Registration Dossier

Diss Factsheets

Administrative data

Key value for chemical safety assessment

Toxic effect type:
dose-dependent

Effects on fertility

Description of key information

Reproductive toxicity study

Based on the data available from different studies, NOAEL for test material was considered to be 50 mg/kg /day for reproductive toxicity, when male and female rats were treated with test material orally. Thus, comparing this value with the criteria of CLP regulation test material is not likely to classify as reproductive toxicant.

Link to relevant study records

Referenceopen allclose all

Endpoint:
reproductive toxicity, other
Remarks:
organ toxicity
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Justification for type of information:
Data from study report
Qualifier:
according to guideline
Guideline:
other: OECD Guideline 407
Principles of method if other than guideline:
Effects on male and female reproductive organs were studies in the 28 day repeated oral toxicity study
GLP compliance:
yes
Limit test:
no
Justification for study design:
No data available
Species:
rat
Strain:
Sprague-Dawley
Details on species / strain selection:
No data available
Sex:
male/female
Details on test animals or test system and environmental conditions:
Source: Central Animal Facility (CAF), NIPER, Sector-67, S.A.S. Nagar, 160 062, Punjab, India.
- Age at study initiation: (P) x wks; (F1) x wks:
( P) 7 to 8 weeks old
- Weight at study initiation: (P) Males: x-x g; Females: x-x g: Male 196.26 - 241.83 g,
Female 182.80-213.04 g
(F1) Males: x-x g; Females: x-x g: No data available
- Fasting period before study: A fast of 2h before chemical administered.
- Housing: Animals were housed four rats per sex per cage in sterilized solid bottom polypropylene cages with stainless steel grill tops with facilities for food, water bottles and bedding of clean paddy husk. The cages were suspended on stainless steel racks. Identified by assigned a unique identification (ID) number written on the tail, also specified on individual cage tag.
- Diet (e.g. ad libitum): Standard laboratory sterile extruded pelleted rodent feed, ad libitum.
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 3 °C
- Humidity (%): 30-70 %
- Air changes (per hr): 25 ± 5 air changes per hour.
- Photoperiod (hrs dark / hrs light): 12 hours light and 12 hours dark

- Water (e.g. ad libitum): Potable tap water filtered through Reviva Reverse Osmosis
System (water filter cum purifier) of Eureka Forbes was provided in polypropylene bottles with stainless steel sipper tubes, ad libitum.
- Acclimation period: 5 days
Route of administration:
oral: gavage
Vehicle:
corn oil
Details on exposure:
PREPARATION OF DOSING SOLUTIONS: Dose of the test item was freshly prepared prior to dosing on each day. The test chemical was administered to each rat at the dose levels of 50, 150 or 450 mg/kg in the dose volume of 10 ml/kg body weight. The test item was weighed on a weighing balance. Then, it was transferred to calibrated falcon tube. Some quantity of the corn oil was added initially and vortexed. The sufficient quantity of vehicle was added to make up the required volume of dose.
Justification for use and choice of vehicle (if other than water): Corn oil was used as a vehicle for this study as the test item was not soluble in water and to deliver the desired dose levels because it is also recommended in the toxicological evaluation guidelines.
- Concentration in vehicle: 0, 50, 150 or 450 mg/kg body weight /day
Amount of vehicle (if gavage): 10 ml/kg body weight
- Lot/batch no. (if required): No data available
Details on mating procedure:
No data available
Analytical verification of doses or concentrations:
yes
Duration of treatment / exposure:
28 days
Frequency of treatment:
Daily
Details on study schedule:
No data available
Remarks:
0, 50, 150 or 450 mg/kg/body weight/day
No. of animals per sex per dose:
Total : 56
0 mg/kg/body weight/day: 7 male, 7 female
50 mg/kg/body weight/day: 7 male, 7 female
150 mg/kg/body weight/day: 7 male, 7 female
450 mg/kg/body weight/day: 7 male, 7 female
Control animals:
yes, concurrent vehicle
Details on study design:
No data available
Positive control:
No data available
Parental animals: Observations and examinations:
Mortality and changes in body weight of the male and female reproductive organs like the testis, epidydimydes, uterus and ovary respectively were noted. In addition, food consumption, water consumption and locomotor activity effects were also recorded.
In male rats, relative organ weight of brain was significantly increased while no changes were observed in female organ weight when treated with 50 mg/kg/body weight/day as compare to control.
Oestrous cyclicity (parental animals):
No data available
Sperm parameters (parental animals):
No data available
Litter observations:
No data available
Postmortem examinations (parental animals):
Testes, ovaries and uterus were pathologically examined after termination. Examinations also included weight of brain, epididymides, and ovaries (incl. paired ovaries and uterus, including cervix).
Postmortem examinations (offspring):
No data available
Statistics:

