 75 or 250 mg/kg/day
Basis:
no data - No. of animals per sex per dose:
- No data available
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- No Data Available
- Positive control:
- No Data Available
- Parental animals: Observations and examinations:
- Clinical sign, Body weight, Food consumption, Hematology, clinical chemistry and FOB were examined
- Oestrous cyclicity (parental animals):
- Changes in the estrous cyclicity were observed.
- Sperm parameters (parental animals):
- No data available
- Litter observations:
- Pup Viability, Sex Ratio, Birth Index, Body weight of pups were observed.
- Postmortem examinations (parental animals):
- Organ weight and histopatholgy were examined
- Postmortem examinations (offspring):
- No data available
- Statistics:
- No data available
- Reproductive indices:
- Implantation Index, Resorption Index, Gestational Index.
- Offspring viability indices:
- Pup viability index.
- Clinical signs:
- no effects observed
- Description (incidence and severity):
- No effect was observed on clinical sign of treated male and female rats as compared to control.
- Dermal irritation (if dermal study):
- not specified
- Mortality:
- not specified
- Body weight and weight changes:
- no effects observed
- Description (incidence and severity):
- Body weight: No effect was observed on body weight of treated male and female rats as compared to control.
- Food consumption and compound intake (if feeding study):
- no effects observed
- Description (incidence and severity):
- Food consumption: No effect was observed on food consumption of treated male and female rats as compared to control.
- Food efficiency:
- not specified
- Water consumption and compound intake (if drinking water study):
- not specified
- Ophthalmological findings:
- not specified
- Haematological findings:
- effects observed, treatment-related
- Description (incidence and severity):
- In male rats, when treated with 75 mg/kg/day, prolongation in the PT and APTT were observed as compared to control. When treated with 250 mg/kg/day, prolongation in APTT were observed as compared to control.
In female rats, decrease in the RBC and MCHC and increase in the RET was observed at recovery(250 mg/kg/day) as compared to control - Clinical biochemistry findings:
- no effects observed
- Description (incidence and severity):
- No effect was observed on clinical chemistry of treated male and female rats as compared to control.
- Urinalysis findings:
- not specified
- Behaviour (functional findings):
- no effects observed
- Description (incidence and severity):
- No effect was observed on functional observation battery (FOB) of treated male and female rats as compared to control.
- Immunological findings:
- not specified
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Histopathological findings: non-neoplastic:
- no effects observed
- Description (incidence and severity):
- No Histopathological changes were observed in treated male and female rats as compared to control.
- Histopathological findings: neoplastic:
- not specified
- Other effects:
- not specified
- Reproductive function: oestrous cycle:
- no effects observed
- Description (incidence and severity):
- No changes were observed in the estrous cycles of female rats.
- Reproductive function: sperm measures:
- not specified
- Reproductive performance:
- no effects observed
- Dose descriptor:
- NOAEL
- Effect level:
- 250 mg/kg bw/day
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: No adverse effect on clinical sign, Body weight, Food consumption, clinical chemistry, FOB, Organ weight, Histopathology and reproductive performance
- Remarks on result:
- other: Not Specified
- Critical effects observed:
- not specified
- System:
- other: Not Specified
- Clinical signs:
- not specified
- Dermal irritation (if dermal study):
- not specified
- Mortality / viability:
- no mortality observed
- Body weight and weight changes:
- no effects observed
- Description (incidence and severity):
- The test chemical had no effects on the body weight of the pups.
- 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:
- no effects observed
- Organ weight findings including organ / body weight ratios:
- not specified
- Gross pathological findings:
- no effects observed
- Histopathological findings:
- no effects observed
- Other effects:
- not specified
- Behaviour (functional findings):
- not specified
- Developmental immunotoxicity:
- not specified
- Dose descriptor:
- NOAEL
- Generation:
- F1
- Effect level:
- 250 mg/kg bw/day
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- viability
- sexual maturation
- mortality
- gross pathology
- histopathology: non-neoplastic
- Remarks on result:
- other: Not Specified
- Critical effects observed:
- not specified
- System:
- other: Not Specified
- Reproductive effects observed:
- not specified
- Treatment related:
- not specified
- Conclusions:
- Based on all the observations and results, it was concluded that the NOAEL was considered to be 250 mg/kg/day when Crl:CD (SD) male and female rat were treated with the test chemical.
- Executive summary:
In a combined repeated dose and reproduction/developmental screening test, male and female Crl:CD (SD) rats were treated orally with the test chemical in concentration of 0, 25, 75 or 250 mg/kg/day with recovery dose group of 0 and 250 mg/kg/day.No effect were observe on clinical sign, body weight and food consumption of treated rats as compared to control. Similarly, no effects were observed on blood chemistry, organ weight and histopathology of treated rats as compared to control. In addition, changes were observed as tendency to prolongation in the PT and prolongation in the APTT in male rats at 75 and 250 mg/kg/day dose group and decrease in the RBC and MCHC. An increase in the RET at 250 mg/kg/day dose group during recovery in female rats as compared to control. No reproductive effect were observed in treated male or female rats and on offspring’s as compared to control. Therefore,NOAEL for the parental generation and the F1 generation were considered to be 250 mg/kg/day when male and female Crl:CD (SD) rats were treated orally by gavage with the test chemical.
Haematology:
In male rats, when treated with 75 mg/kg/day, prolongation in the PT and APTT were observed as compared to control.
When treated with 250 mg/kg/day, prolongation in APTT were observed as compared to control.
In female rats, decrease in the RBC and MCHC and increase in the RET was observed at recovery (250 mg/kg/day) as compared to control
Clinical chemistry
No effect was observed on clinical chemistry of treated male and female rats as compared to control.
Neurobehaviour
No effect was observed on functional observation battery (FOB) of treated male and female rats as compared to control.
In male rats, when treated with 75 mg/kg/day, prolongation in the PT and APTT were observed as compared to control.
When treated with 250 mg/kg/day, prolongation in APTT were observed as compared to control.
In female rats, decrease in the RBC and MCHC and increase in the RET was observed at recovery (250 mg/kg/day) as compared to control
Clinical chemistry
No effect was observed on clinical chemistry of treated male and female rats as compared to control.
Neurobehaviour
No effect was observed on functional observation battery (FOB) of treated male and female rats as compared to control.
No effect of the test chemical was observed on live pup index, viability index, and external anomalies.
