Registration Dossier

Administrative data

Description of key information

Repeated dose toxicity oral:

The No Observed Adverse Effect Level (NOAEL) was considered to be 1000 mg/kg bw/day when rats were exposed to the test chemical orally.

Repeated dose toxicity: Inhalation

The repeated dose inhalation toxicity study need not be conducted because exposure to humans via inhalation route is not likely taking into account due to the low vapour pressure of the test chemical, which is reported to be 0.00859 mm Hg. Thus, exposure to inhalable dust, mist and vapour of the chemical is highly unlikely. Therefore this study for repeated dose toxicity by inhalation route of exposure is considered for waiver.

Repeated dose toxicity: Dermal

The acute dermal toxicity value for phenethyl butyrate (CAS no 103-52 -6) (as provided in section 7.2.3) is >2000 mg/kg body weight. Considering this, the end point for repeated dermal toxicity is considered as waiver.

Key value for chemical safety assessment

Toxic effect type:
dose-dependent

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records
Reference
Endpoint:
short-term 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
Reason / purpose for cross-reference:
read-across source
Reason / purpose for cross-reference:
read-across source
Qualifier:
according to guideline
Guideline:
OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)
Principles of method if other than guideline:
WoE for the target CAS is summarized based on data from various test chemicals
GLP compliance:
not specified
Limit test:
no
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals or test system and environmental conditions:
2. 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 - 175.6 g
Female 152.35 g- 162.7 g
- Fasting period before study: No data available
- Housing: Animals were housed in polycarbonate cages as 3/sex/cage. 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.
- Quarantine period: 7 days

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

3. The animals had access to food and water at all times

TEST ANIMALS
- Housing: he animals were housed individually in wire cages
- Diet (e.g. ad libitum): Rodent diet ad libitum
- Water (e.g. ad libitum): water ad libitum
Route of administration:
other: 2. Gavage; 3. Feed
Vehicle:
other: 2. Corn oil; 3. Rodent diet
Details on oral exposure:
2. PREPARATION OF DOSING SOLUTIONS: The test chemical was diluted with Corn oil for preparation of dosing solution(s). The solution(s) of test item was made at volumes suitable for daily use for 28 days. 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 body weight respectively were administered. The concentration of the test item was varied so as to maintain the dose volume constant at or upto 10 ml/kg body weight.


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): Corn oil
- 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): 10 mL/Kg
- Lot/batch no. (if required): No data available
- Purity: No data available

3. DIET PREPARATION
- Rate of preparation of diet (frequency):The compound was fed in the diet and fresh diets were made
and distributed weekly.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
2. Analysis for concentration and stability of the test chemical were conducted at Subcontracted Laboratory. Test item formulation samples prepared day 1 (pre-dosing) were sent to Subcontracted Laboratory.
Duration of treatment / exposure:
2. 28 days consecutively
3. 17 days
Frequency of treatment:
Once daily
Remarks:
Doses / Concentrations: / 2
0 (vehicle), 250, 500 and 1000 mg/kg bw/day.
Basis:
actual ingested
Remarks:
Doses / Concentrations: / 3
1000, 2500 and 10000 ppm, corresponding to an average daily intake of 0, 50, 250 or 500 mg/kg bw
Basis:
no data
No. of animals per sex per dose:
2. 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

3. Total number of animals 80
0 mg/kg/day-10 male and 10 female
50 mg/kg/day-10 male and 10 female
250 mg/kg/day-10 male and 10 female
500 mg/kg/day-10 male and 10 female
Control animals:
yes, concurrent vehicle
Details on study design:
2. - Dose selection rationale: The doses were selected based on the results of the Dose Range Finder study. The study was conducted at the dose levels of 0 mg/kg, 50 mg/kg, 100 mg/kg, 250 mg/kg, 500 mg/kg and 1000 mg/kg body weight. Based on results from a preliminary 14-day study there was no change in the survival, 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

3. Groups of 10 male and 10 female Osborne-Mendel rats were given diets containing the test chemical at a concentration of 0, 1000, 2500 or 10000 ppm, corresponding to an average daily in take of 0, 50, 250 or 500 mg/kg bw, for 17 weeks. The compound was fed in the diet and fresh diets were made and distributed weekly. The rat's weight, food intake and general condition were recorded every week.
Positive control:
No data
Observations and examinations performed and frequency:
2. CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Twice daily
- Cage side observations checked in table [No.?] were included. : Rats were observed for Viability, Behavior, Alterations, Vocalizations, Respiration and Palpebral closure. The rats were observed for reaction to removal, reaction to handling, urination, defecation, prominence of eye, lacrimation, salivation, piloerection, examination of mucous membrane, examination of skin / fur, examination of natural orifices and animal appearance. The animals were also placed in the open field and its appearance and behavior were observed

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Clinical observations were made for individual animal once before the start of dose administration and at least once a week thereafter until scheduled sacrifice.