Statistical analysis was carried out by using Microsoft Excel and IBM SPSS statistics version- 20.0. All analyses and comparisons were evaluated at the 5 % level, statistically significant differences (p ≤ 0.05) indicated by appropriate notation. The focus was to examine the mean differences and their significance in control vs low-dose group only as there was total mortality observed in mid and high-dose groups in both the sexes. The statistical decision was taken by preparing the univariant GLM MODEL to check the significance between above mentioned groups. For multiple comparisons Turkey’s HSD test was applied.
Reproductive indices:
No data available
Offspring viability indices:
No data available
Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
Some abnormalities like nasal discharge, red crust around nostrils and soft feces were common to all the groups in both the sexes and hence can be considered as background notations. Vocalization on handling was observed in low and mid-dose groups of both sexes. Decreased locomotion was confined to few mid and high-dose groups. Shallow/abdominal breathing was observed in both mid and high-dose groups. There was one case of dehydration and thin body condition in mid-dose male animals. The staining of fore paw was confined to high–dose group of male and female animals.
Dermal irritation (if dermal study):
not specified
Mortality:
mortality observed, treatment-related
Description (incidence):
In high-dose group of male rats the mortality was observed on the day 3, 4, 5, whereas in the mid-dose male rats the mortality was observed in the day 4, 5, 7, 8, and 11. In high-dose females the mortality was seen on day 3, 4 and 5 and in the mid-dose female animals of the mortality was found on day 5, 6, 7, 8, and 10. Only the animals of control and low-dose group survived throughout the treatment period of 28 days.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
The mean body weights of all dose groups of surviving animals were calculated and compared with the control animal data. In male animals, a significant decrease has been noticed in the body weight of low-dose group as compared to control animals on days 15, 22, 28 and also on terminal day. A significant decrease was also noticed in the body weight of female animal treated with low-dose taken on days 22, 28 and terminal day.
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
In low-dose group animals the average food consumption (g/rat/day) was calculated and compared with the control. No difference was observed among low-dose group of male as well as female animals. The data of mid-dose and high-dose group could not be used for statistics as there was mortality observed in both the sexes in the first week itself.
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
no effects observed
Description (incidence and severity):
Average water consumption (ml/rat/day) was calculated and compared with the control. No difference was observed among low-dose group of male as well as female animals. The data of mid-dose and high-dose group could not be used for statistics as there was mortality observed in
both the sexes in the first week itself.
Ophthalmological findings:
no effects observed
Description (incidence and severity):
No abnormalities were found in the ophthalmological examination (control vs. low-dose treated group).
Haematological findings:
effects observed, treatment-related
Description (incidence and severity):
In male rats, RBC count and percentage of monocytes increased significantly (p≤0.05) in lowdose treated group as compared to control animals. However, in female rats, no significant changes were observed in any of the hematological parameters.
Clinical biochemistry findings:
effects observed, treatment-related
Description (incidence and severity):
In male rats, the levels of potassium and total proteins were elevated significantly (p≤0.05) in low-dose group as compared to control animals. In female rats, low-dose treatment resulted in significant decrease in the level of total bile acid (p≤0.01) as compared to the control animals
Urinalysis findings:
not specified
Behaviour (functional findings):
no effects observed
Description (incidence and severity):
Locomotor activity was decreased significantly in the female animals of low-dose group as compared to control animals.
Immunological findings:
not specified
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
No significant changes were observed in control as well as in low-dose group animals. Few microscopic findings were observed in control as well as in low-dose treated animals which include excess of lymphocytes in bronchi and alveoli of lungs, in ileum and colon. These types of findings may be considered to be within the range of normal background lesions which may be seen in rats of this strain and age of this study type and were considered incidental in nature with carbon dioxide inhalation and terminal changes at sacrifice, reflecting the usual individual variability.
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:
50 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
water consumption and compound intake
ophthalmological examination
haematology
clinical biochemistry
organ weights and organ / body weight ratios
gross pathology
histopathology: non-neoplastic
Remarks on result:
other: No effects on reproductive organ weight
Critical effects observed:
not specified
System:
other: not specified
Organ:
not specified
Clinical signs:
not specified
Dermal irritation (if dermal study):
not examined
Mortality / viability:
not examined
Body weight and weight changes:
not examined
Food consumption and compound intake (if feeding study):
not examined
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Sexual maturation:
not examined
Anogenital distance (AGD):
not examined
Nipple retention in male pups:
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
not examined
Histopathological findings:
not examined
Other effects:
not examined
Behaviour (functional findings):
not examined
Developmental immunotoxicity:
not examined
Dose descriptor:
other: not specified
Generation:
other: not specified
Based on:
not specified
Sex:
not specified
Basis for effect level:
other: not specified
Remarks on result:
not measured/tested
Critical effects observed:
not specified
System:
other: not specified
Organ:
not specified
Reproductive effects observed:
not specified
Treatment related:
not specified

