Benzyl propionate

Toxicity to reproduction

Administrative data

Endpoint:

reproductive toxicity, other

Remarks:

Repreted dose toxicity

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Justification for type of information:

Data from SSS study reprot

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2014

Report date:

2014

Materials and methods

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

other: OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity in Rodents)

Principles of method if other than guideline:

Reproductive toxicity evaluation of Benzyl Propionate was performed on Rats rats by repeated oral exposure for 28 days

GLP compliance:

yes

Limit test:

no

Justification for study design:

No data available

Test material

Test material information

Constituent 1

Reference substance name:

Benzyl propionate

EC Number:

204-559-3

EC Name:

Benzyl propionate

Cas Number:

122-63-4

Molecular formula:

C10H12O2

IUPAC Name:

benzyl propanoate

Test material form:

liquid

Details on test material:

- Name of test material: benzyl propionate
- Molecular formula: C10H12O2
- Molecular weight: 164.20 g/mol
- Substance type: Organic
- Physical state: Liquid

Specific details on test material used for the study:

- Name of test material: Benzyl Propionate
- Molecular formula: C10H12O2
- Molecular weight: 164.2 g/mol
- Substance type: Organic
- Physical state:Liquid

Test animals

Species:

rat

Strain:

Sprague-Dawley

Details on species / strain selection:

No data available

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: National Institute of Biosciences, Pune.
- Age at study initiation: 6 to 8 weeks old
- Weight at study initiation:
Male 169.50 gg
Female 152.35 g
- Fasting period before study: No data available
- Housing: Animals were housed in polycarbonate cages. Three rats of same sex were housed together in each cage of size 39 cm X 28 cm X 14 cm. Paddy husk was used as bedding material.
- Diet (e.g. ad libitum): Rodent feed supplied by the Nutrivet Life Sciences, Pune, was provided ad libitum from individual feeders on cage top.
- Water (e.g. ad libitum): Water was provided ad libitum from individual bottles attached to the cages. Water was from a local source and passed through the reverse osmosis membrane before use.
- Acclimation period: 5 days prior to dosing.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 3°C (actual range: 19.5 °C to 22.8 °C)
- Humidity (%):30% to 70% (actual range: 53.3% to 58.1%).
- Air changes (per hr): Ten air changes per hour of 100% fresh air that has been passed through the HEPA filters.
- Photoperiod (hrs dark / hrs light): An artificial light and dark cycle of 12

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

corn oil

Details on exposure:

PREPARATION OF DOSING SOLUTIONS: Benzyl Propionate was diluted with Corn oil for preparation of dosing solution(s).

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): No data available
- Concentration in vehicle:The solution(s) were prepared at concentrations of 0, 25, 50 and 100 mg/ml such that dosage of 0 (vehicle), 250, 500 and 1000 mg/kg bw/day.
- Amount of vehicle (if gavage): 0.00 mg/ml/day, 26.60 mg/ml/day, 52.38 mg/ml/ day and 105.27 mg/ml/day.
- 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:

yes

Details on analytical verification of doses or concentrations:

Analysis for concentration and stability of Benzyl Propionate were conducted at Subcontracted Laboratory. Test item formulation samples prepared day 1 (pre-dosing) were sent to Subcontracted Laboratory.

Duration of treatment / exposure:

28 days consecutively

Frequency of treatment:

Once daily

Details on study schedule:

No data available

Doses / concentrations

Remarks:

0 (vehicle), 250, 500 and 1000 mg/kg bw/day.
Basis:actual ingested

No. of animals per sex per dose:

Total:48
Control: 6 male, 6 female
250 mg/kg bw/day: 6 male, 6 female
500 mg/kg bw/day: 6 male, 6 female
100 0mg/kg bw/day: 6 male, 6 female

Control animals:

yes, concurrent vehicle

Details on study design:

Details on study design
- Dose selection rationale:
Based on results from a preliminary 14-day study there was no chenge in the survivel, body weight, Daily clinical observations and Gross pathological examination of 1000 mg/kg/bw/day group. Based on these results, the 28 day study dose levels were finalized as 0 mg/kg, 250 mg/kg, 500 mg/kg and 1000 mg/kg body weight.