- Reason / purpose for cross-reference:
- read-across source
Reference
- Endpoint:
- extended one-generation reproductive toxicity - basic test design (Cohorts 1A, and 1B without extension)
- Data waiving:
- other justification
- Justification for data waiving:
- other:
Data source
Referenceopen allclose all
- Reference Type:
- review article or handbook
- Title:
- Unnamed
- Year:
- 2 006
- Reference Type:
- review article or handbook
- Title:
- Unnamed
- Year:
- 2 009
- Reference Type:
- other: Secondary source
- Title:
- Unnamed
- Year:
- 2 006
- Reference Type:
- publication
- Title:
- Chronic Toxicity of Diphenylamine to Albino Rats
- Author:
- John 0. Thomas, William E. Ribelin,Robert H. Wilson, Douglas C. Kepplera,And Floyd Deeds.
- Year:
- 1 967
- Bibliographic source:
- TOXICOLOGY AND APPLIED PHARMACOLOGY 10, 362-374 (1967)
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 007
Materials and methods
Test guideline
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
- Principles of method if other than guideline:
- According to OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
- GLP compliance:
- yes
- Limit test:
- no
- Justification for study design:
- No Data Available
Test material
- Reference substance name:
- Bis(4-(1,1,3,3-tetramethylbutyl)phenyl)amine
- EC Number:
- 239-816-9
- EC Name:
- Bis(4-(1,1,3,3-tetramethylbutyl)phenyl)amine
- Cas Number:
- 15721-78-5
- Molecular formula:
- C28-H43-N
- IUPAC Name:
- 4-(2,4,4-trimethylpentan-2-yl)-N-[4-(2,4,4-trimethylpentan-2-yl)phenyl]aniline
- Details on test material:
- Details on test material
- Name of test material (as cited in study report): 4,4'-Bis(1,1,3,3-tetramethylbutyl)diphenylamine
- Molecular formula (if other than submission substance): C28-H43-N
- Molecular weight (if other than submission substance): 393.655 g/mol
- Substance type: Organic
- Physical state: No Data Available
- Impurities (identity and concentrations): No Data Available
Constituent 1
Test animals
- Species:
- other: Study 2: rat Study 3: rat Study 4: rat; Study 5: rat
- Strain:
- other: Study 2: Sprague-Dawley Study 3: Sprague-Dawley Crl:CD· (SD) IGS DR Strain Rat Study 4: Slonaker-Addis; Study 5: Crj: CD(SD)
- Details on species / strain selection:
- No Data Available
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- Study 2: No Data Available
Study 3: TEST ANIMALS
- Source: Charles River Limited. (UM) , Margate, kent .
- Age at study initiation: Approximately 8 weeks
- Weight at study initiation: Parental males weighed 185-230g and parental females weighed 150-187g.
- Housing: Animals were housed in groups of five in polypropylene cages with stainless steel grid floors and tops, suspended over polypropylene trays lined with absorbent paper. Mated females were housed individually during gestation and lactation, in polypropylene cages with
solid floors and stainless steel lids, furnished with softwood flakes.
- Diet (e.g. ad libitum): Rodent PMI 5002 pelleted diet, ad libitum
- Water (e.g. ad libitum): drinking water was supplied from polycarbonate bottles attached to the cage, Ad libitum
- Acclimation period: At least 13 days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 2 1±2°C
- Humidity (%): 55 ±15%
- Air changes (per hr): At least fifteen air changes per hour
- Photoperiod (hrs dark / hrs light): 12-hr dark/12-hr light
Other details :
The animals were allocated to dose groups using a randomization procedure based on stratified bodyweights and the group mean body weights were then determined to ensure similarity between the dose groups. The animals were uniquely identified within the study, by an ear punching system.
Study 4: - Age : 5 weeks old
-Diet (e.g. ad libitum) : The Addis diet,ad libitum
-Water (e.g. ad libitum): Ad libitum
Study 5: Details on test animal
TEST ANIMALS
- Source: No data available
- Age at study initiation: (P) x wks; (F1) x wks: P- 9 weeks old
- Weight at study initiation: (P) Males: x-x g; Females: x-x g; (F1) Males: x-x g; Females: x-x g: No data available
- Fasting period before study: No data available
- Housing: No data available
- Diet (e.g. ad libitum): No data available
- Water (e.g. ad libitum): No data available
- Acclimation period: No data available
ENVIRONMENTAL CONDITIONS
- Temperature (°C): No data available
- Humidity (%):No data available
- Air changes (per hr): No data available
- Photoperiod (hrs dark / hrs light): No data available
Administration / exposure
- Route of administration:
- other: Study 2: oral: gavage; Study 3: oral: gavage; Study 4: oral: feed; Study 5: oral: gavage
- Vehicle:
- other: Study 2: corn oil; Study 3: not specified; Study 4: Basal diet; Study 5: olive oil
- Details on exposure:
- Study 2: The test material was administered by gavage to three groups each of ten male and ten female Sprague-Dawley Crl:CD® (SD) IGS BR strain rats, for up to fifty-four consecutive days, at dose levels of 50, 250 and 600 mg/kg/day.A control group of ten males and ten females was dosed with vehicle alone (corn oil).
Exposure period: Males: 43 days; Females: up to 54 days
Study 3: 48 consecutive days
Study 4: The test chemical was mixed into the basal diet of commercial laboratory chow at concentrations of 0.0 (vehicle), 67 mg/kg bw/d (0.1%),167 mg/kg bw/d (0.25%)or 333 mg/kg bw/d (0.50%) over a period of 734 days.
Study 5: No data available
- Details on mating procedure:
- Study 2: - M/F ratio per cage:one male:one female
- Proof of pregnancy: [vaginal plug / sperm in vaginal smear] referred to as [day 0 / day 1] of pregnancy : The presence of sperm within the vaginal smear and/or vaginal plug in situ was taken as positive evidence of mating.
- After ... days of unsuccessful pairing replacement of first male by another male with proven fertility. : N/A
- Further matings after two unsuccessful attempts: [no / yes (explain)] : no
Study 3: - M/F ratio per cage: 1:1
- Length of cohabitation: A maximum of 14 days
- Proof of pregnancy: [vaginal plug / sperm in vaginal smear] referred to as [day 0 / day 1] of pregnancy : The presence of sperm within the vaginal smear and/or vaginal plug in situ was taken as positive evidence of mating (Day 0 of gestation)
- Further matings after two unsuccessful attempts: [no / yes (explain)] : no
- After successful mating each pregnant female was caged (how): Mated females were housed individually during gestation and lactation.
