Registration Dossier

Administrative data

Key value for chemical safety assessment

Toxic effect type:
dose-dependent

Effects on fertility

Description of key information

Based on the available studies and applying weight of evidence approach, the test chemical can be considered to be non-reprotoxic when exposed to living organisms.The No Observed Adverse Effect Level can be considered to be 1000 mg/kgbw/day. Comparing the above annotations with the criteria of CLP Regulation, the test chemical can be classified under the category “Not Classified”.

Link to relevant study records
Reference
Endpoint:
screening for reproductive / developmental toxicity
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
data from handbook or collection of data
Remarks:
Weight of evidence approach based on various test chemicals
Justification for type of information:
Weight of evidence approach based on various test chemicals
Reason / purpose for cross-reference:
read-across source
Reason / purpose for cross-reference:
read-across source
Qualifier:
according to guideline
Guideline:
other: Weight of evidence approach based on various test chemicals
Principles of method if other than guideline:
Weight of evidence approach based on various test chemicals
GLP compliance:
not specified
Limit test:
no
Species:
rat
Strain:
other: 2.Sprague- Dawley ;3. Harlan-Wistar
Sex:
male/female
Route of administration:
oral: gavage
Type of inhalation exposure (if applicable):
not specified
Vehicle:
other: 2. corn oil; 3. feed
Details on exposure:
2. PREPARATION OF DOSING SOLUTIONS: The test item was diluted with corn oil for preparation of solution(s).The solution(s) of the test chemical were made at volumes suitable for daily use for 28 days. The solution(s) were prepared at concentrations of 0, 25, 50 and 100 mg/ml such that dosage of 0 (vehicle),250, 500 and 1000 mg/kg body weight respectively were administered.
DIET PREPARATION
- Rate of preparation of diet (frequency):
- Mixing appropriate amounts with (Type of food):
- Storage temperature of food:
VEHICLE
- Justification for use and choice of vehicle (if other than water): Corn oil
- Concentration in vehicle: 0 (vehicle), 250, 500 and 1000 mg/kg body weight
- Amount of vehicle (if gavage): upto 10 ml/kg body weight
Details on mating procedure:
2. Reproductive organ weigth and histopathology were examined.
3. no specific details mentioned
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
2. stability determined by UV
Duration of treatment / exposure:
2. 28 days
3. 3 generation study
Frequency of treatment:
2. daily
3. daily
Details on study schedule:
not specified
Remarks:
Study 2: 0, 250, 500, 1000 mg/kg/day
Remarks:
Study 3: 0, 5, 50, 150 or 500 mg/kg
No. of animals per sex per dose:
2. Total: 72
0 mg/kg bw: 6 male, 6 female
250 mg/kg bw: 6 male, 6 female
500 mg/kg bw: 6 male, 6 female
1000 mg/kg bw: 6 male, 6 female
Reversal group
0 mg/kg bw: 6 male, 6 female
1000 mg/kg bw: 6 male, 6 female
Control animals:
yes, concurrent vehicle
Details on study design:
2. - Dose selection rationale:
- Rationale for animal assignment (if not random):The animals of uniform body weight were selected.The individual body weights of the animals did not exceed ± 20% of group mean body weight. The group means body weights of all the groups were approximately equal.
Positive control:
not specified
Parental animals: Observations and examinations:
2. CAGE SIDE OBSERVATIONS: Yes
- Time schedule:twice daily
- Cage side observations checked in table [No.?] were included. Viability were observed
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule:daily
BODY WEIGHT: Yes
- Time schedule for examinations:Body weights were recorded on the day of randomization, day of first dosing, weekly thereafter and a fasting body weight at scheduled sacrifice on day 29 and day
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Yes
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: Yes
FOOD EFFICIENCY:Not specified
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: Not specified
WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): Not specified
- Time schedule for examinations:Not specified
OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: prior to the initiation of the dosing and at scheduled sacrifice.
- Dose groups that were examined: All dose group were examined.
HAEMATOLOGY: Yes
- Time schedule for collection of blood:At the end of dosing period on day 29 and at termination of recovery period on day 43.
- Anaesthetic used for blood collection: Not specified
- Animals fasted: Yes, overnight
- How many animals: All 72 animals were examined.
