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Toxicological information

Repeated dose toxicity: oral

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Administrative data

Endpoint:
repeated dose toxicity: oral
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
data from handbook or collection of data
Remarks:
Experimental data from various test chemicals
Justification for type of information:
Data for the target chemical is summarized based on data from various test chemicals
Cross-referenceopen allclose all
Reason / purpose for cross-reference:
read-across source
Reference
Endpoint:
repeated dose toxicity: oral
Remarks:
combined repeated dose and reproduction / developmental screening
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
4 (not assignable)
Rationale for reliability incl. deficiencies:
secondary literature
Justification for type of information:
Data is from secondary literature
Qualifier:
according to guideline
Guideline:
other: Refer below principle
Principles of method if other than guideline:
A range finding study was performed to establish the maximum tolerated dose level (up to 1000 mg/kg/day) of the test material following repeated oral administration to the Sprague DawleyCrl:CD (SD) IGS BR strain rat.
GLP compliance:
not specified
Species:
rat
Strain:
other: Sprague-Dawley (SD) IGS BR
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River (UK) Limited
- Weight at study initiation:Male rats weighed 202-240 g and females weighed 155-186 g
- Housing:Animals were housed in groups of 3 by sex in polypropylene grid-floor cages suspended over trays containing absorbent paper I a controlled environment.
- Diet (e.g. ad libitum): Rodent PMI 5002 Diet, ad libitum
- Water (e.g. ad libitum):Ad libitum
- Acclimation period:At least 7 days

ENVIRONMENTAL CONDITIONS :
- Temperature (°C):21 ± 2°C
- Humidity (%):55 ± 15%
- Air changes (per hr):At least fifteen air changes per hour
- Photoperiod (hrs dark / hrs light):12-hr dark/12-hr light

Route of administration:
oral: gavage
Vehicle:
corn oil
Details on oral exposure:
PREPARATION OF DOSING SOLUTIONS
The test material was prepared as a solution in corn oil. A fresh formulation was made each day. The animals were dosed within three hours of preparation.

DIET PREPARATION
- Rate of preparation of diet (frequency): N/A
- Mixing appropriate amounts with (Type of food): N/A
- Storage temperature of food: N/A

VEHICLE
- Justification for use and choice of vehicle (if other than water): Corn oil
- Concentration in vehicle: 0, 100, 600 or 1000 mg/kg/day
- Amount of vehicle (if gavage): 4 ml/kg/day
- Lot/batch no. (if required): No data available
- Purity: No data available
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
The concentration and stability of the test material formulations were not determined analytically.
Duration of treatment / exposure:
14 days
Frequency of treatment:
Daily
Remarks:
Doses / Concentrations:
0 ,100,600 or1000 mg/kg/day
Basis:
nominal in diet
No. of animals per sex per dose:
Control: 3 males, 3 females
100 mg/kg/day: 3 males, 3 females
300 mg/kg/day: 3 males, 3 females
1000 mg/kg/day: 3 males, 3 females
Control animals:
yes, concurrent vehicle
Details on study design:
Animals were selected at random and given a unique number by ear punching.
Positive control:
No data
Observations and examinations performed and frequency:
DETAILED CLINICAL OBSERVATIONS: Yes
All animals were examined for overt signs of toxicity, ill health or behavioral change immediately before dosing and one hour after dosing.

BODY WEIGHT: Yes
Individual bodyweights were recorded on Days 1, 4, 8, 11 and 14.



Sacrifice and pathology:
GROSS PATHOLOGY: Yes
All animals were killed by cervical dislocation and immediately subjected to an internal and external macroscopic examination. No tissues were retained.

HISTOPATHOLOGY: Yes
Other examinations:
Necropsy data, bodyweights and clinical observations were examined for any adverse effects resulting from treatment.
Statistics:
No data
Clinical signs:
no effects observed
Description (incidence and severity):
No clinically observable signs of toxicity were detected for animals of either sex treated with 600 and 100 mg/kg/day.
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Description (incidence and severity):
No adverse effects on bodyweight development were detected for 600 mg/kg/d any males or for animals of either sex treated with 100 mg/kg/day.
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 examined
Urinalysis findings:
not specified
Behaviour (functional findings):
not specified
Immunological findings:
not specified
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
no effects observed
Description (incidence and severity):
No macroscopic abnormalities were detected for animals of either sex treated with 600 and 100 mg/kg/day or control animals at terminal kill.
Neuropathological findings:
not specified
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Histopathological findings: neoplastic:
not specified
Other effects:
not specified
Details on results:
mortality :
One male treated with 1000 mg/kg/day was killed in extremis on Day 10.