Study 4: - M/F ratio per cage: 1:4
- Length of cohabitation: once a week for 3 weeks
- After successful mating each pregnant female was caged (how): Females were placed in individual cages.
Study 5: No data available
- Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Study 3: Gas Chromatography (GC) using an external standard technique.
- Duration of treatment / exposure:
- Study 2: 14 days prior to mating, throughout mating and gestation and continuing through lactation day 3.
Study 3: 48 consecutive days
Study 4: 734 days
Study 5: Male: 42 days
Female: 41 - 55 days (from 14 days before mating to day 4 of lactation) - Frequency of treatment:
- Study 2: daily
Study 3: Daily
Study 4: Daily
Study 5: daily - Details on study schedule:
- Study 2: No Data Available
Study 3: No Data Available
Study 4: No Data Available
Study 5: No Data Available
Doses / concentrations
- Remarks:
- Study 2: Doses / Concentrations:
0, 50, 250 and 600 mg/kg-bw/day
Basis:
no data
Study 3: Doses / Concentrations:
0, 50, 250 and 600 mg/kg/day
Basis:
analytical conc.
Study 4: Doses / Concentrations:
0.0 (vehicle), 67 mg/kg bw/d (0.1%),167 mg/kg bw/d (0.25%) and 333 mg/kg bw/d (0.50%)
Basis:
Study 5: Doses / Concentrations:
0, 25, 75 or 250 mg/kg/day
Basis:
no data
- No. of animals per sex per dose:
- Study 2: Number of Animals per Dose: 20
0 mg/kg/day (control) - 10 males and 10 females
50 mg/kg/day - 10 males and 10 females
250 mg/kg/day - 10 males and 10 females
600 mg/kg/day - 10 males and 10 females
Study 3: Control: 10 males and 10 females
50 mg/kg/day: 10 males and 10 females
250 mg/kg/day: 10 males and 10 females
600 mg/kg/day: 10 males and 10 females
Study 4: PART I
Control: 3 males and 12 females
67 mg/kg bw /d (0.1%) : 3 males and 12 females
167 mg/kg bw/d (0.25%) : 3 males and 12 females
333 mg/kg bw/d (0.50%) :3 males and 12 females
PART II
Control: 3 males and 12 females
67 mg/kg bw/d (0.1%) : 3 males and 12 females
167 mg/kg bw /d (0.25%) : 3 males and 12 females
333 mg/kg bw/d (0.50%) :3 males and 12 females
PART III
Control: 3 males and 12 females
67 mg/kg bw/d (0.1%) : 3 males and 12 females
167 mg/kg bw/d (0.25%) : 3 males and 12 females
333 mg/kg bw/d (0.50%) :3 males and 12 females
Study 5: No data available - Control animals:
- yes, concurrent vehicle
- Details on study design:
- Study 2: No Data Available
Study 3: No Data Available
Study 4: No Data Available
Study 5: No Data Available - Positive control:
- No Data Available
Examinations
- Parental animals: Observations and examinations:
- Study 2: Pregnancy and parturition: The following was recorded for each female:
i) Date of mating
jj) Date and time of observed start of parturition
iii) Date and time of observed completion of parturition
iv) Duration of gestation
Study 3: DETAILED CLINICAL OBSERVATIONS: Yes
All animals were examined for overt signs of toxicity, ill-health and behavioral change immediately before and after dosing, and one and 5 hours after dosing during the working week.
BODY WEIGHT: Yes
Individual body weights were recorded on Day 1 (prior to the start of treatment) and then weekly for males until termination. Females were weighed weekly until mating was evident. Body weights were recorded on Days 0, 7. 14 and 20 post coitumand on Days 1 and 4 post-parium.
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
During the maturation period, weekly food consumption was recorded for each cage of adults. Food consumption was recorded for the periods covering Days 1-7, 7-14 and 14-21. For females with live litters, food consumption was recorded on Days 1 and 4 post-partum.
WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): Yes
Water intake was observed daily by visual inspection of water bottles for any overt change.
OTHER:
reproductive function: corpora lutea and inplantation sites were examined.
Reproductive Indites:
Mating Index, pregnancy index and fertility index were examined.
organ weight:
Adrenals, Brain, Epididymides, Heart, Kidneys,, Liver, Ovaries, Spleen, Testes and Thymus were weighted.
Haematological and blood chemical observations :
Hematological and blood chemical investigations were performed on 5 males and 5 females selected from each test and control group on Day 14 (day prior to pairing).Blood samples were obtained from the lateral tail vein. Animals were not fasted prior to sampling.
Pregnancy and Parturition:
Each pregnant female was observed in the morning, around noon and in the afternoon and around the period of expected parturition. At weekends and public holidays, observations were carried out at in the morning and around noon. For each female date of mating, date and time of observed start of parturition, date and time of observed completion of parturition and duration of gestation was recorded.
Study 4: Following parameters were examined:
-Body weight and food consumption
-Live pups per litter
-Pup body weights
-Pup survival
-Histopathology
-Urine examination
-Gross Pathology : The 2-year ingestion of the test chemical caused lesions only in the urinary tract, namely, cystic dilatation of renal tubules with interstitial inflammation. Glomeruli were never altered. Lower tubules were sometimes filled with a proteinaceous fluid, and at other times with a blood-derived pigment. These accumulations were in some cases found in the renal pelvis or bladder, accompanied by mild epithelial hyperplasia or squamous metaplasia. The break-point for the occurrence of cystic change lies in the region of the 0.1% dietary concentration; and that for chronic nephritis, between 0.1 and 0.5%. The incidence of tumors was due to the senility of the rats at autopsy, not to treatment.
Study 5: Clinical sign, Body weight, Food consumption, Hematology, clinical chemistry and FOB were examined - Oestrous cyclicity (parental animals):
- Study 2: No Data Available
Study 3: No Data Available
Study 4: No Data Available
Study 5: Changes in the estrous cyclicity were observed. - Sperm parameters (parental animals):
- Study 2: No Data Available
Study 3: No Data Available
Study 4: No Data Available
Study 5: No data available - Litter observations:
- Study 2: Offspring Litter Size and Viability
Study 3: Number of offspring born, Number and sex of offspring alive recorded daily and reported on Day 1 and 4 post partum, Clinical condition, Individual offspring and litter weights and surface righting reflex on Day 1 and 4 were observed.
