Registration Dossier

Toxicological information

Endpoint summary

Currently viewing:

Administrative data

Key value for chemical safety assessment

Effects on fertility

Description of key information

Reproductive toxicity study

Based on the data available from different studies, NOAEL was considered to be 244 mg/kg body weight/day for male and 288 mg/kg bw for female when CFE male and female rat 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:
toxicity to reproduction
Remarks:
other: Chronic repeated dose 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 peer- reviewed journal
Qualifier:
according to guideline
Guideline:
other: as below
Principles of method if other than guideline:
Chronic repeated dose toxicity study of tets material in rats.
GLP compliance:
not specified
Limit test:
no
Species:
rat
Strain:
other: CFE
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: SPF colony
- Age at study initiation: (P) x wks; (F1) x wks: No data available
- Weight at study initiation: (P) Males: x-x g; Females: x-x g; (F1) Males: x-x g; Females: x-x g: No data available
- Fasting period before study: No data available
- Housing: Animals were housed 5 rat per cage
- Diet (e.g. ad libitum): Spillers' Laboratory Small Animal Diet, ad libitum
- Water (e.g. ad libitum): Water, ad libitum
- 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: feed
Vehicle:
other: Spillers' Laboratory Small Animal Diet
Details on exposure:
No data available
Details on mating procedure:
No data available
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
By using Pye 104 dual flame ionization chromatograph.
Duration of treatment / exposure:
90 days
Frequency of treatment:
Daily
Details on study schedule:
No data available
Remarks:
Doses / Concentrations:
0, 300, 1200 and 3600 ppm (21, 82 and 244 mg/kg/day for the three dose levels in males and 24, 95 and 280 mg/kg/ day in females.)
Basis:
actual ingested
No. of animals per sex per dose:
Total: 120
0 ppm : 15 male, 15 female
300 ppm : 15 male, 15 female
1200 ppm : 15 male, 15 female
3600 ppm : 15 male, 15 female
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: Because of the small amount of flavoring lost from the test diets and its apparent palatability, the material was administered in the diet at 0, 300, 1200 and 3600 ppm
Positive control:
No data available
Parental animals: Observations and examinations:
Clinical sign, Body Weight, Food consumption, Water Consumption, Haematology, Clinical Chemistry and Urinalysis were observed .
Oestrous cyclicity (parental animals):
No data available
Sperm parameters (parental animals):
No data available
Litter observations:
No data available
Postmortem examinations (parental animals):
Reporductive organ weight, gross pathology and histopathology were exmined.
Postmortem examinations (offspring):
No data available
Statistics:
Statistical analysis is performed by using Student's t test for the significance of Haematological examination and Absolute and relative organ weights.
Reproductive indices:
No data available
Offspring viability indices:
No data available
Clinical signs:
no effects observed
Dermal irritation (if dermal study):
not specified
Mortality:
not specified
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not specified
Haematological findings:
not specified
Clinical biochemistry findings:
not specified
Urinalysis findings:
not specified
Behaviour (functional findings):
not specified
Immunological findings:
not specified
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
not specified
Other effects:
no effects observed
Reproductive function: oestrous cycle:
not specified
Reproductive function: sperm measures:
not specified
Reproductive performance:
not specified
Mortality: No data available

Clinical signs:No signs of ill health were observed in treated rat during the study as compared to control.

Body weight: No effect was observed on body weight and weight gain of treated rat as compared to control.

Food consumption: No effect was observed on food consumption of treated rat as compared to control.

Test substance intake:Average intakes of were 21, 82 and 244 mg/kg/day for the three dose levels in males and 24, 95 and 280 mg/kg/ day in females.

Organ weights: When male and female rats treated with 244 and 280 mg/kg bw, Absolute and relative kidney weight was significantly increased in male and relative weight in female as compared to control.
When male and female rats treated with 82 and 95 mg/kg bw, Absolute and relative kidney weight was significantly increased in male and relative kidney, adrenals and ovaries weight in female as compared to control.
No effect on reproductive oragn weight of female gonads were observed at 288 mg/kg bw.

Gross pathology: No gross abnormalities were observed in Gonads of treated male and female rat as compared to control.

