3-nitrobenzoic acid

Endpoint summary

Key value for chemical safety assessment

Toxic effect type:

concentration-driven

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 100 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

Reference

Endpoint:

one-generation reproductive toxicity

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

data from handbook or collection of data

Justification for type of information:

Data is from J check

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:

Combined repeated dose reproduction / developmental toxicity Screen of test chemical was performed in rats orally

GLP compliance:

not specified

Limit test:

no

Justification for study design:

Data is from J check

Species:

rat

Strain:

Crj: CD(SD)

Details on species / strain selection:

No data

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: No data available
- Age at study initiation: 9 weeks old (initiation of dosing)
- Weight at study initiation: 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

IN-LIFE DATES: From: To: No data available

Route of administration:

oral: gavage

Type of inhalation exposure (if applicable):

not specified

Vehicle:

other: 0.1w/v% Tween 80 + 0.5w/v% Sodium carboxymethylcellulose solution

Details on exposure:

PREPARATION OF DOSING SOLUTIONS: Test chemical was dissolved in 0.1 w/v% Tween 80 + 0.5 w/v% Sodium carboxymethylcellulose solution at dose levels of 0, 20, 100 or 500 mg/Kg bw/day

DIET PREPARATION
- Rate of preparation of diet (frequency): No data available
- Mixing appropriate amounts with (Type of food): No data available
- Storage temperature of food: No data available

VEHICLE
- Justification for use and choice of vehicle (if other than water): 0.1 w/v% Tween 80 + 0.5 w/v% Sodium carboxymethylcellulose solution
- Concentration in vehicle: 0, 20, 100 or 500 mg/kg bw/day
- Amount of vehicle (if gavage): No data available
- Lot/batch no. (if required): No data available
- Purity: No data available

Details on mating procedure:

No data available

Analytical verification of doses or concentrations:

not specified

Details on analytical verification of doses or concentrations:

No data

Duration of treatment / exposure:

42 days

Frequency of treatment:

Daily

Details on study schedule:

No data available

Remarks:

Doses / Concentrations:
0, 20, 100 or 500 mg/kg/day
Basis:
no data

No. of animals per sex per dose:

Total: 116
0 mg/kg/day: 12 male, 12 female
20 mg/kg/day: 12 male, 12 female
100 mg/kg/day: 12 male, 12 female
500 mg/kg/day: 12 male, 12 female

Recovery:
0 mg/kg/day: 5 male, 5 female
500 mg/kg/day: 5 male, 5 female

Control animals:

yes, concurrent vehicle

Details on study design:

No data

Positive control:

No data

Parental animals: Observations and examinations:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: No data available
- Cage side observations checked in table [No.?] were included. Mortality were observed

DETAILED CLINICAL OBSERVATIONS: Yes, animal were observed for salivation
- Time schedule: No data available

BODY WEIGHT: Yes
- Time schedule for examinations: Observed during dosing period

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- 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 : No data

FOOD EFFICIENCY:
- 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: No data

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No data
- Time schedule for examinations:
No data

HAEMATOLOGY: Yes
- Time schedule for collection of blood: No data
- Anaesthetic used for blood collection: No data
- Animals fasted: No data
- How many animals: No data
- Parameters checked in table [No.?] were examined. Red blood cell count, hemoglobin concentration and hematocrit value were examined.

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: No data
- Animals fasted: No data
- How many animals: No data
- Parameters checked in table [No.?] were examined. A/G ratio, Pi, K, BUN, TP, Cl and ALT were examined.

OTHER:
Organ weight: Brain R, Liver R, Kidney R, Testes A/R, Epididymides A/R, Thymus A and Spleen A/R were weighed.

Oestrous cyclicity (parental animals):

Any irregularities in the estrous cycle were investigated.

Sperm parameters (parental animals):

No data

Litter observations:

Number of live offspring, clinical signs and body weight were observed.