- Parameters checked in table [No.?] were examined.Hemoglobin (g/dL), Red Blood Corpuscles (x106 /μL), Hematocrit (%), Mean Corpuscular Volume (fL), Mean Corpuscular Hemoglobin (pg), MeanCorpuscular Hemoglobin Concentration (g/dL), Platelets (x 103 /μL), White Blood Corpuscles (x103 /μL), Reticulocytes (%), Neutrophils (%), Lymphocytes (%), Eosinophils (%), Monocytes (%),Basophil (%) and Prothrombin time (sec.) were examined.
CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood:At the end of dosing period on day 29 and at termination of
recovery period on day 43.
- Anaesthetic used for blood collection: Not specified
- Animals fasted: Yes, overnight
- How many animals: All 72 animals were examined.
- Parameters checked in table [No.?] were examined.: Total Protein (g/dL), Blood Urea Nitrogen (mg/dL), Urea Nitrogen (mg/dL) Calculated, Alanine Aminotransferase (U/L), Aspartate Aminotransferase(U/L), Alkaline Phosphatase (U/L), Gamma Glutamyl Transferase (U/L), Glucose (mg/dL), Calcium (mmol/L), Phosphorous (mg/dL), Albumin (g/dL), Total Bilirubin (mg/dL), Creatinine (mmol/L), Total Cholesterol (mg/dL), Triglycerides (mg/dL), Globulin (g/dL) Calculated, Sodium (mmol/L), Potassium(mmol/L), Chloride (mmol/L) and Bile acid (mmol/L) were examined.
URINALYSIS: Yes
- Time schedule for collection of urine: during the last week of dosing period and on reversal grouprats at termination of recovery period on day 43.
- Metabolism cages used for collection of urine: Yes
- Animals fasted: Not specified
- Parameters checked in table [No.?] were examined.: Volume, Appearance, Colour, pH, Specific Gravity, Proteins, Glucose, Ketones, Bilirubin, Urobililogen, Occult Blood and Nitrite were examined.
NEUROBEHAVIOURAL EXAMINATION: Yes
- Time schedule for examinations: Towards the end of the exposure period of 28 days and towards the end of the recovery period on day 42
- Dose groups that were examined:All dose group were examined.
- Battery of functions tested: sensory activity, grip strength, motor activity, Visual Placing Response
were examined.
Oestrous cyclicity (parental animals):
not specified
Sperm parameters (parental animals):
not specified
Litter observations:
not specified
Postmortem examinations (parental animals):
2. GROSS PATHOLOGY: Yes, after 28 consecutive days of oral administration, all surviving study rats were sacrificed on day 29 (Group I, III, IV, V). In addition all rats from reversal groups were sacrificed on day 43 (Group II and VI).
HISTOPATHOLOGY: Yes
From each rat, samples or the whole of the tissues listed below were preserved. All tissues were fixed in 10% neutral buffered formalin except, eyes and testes of all animals were preserved in Davidson’s solution for 24 hours and transferred to 10% neutral buffered formalin.
Postmortem examinations (offspring):
no data available
Statistics:
2. Raw data was processed and analyzed for reporting group means and standard deviations with significance between the controls and treated groups, using SYSTAT 13 validated statistical software supplied by Starcom Information Technology Limited, Bangalore developed by Systat Software, Inc. USA. All the parameters characterized by continuous data such as body weight, feed consumption (calculated as gram per animal), organ weight, relative organ weight, haematological and clinical chemistry data were subjected to Bartlett’s test to meet the homogeneity of variance before conducting Analysis of Variance (ANOVA) and Dunnett’s t-test. Where the data was not meet the homogeneity of variance, Student’s t-test were performed to calculate significance. Significance was calculated at 5% level and indicated in the summary tables as follows:
* = Significant than control at 95% level of confidence (p<0.05).
Reproductive indices:
not specified
Offspring viability indices:
not specified
Clinical signs:
no effects observed
Description (incidence and severity):
2. Male -
Group I (Control, 0 mg/kg): No clinical signs of toxicity were observed in the animals throughout the dosing period of 28 days (animal nos.1 to 6).
Group II (Control, 0 mg/kg, Reversal): No clinical signs of toxicity were observed in the animals throughout the dosing period of 28 days and during the post-dosing recovery period (animal nos.13 to 18).
Group III (250 mg/kg): Test item coloured faeces were observed in all animals (animal nos.25 to 30, with onset from day 2) during the dosing period of 28 days.
Group IV (500 mg/kg): Test item coloured faeces were observed in all animals (animal nos.37 to 42, with onset from day 2) during the dosing period of 28 days.
Group V (1000 mg/kg): Test item coloured faeces were observed in all animals (animal nos.49 to 54, with onset from day 2) during the dosing period of 28 days.
Group VI (1000 mg/kg, Reversal): Test item coloured faeces were observed in all animals (animal nos.61 to 66, with onset from day 2) throughout the dosing period of 28 days and during the post-dosing recovery period.