Histopathology: No histopathological changes were observed in Gonads of treated male and female rat as compared to control.

other findings:
Water consumption: No effect was observed on water consumption of treated rat as compared to control.

Haematology:
At 6 week,
When treated with 244 and 280 mg/kg bw, in male rat significant decrease were observed in hemoglobin, RBC and WBC (particularly the lymphocytes) and in female significant decrease hemoglobin were observed.

When treated with 82 and 96 mg/kg bw, in male rat significant decrease were observed in WBC (particularly the lymphocytes) and in female hemoglobin level as compared to control.

At autopsy,
No significant differences between treated and control groups were observed.

Clinical chemistry:No significant differences were observed in treated rat as compared to control.

Urinanalysis: No significant differences were observed in urine analyses of treated rat as compared to control.


Dose descriptor:
NOAEL
Effect level:
244 mg/kg bw/day
Based on:
test mat.
Sex:
male
Basis for effect level:
other: No effect on reporductive organweight, gorss pathology and histopathology
Remarks on result:
other: No effect on reporductive organ weight
Dose descriptor:
NOAEL
Effect level:
288 mg/kg bw/day
Based on:
test mat.
Sex:
female
Basis for effect level:
other: No effect on reporductive organ weight, gorss pathology and histopathology
Remarks on result:
other: No effect on reporductive organ weight
Critical effects observed:
not specified
System:
other: not specified
Organ:
not specified
Treatment related:
not specified
Dose response relationship:
not specified
Relevant for humans:
not specified
Clinical signs:
not specified
Dermal irritation (if dermal study):
not specified
Mortality / viability:
not specified
Body weight and weight changes:
not specified
Food consumption and compound intake (if feeding study):
not specified
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not specified
Haematological findings:
not specified
Clinical biochemistry findings:
not specified
Urinalysis findings:
not specified
Sexual maturation:
not specified
Organ weight findings including organ / body weight ratios:
not specified
Gross pathological findings:
not specified
Histopathological findings:
not specified
Other effects:
not specified
Behaviour (functional findings):
not specified
Developmental immunotoxicity:
not specified
Dose descriptor:
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
Treatment related:
not specified
Dose response relationship:
not specified
Relevant for humans:
not specified
Reproductive effects observed:
not specified
Treatment related:
not specified
Relation to other toxic effects:
not specified
Dose response relationship:
not specified
Relevant for humans:
not specified

Absolute and relative organ weights of rats fed at 0-3600 ppm of the diet for 13 wk

Sex and dietary level (ppm)

Organ weights

Terminal body weight (g)

Brain

Heart

Liver

Spleen

Stomach

Intestine

Caecum

Kidneys

Adrenalst

Gonads

Pituitaryt

Thyroid

Male

Absolute organ weight (g)

0

1.88

1.29

10.31

0.75

1.52

5.67

1.07

2.79

55

3.62

12

22

415

300

1.87

1.31

10.24

0.72

1.52

5.96

1.09

2.92

52

3.53  

12

22

420

1200

1.85

1.30

10.49

0.77

1.50

5.84

1.01

2.97**

54

3.57

12

23

42

3600

1"86

1-28

10.57

0'75

1.56

5.76

1.16

3.04**

53

3.47

12

22

414

Female

 

 

 

 

 

 

 

 

 

 

 

 

 

0

1.76

0.96

0.62

1.38

5.43

0.89

0.89

1.83

61

0.13

15

19

286

300

1.74

0.93

6.35

0-58

1.36

5.60

0.92

1.85

62

0.14

15

19

283

1200

1.76

0.93

6.25

0.60

1.32

5.34

0.89

1.88

66

0.15

15

20

27

3600

1.87

0.93

6.58

0.59

1.33

5.66

0.94

1.91

64

0.13

16

19

282

Male

Relative organ weight (g/100 g body weight

0

0.45

0.31

2.50

0.18

0.37

1.37

0.25

0.67

13.2

0.87

2.82

5.26

 

300

0.44

0.31

2.44

0.17

0.36

1.42

0.25

0.69

12.4

0.84

2.85

5.22

 