Clinical signs:
when treated with 1000 mg/kg/day, in male rats increased salivation, hunced posture, tiptoe gait and pallor, piloerection, gasping and decreased respiration staining of the external body surface and one male displayed facial swelling and in female rats, hunched posture and tiptoe gait on day 10 and hunched posture was evident from Day 11 onwards, with increased salivation detected up to ten minute after dosing on day 13 and 14 as compared to control.
no effect were observed on 100 and 600 mg/kg/day treated male and female rats as compared to control.

Body Weight:
when treated with 1000 mg/kg/day, significant decrease in body weight gain were observed in treated male and female rats as compared to control.
when treated with 600 mg/kg/day, significant decrease in body weight gain were observed in treated and female rats as compared to control.

Gross Pathology:
when treated with 1000 mg/kg/day, pale liver and spleen in male and female, dark contents in Stomach and Small intestine of female rats were observed as compared to control.
no gross changes were observed in 100 and 600 mg/kg/day treated rats as compared to control.

Histo pathology:
enlarged liver in male rat and thickening of the gastric epithelia were observed in male and female rats treated with 1000 mg/kg/day as compared to control.

no histopathological changes were observed in 100 and 600 mg/kg/day treated rats as compared to control.
Dose descriptor:
NOAEL
Effect level:
600 mg/kg diet
Based on:
test mat.
Sex:
male
Basis for effect level:
other: No adverse effect on survival, clinical sign, body weight and gross pathology
Dose descriptor:
NOAEL
Effect level:
100 other: mg/kg/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No adverse effect on survival, clinical sign, body weight and gross pathology
Critical effects observed:
not specified
Conclusions:
The no observed adverse effect level (NOAEL) was considered to be 600 mg/kg/day for male rats and 100 mg/kg/day for female rats when Sprague-Dawley (SD) IGS BR male and female rats treated with the test chemical in 14 days repeated dose toxicity study.
Executive summary:

In a 14 day repeated dose toxicity study, Sprague-Dawley (SD) IGS BR male and female rats treated with the test chemical in the concentration of 0, 100, 600 and 1000 mg/kg/day orally by gavage. One male treated with 1000 mg/kg/day was killed in extremis on Day 10 and n male rats increased salivation, hunced posture, tiptoe gait and pallor, piloerection, gasping and decreased respiration staining of the external body surface and one male displayed facial swelling and in female rats, hunched posture and tiptoe gait on day 10 and hunched posture was evident from Day 11 onwards, with increased salivation detected up to ten minute after dosing on day 13 and 14 as compared to control. No effects were observed in 600 and 1000 mg/kg/day treated male and female rats. Significant decrease in body weight gain were observed in treated male and female rats at 1000 mg/kg/day and in female rats at 600 mg/kg/day as compared to control. in addition, Pale liver and spleen in male and female, dark contents in Stomach and Small intestine of female rats and enlarged liver in male rat and thickening of the gastric epithelia were observed in male and female rats treated with 1000 mg/kg/day as compared to control. Therefore, the no observed adverse effect level (NOAEL) was considered to be 600 mg/kg/day for male rats and 100 mg/kg/day for female rats when Sprague-Dawley (SD) IGS BR male and female rats were treated with the test chemical orally by gavage for 14 days

Reason / purpose for cross-reference:
read-across source
Reference
Endpoint:
short-term repeated dose toxicity: oral
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
4 (not assignable)
Rationale for reliability incl. deficiencies:
secondary literature
Justification for type of information:
Data is from secondary literature
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:
Repeated dose oral toxicity study was performed to determine the toxic nature of the test chemical
GLP compliance:
no
Species:
rat
Strain:
other: Sprague-Dawley Crl:CD® (SD) IGS BR
Sex:
male/female
Details on test animals or test system and environmental conditions:
No data
Route of administration:
oral: gavage
Vehicle:
corn oil
Details on oral exposure:
The test material was administered by gavage to three groups each of ten male and ten female Sprague-Dawley Crl:CD® (SD) IGS BR strain rats, for up to fifty-four consecutive days, at dose levels of 50, 250 and 600 mg/kg/day. A control group of ten males and ten females was dosed with vehicle alone (corn oil).
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
Males: 43 days; Females: up to 54 days
Frequency of treatment:
daily
Remarks:
Doses / Concentrations:
0, 50, 250, and 600 mg/kg/day
Basis:

No. of animals per sex per dose:
Number of Animals per Dose: 20
0 mg/kg/day (control) - 10 males and 10 females
50 mg/kg/day - 10 males and 10 females
250 mg/kg/day - 10 males and 10 females
600 mg/kg/day - 10 males and 10 females
Control animals:
yes, concurrent vehicle
Details on study design:
Pairing of animals within each dose group was undertaken on a one male: one female basis on Day 15 of the study, to produce litters.

Extensive functional observations were performed on five selected parental males from each dose group after the completion of the mating phase, and for five selected parental females rom each dose group on Day 4 post partum.
Positive control:
No data
Observations and examinations performed and frequency:
DETAILED CLINICAL OBSERVATIONS: Yes
BODY WEIGHT: Yes
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):yes
WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): Yes
HAEMATOLOGY: Yes,Haematology was evaluated prior to mating on five selected males and females from each dose group.
CLINICAL CHEMISTRY: Yes,blood chemistry was evaluated prior to mating on five selected males and females from each dose group.
ORGAN WEIGHTS : Yes,examined.
Sacrifice and pathology:
Sacrifice :
Males were terminated on Day 43, followed by the termination of all surviving females and offspring on Day 5 post partum. All animals were subjected to a gross necropsy examination and histopathological evaluation of selected tissues was performed.
GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes
Other examinations:
No data
Statistics:
No data
Clinical signs:
no effects observed
Description (incidence and severity):
No sign of toxicity were observed in treated rats as compared to control.
Mortality:
no mortality observed
Description (incidence):
No effect were observed on survival of treated rats as compared to control
Body weight and weight changes:
no effects observed
Description (incidence and severity):
No adverse effect on body weight was observed for males throughout the treatment period, or for females during the maturation, gestation or lactation phases of the study.
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
No adverse effect on dietary intake was detected for males throughout the treatment period, or for females during the maturation, gestation or lactation phases of the study.
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
no effects observed
Description (incidence and severity):
No overt intergroup differences were detected.
Ophthalmological findings:
not examined
Haematological findings:
no effects observed
Description (incidence and severity):
No treatment-related changes were detected prior to mating.
Clinical biochemistry findings:
effects observed, treatment-related
Description (incidence and severity):
When treated with 600 mg/kg/day, increased alkaline phosphatase levels and decreased cholesterol levels were observed in male rats as compare to control.
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Immunological findings:
not specified
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
When treated with 600 mg/kg/day, increased absolute and relative liver and adrenal weight were observed in male and female rats as compared to control.
Gross pathological findings:
no effects observed
Description (incidence and severity):
No treatment-related macroscopic abnormalities were detected for the interim death female or for the remaining animals at terminal kill.
Neuropathological findings:
not specified
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
Centrilobular hepatocyte enlargement of Liver were observed in 250 and 600 mg/kg/day treated male and female rats as compare to control.
Histopathological findings: neoplastic:
not specified
Other effects:
not specified
Details on results:
Behavioural Assessments:No treatment-related effects were detected.
Functional Performance Tests: No treatment-related effects were detected.
Sensory reactivity Assessments: No treatment-related effects were detected.
CLINICAL CHEMISTRY :
Blood Chemistry Elevated alkaline phosphatase levels were detected for males treated with 600 mg/kg/day. Males treated with 600 and 250 mg/kg/day also showed reduced cholesterol levels. No such effects were detected for females treated with 600 or 250 mg/kg/day or for animals of either sex treated with 50 mg/kg/day.
HISTOPATHOLOGY: NON-NEOPLASTIC
Histopathological examination of adult tissue revealed the following treatment-related changes:
Liver: Centrilobular hepatocyte enlargement was observed for animals of either sex treated with 600 and 250 mg/g/day, with the effect extending into the female 50 mg/kg/day dose group.
Thyroid glands: Follicular cell hypertrophy was observed for males treated with 600 and probably also at 250 mg/kg/day. No such effects were detect ed for females at these dose levels, or for animals of either sex treated with 50 mg/kg/day.
Dose descriptor:
NOAEL
Effect level:
250 other: mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: no adverse effect on survival, clinical sign, body weight, food consumption, water consumption, hematology, clinical chemistry, organ weight ,nurobehavioral parameters, gross pathology and histopathology
Dose descriptor:
LOAEL
Effect level:
600 other: mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: based on increased liver and adrenal weights and toxicity in liver and thyroid glands.
Critical effects observed:
not specified
Conclusions:
The repeated dose toxicity of the test chemical in rats by oral (gavage) route was observed at a dose concentration of 250 mg/Kg bw/day, resulted in no deaths or treatment-related changes in body weight, growth, food and water intake or behavioral assessments.Therefore the “ No observed adverse effect level (NOAEL)" for repeated dose toxicity study was considered to be 250 mg/Kg bw/day.