Summary of Reproductive Organ Weights (Male Rats)

Group/Dose

 

Testes

Epididymides

1/0 mg/kg bw

Mean

0.9930

0.4157

SD

0.1199

0.0675

SEM

0.0453

0.0255

2/50 mg/kg bw

Mean

1.0826

0.4780

SD

0.1111

0.0530

SEM

0.0420

0.0200

No significance attributed to the body weight changes in comparison to control groups

Summary of Reproductive Organ Weights (Female Rats)

Group/Dose

 

Uterus

Ovaries

5/0 mg/kg bw

Mean

0.2915

0.0441

SD

0.0519

0.0188

SEM

0.0196

0.0071

6/50 mg/kg bw

Mean

0.2346

0.0412

SD

0.0701

0.0155

SEM

0.0265

0.0059

No significance attributed to the body weight changes in comparison to control groups

 

Conclusions:
Male and female rats dosed with 50 mg/kg bw of Solvent blue 4 did not show appreciable difference in the weight of testes & epidydimides and uterus and ovaries respectively, as compared to the control. No significance attributed to the reproductive organ body weight changes in comparison to control groups. Hence the no observed adverse effect level (NOAEL) for the parents has been concluded to be 50 mg/kg bw
Executive summary:

In a 28 days repeated dose toxicity study, the effect of test chemical (containing less than 0.1% Michler's Ketone) was evaluated in male and female Sprague Dawley rats .TheSprague Dawley (SD) rats of 7-8 weeks old were divided into four groups of each sex and each group comprised of either 7 males or 7 females. Test chemical was administered at the dose levels of 50, 150 and 450 mg/kg/day for 28 consecutive days by oral route. Male animals were divided into four groups, group 1 served as control and group 2, 3 and 4 served as low, mid and high-dose group respectively. Female animals were divided into four groups, group 5 served as control and group 6, 7 and 8 served as low, mid and high-dose group respectively. Corn oil was used as vehicle for the present study.

In 450 mg/kg/day dose treatment group in male, the mortality was observed on the day 3, 4, 5, whereas in the 150 mg/kg/day dose treatment group in male rats the mortality was observed in the day 4, 5, 7, 8, and 11. In 450 mg/kg/day dose treatment group in females the mortality was seen on day 3, 4 and 5 and in the 150 mg/kg/day –dose treatment group in female animals’ mortality was found on day 5, 6, 7, 8, and 10 after the administration of test chemical.At the end of the 28 days study only male and female animals of control and 50 mg/kg/day dose groupsurvived up to the completion of the treatment period. During the treatment period, detailed clinical signs, body weight, food and water consumption were recorded weekly. In the groups survived after 28 days of treatment, no abnormalities were found in the ophthalmological examination (control vs. low-dose treated group). However, a significant decrease was observed in the motor activity of treated female animals as compared to the control animals.After the completion of dosing period, blood was collected from all the surviving animals forhematology and clinical biochemistry analysis. All survived animals were sacrificed on the day of

study termination and gross lesions as well as the weight of different organs were recorded. Allorgans were fixed in 10 % formal saline, except the reproductive organs, which were fixed inBouin’s fixative for short duration and thereafter shifted to 10 % formal saline.