Study 4: -Live pups per litter
-Pup body weights
-Pup survival
-Histopathology
Study 5: Pup Viability, Sex Ratio, Birth Index, Body weight of pups were observed. - Postmortem examinations (parental animals):
- Study 2: No Data Available
Study 3: GROSS NECROPSY:All adult animals , including those dying during the study, were subjected to a full external and internal examination, and any macroscopic abnormalities were recorded.
Study 4: - Gross Pathology : The 2-year ingestion of the test chemical caused lesions only in the urinary tract, namely, cystic dilatation of renal tubules with interstitial inflammation. Glomeruli were never altered. Lower tubules were sometimes filled with a proteinaceous fluid, and at other times with a blood-derived pigment. These accumulations were in some cases found in the renal pelvis or bladder, accompanied by mild epithelial hyperplasia or squamous metaplasia. The break-point for the occurrence of cystic change lies in the region of the 0.1% dietary concentration; and that for chronic nephritis, between 0.1 and 0.5%. The incidence of tumors was due to the senility of the rats at autopsy, not to treatment.
Study 5: Organ weight and histopatholgy were examined - Postmortem examinations (offspring):
- Study 2: No Data Available
Study 3: GROSS NECROPSY: All offspring were subjected to a full external and internal examination, and any macroscopic abnormalities were recorded.
Study 4: -Live pups per litter
-Pup body weights
-Pup survival
-Histopathology
Study 5: No Data Available - Statistics:
- Study 2: No Data Available
Study 3: Methods used included Dunnetts test or a pair wise Students t-test or Kruskal-Wallis non parametric one way analysis of variance and Mann Whitney “U” test/Wilcoxon signed rank test.
Study 4: No Data Available
Stduy 5: No Data Available - Reproductive indices:
- Study 2: No Data Available
Study 3: No Data Available
Study 4: No Data Available
Study 5: Implantation Index, Resorption Index, Gestational Index. - Offspring viability indices:
- Study 2: No Data Available
Study 3: No Data Available
Study 4: No Data Available
Study 5: Pup viability index.
Results and discussion
Results: P0 (first parental generation)
General toxicity (P0)
- Clinical signs:
- effects observed, treatment-related
- Description (incidence and severity):
- Study 3: In 600 mg/kg/day, Increased salivation, pink staining was evident 00 cage tray liners from the male, red coloured urine, red brown staining around the snout and physical injury to the tail tip were observed pilo-erection, tiptoe gait, hunched posture, and skin pallor by day 11 and decrease respiratory rat on Day 12 the dose group terminated on Day 13.
in 250 mg/kg/day,Increased salivation and Hunched posture 'and tiptoe gait were observed in male and female rats as comarped to control.
Study 5: No effect was observed on clinical sign of treated male and female rats as compared to control. - Dermal irritation (if dermal study):
- not specified
- Mortality:
- mortality observed, treatment-related
- Description (incidence):
- Study 3: When treated with 600 mg/kg/day, one male killed on day 13, on efemale dead on day 15, two on day 16 and all animals are sacrificed on day 17 of study. In 150 mg/kg/day dose group, significant decease in survival were observed and this dose level was terminated on Day 31.
Study 4: Respiratory infections were responsible for the few mortalities. The animals that were visibly ill between that time and the 2-year period were sacrificed and were autopsied. - Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- Study 3: Slight reduction body weight gain were observed in 250 and 600 mg/kg/day treated rats as compared to control. In 50 mg/kg/day, no statistical significance effect were observed in treated rats as compared to control.
Study 4: Mean weights of males were found to be deviated at 0.1% dose group while, no changes in weights were observed in females from all the dose groups.
Study 5: Body weight: No effect was observed on body weight of treated male and female rats as compared to control. - Food consumption and compound intake (if feeding study):
- effects observed, treatment-related
- Description (incidence and severity):
- Study 3: Slight reduction body weight gain were observed in 250 and 600 mg/kg/day treated rats as compared to control. In 50 mg/kg/day, no statistical significance effect were observed in treated rats as compared to control.
Study 4: No effects were seen on food consumption
Study 5: Food consumption: No effect was observed on food consumption of treated male and female rats as compared to control. - Food efficiency:
- not specified
- Water consumption and compound intake (if drinking water study):
- not specified
- Ophthalmological findings:
- not specified
- Haematological findings:
- effects observed, treatment-related
- Description (incidence and severity):
- Study 3: A significantly lower platelet count was apparent for males receiving 250 mg/kg/day compared to controls. For females treated with 250 mg/kg/day, platelet count at pre-mating assessment was only marginally lower than controls.
Males receiving 50 or 250 mg/kg/day showed a significant reduction in white blood cell count at pre-mating assessment, compared with control. No similar effects were observed for females.
Study 5: In male rats, when treated with 75 mg/kg/day, prolongation in the PT and APTT were observed as compared to control. When treated with 250 mg/kg/day, prolongation in APTT were observed as compared to control. In female rats, decrease in the RBC and MCHC and increase in the RET was observed at recovery(250 mg/kg/day) as compared to control - Clinical biochemistry findings:
- no effects observed
- Description (incidence and severity):
- Study 5: No effect was observed on clinical chemistry of treated male and female rats as compared to control.
- Urinalysis findings:
- no effects observed
- Description (incidence and severity):
- Study 4: At 333 mg/kg bw/d (0.50%) :Prolonged test chemical ingestion did not increase protein excretion by rats fed as much as 0.50%
- Behaviour (functional findings):
- no effects observed
- Description (incidence and severity):
- Study 5: No effect was observed on functional observation battery (FOB) of treated male and female rats as compared to control.
- Immunological findings:
- not specified
- Organ weight findings including organ / body weight ratios:
- effects observed, non-treatment-related
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Description (incidence and severity):
- Study 3: When treated with 600 mg/kg/day, Higher grades of severity of trabecular bone formation in female , Centrilobular hepatocyte enlargement of liver, Hypertrophy of the collecting duct epithelium of the renal papilla and extramadullary haemopiesis of spleen were observed male and female rats. When treated with 250 mg/kg/day, Higher grades of severity of trabecular bone formation in female , Centrilobular hepatocyte enlargement of liver in male and female, Hypertrophy of the collecting duct epithelium of the renal papilla and extramadullary haemopiesis of spleen were observed female rats as compared to control.
Study 5: No Histopathological changes were observed in treated male and female rats as compared to control. - Histopathological findings: neoplastic:
- not specified
- Other effects:
- no effects observed
Reproductive function / performance (P0)
- Reproductive function: oestrous cycle:
- no effects observed
- Description (incidence and severity):
- Study 5: No changes were observed in the estrous cycles of female rats.