Female -
Group I (Control, 0 mg/kg): No clinical signs of toxicity were observed in the animals throughout the dosing period of 28 days (animal nos.7 to 12).
Group II (Control, 0 mg/kg, Reversal): No clinical signs of toxicity were observed in the animals throughout the dosing period of 28 days and during the post-dosing recovery period (animal nos.19 to 24).
Group III (250 mg/kg): Test item coloured faeces were observed in all animals (animal nos.31 to 36, with onset from day 2) during the dosing period of 28 days
Group IV (500 mg/kg): Test item coloured faeces were observed in all animals (animal nos.43 to 48, with onset from day 2) during the dosing period of 28 days
Group V (1000 mg/kg): Test item coloured faeces were observed in all animals (animal nos.55 to 60, with onset from day 2) during the dosing period of 28 days
Group VI (1000 mg/kg, Reversal): Test item coloured faeces were observed in all animals (animal nos.67 to 70, with onset from day 2) throughout the dosing period of 28 days and during the post-dosing recovery period

Before commencement of treatment:
In home cage observation, rat from different dose groups and control group revealed normal behavior, alterations, vocalization, respiration and palpebral closer.
During handling observation, handling of rats did not reveal any abnormality from different dose groups and control group.
In the open field observation, rat did not reveal any abnormality from different dose groups and control group.
During treatment:
In home cage observation, rat from different dose groups and control group revealed normal behavior, alterations, vocalization, respiration and palpebral closer.
During handling observation, handling of rats did not reveal any abnormality from different dose groups and control group.
In the open field observation, rat did not reveal any abnormality from different dose groups and control group.
Detailed clinical observation did not reveal any abnormality in all groups during the dosing period of 28 days and during the post-dosing recovery period.
Dermal irritation (if dermal study):
not specified
Mortality:
no mortality observed
Description (incidence):
2. All animals from control and different dose groups survived throughout the dosing period of 28 days and the post-dosing recovery period of 14 days.
Body weight and weight changes:
no effects observed
Description (incidence and severity):
2. Male -
Animals from control and different dose groups exhibited normal body weight gain throughout the dosing period of 28 days. Reduced body weight gain of 5.48% was observed in male animals from 1000 mg/kg dose group and this effect was attributed to the biological variation within the test system and considered to be of no toxicological importance.
During the post-dosing recovery period, animals from 1000 mg/kg reversal group exhibited normal body weight gain when compared with that of control animals.
Female -
Animals from control and different dose groups exhibited normal body weight gain throughout the dosing period of 28 days.
During the post-dosing recovery period, animals from 1000 mg/kg reversal group exhibited normal body weight gain when compared with that of control animals.
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
2. Male and Female -
Animals from control and different dose groups exhibited normal feed consumption at the end of the dosing period of 28 days.Animals from control reversal and high reversal dose groups exhibited normal feed consumption at the end of the recovery period of 14 days.
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
no effects observed
Description (incidence and severity):
2. No ocular abnormalities were observed on ophthalmological examination in the animals during preexposure and at the end of the respective termination.
Haematological findings:
no effects observed
Description (incidence and severity):
2. Male and Female -
Haematological investigations conducted at the end of dosing period on day 29 and at the end of recovery period on day 43, revealed following significant changes in the values of different parameters studied when compared with that of respective controls, however the increase/decrease in the values obtained was within normal biological and laboratory limits or the effect was not dose dependent.
Male :
MCHC : Increased levels were observed in animals from 1000 mg/kg reversal dose group, sacrificed on day 43 (p<0.05)