- Rationale for animal assignment (if not random): Animals were randomized by sex and body weight

- Rationale for selecting satellite groups: No data available

- Post-exposure recovery period in satellite groups: No data available

- Section schedule rationale (if not random): No data available

Positive control:

No data available

Examinations

Parental animals: Observations and examinations:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: No data available
- Cage side observations checked in table [No.?] were included. : Rats were observed for Behavior, Alterations, Vocalizations, Respiration and Palpebral closure.

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Once daily, At least once a week there after until

BODY WEIGHT: Yes
- Time schedule for examinations: On the day of randomization, first day of dosing, weekly thereafter and a fasting body weight at scheduled sacrifice on day 29.

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): No data available
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: No data available
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: No data available

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: Yes / No / No data

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

OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: Once a day
- Dose groups that were examined: 0 mg/kg, 250 mg/kg, 500 mg/kg and 1000 mg/kg bw/day.

HAEMATOLOGY: Yes, By using Beckman Coulter haematology analyzer.
- Time schedule for collection of blood: At termination.
- Anaesthetic used for blood collection: No data available
- Animals fasted: Yes, overnight fasted prior to sampling.
- How many animals: Blood collected from all rats of 0 mg/kg, 250 mg/kg, 500 mg/kg and 1000 mg/kg bw/day group at termination.
- Parameters checked in table [No.?] were examined. : Hemoglobin, Red Blood Corpuscles, Hematocrit, Mean Corpuscular Volume, Mean Corpuscular Hemoglobin, Mean Corpuscular Hemoglobin Concentration, Platelets, White Blood Corpuscles, Neutrophils, Lymphocytes, Eosinophils, Monocytes, Basophil and Prothrombin time were checked, Table No.H; Appendix No.VII.

CLINICAL CHEMISTRY: Yes, By using Dimension XpandPlus and Acculyte 5P.
- Time schedule for collection of blood: At termination.
- Animals fasted: Yes, overnight fasted prior to sampling.
- How many animals: Blood collected from all rats of 0 mg/kg, 250 mg/kg, 500 mg/kg and 1000 mg/kg bw/day group at termination.
- Parameters checked in table [No.?] were examined. : Total Protein, Blood Urea Nitrogen, Urea Nitrogen, Alanine Aminotransferase, Aspartate Aminotransferase, Alkaline Phosphatase, Gamma Glutamyl Transferase, Glucose, Calcium, Phosphorous, Albumin, Total Bilirubin, Creatinine , Total Cholesterol, Triglycerides, Globulin Calculated Sodium, Potassium, Chloride were checked, Table No.I; Appendix No.VIII.

URINALYSIS: No data available
- Time schedule for collection of urine: No data available
- Metabolism cages used for collection of urine: No data available
- Animals fasted: No data available
- Parameters checked in table [No.?] were examined. : No data available

NEUROBEHAVIOURAL EXAMINATION: No data available
- Time schedule for examinations: No data available
- Dose groups that were examined: No data available
- Battery of functions tested: sensory activity / grip strength / motor activity / other: Yes

OTHER: Viability, Behavior in Home cage, Vocalizations, Respiration, Palpebral closure, Handling Observations, Urination, Defecation, Prominence of Eye, Lacrimation, Salivation, Piloerection, Examination of Skin / Fur, Stereotype Behaviour, Rearing (Rears), Clonic and Tonic Movements and Severity of Gait 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):

Postmortem examinations (Parent Animal)
SACRIFICE: male and female animals sacrificed on day 29,
GROSS PATHOLOGY: Yes
Gross necropsy was conducted. All the animals of 0 mg/kg, 250 mg/kg, 500 mg/kg and 1000 mg/kg/bw/day group were sacrificed and gross lesions were noted.

HISTOPATHOLOGY: Yes
Control and treated at the highest dose level of 1000 mg/kg were subjected to sacrifice.