- Reproductive function: sperm measures:
- not specified
- Reproductive performance:
- no effects observed
- Description (incidence and severity):
- Study 2: No adverse effects on mating performance, fertility or gestation were detected.
Study 3: No effect were observed on mating performance or fertility and corpora lutea and implantation of treated rats as compared to control.
Study 4: no effects observed
Study 5: no effects observed
Details on results (P0)
Study 2: No adverse effects on mating performance, fertility or gestation were detected.
Study 3: Clinical toxicity:
mortality:
when treated with 600 mg/kg/day, one male killed on day 13, on efemale dead on day 15, two on day 16 and all animals are sacrificed on day 17 of study. In 150 ma/kg/day dose group, significant decease in survival were observed and this dose level was terminated on Day 31
Clinical signs:
in 600 mg/kg/day, Increased salivation, pink staining was evident 00 cage tray liners from the male, red coloured urine, red brown staining around the snout and physical injury to the tail tip were observed pilo-erection, tiptoe gait, hunched posture, and skin pallor by day 11 and decrease respiratory rat on Day 12 the dose group terminated on Day 13.
in 250 mg/kg/day,Increased salivation and Hunched posture 'and tiptoe gait were observed in male and female rats as comarped to control.
BODY WEIGHT AND FOOD CONSUMPTION (PARENTAL ANIMALS)
No adverse effect was detected for males throughout the treatment period or for females during maturation or gestation. However, a slight reduction in body weight gain was observed for females treated with 125 mg/kg/day during lactation.
TEST SUBSTANCE INTAKE (PARENTAL ANIMALS)
No adverse effect was detected for males. There were no adverse effects on dietary intake or food efficiency for females throughout the maturation or gestation phases of the study. However, during lactation reduced dietary intake was detected for females receiving 125 mg/kg/day compared with controls.
REPRODUCTIVE PERFORMANCE (PARENTAL ANIMALS)
There was no effect on mating or fertility, however, a shorter gestation length was observed in females treated with 25 and 125 mg/kg/day.
OTHER FINDINGS (PARENTAL ANIMALS) :
Haematology
A significantly lower platelet count was apparent for males receiving 250 mg/kg/day compared to controls. For females treated with 250 mg/kg/day, platelet count at pre-mating assessment was only marginally lower than controls.
Males receiving 50 or 250 mg/kg/day showed a significant reduction in white blood cell count at pre-mating assessment, compared with control. No similar effects were observed for females.
Blood Chemistry
Clear reductions in total protein, albumin. and albumin:globulin ratio, compared to control levels were apparent for both sexes at 250 mg/kg/day, with similar changes also being observed, to a lesser degree, for both sexes at 50 mg/kg/day. Alkaline phosphatase levels during pre-mating and terminal assessments were elevated, in comparison to control for both sexes at 250 rug/kg/day and for males at 5 mg/kg/day.
Gross Pathalogy:
In 600 mg/kg/day dose group, skin pallor, pillo-erection, and staining around the snout, and pallor of lings, spleen, stomach, liver, small intestine and dark enlarge liver, thymus, kidney, left testis and prostate of treated male and female rats.
in 250 mg/kg/day dose group, pallor of the extremities and vaginal bleeding and all tissues was pale and dark contents evident in gastro intestinal and uterus with red fluid. Liver pallor was prevalent for animals of either sex treated at this dose level.
no effect were observed in 50 mg/kg/day dose group as comapred to control.
Histopathology:
When treated with 600 mg/kg/day, Higher grades of severity of trabecular bone formation in female , Centrilobular hepatocyte enlargement of liver, Hypertrophy of the collecting duct epithelium of the renal papilla and extramadullary haemopiesis of spleen were observed male and female rats.
when treated with 250 mg/kg/day, Higher grades of severity of trabecular bone formation in female , Centrilobular hepatocyte enlargement of liver in male and female, Hypertrophy of the collecting duct epithelium of the renal papilla and extramadullary haemopiesis of spleen were observed female rats as compared to control.
Study 4: FOOD CONSUMPTION (PARENTAL ANIMALS):-No effects were seen on food consumption
GROSS PATHOLOGY (PARENTAL ANIMALS) :-At 67 mg/kg bw/d (0.1%) and 333 mg/kg bw/d (0.50%) :A lesion characteristically seen in the kidneys of untreated old rats becomes greatly exaggerated in degree.
At dietary levels of 0.01% and below : the renal lesions present were indistinguishable from those of the control group.
URINE EXAMINATION:At 333 mg/kg bw/d (0.50%) :Prolonged test chemical ingestion did not increase protein excretion by rats fed as much as 0.50%
EFFECT ON GROWTH: At 333 mg/kg bw/d (0.50%) - caused growth arrests which were partly due to lowered food intakes.
At 67 mg/kg bw/d (0.1%) :Caused no growth inhibition in either sex.
At 333 mg/kg bw/d (0.50%) : Distinct growth inhibition observed.
Study 5: Haematology:
In male rats, when treated with 75 mg/kg/day, prolongation in the PT and APTT were observed as compared to control.
When treated with 250 mg/kg/day, prolongation in APTT were observed as compared to control.
In female rats, decrease in the RBC and MCHC and increase in the RET was observed at recovery (250 mg/kg/day) as compared to control
Clinical chemistry
No effect was observed on clinical chemistry of treated male and female rats as compared to control.
Neurobehaviour
No effect was observed on functional observation battery (FOB) of treated male and female rats as compared to control.
Study 3: Clinical toxicity:
mortality:
when treated with 600 mg/kg/day, one male killed on day 13, on efemale dead on day 15, two on day 16 and all animals are sacrificed on day 17 of study. In 150 ma/kg/day dose group, significant decease in survival were observed and this dose level was terminated on Day 31
Clinical signs:
in 600 mg/kg/day, Increased salivation, pink staining was evident 00 cage tray liners from the male, red coloured urine, red brown staining around the snout and physical injury to the tail tip were observed pilo-erection, tiptoe gait, hunched posture, and skin pallor by day 11 and decrease respiratory rat on Day 12 the dose group terminated on Day 13.
in 250 mg/kg/day,Increased salivation and Hunched posture 'and tiptoe gait were observed in male and female rats as comarped to control.