HCT : Decreased levels were observed in animals from 1000 mg/kg reversal dose group, sacrificed on day 43 (p<0.05).
Female :
Platelets : Increased values were obtained for animals from 250 mg/kg, 500 mg/kg and 1000 mg/kg dose groups, sacrificed on day 29 (p<0.05),
Hb, HCT and MCHC : Decreased values were obtained for animals from 250 mg/kg, 500 mg/kg and 1000 mg/kg dose groups, sacrificed on day 29 (p<0.05),
Total RBC : Decreased values were obtained for animals from 500 mg/kg and 1000 mg/kg dose groups, sacrificed on day 29 (p<0.05)
Total RBC : Decreased levels were observed in animals from 1000 mg/kg reversal dose group, sacrificed on day 43 (p<0.05).
Clinical biochemistry findings:
no effects observed
Description (incidence and severity):
2. Male and Female -
Biochemical investigations conducted at the end of dosing period on day 29 and at the end of recovery period on day 43, revealed following significant changes in the values of different parameters studied when compared with that of respective controls, however the increase/decreased in the values obtained was within normal biological and laboratory limits or the effect was not dose dependent.
Male :
Total Bilirubin : Elevated levels were observed in animals from 1000 mg/kg dose group, sacrificed on day 29 (p<0.05),
Creatinine : Elevated levels were observed in animals from 250 mg/kg dose group, sacrificed on day 29 (p<0.05),
Glucose : Decreased levels were observed in animals from 500 mg/kg dose group, sacrificed on day 29 (p<0.05),
Calcium : Decreased levels were observed in animals from 500 mg/kg and 1000 mg/kg dose groups, sacrificed on day 29 (p<0.05),
Globulin and Bile Acid : Decreased levels were observed in animals from 250 mg/kg dose group, sacrificed on day 29 (p<0.05),
Total Cholesterol : Elevated levels were observed in animals from 1000 mg/kg reversal dose group,sacrificed on day 43 (p<0.05) and
Glucose : Decreased levels were observed in animals from 1000 mg/kg reversal dose group, sacrificed on day 43 (p<0.05).
Female :
Total Protein and Aspartate Aminotransferase : Elevated levels were observed in animals from 250 mg/kg and 500 mg/kg dose groups, sacrificed on day 29 (p<0.05),
Total Bilirubin : Elevated levels were observed in animals from 250 mg/kg, 500 mg/kg and 1000 mg/kg dose groups, sacrificed on day 29 (p<0.05),
Albumin : Elevated levels were observed in animals from 500 mg/kg dose group, sacrificed on day 29 (p<0.05),
Calcium : Decreased levels were observed in animals from 250 mg/kg and 500 mg/kg dose groups, sacrificed on day 29 (p<0.05),
Triglycerides : Decreased levels were observed in animals from 250 mg/kg dose group, sacrificed on day 29 (p<0.05)
Total Protein : Elevated levels were observed in animals from 1000 mg/kg reversal dose group, sacrificed on day 43 (p<0.05).
Urinalysis findings:
no effects observed
Description (incidence and severity):
2. No statistically significant variation was observed in the urine analyses conducted at the end of the dosing period in week 4 and 6 (on day 23, 24, 25, 26 and 43) in male and female animals of different dose groups as compared to control group animals, except for higher volume of urine was observed in female animals from 250 mg/kg dose group (p<0.05). This higher volume of urine analyses were considered to be incidental and of no toxicological importance
Behaviour (functional findings):
no effects observed
Description (incidence and severity):
2. Sensory Reactivity Observations:
All animals from control and different dose groups showed normal arousal level, visual response,touch response, auditory response, tail pinch response and visual placing response. Normal air righting reflex was observed in all animals from control and different dose groups in week 4.
Grip Strength:
Grip strength values observed in male and female animals for control and different dose groups were comparable.
Motor Activity:
Motor activity values observed in male and female animals for control and different dose groups were comparable.
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):