Postmortem examinations (parental animals):

SACRIFICE
- Male animals: No detailed data available
- Maternal animals: No data available

GROSS NECROPSY and HISTOPATHOLOGY / ORGAN WEIGHTS
The target organs for the study were Stomach, Bone, Testes, Epididymides, (Female genital tract)

Postmortem examinations (offspring):

No detailed data available

Statistics:

No data

Reproductive indices:

Gestation index, delivery index, number of corpora lutea, number of implantations, implantation index and number of offspring delivered were observed

Offspring viability indices:

Offspring viability on day 0 and 4 were observed

Clinical signs:

effects observed, treatment-related

Description (incidence and severity):

Salivation was observed in 500 mg/kg bw/day treated male and female rats as compared to control and and decrease in locomotor activity, irregular respiration, prone position and drastic worsening was observed in female rat.

Dermal irritation (if dermal study):

not specified

Mortality:

mortality observed, treatment-related

Description (incidence):

When treated with 500 mg/kg bw/day, three female rats died as compared to control.

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

Restrained body weight gain was observed in 500 mg/kg bw/day treated male rat as compared to control.

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Description (incidence and severity):

On day 8, Decrease in the food consumption was observed in 500 mg/kg bw/day treated male and female rat 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

Clinical biochemistry findings:

effects observed, treatment-related

Urinalysis findings:

no effects observed

Description (incidence and severity):

No effects was observed in treated male and female rat as compared to control.

Behaviour (functional findings):

no effects observed

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):

In male rat, Squamous hyperplasia, Erosion and Focal inflammatory cell infiltration in the forestomach, Small and soft testes, Small epididymides, Degeneration in seminiferous tubular epithelium of testes, Decrease sperm in the epididymides duct, Cell debris in epididymides duct and Increase in the trabecular bone in femur bone were observed in 500 mg/kg bw/day during treatment and recovery.

In female rat, Squamous hyperplasia and Erosion in forestomach during test and Increase in trabecular bone in femur bone during test and Recovery at in 500 mg/kg bw/day treated female rats.

Histopathological findings: neoplastic:

not specified

Other effects:

not specified

Reproductive function: oestrous cycle:

no effects observed

Description (incidence and severity):

No effects were observed on estrous cycle, irregular estrous cycle, mating index, mating days until copulation, number of estrous stages without mating.

Reproductive function: sperm measures:

not specified

Reproductive performance:

effects observed, treatment-related

Description (incidence and severity):

No effects were observed on estrous cycle, irregular estrous cycle, mating index, mating days until copulation, number of estrous stages without mating, fertility index, gestation period and parturition or maternal behavior of treated rat.

Reproductive performance:
Decrease in gestation index, delivery index, number of corpora lutea, number of implantation sites, implantation index and number of pups delivered were observed in 500 mg/kg bw/day treated female rats.

Mortality:
When treated with 500 mg/kg bw/day, three female rats died as compared to control.

Clinical signs:
Salivation was observed in 500 mg/kg bw/day treated male and female rats as compared to control and and decrease in locomotor activity, irregular respiration, prone position and drastic worsening was observed in female rat.

Body weight and weight gain:
Restrained body weight gain was observed in 500 mg/kg bw/day treated male rat as compared to control.

Food consumption:
On day 8, Decrease in the food consumption was observed in 500 mg/kg bw/day treated male and female rat as compared to control.

Urinalysis:
No effects was observed in treated male and female rat as compared to control.

Hematology:
Decrease in the RBC, Hgb and Hct level were observed in 500 mg/kg bw/day treated male and female rat as compared to control.

Blood chemistry:
In male rats, Increase in the A/G ratio, Pi, K, and Decrease in Blood Urea Nitrogen, total protein and Cl level were observed in 500 mg/kg bw/day.

In female rats, Increase in ALT was observed in 500 mg/kg bw/day.

Organ weight:
In male rats, Increase in Relative brain, liver and kidney weight and Decrease in Absolute and Relative testes and epididymides weight during test and recovery and Absolute thymus weight during test were observed in 500 mg/kg bw/day.