In the terminally sacrificed and the animals died during treatment, the necropsy findings that werecommon to all the dosed treated groups include bluish stained perineum and alimentary canal whichinclude stomach and intestine.The finding of stomach blotted with gastric content was common to all the treated group maleanimals and in one female animal of 450 mg/kg/day dose treated group. Mild blue tinged patches were observed in 50 mg/kg/day dose treated male rats. The enlargement of atria in heart, lung congestion and marked thinning of fore stomach wall was confined to 150 mg/kg/day and 450 mg/kg/day dose groups of both the sexes as observed after mortality. White / pale patches on liver / liver congestion / dark reddish liver were confined to 450 mg/kg/day dose group of male and female animals during the time of gross necropsy after mortality. In male rats, the relative weight of brain was significantly increased in 50 mg/kg/day -dose group as compared to control group.Hematology of male animals showed a significant elevation in the red blood cell count as well asthe percentage of monocytes in the 50 mg/kg/day dose group as compared to control animals.

In male rats, significant elevation in the levels of potassium and total proteins was noticed with 50 mg/kg/day dose treatment as compared to control animals.In female rat, significant decrease in the level of total bile acid was noticed in the 50 mg/kg/day dose treated animals as compared to control animals.In the microscopic histopathological study there was no significant change observed in 50 mg/kg/day dose group animals as compared to control animals. Few microscopic findings were observed in control

as well as in 50 mg/kg/day dose treated animals, which include excess of lymphocytes in bronchi and alveoli of lungs, ileum and colon. These types of findings may be considered within the range of normalbackground lesions, which are seen in rats with the age groups used in the present study. Further,these types of changes were considered incidental in nature with carbon dioxide inhalation. Male and female rats dosed with 50 mg/kg bw of Solvent blue 4 did not show appreciable difference in the weight of testes & epidydimides and uterus and ovaries respectively, as compared to the control. No significance attributed to the reproductive organ body weight changes in comparison to control groups. Hence the no observed adverse effect level (NOAEL) for the parents has been concluded to be 50 mg/kg bw

Endpoint:
screening for reproductive / developmental toxicity
Data waiving:
other justification
Justification for data waiving:
other:
Justification for type of information:
The study is ongoing and this information will be submitted later based on ECHA communication/decision number CCH-D-2114554511-55-01/F.
Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
50 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Quality of whole database:
Data is Klimicsh 1 and from study report

Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

Reproductive toxicity study

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

Study 1

In a 28 days repeated dose toxicity study, the effect of test chemical (containing less than 0.1% Michler's Ketone) was evaluated in male and female Sprague Dawley rats .TheSprague Dawley (SD) rats of 7-8 weeks old were divided into four groups of each sex and each group comprised of either 7 males or 7 females. Test chemical was administered at the dose levels of 50, 150 and 450 mg/kg/day for 28 consecutive days by oral route. Male animals were divided into four groups, group 1 served as control and group 2, 3 and 4 served as low, mid and high-dose group respectively. Female animals were divided into four groups, group 5 served as control and group 6, 7 and 8 served as low, mid and high-dose group respectively. Corn oil was used as vehicle for the present study.