Executive summary:

In a combined repeated-dose/reproductive/developmental toxicity screening test, Sprague-Dawley rats (10/sex/dose) were administered test chemical suspension in corn oil, via gavage at 0, 50, 250 and 600 mg/kg-bw/day for 43 (males) and 54 (females) days. No deaths or treatment-related changes in body weight, growth, food and water intake or behavioral assessments were seen in any treatment groups. However, absolute and relative liver and adrenal weights were increased in both sexes at the 600 mg/kg-bw/day. Reduced cholesterol levels were reported in males at 250 and 600 mg/kg-bw/day, and an increased activity for alkaline phosphatase was noted in males at 600 mg/kg-bw/day; both of these effects are indicative of liver toxicity. Histopathological examination of the liver revealed centrilobular hepatocyte enlargement in all treated females and in males treated with 250 and 600 mg/kg-bw/day. In males, follicular cell hypertrophy in the thyroid glands was also observed at 600 mg/kg-bw/day.Therefore NOAEL and LOAEL of the study was considered to be 250 mg/kg-bw/day and 600 mg/kg-bw/day respectively. The repeated dose toxicity of the test chemical in rats by oral (gavage) route was observed at a dose concentration of 250 mg/Kg bw/day, resulted in no deaths or treatment-related changes in body weight, growth, food and water intake or behavioral assessments.Therefore the “ No observed adverse effect level (NOAEL)" for repeated dose toxicity study was considered to be 250 mg/Kg bw/day.

Data source

Reference
Reference Type:
review article or handbook
Title:
WoE of repeated dose oral toxicity study for CAS no 15721-78-5
Author:
Sustainability Support Services (Europe) AB
Year:
2018
Bibliographic source:
WoE report, Sustainability Support Services (Europe) AB, 2018

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
other: Refer below principle
Principles of method if other than guideline:
WoE derived based on the experimental data from various test chemicals
GLP compliance:
not specified
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
Bis(4-(1,1,3,3-tetramethylbutyl)phenyl)amine
EC Number:
239-816-9
EC Name:
Bis(4-(1,1,3,3-tetramethylbutyl)phenyl)amine
Cas Number:
15721-78-5
Molecular formula:
C28-H43-N
IUPAC Name:
4-(2,4,4-trimethylpentan-2-yl)-N-[4-(2,4,4-trimethylpentan-2-yl)phenyl]aniline
Details on test material:
CAS Number: 15721-78-5
Chemical Name: Bis(4-(1,1,3,3-tetramethylbutyl)phenyl)amine
Molecular Formula: C28H43N
Molecular Weight: 393.65 g/mol
Nature of chemical: Organic

Test animals

Species:
rat
Strain:
other: 1. Sprague-Dawley (SD) IGS BR; 2. Sprague-Dawley Crl:CD® (SD) IGS BR
Sex:
male/female
Details on test animals or test system and environmental conditions:
1. TEST ANIMALS
- Source: Charles River (UK) Limited
- Weight at study initiation:Male rats weighed 202-240 g and females weighed 155-186 g
- Housing:Animals were housed in groups of 3 by sex in polypropylene grid-floor cages suspended over trays containing absorbent paper I a controlled environment.
- Diet (e.g. ad libitum): Rodent PMI 5002 Diet, ad libitum
- Water (e.g. ad libitum):Ad libitum
- Acclimation period:At least 7 days