In female, Increase in Relative liver and spleen weight during test and recovery and Absolute spleen and kidney weight in recovery and Decrease in Absolute thymus weight during test were observed in 500 mg/kg bw/day.

Histopathology:
In male rat, Squamous hyperplasia, Erosion and Focal inflammatory cell infiltration in the forestomach, Small and soft testes, Small epididymides, Degeneration in seminiferous tubular epithelium of testes, Decrease sperm in the epididymides duct, Cell debris in epididymides duct and Increase in the trabecular bone in femur bone were observed in 500 mg/kg bw/day during treatment and recovery.

In female rat, Squamous hyperplasia and Erosion in forestomach during test and Increase in trabecular bone in femur bone during test and Recovery at in 500 mg/kg bw/day treated female rats.

Reproductive function:
No effects were observed on estrous cycle, irregular estrous cycle, mating index, mating days until copulation, number of estrous stages without mating, fertility index, gestation period and parturition or maternal behavior of treated rat.

Reproductive performance:
Decrease in gestation index, delivery index, number of corpora lutea, number of implantation sites, implantation index and number of pups delivered were observed in 500 mg/kg bw/day treated female rats.

Dose descriptor:

NOAEL

Effect level:

100 mg/kg bw/day

Based on:

test mat.

Sex:

male/female

Basis for effect level:

reproductive function (oestrous cycle)

reproductive performance

other: Effects were observed at 500 mg/kg bw/day

Remarks on result:

other: effects observed at 500mg/kg bw

Critical effects observed:

not specified

Clinical signs:

no effects observed

Description (incidence and severity):

No effect were observed on Clinical signs of pups

Dermal irritation (if dermal study):

not specified

Mortality / viability:

mortality observed, treatment-related

Description (incidence and severity):

When treated with 500 mg/kg/day, decrease in number of live pups on day 4 were observed as compared to control.

Body weight and weight changes:

no effects observed

Description (incidence and severity):

No change in body weight of pups was observed in treated rats.

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:

no effects observed

Description (incidence and severity):

No abnormal changes were observed in Gross pathology of pups.

Histopathological findings:

not specified

Other effects:

not specified

Behaviour (functional findings):

not specified

Developmental immunotoxicity:

not specified

Mortality: When treated with 500 mg/kg/day, decrease in number of live pups on day 4 were observed as compared to control.

Clinical signs: No effect were observed on Clinical signs of pups

Body weight: No change in body weight of pups was observed in treated rats.

Food consumption: No data available

Gross pathology: No abnormal changes were observed in Gross pathology of pups.

Dose descriptor:

NOAEL

Generation:

F1

Effect level:

100 mg/kg bw/day

Based on:

test mat.

Sex:

male/female

Basis for effect level:

viability

clinical signs

mortality

body weight and weight gain

gross pathology

other: No of pups delivered. The effects were observed at 500 mg/Kg bw/day

Remarks on result:

other: No of pups delivered. The effects were observed at 500 mg/Kg bw/day

Critical effects observed:

not specified

Reproductive effects observed:

not specified

Treatment related:

not specified

Conclusions:

The no-observed-adverse-effect-level (NOAEL) was considered to be 100 mg/kg/day for F0 and F1 generation when Crl:CD(SD) male and female rat were treated with test chemical orally.

Executive summary:

In Combined Repeated Dose Toxicity Study with the Reproduction/ Developmental Toxicity Screening Test, Crl:CD (SD) male and female rats were treated with test chemical in the concentration of 0, 20, 100 and 500 mg/kg bw/day orally by gavage. In F0 generation, when treated with 500 mg/kg/day, three female rats died, Salivation in male and female rat was noted, restrained body weight gain in male rat and decrease in the food consumption on day 8 in male and female rat were observed. Similarly, Decrease in the RBC, Hgb and Hct level in male and female rat, Increase in A/G ratio, Pi, K and Decrease in Blood Urea Nitrogen, total protein, Cl level in male rat and Increase in ALT level in female rat were observed in 500 mg/kg/day. In addition, Increase in Relative brain, liver and kidney weight and Decrease in absolute and relative testes and epididymides weight during test and recovery and absolute thymus weight during test in male rat and Increase in relative liver and spleen weight during test and recovery and absolute spleen and kidney weight in recovery and Decrease in absolute thymus weight during test in female, Squamous hyperplasia, Erosion and Focal inflammatory cell infiltration in the forestomach, Small and soft testes, Small epididymides, Degeneration in seminiferous tubular epithelium of testes, decrease sperm and cell debris in epididymides duct and an increase in the trabecular bone in femur bone in male rat and squamous hyperplasia and erosion in forestomach during test and an increase in trabecular bone in femur bone during test and recovery in female rat treated with 500 mg/kg/day. Decrease in gestation index, delivery index, number of corpora lutea, number of implantation sites, implantation index and number of pups delivered in F0 female and a decrease in number of pups delivered, number of live pups on day 0 and number of live pups on day 4 were observed in F1 generation treated with 500 mg/kg bw/day female rats. Based on the observations made, the reproductive No Observed Adverse Effect Level (NOAEL) was considered to be 100 mg/kg body/day for F0 and F1 generation when Crl:CD (SD) male and female rats were treated with test chemical.

Effect on fertility: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

100 mg/kg bw/day

Study duration:

chronic

Species:

rat

Quality of whole database:

Data is Klimicsh 2 and from authoritative database

Effect on fertility: via inhalation route

Endpoint conclusion:

no study available

Effect on fertility: via dermal route

Endpoint conclusion:

no study available

Additional information

Reproductive toxicity study

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

Study 1

InCombined repeated dose reproduction /developmental toxicity study ,Crl: CD (SD) male and female rat treated withtest chemicalin the concentration of0, 20, 100, 500 mg/kg/dayorally.Toxic changes were observed as death in females at 500mg/kg/day,Salivation in male and female, decrease in locomotor activity, irregular respiration, prone position and drastic worsening in female, decrease in body weight gain andincrease food consumption in male rats. Significant decreases in red blood cell count, hemoglobin concentration, and hematocrit value of male and female rat, increase in A/G ratio, Pi, K and decreased BUN, TP and Cl level were observed in male rat and increase in ALT level in female rats when treated with 500 mg/kg/day. Changes in absolute and relative weigh of Brain, Liver, Kidney, Testes, Epididymides, Thymus and Spleen were observed. Squamous hyperplasia, Erosion and Focal inflammatory cell infiltration in the forestomach, Small and soft testes, Small epididymides, Degeneration in seminiferous tubular epithelium in the testes, Decrease in sperm and Cell debris in the epididymides duct and increase in trabecular bone in the femur bone were observed in 500 mg/kg/day treated and in recovery period male and female rats.In addition,Decrease in gestation index,delivery index, number of corpora lutea, number of implantations, implantation index, number of offspring delivered and number of live offspring on days 0 and 4 were observed in 500 mg/kg/day.Therefore, NOAEL was considered to be100 mg/kg/dayforF0 and F1 generation when Crl:CD(SD) male and female rat treated withtest chemical orally for 42 days.

 