2. No treatment related histopathological changes were evident in male and female animals from control and high dose groups.Incidental, physiological and congenital histopathological changes which were covered in the background historical data of the pathology from control and high dose groups includes minimal, focal to multifocal periportal mononuclear cells infiltration in liver; minimal, multifocal tubular eosinophilic luminal secretion in the kidneys; minimal, multifocal brown pigmentation in spleen; minimal, diffuse dilatation of zona reticularis and/or minimal, multifocal vacuolation in zona fasciculata in the adrenals; minimal, luminal seminal coagulum in urinary bladder; minimal, luminal dilatation in the uterus;minimal, multifocal dilatation of Brunner’s gland in the duodenum; presence of persistent Rathke’s pouch in the pituitary in male and female animals from control and high dose group.No histopathological changes were observed in reproductive organ of treated male and female rats as compared to control.
Histopathological findings: neoplastic:
not specified
Other effects:
no effects observed
Description (incidence and severity):
2. Functional Observations
Sensory Reactivity Observations:
All animals from control and different dose groups showed normal arousal level, visual response, touch response, auditory response, tail pinch response and visual placing response. Normal air righting reflex was observed in all animals from control and different dose groups in week 4.
Grip Strength:
Grip strength values observed in male and female animals for control and different dose groups were comparable.
Motor Activity:
Motor activity values observed in male and female animals for control and different dose groups were comparable
Reproductive function: oestrous cycle:
not specified
Reproductive function: sperm measures:
not specified
Reproductive performance:
not specified
Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
clinical signs
mortality
body weight and weight gain
food consumption and compound intake
haematology
clinical biochemistry
urinalysis
organ weights and organ / body weight ratios
gross pathology
histopathology: non-neoplastic
Remarks on result:
other: no effects
Critical effects observed:
no
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
Gross pathological findings:
not specified
Neuropathological findings:
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:
not specified
Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: no effects
Remarks on result:
other: no effects
Critical effects observed:
not specified
Sexual maturation:
not specified
Anogenital distance (AGD):
not specified
Nipple retention in male pups:
not specified
Other effects:
not specified
Behaviour (functional findings):
not specified
Developmental immunotoxicity:
not specified
Dose descriptor:
NOAEL
Generation:
F1
Effect level:
1 000 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No deleterious effects were associated with the inclusion of the test chemical in the diet of rats for 3 generation.
Remarks on result:
other: No deleterious effects were associated with the inclusion of the test chemical in the diet of rats for 3 generation.
Critical effects observed:
no
Clinical signs:
not specified
Dermal irritation (if dermal study):
not specified
Mortality / viability:
not specified
Body weight and weight changes:
not specified
Food consumption and compound intake (if feeding study):
not specified
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not specified
Haematological findings:
not specified
Clinical biochemistry findings:
not specified
Urinalysis findings:
not specified
Sexual maturation:
not specified
Anogenital distance (AGD):
not specified
Nipple retention in male pups:
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:
NOAEL
Generation:
F2
Effect level:
1 000 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No deleterious effects were associated with the inclusion of the test chemical in the diet of rats for 3 generation.
Remarks on result:
other: No deleterious effects were associated with the inclusion of the test chemical in the diet of rats for 3 generation.
Critical effects observed:
no
Reproductive effects observed:
no
Conclusions:
Based on the available studies and applying weight of evidence approach, the test chemical can be considered to be non-reprotoxic when exposed to living organisms.The No Observed Adverse Effect Level can be considered to be 1000 mg/kgbw/day. Comparing the above annotations with the criteria of CLP Regulation, the test chemical can be classified under the category “Not Classified”.
Executive summary:

Various studies have been reviewed to determine the exact toxic dose of the test chemical which can cause effects on reproductive parameters. These include in vivo experimental studies performed on rats for the test chemicals.

In a Repeated Dose 28-day Oral Toxicity study, Sprague Dawley male and female rats were treated with the test chemical in the concentration of 0, 250 mg/kg, 500 mg/kg and 1000 mg/kg body weight orally by gavage in corn oil. Two additional dose levels were added to the study as control 0 mg/kg (Rev.) and test item 1000 mg/kg (Rev.), in order to study the reversibility or delayed occurrence of symptoms, if any. No effect on survival, clinical sign, body weight, Feed intake, Ophthalmoscopic examination and functional observation battery of treated male and female rats at the end of dosing period of 28 days and the recovery period of 14 days. Similarly, in male animals at the end of the recovery period on day 43, revealed statistically significant increase in the values of MCHC and statistically significant decrease in the values of HCT at 1000 mg/kg and in female on day 29, revealed statistically significant increase in the values of Platelets at 250 mg/kg, 500 mg/kg and 1000 mg/kg, and statistically significant decrease in the values of Hb, HCT and MCHC at 250 mg/kg, 500 mg/kg and 1000 mg/kg, and Total RBC at 500 mg/kg and 1000 mg/kg, Haematological analysis in female animals conducted at the end of the recovery period on day 43, revealed statistically significant decrease in the values of Total RBC at 1000 mg/kg. In male and female animals at the end of the dosing period on day 29, revealed statistically significant increase in the values of Total Bilirubin at 1000 mg/kg and Creatinine at 250 mg/kg, in male, Total Protein and Aspartate Aminotransferase at 250 mg/kg and 500 mg/kg, Total Bilirubin at 250, 500 and 1000 mg/kg, and Albumin at 500 mg/kg in female rat. In addition, statistically significant decrease was observed in the values of Glucose at 500 mg/kg, Calcium at 500 mg/kg and 1000 mg/kg, Globulin and Bile Acid at 250 mg/kg in male rat and, Calcium at 250 and 500 mg/kg, and Triglycerides at 250 mg/kg in female rat. At the end of the recovery period on day 43 (Reversal groups) statistically significant increase were observed in the values of Total Cholesterol at 1000 mg/kg in male rat and Total Protein at 1000 mg/kg in female rat. In addition, statistically significant decrease was observed in the values of Glucose at 1000 mg/kg in male rat. The increase/decrease in the values of various parameters was marginal and within the normal biological and laboratory limits for hematology and clinical chemistry parameters. In Urine analysis conducted during 4th and 6th week of dosing period (on day 23, 24, 25, 26 and 43), revealed no abnormality attributable to the treatment except for higher volume of urine was observed in female animals from 250 mg/kg dose group and considered to be incidental and of no toxicological importance. In addition, at termination of dosing on day 29, male animals from 250, 500 and 1000 mg/kg dose groups revealed increased relative weights of liver when compared with that of controls. In addition, increased relative weights of kidneys were observed in male animals from 250 mg/kg dose group, when compared with that of controls. Decreased relative weights of kidneys and heart weight at 1000 mg/kg in male as compared to controls. In addition, decreased relative weights of adrenals were observed in male animals from 250 and 1000 mg/kg dose groups when compared with that of controls. Decreased relative weights of thymus were observed in male animals from 500 mg/kg and 1000 mg/kg dose groups when compared with that of controls. Organ weight data of male animals sacrificed on day 43 from 1000 mg/kg reversal group, revealed decreased relative weights of kidneys and prostate + seminal vesicle with coagulation gland as whole when compared with that of controls.At termination of dosing on day 29, female animals from 250 mg/kg, 500 mg/kg and 1000 mg/kg dose groups revealed increased relative weights of liver. Organ weight data of female animals sacrificed on day 43 from 1000 mg/kg reversal group, was found to be comparable with that of controls. No effect on Epididymides and Testes of male rat and Ovaries, Uterus Dilatation and Vagina of female rats were observed as compared to control. Although significant changes in the values of organ weight were observed in male and female animals from different dose groups, no related gross pathological and histopathological findings were seen, hence these findings were considered to be of no toxicological importance. Test item coloured perianal region externally and test item coloured stomach mucosa in male and female animals at 250, 500 and 1000 mg/kg dose groups. Gross pathological examination in male and female animals from control, control reversal and 1000 mg/kg reversal dose groups did not reveal any abnormality. Histopathological examination did not reveal any abnormality attributable to the treatment in reproductive organ. Therefore, No Observed Adverse Effect Level (NOAEL) of the test chemical in the Sprague Dawley rat via oral route, over a period of 28 days was found to be 1000 mg/kg body weight in male and female animals.