Organs examined: Adrenals, Aorta, Brain (cerebrum, cerebellum and pons), Caecum, Cervix, Colon, Duodenum, Epididymides, Eyes, Heart, Ileum, Jejunum, Kidneys, Liver, Lungs, Mesenteric Lymphnodes, Oesophagus, Ovaries, Pancreas, Pituitary gland, Pharyngeal Lymphnodes, Prostate, Rectum, Skeletal Muscles, Skin with Mammary Gland, Spleen, Sternum with bone marrow, Sciatic Nerve, Spinal Cord (Cervical, mid thoracic and lumbar), Stomach, Seminal Vesicles with Coagulation Gland, Testes, Thymus, Thyroid, Trachea, Vagina, Urinary Bladder and Uterus of 1000 mg/kg/bw/day group.

Postmortem examinations (offspring):

No data available

Statistics:

Data were analysed for reporting group means and standard deviations with significance between the controls and treated groups, using in-house developed and validated MS-Excel 2003 based statistical software. All the parameters characterized by continuous data such as body weight, per cent body weight change, feed consumption, organ weight, relative organ weight, haematological and clinical chemistry data were subjected to Bartlett’s test to meet the homogeneity of variance before conducting Analyses of Variance (ANOVA) and Dunnett’s t-test. Where the data did not meet the homogeneity of variance, Student’s t-test was performed to calculate significance.

Significance was calculated at 1% as well as 5% level and indicated in the summary tables as follows:

* = Significant than control at 95% level of confidence (p≤ 0.05).
** = Significant than control at 99% level of confidence (p≤ 0.01).

Reproductive indices:

No data available

Offspring viability indices:

No data available

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:

no effects observed

Description (incidence and severity):

No clinical signs of toxicity were observed in the animals throughout the dosing period of 28 days
Before commencement of treatment:
Home cage observations in rats from all treated groups and control group revealed normal behavior, alterations, vocalization, respiration and palpebral closure.
During handling observation, handling of rats did not reveal any abnormality from all treated groups and control group.
Open field observation of rats did not reveal any abnormality from all treated groups and control group.
During study period:
At the end of dosing period: Week 1,
Home cage observations in animals from all treated groups and control group revealed normal behavior, alterations, vocalization, respiration and palpebral closure.
During handling observation, handling of animals did not reveal any abnormality from all treated groups and control group.
Open field observation of animals did not reveal any abnormality from all treated groups and control group.
Week 2:
Home cage observations in animals from all treated groups and control group revealed normal behavior, alterations, vocalization, respiration and palpebral closure.
During handling observation, handling of animals did not reveal any abnormality from all treated groups and control group.
Open field observation of animals did not reveal any abnormality from all treated groups and control group.
Week 3:
Home cage observations in animals from all treated groups and control group revealed normal behavior, alterations, vocalization, respiration and palpebral closure.
During handling observation, handling of animals did not reveal any abnormality from all treated groups and control group.
Open field observation of animals did not reveal any abnormality from all treated groups and control group.
Week 4:
Home cage observations in animals from all treated groups and control group revealed normal behavior, alterations, vocalization, respiration and palpebral closure.
During handling observation, handling of animals did not reveal any abnormality from all treated groups and control group.
Open field observation of animals did not reveal any abnormality from all treated groups and control group.

Dermal irritation (if dermal study):

not specified

Mortality:

no mortality observed

Body weight and weight changes:

no effects observed

Description (incidence and severity):

Animals from control and different dose groups exhibited normal body weight gain throughout the dosing period of 28 days.

Food consumption and compound intake (if feeding study):

no effects observed

Description (incidence and severity):

Animals from control and all treated dose groups exhibited normal feed consumption at the end of the dosing period of 28 days

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

Description (incidence and severity):

Male and Female -
Haematological investigations conducted at the end of dosing period on day 29, revealed following significant changes in the values of different parameters studied when compared with that of respective controls.
Male :
Hb : Increased values were obtained for animals from 500 mg/kg (p≤0.01) and 1000 mg/kg (p≤0.05) dose groups,
MCHC : Increased values were obtained for animals from 500 mg/kg dose group (p≤0.01) and
Total WBC : Increased values were obtained for animals from 1000 mg/kg dose group (p≤0.05).
Female :
Platelets : Increased values were obtained for animals from 1000 mg/kg dose group (p≤0.05).