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): Yes, The quantity of feed consumed by control and different treatment groups was recorded weekly until scheduled sacrifice
- 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 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: 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 on day 29
- 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

CLINICAL CHEMISTRY: Yes, By using Dimension XpandPlus and Acculyte 5P.
- Time schedule for collection of blood: At termination on day 29.
- 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: Yes
- 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.

3. CAGE SIDE OBSERVATIONS: Yes

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: weekly

BODY WEIGHT: Yes
- Time schedule for examinations: weekly

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

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: Not specified

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): Not specified
- Time schedule for examinations: No data

OPHTHALMOSCOPIC EXAMINATION: Not specified
- Time schedule for examinations: Not specified
- Dose groups that were examined: Not specified

HAEMATOLOGY: Yes
- Time schedule for collection of blood: Haematological examinations were made at termination of the subacute studies
- Parameters checked in table [No.?] were examined. These examinations included white cell counts, red cell counts, haemoglobins and haematocrits

CLINICAL CHEMISTRY: Not specified

URINALYSIS: Not specified

NEUROBEHAVIOURAL EXAMINATION: Not specified

IMMUNOLOGY: Not specified

OTHER: The viscera were removed and the liver, kidneys, spleen, heart, and testes were weighed
Sacrifice and pathology:
2. GROSS PATHOLOGY: Yes, The rats were sacrificed by CO2 asphyxiatio and 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. 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 were weighed together.

HISTOPATHOLOGY: Yes, 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. 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.

3. GROSS PATHOLOGY: Yes , At the termination of the experiments the rats were sacrificed and exsanguinated.

HISTOPATHOLOGY: Yes , The tissues of all the rats were examined macroscopically at the time of sacrifice. These organs, the remaining abdominal and thoracic viscera, and one hind leg, for bone, bone marrow, and muscle, were preserved in 10 % buffered formalin-saline solution for histopathological examination. For routine histopathology, sections were embedded in paraffin wax and stained with haematoxylin and eosin.
Other examinations:
3. Tissues from rats dying during the experiment were examined for gross changes and were preserved if autolysis was not advanced. Organs were not weighed but abnormalities and the suspected reason for death were noted
Statistics:
2. Data were analyzed 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).
Clinical signs:
no effects observed
Description (incidence and severity):
3. No significant effect were observed at doses 0, 50, 250 or 500 mg/kg bw in treated group compare to control.
Mortality:
no mortality observed
Description (incidence):
3. No mortality were observed at doses 0, 50, 250 or 500 mg/kg bw in treated group compare to control.
Body weight and weight changes:
no effects observed
Description (incidence and severity):
3. Weekly measurement of body weight showed no significant difference between test and control animals.
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
3. Weekly measurement of food intake showed no significant difference between test and control animals.
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not specified
Haematological findings:
no effects observed
Description (incidence and severity):
3. At termination, haematological examination revealed no effects due to treatment. No significant effect were observed at doses 0, 50, 250 or 500 mg/kg bw in treated group compare to control.
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
not specified
Behaviour (functional findings):
not specified
Immunological findings:
not specified
Organ weight findings including organ / body weight ratios:
no effects observed
Description (incidence and severity):
3. At necropsy, no difference between test and control animals in the weights of major organs was reported.
Gross pathological findings:
no effects observed
Description (incidence and severity):
3. No significant effect were observed at doses 0, 50, 250 or 500 mg/kg bw in treated group compare to control.
Neuropathological findings:
not specified
Histopathological findings: non-neoplastic:
no effects observed
Description (incidence and severity):
3. Gross examination of tissues from all animals revealed no remarkable changes, and histological examination of three to four animals of each sex at the high dose and from the control group revealed no treatment-related lesions.
Histopathological findings: neoplastic:
no effects observed
Other effects:
not specified
Details on results:
2. Clinical signs and mortality
Clinical signs :
Daily clinical observations did not reveal any signs of toxicity in male and female animals from of 0 mg/kg, 250 mg/kg, 500 mg/kg and 1000 mg/kg bw/day dose groups . 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. There was no change in animals before commencement of of treatment and during study period.