BODY WEIGHT AND FOOD CONSUMPTION (PARENTAL ANIMALS)
No adverse effect was detected for males throughout the treatment period or for females during maturation or gestation. However, a slight reduction in body weight gain was observed for females treated with 125 mg/kg/day during lactation.
TEST SUBSTANCE INTAKE (PARENTAL ANIMALS)
No adverse effect was detected for males. There were no adverse effects on dietary intake or food efficiency for females throughout the maturation or gestation phases of the study. However, during lactation reduced dietary intake was detected for females receiving 125 mg/kg/day compared with controls.
REPRODUCTIVE PERFORMANCE (PARENTAL ANIMALS)
There was no effect on mating or fertility, however, a shorter gestation length was observed in females treated with 25 and 125 mg/kg/day.
OTHER FINDINGS (PARENTAL ANIMALS) :
Haematology
A significantly lower platelet count was apparent for males receiving 250 mg/kg/day compared to controls. For females treated with 250 mg/kg/day, platelet count at pre-mating assessment was only marginally lower than controls.
Males receiving 50 or 250 mg/kg/day showed a significant reduction in white blood cell count at pre-mating assessment, compared with control. No similar effects were observed for females.
Blood Chemistry
Clear reductions in total protein, albumin. and albumin:globulin ratio, compared to control levels were apparent for both sexes at 250 mg/kg/day, with similar changes also being observed, to a lesser degree, for both sexes at 50 mg/kg/day. Alkaline phosphatase levels during pre-mating and terminal assessments were elevated, in comparison to control for both sexes at 250 rug/kg/day and for males at 5 mg/kg/day.
Gross Pathalogy:
In 600 mg/kg/day dose group, skin pallor, pillo-erection, and staining around the snout, and pallor of lings, spleen, stomach, liver, small intestine and dark enlarge liver, thymus, kidney, left testis and prostate of treated male and female rats.
in 250 mg/kg/day dose group, pallor of the extremities and vaginal bleeding and all tissues was pale and dark contents evident in gastro intestinal and uterus with red fluid. Liver pallor was prevalent for animals of either sex treated at this dose level.
no effect were observed in 50 mg/kg/day dose group as comapred to control.
Histopathology:
When treated with 600 mg/kg/day, Higher grades of severity of trabecular bone formation in female , Centrilobular hepatocyte enlargement of liver, Hypertrophy of the collecting duct epithelium of the renal papilla and extramadullary haemopiesis of spleen were observed male and female rats.
when treated with 250 mg/kg/day, Higher grades of severity of trabecular bone formation in female , Centrilobular hepatocyte enlargement of liver in male and female, Hypertrophy of the collecting duct epithelium of the renal papilla and extramadullary haemopiesis of spleen were observed female rats as compared to control.
Study 4: FOOD CONSUMPTION (PARENTAL ANIMALS):-No effects were seen on food consumption
GROSS PATHOLOGY (PARENTAL ANIMALS) :-At 67 mg/kg bw/d (0.1%) and 333 mg/kg bw/d (0.50%) :A lesion characteristically seen in the kidneys of untreated old rats becomes greatly exaggerated in degree.
At dietary levels of 0.01% and below : the renal lesions present were indistinguishable from those of the control group.
URINE EXAMINATION:At 333 mg/kg bw/d (0.50%) :Prolonged test chemical ingestion did not increase protein excretion by rats fed as much as 0.50%
EFFECT ON GROWTH: At 333 mg/kg bw/d (0.50%) - caused growth arrests which were partly due to lowered food intakes.
At 67 mg/kg bw/d (0.1%) :Caused no growth inhibition in either sex.
At 333 mg/kg bw/d (0.50%) : Distinct growth inhibition observed.
Study 5: Haematology:
In male rats, when treated with 75 mg/kg/day, prolongation in the PT and APTT were observed as compared to control.
When treated with 250 mg/kg/day, prolongation in APTT were observed as compared to control.
In female rats, decrease in the RBC and MCHC and increase in the RET was observed at recovery (250 mg/kg/day) as compared to control
Clinical chemistry
No effect was observed on clinical chemistry of treated male and female rats as compared to control.
Neurobehaviour
No effect was observed on functional observation battery (FOB) of treated male and female rats as compared to control.
Effect levels (P0)
- Dose descriptor:
- NOAEL
- Effect level:
- 250 mg/kg bw/day
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: No adverse effects on mating performance, fertility or gestation were observed.
- Remarks on result:
- other: Not Specified
Target system / organ toxicity (P0)
- Critical effects observed:
- not specified
- System:
- other: Not Specified
Results: F1 generation
General toxicity (F1)
- Clinical signs:
- effects observed, treatment-related
- Description (incidence and severity):
- Study 2: No effect were observed on growth of 50 mg/kg/day treated offspring as compared to control.
- Dermal irritation (if dermal study):
- not specified
- Mortality / viability:
- mortality observed, treatment-related
- Description (incidence and severity):
- Study 2: Females treated with 600 mg/kg/day showed a higher percentage of pre-implantation losses in comparison to controls, resulting in the birth of less offspring per litter and lower total litter weights at this dose level.
Study 3: The number of interim offspring deaths at 50 mg/kg/day was considerably higher than observed for controls.
Study 4: No test chemical related mortality was observed.
Study 5: no mortality observed - Body weight and weight changes:
- effects observed, non-treatment-related
- Description (incidence and severity):
- Study 3: Offspring weights on Day 1 and subsequent weight gain at lower dose levels were similar to control and unaffected by treatment. For offspring at 250 mg/kg/day, bodyweight on Day 1 of age was slightly lower than control; differences failed to attain statistical significance and may reflect the generally shorter gestation length for litters at this dose level.
Study 4: Decreased weights of the pups was observed probably due to inadequate food intakes by their gestating and lactating mothers fed with test chemical through diet.
Study 5: The test chemical had no effects on the body weight of the pups. - 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:
- effects observed, non-treatment-related
- Description (incidence and severity):
- Study 3: Males treated with 250 mg/kg/day showed elevated liver weights in comparison to controls, however, statistical significance was not achieved. Females treated with 250 mg/kg/day showed a statistically significant reduction in spleen weights.
- Gross pathological findings:
- effects observed, non-treatment-related
- Description (incidence and severity):
- Study 3: Necropsy
Interim death and terminal kill offspring did not show any abnormalities considered to be related to treatment. Two males treated with 250 mg/kg/day displayed liver pallor at terminal kill.