Clinical biochemistry findings:

effects observed, treatment-related

Description (incidence and severity):

Male and Female -
Biochemical investigations conducted at the end of dosing period on day 29, revealed following significant changes in the values of different parameters studied when compared with that of respective controls.
Male :
Sodium : Elevated levels were observed in animals from 250 mg/kg and 1000 mg/kg dose groups (p≤0.01) and
Chloride : Elevated levels were observed in animals from 250 mg/kg dose group (p≤0.05).
Female :
Calcium : Elevated levels were observed in animals from 250 mg/kg dose group (p≤0.01),
Bilirubin : Elevated levels were observed in animals from 500 mg/kg dose group (p≤0.05),
Sodium : Elevated levels were observed in animals from 250 mg/kg (p≤0.01), 500 mg/kg (p≤0.05) and 1000 mg/kg (p≤0.01) dose groups,
Alkaline Phosphatase : Decreased levels were observed in animals from 250 mg/kg dose group (p≤0.05),
Potassium : Decreased levels were observed in animals from 250 mg/kg and 1000 mg/kg dose groups (p≤0.05) and
Chloride : Decreased levels were observed in animals from 1000 mg/kg dose group (p≤0.05).

Urinalysis findings:

not specified

Behaviour (functional findings):

no effects observed

Description (incidence and severity):

Sensory Reactivity Observations:
All animals from control and different dose groups showed normal arousal level, visual response, touch response, auditory response, tail pinch response and visual placing response. Normal air righting reflex was observed in all animals from control and different dose groups in week 4.
Grip Strength:
Grip strength values observed in male and female animals for control and different dose groups were comparable.
Motor Activity:
Higher values were observed in male animals from 500 mg/kg dose group for first interval (p≤0.05). Lower values were observed in female animals from 500 mg/kg dose group for first interval (p≤0.01) and for second interval (p≤0.05).
These changes were within laboratory range and were considered to be of no toxicological importance.

Immunological findings:

not specified

Organ weight findings including organ / body weight ratios:

no effects observed

Histopathological findings: non-neoplastic:

no effects observed

Description (incidence and severity):

No treatment related histopathological changes were evident in male and female rats from control and high dose groups.
Histopathological examination revealed minimal focal to multifocal periportal mononuclear cell infiltration in the liver; minimal interstitial haemorrhages in the kidneys; minimal alveolar haemorrhages and/or alveolar histiocytosis in the lungs; minimal multifocal haemosiderosis and/or diffused congestion in spleen; minimal eosinophilic infiltration and/or luminal dilatation in uterus; minimal luminal seminal coagulum in the urinary bladder; minimal dilatation of zona reticularis and/or presence of accessory adrenocortical tissue in adrenals; minimal multifocal haemorrhages in thymus; presence of ultimobranchial cysts in thyroid; in male or female animals from control and high dose group. All the changes observed in the control and high dose treatment group animals were similar, incidental and mode of death related, physiological and are covered in the facility historical data of the histopathology findings.

Histopathological findings: neoplastic:

not specified

Other effects:

not specified

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:

not specified

Reproductive function: sperm measures:

not specified

Reproductive performance:

not specified

Effect levels (P0)

Dose descriptor:

NOAEL

Effect level:

1 000 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

mortality

body weight and weight gain

food consumption and compound intake

organ weights and organ / body weight ratios

gross pathology

histopathology: non-neoplastic

Remarks on result:

other: No effects on reproductive organ was observed

Target system / organ toxicity (P0)

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

Results: F1 generation

General toxicity (F1)

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

Developmental neurotoxicity (F1)

Behaviour (functional findings):

not specified

Developmental immunotoxicity (F1)

Developmental immunotoxicity:

not specified

Effect levels (F1)

Remarks on result:

not determinable

Target system / organ toxicity (F1)

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

Overall reproductive toxicity

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

Applicant's summary and conclusion

Conclusions:

In reproductive toxicity study , No Observed Adverse Effect Level (NOAEL )was considered to be 1000mg/kg bw on the bases of no effects on reproductive organ .when male and female Sprague-Dawley rats were treated with Benzyl Propionate (122-63-4) orally for 28 days.