Study 2

In a Combined repeated dose reproduction /developmental toxicity study, VAF Crl: Swiss CD-l (ICR) BR outbred albino male and female mice treated with test chemical in the concentration of0, 0.35, 0.75 or 1.50% (Males: 0, 520, 1220 or 2780 mg/Kg/day; Females: 0, 540, 1340 or 3050 mg/Kg/day)  orally in diet. Significant decrease were observed in body weight of male and female mice, Significant decrease in kidney weights (both absolute and adjusted), absolute ovary weight and absolute liver weight in female mice and absolute seminal vesicles weights in male mice when treated with 0.75 and 1.50 %. Significant decrease in mean number of litters per fertile pair, mean number of live pups per litter (both sexes) and live pup weight (absolute and adjusted) and Significant increase in cumulative days to litter for pairs were observed in 0.75 and 1.50 % treated mice. Mild Cystic Left Ovary and Amyloidosis were observed in 1.50 % treated female mice as compared to control in f0 generation. On F1 pups evaluation, Decreased in postnatal male and female pups survival, Significant decreased in postnatal body weight, absolute ovary, liver, absolute and adjusted kidney, seminal vesicle, right cauda and epididymis weights of treated male pups and absolute ovary, liver, kidney, seminal vesicle, right cauda and epididymis weights were significantly decrease and adjusted liver weight was significantly increased in female pups when treated with 1.50 %. Significant decreased in absolute liver weight of male pups at 0.75 % were observed. In addition, decreased in number of live female pups per litter and Minimal to Mild Cystic Ovary were observed in 0.75 and 1.50 % treated pups as compared to control. Therefore, The no-observed-adverse-effect-level (NOAEL) was considered to be 0.35 % (520 mg/kg/day for males and 540 mg/kg/day for females) for F0 and F1 generation when VAF Crl:Swiss CD-l (ICR)BR outbred albino male and female mice treated with test chemical.

 

Thus based on the above annotation and CLP criteria the test chemical is not likely to exhibit reproductive toxicant substance. Hence the substance cannot be classified as reproductive toxicant.

 

Effects on developmental toxicity

Description of key information

Developmental toxicity study

Based on the various studies available for the test chemical were reviewed to determine the developmental toxicity, NOAELfor test chemical was considered to be100 mg /kg bw/day .When rats were treated with test chemical orally. Thus, comparing this value with the criteria ofCLP regulationtest chemicalis not likely to classify as reproductive and developmental toxicant.

Link to relevant study records

Reference

Endpoint:

developmental toxicity

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

data from handbook or collection of data

Justification for type of information:

Data is from J check

Qualifier:

according to guideline

Guideline:

other: OECD Test Guideline 422

Principles of method if other than guideline:

The 42 days feeding study was conducted on groups of 12 Males and 12 females Crl:CD(SD) rats to determine the developmental toxicity effect of test chemical

GLP compliance:

not specified

Limit test:

no

Species:

rat

Strain:

Crj: CD(SD)

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: No data available
- Age at study initiation: 9 weeks old (initiation of dosing)
- Weight at study initiation: 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

IN-LIFE DATES: From: To: No data available

Route of administration:

oral: gavage

Type of inhalation exposure (if applicable):

not specified

Vehicle:

other: 0.1w/v% Tween 80 + 0.5w/v% Sodium carboxymethylcellulose solution

Details on exposure:

PREPARATION OF DOSING SOLUTIONS:test chemical was disssolved in 0.1 w/v% Tween 80 + 0.5 w/v% Sodium carboxymethylcellulose solution at dose levels of 0, 20, 100 or 500 mg/Kg bw/day

DIET PREPARATION
- Rate of preparation of diet (frequency): No data available
- Mixing appropriate amounts with (Type of food): No data available
- Storage temperature of food: No data available

VEHICLE
- Justification for use and choice of vehicle (if other than water): 0.1 w/v% Tween 80 + 0.5 w/v% Sodium carboxymethylcellulose solution
- Concentration in vehicle: 0, 20, 100 or 500 mg/kg bw/day
- Amount of vehicle (if gavage): No data available
- Lot/batch no. (if required): No data available
- Purity: No data available

Analytical verification of doses or concentrations:

not specified

Details on analytical verification of doses or concentrations:

No data

Details on mating procedure:

No data available

Duration of treatment / exposure:

Males, 42 days
Females, from 14 days before mating to day 4 of lactation
Females (satellite), 42 days

Frequency of treatment:

daily

Duration of test:

Males, 42 days
Females, from 14 days before mating to day 4 of lactation
Females (satellite), 42 days

Remarks:

Doses / Concentrations:
0, 20, 100 or 500 mg/kg bw/day
Basis:
no data

No. of animals per sex per dose:

Total: 116
0 mg/kg bw/day: 12 males, 12 females
20 mg/kg bw/day: 12 males, 12 females
100 mg/kg bw/day: 12 males, 12 females
500 mg/kg bw/day: 12 males, 12 females

For recovery
0 mg/kg bw/day: 5 males, 5 females
500 mg/kg bw/day: 5 males, 5 females

Control animals:

yes, concurrent vehicle

Details on study design:

- Dose selection rationale: No data available
- Rationale for animal assignment (if not random): No data available
- Other: No data available

Maternal examinations:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule:
- Cage side observations checked in table [No.?] were included. The animals were observed for mortality

DETAILED CLINICAL OBSERVATIONS: Yes, the animals were observed for salivation
- Time schedule: No data

BODY WEIGHT: Yes
- Time schedule for examinations: No data

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: No data
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: No data

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No data
- Time schedule for examinations: No data

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day # No data
- Organs examined: Liver, sleen, thymus and kidney weight was examined

OTHER: Histopathology of forestomach, small and soft testes, small epididymides, seminiferous tubular epithelium in the testes, sperm in the epididymides duct, Cell debris in the epididymides duct, trabecular bone in the femur bone

Ovaries and uterine content:

Implantation sites and corpora lutea were observed

Fetal examinations:

Number of pups delivered and number of live pups were examined.

Statistics:

No data available

Indices:

Gestation index, delivery index and implantation index were examined.

Historical control data:

No data available

Clinical signs:

effects observed, treatment-related

Dermal irritation (if dermal study):

not specified

Mortality:

mortality observed, treatment-related

Body weight and weight changes:

effects observed, treatment-related

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

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

Clinical biochemistry findings:

effects observed, treatment-related

Urinalysis findings:

no effects observed

Behaviour (functional findings):

not specified

Immunological findings:

not specified

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Gross pathological findings:

not specified

Neuropathological findings:

not specified

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Histopathological findings: neoplastic:

not specified

Other effects:

not specified

Number of abortions:

not specified

Pre- and post-implantation loss:

effects observed, treatment-related

Total litter losses by resorption:

not specified

Early or late resorptions:

not specified

Dead fetuses:

not specified

Changes in pregnancy duration:

not specified

Changes in number of pregnant:

not specified

Other effects:

not specified

Details on maternal toxic effects:

Maternal toxic effects:yes.
Remark: Decrease in the gestation index, delivery index, number of corpora lutea, number of implantation sites and implantation index (tendency) was noted at 500 mg/Kg/day

Mortality:
When treated with 500 mg/kg bw/day, three female rats died as compared to control.

Clinical signs:
Salivation was observed in 500 mg/kg bw/day treated male and female rats as compared to control.

Body weight and weight gain:
Restrained body weight gain was observed in 500 mg/kg bw/day treated male rat as compared to control.

Food consumption:
On day 8, Decrease in the food consumption was observed in 500 mg/kg bw/day treated male and female rat as compared to control.

Urinalysis:
No effects was observed in treated male and female rat as compared to control.

Hematology:
Decrease in the RBC, Hgb and Hct level were observed in 500 mg/kg bw/day treated male and female rat as compared to control.

Blood chemistry:
In male rats, Increase in the A/G ratio, Pi, K, and Decrease in Blood Urea Nitrogen, total protein and Cl level were observed in 500 mg/kg bw/day.

In female rats, Increase in ALT was observed in 500 mg/kg bw/day.

Organ weight:
In male rats, Increase in Relative brain, liver and kidney weight and Decrease in Absolute and Relative testes and epididymides weight during test and recovery and Absolute thymus weight during test were observed in 500 mg/kg bw/day.

In female, Increase in Relative liver and spleen weight during test and recovery and Absolute spleen and kidney weight in recovery and Decrease in Absolute thymus weight during test were observed in 500 mg/kg bw/day.