Mortality:
No mortality were observed in any of the traeted groups of 0 mg/kg, 250 mg/kg, 500 mg/kg and 1000 mg/kg bw/day.

Body weight and weight gain All the rat of 0 mg/kg, 250 mg/kg, 500 mg/kg and 1000 mg/kg/bw/day dose groups exhibited normal body weight gain at the end of the study period of 28 days.

Food consumption and compound intake Food intake of animals for control and 250 mg/kg, 500 mg/kg and 1000 mg/kg /bw/day dose groups were found to be normal throughout the study period of 28 days.

Food efficiency: No data available

Water consumption and compound intake No data available

Opthalmoscopic examination No data available

Haematology
Male rats: 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 were observed.

Female rats: Plateles of female rats dosed at 1000 mg/kg were also increase. The increase in the values of different parameters is within the normal laboratory limits.

Clinical chemistry
Male and female rats: Increased level of Sodium in male rats dosed at 250 mg/kg and 1000 mg/kg of Benzyl Propionate. Chloride levels increased in male rats dosed at 250 mg/kg of Benzyl Propionate

Female rats: Elevated levels of calcium were observed in animals from 250 mg/kg dose group (p≤0.01). Increased bilirubin levels were found in male rats dosed 500 mg/Kg. Elevated levels od sodium 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 leves were decreased in animals from 250 mg/kg dose group (p≤0.05), a decrease in potassium levels were observed in animals from 250 mg/kg and 1000 mg/kg dose groups (p≤0.05) and Decreased levels od chloride were observed in animals from 1000 mg/kg dose group (p≤0.05).

Urinanalysis: No data available

Neurobehaviour: 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 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.

Organ weights: Organ weight of 100 mg/kg/bw/day dose group male animals sacrificed on day 29, was found to be comparable with that of controls.

Organ weight of female animals sacrificed on day 29, revealed increased relative weights of liver, ovaries and lungs of 1000 mg/kg dose group.The 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 pathology All the treatment groups of control and 250 mg/kg/bw/day, 500 mg/kg/bw/day and 1000 mg/kg/bw/day of Benzyl Propionate did not reveal any abnormality.

Histopathology: 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 of control and 1000 mg/kg/bw/day dose group. All the changes observed in the control and 1000 mg/kg/bw/day dose treatment group animals were similar and the effect observed was not considered to be treatment- related.
Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: Based on Clinical biochemistry, Organ weight, Gross pathological, Histopathology and survival.
Critical effects observed:
not specified
Conclusions:
The No Observed Adverse Effect Level (NOAEL) was considered to be 1000 mg/kg bw/day when rats were exposed to the test chemical orally.
Executive summary:

Data for the target chemical is summarized based on data from various test chemicals. The studies are as mentioned below:

A subacute repeated dose oral toxicity study was conducted to evaluate the toxic effects of repeated administration of the test chemical in male and female Sprague-Dawley rats by gavage. The test chemical was administered to 6 animals/sex/species with vehicle as corn oil at doses of 0, 250, 500 and 1000 mg/kg/bw/day for 28 days. All rats of 250, 500 and 1000 mg/kg/bw/day dose group survive though-out the study, the test chemical have no effect on mortality. Blood samples for Clinical Biochemistry and Haematology were collected. No abnormalities occurred that could be directly attributed to test chemical treatment. Although significant change in relative weights of liver, ovaries and lungs of female were observed in 1000 mg/kg/bw/day dose groups. No treatment related gross pathological or histological changes were seen and findings were not considered to be test chemical dependent and hence considered to be of no toxicological importance. Therefore the No Observed Adverse Effect Level (NOAEL) for repeated dose toxicity study was considered to be 1000 mg/kg/bw/day in male and female Sprague-Dawley rats when exposed to the test chemical by oral route for 28 days.

In another study, Repeated dose oral study for the test chemical was assessed for its possible toxic potential. For this purpose subchronic study for 17 weeks was conducted on Osborne-Mendel male and female rats. The test material was exposed at the concentration of 0, 50, 250 and 500 mg/kg bw (1000, 2500 and 10000 ppm) by oral feed. The animal’s weight, food intake and general condition were recorded every week. Haematological examinations were made at termination of the subacute studies. These examinations included white cell counts, red cell counts, haemoglobins and haematocrits. At the termination of the experiments the rats were sacrificed and exsanguinated. The tissues of all the rats were examined macroscopically at the time of sacrifice. The viscera were removed and the liver, kidneys, spleen, heart, and testes were weighed. These organs, the remaining abdominal and thoracic viscera, and one hind leg, for bone, bone marrow, and muscle, were preserved in 10 % buffered formalin-saline solution for histopathological examination. For routine histopathology, sections were embedded in paraffin wax and stained with haematoxylin and eosin. No mortality observed. No significant effects were observed at doses 0, 50, 250 or 500 mg/kg bw in treated groups compared to control in clinical sign, Body weight, Food intake , Haematology, organ weight , gross and histopathology. Hence the no observed adverse effect level (NOAEL) was considered to be 500 mg/kg bw for the test chemical in male and female rats by oral feed for 17 weeks study.