Executive summary:

The reproductive toxicity ofBenzyl Propionate(122-63-4) was considered on the bases of repeateddose 28-day Oral Toxicity study performedin GLPcompliance lab.The male and female Sprague-Dawley rats were administered with test material in dose concentration 0 mg/kg, 250 mg/kg, 500 mg/kg and 1000 mg/kg bw/day by oral gavage route. Corn oil used as vehicle.Analysis for concentration and stability of Benzyl Propionate were conducted at Subcontracted Laboratory.The animals of uniform body weight were selected. The individual body weight of the animals did not exceed ± 20% of group mean body weight. The group means body weights of all the groups were approximately equal.A total of 48 animals (24 males + 24 females) were selected and randomly distributed into four groups with 6 animals/sex/group and 3/sex/cage. The doses were selected based on the results of the Dose Range Finder study,Based on these results, the 28 day study dose levels were finalized as 0 mg/kg,250 mg/kg, 500 mg/kg and 1000 mg/kg body weight and animals were exposed to the treatment, every day, for a period of 28 days. The test and/or control item was administered by oral gavage route, using a 18 gauge ball–tipped intubation needle fitted onto a gauge syringe of appropriate size. Doses were calculated using recent body weights, 10 ml per kg body weight is considered the volume which could be administered to a rat.

All the animals were observed for viability twice daily.Body weight was recorded on the day of randomization, first day of dosing, weekly thereafter and a fasting body weight at scheduled sacrifice on day 29.The quantity of feed consumed by control and different treatment groups was recorded weekly until scheduled sacrifice and the feed consumption per animal was calculated for each group.All animals were examined for clinical signs such as skin and fur changes, eye and mucous membrane changes, respiratory, circulatory and general changes were recorded once daily.In home cage, rats were observed for Behavior, Alterations, Vocalizations, Respiration and Palpebral closure.After completion of 28 days study period, all surviving study rats were sacrificed on day 29.Liver, Kidneys, Adrenals, Epididymides, Prostate + Seminal Vesicle with Coagulation gland as whole, Thymus, Spleen, Brain, Heart, Lungs, Uterus, Testes/Ovaries were dissected free of fat and weighed. The paired organs wereweighed together. All the rats survived through the dosing period of 28 days and were sacrificed and gross lesions were noted. From each rat, samples or the whole of the tissue were preserved. All tissues were fixed in 10% neutral buffered formalin except, eyes and testes of all animals were preserved in Davidson’s solution for 24 hours and transferred to 10% neutral buffered formalin.Following tissue samples of organs from control and animals treated at different dose groups were preserved and those from control and treated at the highest dose level of 1000 mg/kg were subjected to histopathological examination. Adrenals, Aorta, Brain (cerebrum, cerebellum and pons), Caecum, Cervix, Colon, Duodenum, Epididymides, Eyes, Heart, Ileum, Jejunum, Kidneys, Liver, Lungs, Mesenteric Lymphnodes, Oesophagus, Ovaries, Pancreas, Pituitary gland, Pharyngeal Lymphnodes, Prostate, Rectum, Skeletal Muscles, Skin with Mammary Gland, Spleen, Sternum with bone marrow, Sciatic Nerve, Spinal Cord (Cervical, mid thoracic and lumbar), Stomach, Seminal Vesicles with Coagulation Gland, Testes, Thymus, Thyroid, Trachea, Vagina, Urinary Bladder, Uterus. 