ENVIRONMENTAL CONDITIONS :
- Temperature (°C):21 ± 2°C
- Humidity (%):55 ± 15%
- Air changes (per hr):At least fifteen air changes per hour
- Photoperiod (hrs dark / hrs light):12-hr dark/12-hr light

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
corn oil
Details on oral exposure:
1. PREPARATION OF DOSING SOLUTIONS
The test material was prepared as a solution in corn oil. A fresh formulation was made each day. The animals were dosed within three hours of preparation.

DIET PREPARATION
- Rate of preparation of diet (frequency): N/A
- Mixing appropriate amounts with (Type of food): N/A
- Storage temperature of food: N/A

VEHICLE
- Justification for use and choice of vehicle (if other than water): Corn oil
- Concentration in vehicle: 0, 100, 600 or 1000 mg/kg/day
- Amount of vehicle (if gavage): 4 ml/kg/day
- Lot/batch no. (if required): No data available
- Purity: No data available

2. The test material was administered by gavage to three groups each of ten male and ten female Sprague-Dawley Crl:CD® (SD) IGS BR strain rats, for up to fifty-four consecutive days, at dose levels of 50, 250 and 600 mg/kg/day. A control group of ten males and ten females was dosed with vehicle alone (corn oil).
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
1. The concentration and stability of the test material formulations were not determined analytically.
2. No data
Duration of treatment / exposure:
1. 14 days
2. Males: 43 days; Females: up to 54 days
Frequency of treatment:
1. Daily
2. Daily
Doses / concentrationsopen allclose all
Remarks:
Doses / Concentrations: / 1
0 ,100, 600 or1000 mg/kg/day
Basis:
nominal in diet
Remarks:
Doses / Concentrations: / 2
0, 50, 250, and 600 mg/kg/day
Basis:
No. of animals per sex per dose:
1. Control: 3 males, 3 females
100 mg/kg/day: 3 males, 3 females
300 mg/kg/day: 3 males, 3 females
1000 mg/kg/day: 3 males, 3 females

2. Number of Animals per Dose: 20
0 mg/kg/day (control) - 10 males and 10 females
50 mg/kg/day - 10 males and 10 females
250 mg/kg/day - 10 males and 10 females
600 mg/kg/day - 10 males and 10 females
Control animals:
yes, concurrent vehicle
Details on study design:
1. Animals were selected at random and given a unique number by ear punching.
2. Pairing of animals within each dose group was undertaken on a one male: one female basis on Day 15 of the study, to produce litters.
Positive control:
1. No data

Examinations

Observations and examinations performed and frequency:
1. DETAILED CLINICAL OBSERVATIONS: Yes
All animals were examined for overt signs of toxicity, ill health or behavioral change immediately before dosing and one hour after dosing.

BODY WEIGHT: Yes
Individual bodyweights were recorded on Days 1, 4, 8, 11 and 14.

2. DETAILED CLINICAL OBSERVATIONS: Yes
BODY WEIGHT: Yes
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):yes
WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): Yes
HAEMATOLOGY: Yes,Haematology was evaluated prior to mating on five selected males and females from each dose group.
CLINICAL CHEMISTRY: Yes,blood chemistry was evaluated prior to mating on five selected males and females from each dose group.
ORGAN WEIGHTS : Yes,examined




Sacrifice and pathology:
1. GROSS PATHOLOGY: Yes
All animals were killed by cervical dislocation and immediately subjected to an internal and external macroscopic examination. No tissues were retained.