In 450 mg/kg/day dose treatment group in male, the mortality was observed on the day 3, 4, 5, whereas in the 150 mg/kg/day dose treatment group in male rats the mortality was observed in the day 4, 5, 7, 8, and 11. In 450 mg/kg/day dose treatment group in females the mortality was seen on day 3, 4 and 5 and in the 150 mg/kg/day –dose treatment group in female animals’ mortality was found on day 5, 6, 7, 8, and 10 after the administration of test chemical.At the end of the 28 days study only male and female animals of control and 50 mg/kg/day dose groupsurvived up to the completion of the treatment period. During the treatment period, detailed clinical signs, body weight, food and water consumption were recorded weekly. In the groups survived after 28 days of treatment, no abnormalities were found in the ophthalmological examination (control vs. low-dose treated group). However, a significant decrease was observed in the motor activity of treated female animals as compared to the control animals.After the completion of dosing period, blood was collected from all the surviving animals forhematology and clinical biochemistry analysis. All survived animals were sacrificed on the day of

study termination and gross lesions as well as the weight of different organs were recorded. Allorgans were fixed in 10 % formal saline, except the reproductive organs, which were fixed inBouin’s fixative for short duration and thereafter shifted to 10 % formal saline.

In the terminally sacrificed and the animals died during treatment, the necropsy findings that werecommon to all the dosed treated groups include bluish stained perineum and alimentary canal whichinclude stomach and intestine.The finding of stomach blotted with gastric content was common to all the treated group maleanimals and in one female animal of 450 mg/kg/day dose treated group. Mild blue tinged patches were observed in 50 mg/kg/day dose treated male rats. The enlargement of atria in heart, lung congestion and marked thinning of fore stomach wall was confined to 150 mg/kg/day and 450 mg/kg/day dose groups of both the sexes as observed after mortality. White / pale patches on liver / liver congestion / dark reddish liver were confined to 450 mg/kg/day dose group of male and female animals during the time of gross necropsy after mortality. In male rats, the relative weight of brain was significantly increased in 50 mg/kg/day -dose group as compared to control group.Hematology of male animals showed a significant elevation in the red blood cell count as well asthe percentage of monocytes in the 50 mg/kg/day dose group as compared to control animals.

In male rats, significant elevation in the levels of potassium and total proteins was noticed with 50 mg/kg/day dose treatment as compared to control animals.In female rat, significant decrease in the level of total bile acid was noticed in the 50 mg/kg/day dose treated animals as compared to control animals.In the microscopic histopathological study there was no significant change observed in 50 mg/kg/day dose group animals as compared to control animals. Few microscopic findings were observed in control as well as in 50 mg/kg/day dose treated animals, which include excess of lymphocytes in bronchi and alveoli of lungs, ileum and colon. These types of findings may be considered within the range of normalbackground lesions, which are seen in rats with the age groups used in the present study. Further,these types of changes were considered incidental in nature with carbon dioxide inhalation.Male and female rats dosed with 50 mg/kg bw of Solvent blue 4 did not show appreciable difference in the weight of testes & epidydimides and uterus and ovaries respectively, as compared to the control. No significance attributed to the reproductive organ body weight changes in comparison to control groups. Hence the no observed adverse effect level (NOAEL) for the parents has been concluded to be 50 mg/kg bw