1200

0.44

0.31

2.47

0.18

0.35

1.38

0.23

0.70*

12.8

0.84

2.82

5.52

 

3600

0.45

0.31

2.57

0.18

0.38

1.39

0.28

0.73***

12.8

0.84

2.77

4.99

 

Female

 

 

 

 

 

 

 

 

 

 

 

 

 

0

0.62

0.33

2.40

0.21

0.48

1.89

0.32

0.64

21.6

0.045

5.17

6.62

 

300

0.62

0.33

2.37

0.21

0.48

1.97

0.32

0.66

21.8

0.048

5.23

6.56

 

1200

0.64

0.34

2.42

0.22

0.48

1.94

0.32

0.69**

24.1'*

0.052*

5.53

7.10

 

3600

0.63

0.33

2.47

0.21

0.47

2.00

0.33

0.68*

22.7

0.046

5.68

6.56

 

ϮValues of absolute and relative weights of this organ are expressed in mg and mg[100 g body weight respectively.

Values are the means of groups of 15 animals and those marked with asterisks differ significantly (Student'sttest) from those of controls: *P < 0"05; **P < 0"01; ***P < 0"001.

Conclusions:
NOAEL was considered to be 244 mg/kg body weight/day for male and 288 mg/kg bw for female when CFE male and female rat treated with test material orally.
Executive summary:

In a Chronic repeated dose toxicity study, CFE male and female rat were treated with test material in the concentration of 0, 300, 1200 and 3600 ppm orally in diet equivalant to average intakes of 21, 82 and 244 mg/kg/day for males and 24, 95 and 280 mg/kg/ day for females.No signs of ill health, change in body weight,food and water consumption, Clinical chemistry and Urinanalysis were observed in treated male and female rat during the study as compared to control. At 6 week, significant decrease was observed in hemoglobin, RBC and WBC (particularly the lymphocytes) of male and female rat when treated with 82 and 244 mg/kg bw and 82 and 96 mg/kg bw treated rats. Similarly, Absolute and relative kidney weight was significantly increased in male rat and absolute and relative kidney weight , relative adrenals and ovaries weight in female when treated with 82 and 244 mg/kg bw and 82 and 96 mg/kg bw treated rats as compared to control. As no effect on reproductive oragn weight of female gonads were observed in 288 mg/kg bw, the observed change in relative organ weight of female gonads were considered to be non significant. In addition,No gross abnormalities and histopathological changes were observed in Gonads of treated male and female rat as compared to control.Therefore, NOAEL was considered to be 244 mg/kg body weight/day for male and 288 mg/kg bw for female when CFE male and female rat treated with test material orally in feed for 90 days.

Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
244 mg/kg bw/day
Study duration:
subchronic
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 test chemical.The studies are as mentioned below:

Study 1

In a Chronic repeated dose toxicity study, CFE male and female rat were treated with test material in the concentration of 0, 300, 1200 and 3600 ppm orally in diet equivalant to average intakes of 21, 82 and 244 mg/kg/day for males and 24, 95 and 280 mg/kg/ day for females.No signs of ill health, change in body weight,food and water consumption, Clinical chemistry and Urinanalysis were observed in treated male and female rat during the study as compared to control. At 6 week, significant decrease was observed in hemoglobin, RBC and WBC (particularly the lymphocytes) of male and female rat when treated with 82 and 244 mg/kg bw and 82 and 96 mg/kg bw treated rats. Similarly, Absolute and relative kidney weight was significantly increased in male rat and absolute and relative kidney weight , relative adrenals and ovaries weight in female when treated with 82 and 244 mg/kg bw and 82 and 96 mg/kg bw treated rats as compared to control. As no effect on reproductive oragn weight of female gonads were observed in 288 mg/kg bw, the observed change in relative organ weight of female gonads were considered to be non significant. In addition,No gross abnormalities and histopathological changes were observed in Gonads of treated male and female rat as compared to control.Therefore, NOAEL was considered to be 244 mg/kg body weight/day for male and 288 mg/kg bw for female when CFE male and female rat treated with test material orally in feed for 90 days.