This is supported by the results of a Reproductive and development toxicity study of test chemical performed on male and female Harlan-Wistar rats. The test chemical was administered in diet for up to 3 generation. 10 male and 20 females were used. As no indications of any influence on reproductive parameters and No developmental toxic effects were seen up to the highest dose of 500 mg/kg bw, hence No Observed Adverse Effect Level (NOAEL) for maternal toxicity was considered to be 500 mg/kg/day.

Based on the available studies and applying weight of evidence approach, the test chemical can be considered to be non-reprotoxic when exposed to living organisms.The No Observed Adverse Effect Level can be considered to be 1000 mg/kgbw/day. Comparing the above annotations with the criteria of CLP Regulation, the test chemical can be classified under the category “Not Classified”.

Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
1 000 mg/kg bw/day
Study duration:
subchronic
Experimental exposure time per week (hours/week):
168
Species:
rat
Quality of whole database:
Klimisch Rating 1
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

Various studies have been reviewed to determine the exact toxic dose of the test chemical which can cause effects on reproductive parameters. These include in vivo experimental studies performed on rats for the test chemicals.

In a Repeated Dose 28-day Oral Toxicity study, Sprague Dawley male and female rats were treated with the test chemical in the concentration of 0, 250 mg/kg, 500 mg/kg and 1000 mg/kg body weight orally by gavage in corn oil. Two additional dose levels were added to the study as control 0 mg/kg (Rev.) and test item 1000 mg/kg (Rev.), in order to study the reversibility or delayed occurrence of symptoms, if any. No effect on survival, clinical sign, body weight, Feed intake, Ophthalmoscopic examination and functional observation battery of treated male and female rats at the end of dosing period of 28 days and the recovery period of 14 days. Similarly, in male animals at the end of the recovery period on day 43, revealed statistically significant increase in the values of MCHC and statistically significant decrease in the values of HCT at 1000 mg/kg and in female on day 29, revealed statistically significant increase in the values of Platelets at 250 mg/kg, 500 mg/kg and 1000 mg/kg, and statistically significant decrease in the values of Hb, HCT and MCHC at 250 mg/kg, 500 mg/kg and 1000 mg/kg, and Total RBC at 500 mg/kg and 1000 mg/kg, Haematological analysis in female animals conducted at the end of the recovery period on day 43, revealed statistically significant decrease in the values of Total RBC at 1000 mg/kg. In male and female animals at the end of the dosing period on day 29, revealed statistically significant increase in the values of Total Bilirubin at 1000 mg/kg and Creatinine at 250 mg/kg, in male, Total Protein and Aspartate Aminotransferase at 250 mg/kg and 500 mg/kg, Total Bilirubin at 250, 500 and 1000 mg/kg, and Albumin at 500 mg/kg in female rat. In addition, statistically significant decrease was observed in the values of Glucose at 500 mg/kg, Calcium at 500 mg/kg and 1000 mg/kg, Globulin and Bile Acid at 250 mg/kg in male rat and, Calcium at 250 and 500 mg/kg, and Triglycerides at 250 mg/kg in female rat. At the end of the recovery period on day 43 (Reversal groups) statistically significant increase were observed in the values of Total Cholesterol at 1000 mg/kg in male rat and Total Protein at 1000 mg/kg in female rat. In addition, statistically significant decrease was observed in the values of Glucose at 1000 mg/kg in male rat. The increase/decrease in the values of various parameters was marginal and within the normal biological and laboratory limits for hematology and clinical chemistry parameters. In Urine analysis conducted during 4th and 6th