HISTOPATHOLOGY: Yes

2. Sacrifice :
Males were terminated on Day 43, followed by the termination of all surviving females and offspring on Day 5 post partum. All animals were subjected to a gross necropsy examination and histopathological evaluation of selected tissues was performed.
GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes


Other examinations:
1. Necropsy data, bodyweights and clinical observations were examined for any adverse effects resulting from treatment.
Statistics:
1. No data

Results and discussion

Results of examinations

Clinical signs:
no effects observed
Description (incidence and severity):
1. No clinically observable signs of toxicity were detected for animals of either sex treated with 600 and 100 mg/kg/day.
2. No sign of toxicity were observed in treated rats as compared to control.
Mortality:
no mortality observed
Description (incidence):
2. No effect were observed on survival of treated rats as compared to control
Body weight and weight changes:
no effects observed
Description (incidence and severity):
1. No adverse effects on bodyweight development were detected for 600 mg/kg/d any males or for animals of either sex treated with 100 mg/kg/day.
2. No adverse effect on body weight was observed for males throughout the treatment period, or for females during the maturation, gestation or lactation phases of the study.
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
2. No adverse effect on dietary intake was detected for males throughout the treatment period, or for females during the maturation, gestation or lactation phases of the study.
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
no effects observed
Description (incidence and severity):
2. No overt intergroup differences were detected.
Ophthalmological findings:
not specified
Haematological findings:
no effects observed
Description (incidence and severity):
2. No treatment-related changes were detected prior to mating.
Clinical biochemistry findings:
effects observed, treatment-related
Description (incidence and severity):
2. When treated with 600 mg/kg/day, increased alkaline phosphatase levels and decreased cholesterol levels were observed in male rats as compare to control.
Urinalysis findings:
not specified
Behaviour (functional findings):
not specified
Immunological findings:
not specified
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
2. When treated with 600 mg/kg/day, increased absolute and relative liver and adrenal weight were observed in male and female rats as compared to control.
Gross pathological findings:
no effects observed
Description (incidence and severity):
1. No macroscopic abnormalities were detected for animals of either sex treated with 600 and 100 mg/kg/day or control animals at terminal kill.
2. No treatment-related macroscopic abnormalities were detected for the interim death female or for the remaining animals at terminal kill.
Neuropathological findings:
not specified
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
2. Centrilobular hepatocyte enlargement of Liver were observed in 250 and 600 mg/kg/day treated male and female rats as compare to control.
Histopathological findings: neoplastic:
not specified
Other effects:
not specified
Details on results:
1. mortality :
One male treated with 1000 mg/kg/day was killed in extremis on Day 10.

Clinical signs:
when treated with 1000 mg/kg/day, in male rats increased salivation, hunced posture, tiptoe gait and pallor, piloerection, gasping and decreased respiration staining of the external body surface and one male displayed facial swelling and in female rats, hunched posture and tiptoe gait on day 10 and hunched posture was evident from Day 11 onwards, with increased salivation detected up to ten minute after dosing on day 13 and 14 as compared to control.
no effect were observed on 100 and 600 mg/kg/day treated male and female rats as compared to control.

Body Weight:
when treated with 1000 mg/kg/day, significant decrease in body weight gain were observed in treated male and female rats as compared to control.
when treated with 600 mg/kg/day, significant decrease in body weight gain were observed in treated and female rats as compared to control.

Gross Pathology:
when treated with 1000 mg/kg/day, pale liver and spleen in male and female, dark contents in Stomach and Small intestine of female rats were observed as compared to control.
no gross changes were observed in 100 and 600 mg/kg/day treated rats as compared to control.

Histo pathology:
enlarged liver in male rat and thickening of the gastric epithelia were observed in male and female rats treated with 1000 mg/kg/day as compared to control.

no histopathological changes were observed in 100 and 600 mg/kg/day treated rats as compared to control.

2. Behavioural Assessments:No treatment-related effects were detected.
Functional Performance Tests: No treatment-related effects were detected.
Sensory reactivity Assessments: No treatment-related effects were detected.
CLINICAL CHEMISTRY :
Blood Chemistry Elevated alkaline phosphatase levels were detected for males treated with 600 mg/kg/day. Males treated with 600 and 250 mg/kg/day also showed reduced cholesterol levels. No such effects were detected for females treated with 600 or 250 mg/kg/day or for animals of either sex treated with 50 mg/kg/day.
HISTOPATHOLOGY: NON-NEOPLASTIC
Histopathological examination of adult tissue revealed the following treatment-related changes:
Liver: Centrilobular hepatocyte enlargement was observed for animals of either sex treated with 600 and 250 mg/g/day, with the effect extending into the female 50 mg/kg/day dose group.
Thyroid glands: Follicular cell hypertrophy was observed for males treated with 600 and probably also at 250 mg/kg/day. No such effects were detect ed for females at these dose levels, or for animals of either sex treated with 50 mg/kg/day.