Study 2

In a Combined Repeated Dose Toxicity Study with the Reproduction/ Developmental Toxicity Screening Test,Crl:CD (SD)male and female rats treated with test material in the concentration of 0, 1.6, 8 and 40 mg/kg/day orally by gavage in0.5 % Methylcellulose aqueous solution. 1 male and 4 female died and 3 male and 1 female were sacrificed due to morbidity at 40 mg/kg bw. No effect on survival of treated rats were observed at 1.6 and 8 mg/kg bw as compared to control, Decreased spontaneous activity, Prone position, Bradypnea, Abnormal respiratory tones, Hypothermia, Abnormal gait, Soft stool, Emaciation, Abdominal distention, Dirty around anus, Soiled perineal region, External genital bleeding and test article-colored feces were observed in dead treated rats as compared to control. Soft stool and dirty around anus in male and female and External genital bleeding in Female surviving rats at 40 mg/kg/day. Colored feces were observed in 1.6 and 8 mg/kg bw treated rats.Decrease in body-weight and body-weight gain were observed in male and body weight gain in female rats and decrease in food consumption were observed in male and female rats as compared to control at40 mg/kg/day.Bradypnea, Prone position, Decrease in spontaneous activity,incompleteeyelid opening and abnormal gait in died animals and noeffects on surviving animals wereobserved.No effect on ureinanalysis wasobserved in male rats as compared to control.Similarly,Increase in the PLT was observed in male and female ratsas compared to control at40 mg/kg/day. Increase in the AST and ALT in male, CPK and BUN were observed in extremely killed male and female rat at 40 mg/kg/day. Decrease in the TP and alpha 1-glb, Increase in the Alb, A/G and BUN in male and increase in the BUN (tendency) in Female rats were observed as compared to control in survival animals. No effect on organ weight of treated was male and female rats were observed as compared to control. Light violet aqueous content and discoloration of mucus membrane in all of the alimentary tract containing oral cavity, subcutaneous tissues and uterus (sporadically noticed in Male and Female), Hydrothorax in thoracic cavity (Male 1/4, Female 2/5), Small thymus (Male 3/4, Female 2/5), Small spleen (Male 1/4, Female 2/5), Edema in thymus (Male 1/4), Reddish urine in gallbladder (Male 1/4), Red discoloration in mucosa of the bladder (Male 1/4), Red discoloration of testis (Male 1/4), Red discoloration of adipose tissue around the testis (Male 1/4), Dilatation of stomach (Female 4/5), Enlargement of adrenal (Female 4/5), Gas retention in stomach (Female 2/5), Dark red viscous retention in vagina (Female 2/5), Dilatation of cecum (Female 1/5), Gas retention in cecum (Female 1/5) observed in extremely killed animals and Light violet aqueous content in alimentary tract in surviving male and female rats at 40 mg/kg/day. Light violet aqueous content in stomach and cecum were observed in male rats (3/12) at 8 mg/kg/day. Trachea; Desquamation of epithelium and inflammatory cell infiltration of mucosa (Male 1/4, Female 2/5), Glandular stomach; Atrophy of epithelial cell (Male 1/4, Female 1/5), Small/large intestine; Hypertrophy of epithelial cell (sporadically observed in Male and Female), Liver; Hypertrophy of centrilobular hepatocyte (Male 3/4, Female 3/5), Necrosis (Male 1/4, Female 2/5), Vacuolation (Male 1/4), Adrenal; Hypertrophy of zona fasciculata (Male 2/4, Female 5/5), Bone marrow; Deficient erythropoiesis and granulopoiesis (Male 3/4, Female 2/5), Spleen; Atrophy of follicle / marginal zone (Male 2/4, Female 5/5) and periarterial lymphatic sheath (Male 3/4, Female 5/5), Thymus; Atrophy (Male 4/4, Female 3/5) /necrosis of lymphocyte (Male 3/4, Female 4/5), Lymph node; Atrophy of follicle / paracortex (Male 3/4, Female 5/5), Spinal cord / fourth ventricle / testis / urinary bladder; Hemorrhage or hemorrhagic infarction (Male 1/4), Vagina; Hemorrhage (Female 2/5), Mucoid degeneration of mucosa (Female 2/5), Lung; Hemorrhage of alveolus, edema of alveolus and inflammatory cell infiltration (Female 1/5) were observed as compared to control in extremis killed animals and Liver; Hypertrophy of centrilobular hepatocyte (Male 2/4), Duodenum; Hypertrophy of epithelial cell (Male 2/4, Female 6/7), Mesenteric lymph node and Sinus histiocytosis (Male 1/4, Female 3/7) were observed as compared to control in survival animals at 40 mg/kg/day. In addition no reproductive effect such as Estrous cyclicity, copulation and implantation, Fertility rat, gestation period, implantation index, live birth index, delivery index were observed in treated rats as compared to control. No effect on viability, development and growth of pups were observed in treated rats as compared to control. Therefore, NOAEL was considered to be 40 mg/kg/day for P and F1 generation whenCrl:CD (SD)male and female rats treated with test material orally by gavage.

Based on the data available from different studies, NOAEL for test material was considered to be 50 mg/kg /day for reproductive toxicity, when male and female rats were treated with test material orally. Thus, comparing this value with the criteria of CLP regulation test material is not likely to classify as reproductive toxicant.

Effects on developmental toxicity

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

Justification for classification or non-classification

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

Additional information