All the animals from control and all the treateddose groups survived throughout the dosing period of 28 days.Animals from control and different dose groups exhibited normal body weight gain and normal feed consumption throughout the dosing period of 28 days. No clinical signs of toxicity were observed in the animals throughout the dosing period of 28 days.Home cage observations in rats from all treated groups and control group revealed normal behavior, alterations, vocalization, respiration and palpebral closure. 

During handlingobservation,handling of rats did not reveal any abnormality from alltreated groups and control group. Open field observation of rats did not reveal any abnormality from alltreated groups and control group. All animals from control and different dose groups showed normal arousal level, visual response, touch response, auditory response, tail pinch response and visual placing response. Normal air righting reflex was observed in all animals from control and different dose groups in week 4.

Grip strength values observed in male and female animals for control and different dose groups were comparable. Higher values for motor activity were observed in male animals from 500 mg/kg dose group for first interval (p≤0.05). Lower values were observed in female animals from 500 mg/kg dose group for first interval (p≤0.01) and for second interval (p≤0.05). These changes were within laboratory range and were considered to be of no toxicological importance.

In comparison with controls organ weight data of female animals sacrificed on day 29, revealed increased relative weight of liver (p≤0.05), ovaries (p≤0.01) and lungs (p≤0.05) of animals from 1000 mg/kg dose group.

Although significant changes in organ weights were observed in female animals from high dose group, no related gross pathological or histological changes were seen and hence considered to be of no toxicological importance. Gross pathological examination in male and female animals from control and different treatment groups did not reveal any abnormality.

Haematological analysis performed on 29^thday revealed statistically significant increase in the values of Hb of male rats dosed at 500 mg/kg and 1000 mg/kg, MCHC of male rats dosed at 500 mg/kg, Total WBC of male rats dosed at 1000 mg/kg and Plateles of female rats dosed at 1000 mg/kg. The increase in the values of different parameters was marginal and within the normal laboratory limits. Clinical biochemistry analysis results, when compared between the test and control groups revealed below observations.

Statistically significant increase of Sodium in male rats dosed at 250 mg/kg and 1000 mg/kg of test item.

·        Statistically significant increase of Chloride levels in male rats dosed at 250 mg/kg of test item.

·        Statistically significant increase of Calcium levels in female rats dosed at 250 mg/kg of test item.

·        Statistically significant increase of Bilirubin levels in female rats dosed at 500 mg/kg of test item.

·        Statistically significant increase of Sodium in female rats dosed at 250 mg/kg, 500 mg/kg and 1000 mg/kg of test item.

·        Statistically significant decrease of Alkaline Phosphatase levels in female rats dosed at 250 mg/kg of test item.

·        Statistically significant decrease of Potassium levels in female rats dosed at 250 mg/kg and 1000 mg/kg of test item.

·        Statistically significant decrease of Chloride levels in female rats dosed at 1000 mg/kg of test item.

Although there was an increase/decrease in the values of various biochemical parameters as mentioned above, the deviations were marginal and within the range of normal laboratory limits.

No treatment related histopathological changes were evident in male and female rats from control and high dose groups. Histopathological examination revealed minimal focal to multifocal periportal mononuclear cell infiltration in the liver; minimal interstitial haemorrhages in the kidneys; minimal alveolar haemorrhages and/or alveolar histiocytosis in the lungs; minimal multifocal haemosiderosis and/or diffused congestion in spleen; minimal eosinophilic infiltration and/or luminal dilatation in uterus; minimal luminal seminal coagulum in the urinary bladder; minimal dilatation of zona reticularis and/or presence of accessory adrenocortical tissue in adrenals; minimal multifocal haemorrhages in thymus; presence of ultimobranchial cysts in thyroid; in male or female animals from control and high dose group. All the changes observed in the control and high dose treatment group animals were similar, incidental and mode of death related, physiological and are covered in the facility historical data of the histopathology findings.Hence No Observed Adverse Effect Level (NOAEL) was considered to be 1000mg/kg bw on the bases of no effects on reproductive organ .when male and femaleSprague-Dawleyrats were treated withBenzyl Propionate(122-63-4) orally for 28 days.