Effect levels

open allclose all
Dose descriptor:
NOAEL
Remarks:
1
Effect level:
600 mg/kg diet
Based on:
test mat.
Sex:
male
Basis for effect level:
other: No adverse effect on survival, clinical sign, body weight and gross pathology
Dose descriptor:
NOAEL
Remarks:
1
Effect level:
100 other: mg/kg/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No adverse effect on survival, clinical sign, body weight and gross pathology
Dose descriptor:
NOAEL
Remarks:
2
Effect level:
250 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: no adverse effect on survival, clinical sign, body weight, food consumption, water consumption, hematology, clinical chemistry, organ weight ,nurobehavioral parameters, gross pathology and histopathology

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
The no observed adverse effect level (NOAEL) was considered to be 600 mg/kg/day for male and female rats when Sprague-Dawley male and female rats were treated with the test chemical in 14 days repeated dose toxicity study.
Executive summary:

Data available for the test chemicals was reviewed to determine the toxic nature of the test chemical. The studies are as mentioned below:

In a 14 day repeated dose toxicity study, Sprague-Dawley (SD) IGS BR male and female rats treated with the test chemical in the concentration of 0, 100, 600 and 1000 mg/kg/day orally by gavage. One male treated with 1000 mg/kg/day was killed in extremis on Day 10 and n male rats increased salivation, hunced posture, tiptoe gait and pallor, piloerection, gasping and decreased respiration staining of the external body surface and one male displayed facial swelling and in female rats, hunched posture and tiptoe gait on day 10 and hunched posture was evident from Day 11 onwards, with increased salivation detected up to ten minute after dosing on day 13 and 14 as compared to control. No effects were observed in 600 and 1000 mg/kg/day treated male and female rats. Significant decrease in body weight gain were observed in treated male and female rats at 1000 mg/kg/day and in female rats at 600 mg/kg/day as compared to control. in addition, Pale liver and spleen in male and female, dark contents in Stomach and Small intestine of female rats and enlarged liver in male rat and thickening of the gastric epithelia were observed in male and female rats treated with 1000 mg/kg/day as compared to control. Therefore, the no observed adverse effect level (NOAEL) was considered to be 600 mg/kg/day for male rats and 100 mg/kg/day for female rats when Sprague-Dawley (SD) IGS BR male and female rats were treated with the test chemical orally by gavage for 14 days.

In a combined repeated-dose/reproductive/developmental toxicity screening test, Sprague-Dawley rats (10/sex/dose) were administered test chemical suspension in corn oil, via gavage at 0, 50, 250 and 600 mg/kg-bw/day for 43 (males) and 54 (females) days. No deaths or treatment-related changes in body weight, growth, food and water intake or behavioral assessments were seen in any treatment groups. However, absolute and relative liver and adrenal weights were increased in both sexes at the 600 mg/kg-bw/day. Reduced cholesterol levels were reported in males at 250 and 600 mg/kg-bw/day, and an increased activity for alkaline phosphatase was noted in males at 600 mg/kg-bw/day; both of these effects are indicative of liver toxicity. Histopathological examination of the liver revealed centrilobular hepatocyte enlargement in all treated females and in males treated with 250 and 600 mg/kg-bw/day. In males, follicular cell hypertrophy in the thyroid glands was also observed at 600 mg/kg-bw/day.Therefore NOAEL and LOAEL of the study was considered to be 250 mg/kg-bw/day and 600 mg/kg-bw/day respectively. The repeated dose toxicity of the test chemical in rats by oral (gavage) route was observed at a dose concentration of 250 mg/Kg bw/day, resulted in no deaths or treatment-related changes in body weight, growth, food and water intake or behavioral assessments.Therefore the “ No observed adverse effect level (NOAEL)" for repeated dose toxicity study was considered to be 250 mg/Kg bw/day.

Based on the observations made, the no observed adverse effect level (NOAEL) was considered to be 600 mg/kg/day for male and female rats when Sprague-Dawley male and female rats were treated with the test chemical in 14 days repeated dose toxicity study.