Study 5: no effects observed - Histopathological findings:
- not specified
- Description (incidence and severity):
- Study 3: Minimal centrilobular hepatocyte enlargement 'was observed in relation to treatment for animals of either sex treated with 250 mg/kg/day. Females treated with 50 mg/kg/day were similarly affected.
Study 5: no effects observed - Other effects:
- effects observed, treatment-related
- Description (incidence and severity):
- Study 4: Litter observations :-
-There was no effect on the number of litters born nor on mortality of the offspring.
-The average size of the litters decreased as the concentration of dietary intake of the test chemical increased,with the anomalous exception of the numbers of pups born and weaned in the second generation whose mothers were fed the 67 mg/kg bw/d (0.1%) diet.
-At 333 mg/kg bw/d (0.50%) :
Reduced litter size and the weight of the youngs at 21 days was observed.
Survival:-
At 67 mg/kg bw/d (0.1%) and 333 mg/kg bw/d (0.50%) :There was good survival in all groups, with no significant reduction in the number of survivors at any level of the test chemical.
Developmental neurotoxicity (F1)
- Behaviour (functional findings):
- not specified
Developmental immunotoxicity (F1)
- Developmental immunotoxicity:
- not specified
Details on results (F1)
Study 2: Offspring Litter Size and Viability: Females treated with 600 mg/kg/day showed a higher percentage of pre-implantation losses in comparison to controls, resulting in the birth of less offspring per litter and lower total litter weights at this dose level.
Study 3: BODY WEIGHT (OFFSPRING):
Offspring weights on Day 1 and subsequent weight gain at lower dose levels were similar to control and unaffected by treatment. For offspring at 125 mg/kg/day, bodyweight on Day 1 of age was slightly lower than control; differences failed to attain statistical significance and may reflect the generally shorter gestation length for litters at this dose level.
ORGAN WEIGHTS (OFFSPRING)
Males treated with 125 mg/kg/day showed elevated liver weights in comparison to controls, however, statistical significance was not achieved. Females treated with 125 mg/kg/day showed a statistically significant reduction in spleen weights.
GROSS PATHOLOGY (OFFSPRING)
Necropsy
Interim death and terminal kill offspring did not show any abnormalities considered to be related to treatment. Two males treated with 125 mg/kg/day displayed liver pallor at terminal kill.
HISTOPATHOLOGY (OFFSPRING)
Minimal centrilobular hepatocyte enlargement 'was observed in relation to treatment for animals of either sex treated with 125 mg/kg/day. Females treated with 25 mg/kg/day were similarly affected.
OTHER FINDINGS (OFFSPRING)
Mortality :The number of interim offspring deaths at 25 and 125 mg/kg/day was considerably higher than observed for controls.
Study 4: Body weight :- At weaning: Decreased weights of the pups was observed probably due to inadequate food intakes by their gestating and lactating mothers with dietary intake of the test chemical.
Litter observations :-
-There was no effect on the number of litters born nor on mortality of the offspring.
-The average size of the litters decreased as the concentration of dietary intake of the test chemical increased,with the anomalous exception of the numbers of pups born and weaned in the second generation whose mothers were fed the 67 mg/kg bw/d (0.1%) diet.
-At 333 mg/kg bw/d (0.50%) :
Reduced litter size and the weight of the youngs at 21 days was observed.
Survival:-
At 67 mg/kg bw/d (0.1%) and 333 mg/kg bw/d (0.50%) :There was good survival in all groups, with no significant reduction in the number of survivors at any level of the test chemical.
Study 5: No effect of the test chemical was observed on live pup index, viability index, and external anomalies.
Study 3: BODY WEIGHT (OFFSPRING):
Offspring weights on Day 1 and subsequent weight gain at lower dose levels were similar to control and unaffected by treatment. For offspring at 125 mg/kg/day, bodyweight on Day 1 of age was slightly lower than control; differences failed to attain statistical significance and may reflect the generally shorter gestation length for litters at this dose level.
ORGAN WEIGHTS (OFFSPRING)
Males treated with 125 mg/kg/day showed elevated liver weights in comparison to controls, however, statistical significance was not achieved. Females treated with 125 mg/kg/day showed a statistically significant reduction in spleen weights.
GROSS PATHOLOGY (OFFSPRING)
Necropsy
Interim death and terminal kill offspring did not show any abnormalities considered to be related to treatment. Two males treated with 125 mg/kg/day displayed liver pallor at terminal kill.
HISTOPATHOLOGY (OFFSPRING)
Minimal centrilobular hepatocyte enlargement 'was observed in relation to treatment for animals of either sex treated with 125 mg/kg/day. Females treated with 25 mg/kg/day were similarly affected.
OTHER FINDINGS (OFFSPRING)
Mortality :The number of interim offspring deaths at 25 and 125 mg/kg/day was considerably higher than observed for controls.
Study 4: Body weight :- At weaning: Decreased weights of the pups was observed probably due to inadequate food intakes by their gestating and lactating mothers with dietary intake of the test chemical.
Litter observations :-
-There was no effect on the number of litters born nor on mortality of the offspring.
-The average size of the litters decreased as the concentration of dietary intake of the test chemical increased,with the anomalous exception of the numbers of pups born and weaned in the second generation whose mothers were fed the 67 mg/kg bw/d (0.1%) diet.
-At 333 mg/kg bw/d (0.50%) :
Reduced litter size and the weight of the youngs at 21 days was observed.
Survival:-
At 67 mg/kg bw/d (0.1%) and 333 mg/kg bw/d (0.50%) :There was good survival in all groups, with no significant reduction in the number of survivors at any level of the test chemical.
Study 5: No effect of the test chemical was observed on live pup index, viability index, and external anomalies.
Effect levels (F1)
- Dose descriptor:
- NOAEL
- Generation:
- F1
- Effect level:
- 250 mg/kg bw/day
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- viability
- mortality
- Remarks on result:
- other: Not Specified
Target system / organ toxicity (F1)
- Critical effects observed:
- not specified
- System:
- other: Not Specified
Overall reproductive toxicity
- Reproductive effects observed:
- not specified
- Treatment related:
- not specified
Applicant's summary and conclusion
- Conclusions:
- Study 2: Based on all the observation and results, it was concluded that the NOAEL of the test chemical was 250 mg/kg bw after administration to the test animals.
Study 3: NOAEL was considered to be 50 mg/kg/day for male and LOAEL for female F0 generation and NOAEL F1 ganaration when Sprague-Dawley Crl: CD (SD) IGS BR male and female rats treated with the test chemical.