Reproductive performs:
Decrease in gestation index, delivery index, number of corpora lutea, number of implantation sites, implantation index and number of pups delivered were observed in 500 mg/kg bw/day treated female rats.

Histopathology:
In male rat, Squamous hyperplasia, Erosion and Focal inflammatory cell infiltration in the forestomach, Small and soft testes, Small epididymides, Degeneration in seminiferous tubular epithelium of testes, Decrease sperm in the epididymides duct, Cell debris in epididymides duct and Increase in the trabecular bone in femur bone were observed in 500 mg/kg bw/day during treatment and recovery.

In female rat, Squamous hyperplasia and Erosion in forestomach during test and Increase in trabecular bone in femur bone during test and Recovery at in 500 mg/kg bw/day treated female rats.

Dose descriptor:

NOAEL

Effect level:

100 mg/kg bw/day (actual dose received)

Based on:

test mat.

Basis for effect level:

other: Significant alterations were noted at 500 mg/Kg/day

Remarks on result:

other: Not toxic at the mentioned dose level

Abnormalities:

not specified

Fetal body weight changes:

not specified

Reduction in number of live offspring:

effects observed, treatment-related

Changes in sex ratio:

not specified

Changes in litter size and weights:

not specified

Changes in postnatal survival:

not specified

External malformations:

not specified

Skeletal malformations:

not specified

Visceral malformations:

not specified

Other effects:

not specified

Details on embryotoxic / teratogenic effects:

Embryotoxic / teratogenic effects:yes. Remark: Decrease in number of pups delivered, number of live pups on day 0 and number of live pups on day 4 in 500 mg/kg bw/day treated female rats was noted

Dose descriptor:

NOAEL

Effect level:

100 other: mg/Kg/day

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: Significant treatment related effects were noted at 500 mg/Kg/day

Abnormalities:

not specified

Developmental effects observed:

not specified

Treatment related:

not specified

Conclusions:

The No Observed Adverse Effect Level (NOAEL) was considered to be 100 mg/kg body/day for F0 and F1 generation when Crl:CD (SD) male and female rats were treated with test chemical

Executive summary:

In Combined Repeated Dose Toxicity Study with the Reproduction/ Developmental Toxicity Screening Test, Crl:CD (SD) male and female rats were treated with test chemical in the concentration of 0, 20, 100 and 500 mg/kg bw/day orally by gavage. In F0 generation, when treated with 500 mg/kg/day, three female rats died, Salivation in male and female rat was noted, restrained body weight gain in male rat and decrease in the food consumption on day 8 in male and female rat were observed. Similarly, Decrease in the RBC, Hgb and Hct level in male and female rat, Increase in A/G ratio, Pi, K and Decrease in Blood Urea Nitrogen, total protein, Cl level in male rat and Increase in ALT level in female rat were observed in 500 mg/kg/day. In addition, Increase in Relative brain, liver and kidney weight and Decrease in absolute and relative testes and epididymides weight during test and recovery and absolute thymus weight during test in male rat and Increase in relative liver and spleen weight during test and recovery and absolute spleen and kidney weight in recovery and Decrease in absolute thymus weight during test in female, Squamous hyperplasia, Erosion and Focal inflammatory cell infiltration in the forestomach, Small and soft testes, Small epididymides, Degeneration in seminiferous tubular epithelium of testes, decrease sperm and cell debris in epididymides duct and an increase in the trabecular bone in femur bone in male rat and squamous hyperplasia and erosion in forestomach during test and an increase in trabecular bone in femur bone during test and recovery in female rat treated with 500 mg/kg/day. Decrease in gestation index, delivery index, number of corpora lutea, number of implantation sites, implantation index and number of pups delivered in F0 female and a decrease in number of pups delivered, number of live pups on day 0 and number of live pups on day 4 were observed in F1 generation treated with 500 mg/kg bw/day female rats. Based on the observations made, No Observed Adverse Effect Level (NOAEL) was considered to be 100 mg/kg body/day for F0 and F1 generation when Crl:CD (SD) male and female rats were treated with test