week of dosing period (on day 23, 24, 25, 26 and 43), revealed no abnormality attributable to the treatment except for higher volume of urine was observed in female animals from 250 mg/kg dose group and considered to be incidental and of no toxicological importance. In addition, at termination of dosing on day 29, male animals from 250, 500 and 1000 mg/kg dose groups revealed increased relative weights of liver when compared with that of controls. In addition, increased relative weights of kidneys were observed in male animals from 250 mg/kg dose group, when compared with that of controls. Decreased relative weights of kidneys and heart weight at 1000 mg/kg in male as compared to controls. In addition, decreased relative weights of adrenals were observed in male animals from 250 and 1000 mg/kg dose groups when compared with that of controls. Decreased relative weights of thymus were observed in male animals from 500 mg/kg and 1000 mg/kg dose groups when compared with that of controls. Organ weight data of male animals sacrificed on day 43 from 1000 mg/kg reversal group, revealed decreased relative weights of kidneys and prostate + seminal vesicle with coagulation gland as whole when compared with that of controls.At termination of dosing on day 29, female animals from 250 mg/kg, 500 mg/kg and 1000 mg/kg dose groups revealed increased relative weights of liver. Organ weight data of female animals sacrificed on day 43 from 1000 mg/kg reversal group, was found to be comparable with that of controls. No effect on Epididymides and Testes of male rat and Ovaries, Uterus Dilatation and Vagina of female rats were observed as compared to control. Although significant changes in the values of organ weight were observed in male and female animals from different dose groups, no related gross pathological and histopathological findings were seen, hence these findings were considered to be of no toxicological importance. Test item coloured perianal region externally and test item coloured stomach mucosa in male and female animals at 250, 500 and 1000 mg/kg dose groups. Gross pathological examination in male and female animals from control, control reversal and 1000 mg/kg reversal dose groups did not reveal any abnormality. Histopathological examination did not reveal any abnormality attributable to the treatment in reproductive organ. Therefore, No Observed Adverse Effect Level (NOAEL) of the test chemical in the Sprague Dawley rat via oral route, over a period of 28 days was found to be 1000 mg/kg body weight in male and female animals.

This is supported by the results of a Reproductive and development toxicity study of test chemical performed on male and female Harlan-Wistar rats. The test chemical was administered in diet for up to 3 generation. 10 male and 20 females were used. As no indications of any influence on reproductive parameters and No developmental toxic effects were seen up to the highest dose of 500 mg/kg bw, hence No Observed Adverse Effect Level (NOAEL) for maternal toxicity was considered to be 500 mg/kg/day.

Based on the available studies and applying weight of evidence approach, the test chemical can be considered to be non-reprotoxic when exposed to living organisms.The No Observed Adverse Effect Level can be considered to be 1000 mg/kgbw/day. Comparing the above annotations with the criteria of CLP Regulation, the test chemical can be classified under the category “Not Classified”.

Effects on developmental toxicity

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

Justification for classification or non-classification

Based on the available studies and applying weight of evidence approach, the test chemical can be considered to be non-reprotoxic when exposed to living organisms.Hence, the test chemical can be classified under the category “Not Classified” as per CLP Regulations.

Additional information