Study 4: Based on all the observations and results, it was concluded that the NOAEL for the test chemical is found to be 67 mg/kg bw (0.1%).
Study 5: Based on all the observations and results, it was concluded that the NOAEL was considered to be 250 mg/kg/day when Crl:CD (SD) male and female rat were treated with the test chemical. - Executive summary:
Reproductive Toxicity Study:
The summaries of the reproductive toxicity data is as follows:
Reproductive Toxicity Study 2:
In the combined repeated-dose/reproductive/developmental toxicity screening study, the test material was administered by gavage to three groups each of ten male and ten female Sprague-Dawley Crl:CD® (SD) IGS BR strain rats, for up to fifty-four consecutive days, at dose levels of 50, 250 and 600 mg/kg/day. The following was recorded for each female: Date of mating, Date and time of observed start of parturition, Date and time of observed completion of parturitionand Duration of gestation. After dosing, it was observed that,Females treated with 600 mg/kg/day showed a higher percentage of pre-implantation losses in comparison to controls, resulting in the birth of less offspring per litter and lower total litter weights at this dose level. Thus, no adverse effects (NOAEL) on mating performance, fertility or gestation were observed at 250 mg/kg-bw/day of concentartion. Also, the same NOAEL was considered for fetal parameters. Thus, based on all the observation and results, it was concluded that the NOAEL of the test chemical was 250 mg/kg bw after administration to the test animals.
Reproductive Toxicity Study 3:
In a combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test, Sprague-DawleyCrl: CD (SD) IGS BR male and female rats treated with the test chemical in the concentration of 0, 50, 250 and 500 mg/kg/day orally by gavage. one male killed on day 13, on efemale dead on day 15, two on day 16 and all animals are sacrificed on day 17 of study at 600 mg/kg/day dose group and significant decease in survival were observed and this dose level was terminated on Day 31 at 250 ma/kg/day dose group. Increased salivation, pink staining was evident 00 cage tray liners from the male, red coloured urine, red brown staining around the snout and physical injury to the tail tip were observed. pilo-erection, tiptoe gait, hunched posture, and skin pallor by day 11 and decrease respiratory rat on Day 12 the dose group terminated on Day 13 in 600 mg/kg/day and Increased salivation and Hunched posture 'and tiptoe gait were observed in male and female rats as compared to control in 250 mg/kg/day dose group. slight reduction body weight gain were observed in 250 and 600 mg/kg/day treated rats as compared to control. in addition, skin pallor, pillo-erection, and staining around the snout, and pallor of lings, spleen, stomach, liver, small intestine and dark enlarge liver, thymus, kidney, left testis and prostate of treated male and female rats at 600 mg/kg/day and pallor of the extremities and vaginal bleeding and all tissues was pale and dark contents evident in gastro intestinal and uterus with red fluid. Liver pallor was prevalent for animals of either sex treated at this dose level at 250 mg/kg/day dose group. Higher grades of severity of trabecular bone formation in female , Centrilobular hepatocyte enlargement of liver, Hypertrophy of the collecting duct epithelium of the renal papilla and extramadullary haemopiesis of spleen in 600 mg/kg/day dose group and Higher grades of severity of trabecular bone formation in female , Centrilobular hepatocyte enlargement of liver in male and female, Hypertrophy of the collecting duct epithelium of the renal papilla and extramadullary haemopiesis of spleen were observed female rats as compared to control at 250 mg/kg/day dose group. no effect were observed on mating performance or fertility and corpora lutea and implantation of 50 mg/kg/day treated rats as compared to control. no effect were observed on offspring Viability, clinical sign and body weight of offsprings as compared to control. therefore NOAEL was considered to be 50 mg/kg/day for male and NOAEL for female F0 generation and NOAEL F1 ganaration when Sprague-DawleyCrl: CD (SD) IGS BR male and female rats were treated with the test chemical orally by gavage.
Reproductive Toxicity Study 4:
Two-year feeding of 0.5 and 1.0% dietary levels of the test chemical to male and female albino rats caused growth arrests which were partly due to lowered food intakes. The females’ growth was slightly arrested at 0.1%, an effect apparently due to the test chemical itself. Any such effect at 0.1% on the males could have been obscured by the greater deviations of their weights from their mean weights than the deviations of the females’ weights. Moderate degrees of anemia resulted from prolonged ingestion of 0.5 and 1.0% concentrations of the test chemical, but prompt recoveries of hemoglobin followed feeding of the control diet. Leukocyte numbers and percentages remained within normal ranges. The test chemical did not increase proteinuria or cause glycosuria. It is highly probable that apparent decreases in litter sizes and numbers of pups weaned were largely due to inadequate food intakes by their gestating and lactating mothers fed with the test chemical. The significantly decreased weights of the pups, at weaning, in but one of the nine experimental dietary categories was probably due to the same cause. The 2-year ingestion of the test chemical caused lesions only in the urinary tract, namely, cystic dilatation of renal tubules with interstitial inflammation. Glomeruli were never altered. Lower tubules were sometimes filled with a proteinaceous fluid, and at other times with a blood-derived pigment. These accumulations were in some cases found in the renal pelvis or bladder, accompanied by mild epithelial hyperplasia or squamous metaplasia. The break-point for the occurrence of cystic change lies in the region of the 0.1% dietary concentration; and that for chronic nephritis, between 0.1 and 0.5%. Thus, based on all the observations and results, it was concluded that the NOAEL for the test chemical is found to be 67 mg/kg bw (0.1%).
Reproductive Toxicity Study 5:
In a combined repeated dose and reproduction/developmental screening test, male and female Crl:CD (SD) rats were treated orally with the test chemical in concentration of 0, 25, 75 or 250 mg/kg/day with recovery dose group of 0 and 250 mg/kg/day.No effect were observe on clinical sign, body weight and food consumption of treated rats as compared to control. Similarly, no effects were observed on blood chemistry, organ weight and histopathology of treated rats as compared to control. In addition, changes were observed as tendency to prolongation in the PT and prolongation in the APTT in male rats at 75 and 250 mg/kg/day dose group and decrease in the RBC and MCHC. An increase in the RET at 250 mg/kg/day dose group during recovery in female rats as compared to control. No reproductive effect were observed in treated male or female rats and on offspring’s as compared to control. Therefore,NOAEL for the parental generation and the F1 generation were considered to be 250 mg/kg/day when male and female Crl:CD (SD) rats were treated orally by gavage with the test chemical.
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