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

100 mg/kg bw/day

Study duration:

subacute

Species:

rat

Quality of whole database:

Data available from J check

Effect on developmental toxicity: via inhalation route

Endpoint conclusion:

no study available

Effect on developmental toxicity: via dermal route

Endpoint conclusion:

no study available

Additional information

Developmental toxicity study

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

Study 1

InCombined Repeated Dose Toxicity Study with the Reproduction/ Developmental Toxicity Screening Test,Crl:CD (SD) male and female rats treated with test chemical in the concentration of 0, 20, 100 and 500 mg/kg bw/day orally by gavage. In F0 generation, when treated with 500 mg/kg/day,Three female rats died, Salivation in male and female rat,Restrained body weight gain in male rat andDecrease in the food consumption on day 8 in male and female rat were observed. Similarly, Decrease in the RBC, Hgb and Hct level in male and female rat, Increase in A/G ratio, Pi, K and Decrease in Blood Urea Nitrogen, total protein, Cl level in male rat and Increase in ALT level in female rat were observed in 500 mg/kg/day. In addition, Increase in Relative brain, liver and kidney weight and Decrease in absolute and relative testes and epididymides weight during test and recovery and absolute thymus weight during test in male rat and Increase in relative liver and spleen weight during test and recovery and absolute spleen and kidney weight in recovery and Decrease in absolute thymus weight during test in female, Squamous hyperplasia, Erosion and Focal inflammatory cell infiltration in the forestomach, Small and soft testes, Small epididymides, Degeneration in seminiferous tubular epithelium of testes, Decrease sperm and Cell debris in epididymides duct and Increase in the trabecular bone in femur bone in male rat and Squamous hyperplasia and Erosion in forestomach during test and Increase in trabecular bone in femur bone during test and recovery in female rat treated with 500 mg/kg/day. Decrease in gestation index, delivery index, number of corpora lutea, number of implantation sites, implantation index and number of pups delivered in F0 female andDecrease in number of pups delivered, number of live pups on day 0 and number of live pups on day 4 were observed in F1 generation treated with500 mg/kg bw/day female rats. Therefore,NOAEL was considered to be 100mg/kg body weight/dayfor F0 and F1 generation when Crl: CD (SD) male and female rats were treated with test chemical orally by gavage for 42 days.

 

Study 2

In a Inhalation developmental toxicity, Wistar female rat were treated with test chemicalin the concentration of 0, 0.4, 1.0 and 2.9 mg/m³by whole body inhalation.Significant increase in aspartate aminotransferase, alanine aminotransferase and lipid peroxidation.Dose dependent retardation of the body weight andSignificantly decrease in relative liver weights of 1.0 and 2.9 mg/m³treated female rat were observed.Significantly increased in embryolethalitywas observed in1.0 and 2.9 mg/m³treated female rat.On F1 generation evaluation, Significant changes in behavior in the open field test,significantly decreased in relative weight of liver, heart; lungs and adrenal gland were observed in pups at 0 and 2.9 mg/m³. In addition, Significantly decrease in number of metacarpal bones and number of ribs and Significant delayed in Upper and lower incisor eruption was observed in 2.9 mg/m³treated pups. Therefore, NOEL was considered to be 0.4 mg/m³for Wistar female rat when treated with test chemical by whole body inhalation.

Thus, based on the data available fortest chemical,Low Observed Adverse Effect Level (NOAEL) was considered to be 100 mg /kg bw .When rats were treated with test chemical orally. Thus, comparing this value with the criteria of CLP regulationtest chemicalis not likely to classify as reproductive and developmental toxicant.

 

Justification for classification or non-classification

Test chemical is found to exhibit non toxic reproductive effects. Also, the majority use of this chemical is used as a solvent form to color topical drug preparations and cosmetics. Thus, exposure to high levels of test chemical is likely to be minimal and hence the chemical has not be considered as toxic to reproduction and developmental toxicity for classification