Study 2

Combined repeated dose repro-developmental toxicity study was to provide evaluations of general and reproduction/ developmental toxicity endpoints associated with administration of repeated doses of test material in Wistar rats. The animals were randomly allocated to the four main groups (13/sex/group) and two recovery groups (5/sex/group). The doses selected for main groups were; 0 (G1-control),308 mg/kg body weight (G2), 556 mg/kg body weight (G3) and 1000 mg/kg body weight (G4) daily for 64 days. The recovery groups G1-R and G4-R were dosed with similar doses of respective main groups.Vehicle corn oil to G1 and G1-R and test item to G2, G3, G4 and G4-R animals were administered by oral gavage route each day during the dosing period. No mortality and morbidity were observed any of the groups of animals throughout the study period. Animals of all dose groups were observed for Clinical signs/ symptoms daily once during the experimental period. No apparent treatment related clinical signs were observed in any of the animals throughout the treatment and recovery period. Detailed clinical examinations like Home cage observation, Handling observation and Open field observation of all animals were observed to be normal during study period. Number of rear, urine pools, fecal bolus in animals of all the test groups of both the sexes was comparable and did not show any treatment related significant difference as compared to the respective control groups. Body weight, percent body weight changes and feed consumption in animals of all the test groups of both the sexes was comparable and did not show any treatment related significant difference as compared to the respective control groups. The sensory reactivity measurements were comparable and no statistically significant changes were revealed in animals of treatment groups in both the sexes. Foot splay and fore limb and hind limb grip strength parameters were comparable and no treatment related changes were revealed in any of the animals of all treated groups as compare to the repective control groups. Motor activity measurements were comparable and no changes were revealed in any of the animals of all treated groups of both the sexes as compared to control group. Estrous cycle was evaluated for checking the regularity during treatment period and in cohabitation for confirmation of pregnancy.

No test item related changes in estrous cyclicity and precoital interval were observed. There was statistically significant decrease in G3 (556 mg/kg body weight) as compared to control G1 (0 mg/kg body weight). This is not dose dependent hence not considered as treatment related. There was no statistically significant difference between the control and treatment groups in the maternal and pups parameters, except markedly decreased pregnancy index / fertility index in G4 (1000 mg/kg body weight), which was considered to be treatment related. All hematological and clinical chemistry parameters in animals of different treated groups of both the sexes were comparable to their respective control groups. No treatment related changes were observed in any of the treatment groups.  At the end of treatment and recovery period, absolute and relative weight of organs of treated group rats of either sex did not differ significantly when compared to the respective control group rats. External and visceral examination of all male and female rats of control and all treated groups including recovery groups did not reveal any abnormality of pathological significance. Terminally sacrificed pups of all treated groups did not reveal any lesion of pathological significance in any of the group when compared with control group. Pups that died among the control and treated groups during the course of study, revealed various lesions when examined externally and internally but the observations were not considered treatment related. From the patho-morphological results presented, it is concluded that, the treatment of Methyl Phenyl acetate at 308, 556 and 1000 mg/kg body weight in male and female rats did not affect adversely and no alteration of pathological significance was observed in any of the organs including reproductive organs. Lesions observed in liver, kidneys, lungs, heart, aorta, stomach, lymph nodes, spleen, thymus, trachea, adrenal gland and reproductive organs of high dose treated group rats are well comparable with respective control group rats and exhibited no dose relationship. Further these observed lesions are common in occurrence in rodents during toxicological studies. Hence, occurrence of these lesions could be considered as spontaneous or incidental in nature and not to be attributed to the administration of the Test Item.

Based on the findings of Repeated Dose Oral Toxicity Study in combination with Reproduction/ Developmental Toxicity of test material in Wistar Rats with 14 days recovery, where in 0, 308, 556 and 1000 mg/kg body weight, doses were tested;No Observed Adverse Effect Level (NOAEL) is considered to be 556 mg/kg bw. When male and female wistar rats were treated with test material orally.

Based on the data available from different studies ,test material did not showedreproductive toxicityat dose concentration 244 mg/kg body weight/day for male and 288 mg/kg bw for female, when CFE male and female rat treated with test material orally,Thus, comparing this value with the criteria ofCLP regulationtest materialis 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