Based on the observations made, the No Observed Adverse Effect Level (NOAEL) was considered to be 1000 mg/kg bw/day when rats were exposed to the test chemical orally.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
1 000 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
Data is from K2 source

Repeated dose toxicity: inhalation - systemic effects

Link to relevant study records
Reference
Endpoint:
repeated dose toxicity: inhalation, other
Data waiving:
other justification
Justification for data waiving:
other:
Endpoint conclusion
Endpoint conclusion:
no study available
Quality of whole database:
Waiver

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - systemic effects

Link to relevant study records
Reference
Endpoint:
repeated dose toxicity: dermal, other
Data waiving:
other justification
Justification for data waiving:
other:
Endpoint conclusion
Endpoint conclusion:
no study available
Quality of whole database:
Waiver

Repeated dose toxicity: dermal - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Repeated dose toxicity: Oral

Data for the target chemical is summarized based on data from various test chemicals. The studies are as mentioned below:

A subacute repeated dose oral toxicity study was conducted to evaluate the toxic effects of repeated administration of the test chemical in male and female Sprague-Dawley rats by gavage. The test chemical was administered to 6 animals/sex/species with vehicle as corn oil at doses of 0, 250, 500 and 1000 mg/kg/bw/day for 28 days. All rats of 250, 500 and 1000 mg/kg/bw/day dose group survive though-out the study, the test chemical have no effect on mortality. Blood samples for Clinical Biochemistry and Haematology were collected. No abnormalities occurred that could be directly attributed to test chemical treatment. Although significant change in relative weights of liver, ovaries and lungs of female were observed in 1000 mg/kg/bw/day dose groups. No treatment related gross pathological or histological changes were seen and findings were not considered to be test chemical dependent and hence considered to be of no toxicological importance. Therefore the No Observed Adverse Effect Level (NOAEL) for repeated dose toxicity study was considered to be 1000 mg/kg/bw/day in male and female Sprague-Dawley rats when exposed to the test chemical by oral route for 28 days.

In another study, Repeated dose oral study for the test chemical was assessed for its possible toxic potential. For this purpose subchronic study for 17 weeks was conducted on Osborne-Mendel male and female rats. The test material was exposed at the concentration of 0, 50, 250 and 500 mg/kg bw (1000, 2500 and 10000 ppm) by oral feed. The animal’s weight, food intake and general condition were recorded every week. Haematological examinations were made at termination of the subacute studies. These examinations included white cell counts, red cell counts, haemoglobins and haematocrits. At the termination of the experiments the rats were sacrificed and exsanguinated. The tissues of all the rats were examined macroscopically at the time of sacrifice. The viscera were removed and the liver, kidneys, spleen, heart, and testes were weighed. These organs, the remaining abdominal and thoracic viscera, and one hind leg, for bone, bone marrow, and muscle, were preserved in 10 % buffered formalin-saline solution for histopathological examination. For routine histopathology, sections were embedded in paraffin wax and stained with haematoxylin and eosin. No mortality observed. No significant effects were observed at doses 0, 50, 250 or 500 mg/kg bw in treated groups compared to control in clinical sign, Body weight, Food intake , Haematology, organ weight , gross and histopathology. Hence the no observed adverse effect level (NOAEL) was considered to be 500 mg/kg bw for the test chemical in male and female rats by oral feed for 17 weeks study.

Based on the observations made, the No Observed Adverse Effect Level (NOAEL) was considered to be 1000 mg/kg bw/day when rats were exposed to the test chemical orally.

Repeated dose toxicity: Inhalation

The repeated dose inhalation toxicity study need not be conducted because exposure to humans via inhalation route is not likely taking into account due to the low vapour pressure of the test chemical, which is reported to be 0.00859 mm Hg. Thus, exposure to inhalable dust, mist and vapour of the chemical is highly unlikely. Therefore this study for repeated dose toxicity by inhalation route of exposure is considered for waiver.

Repeated dose toxicity: Dermal

The acute dermal toxicity value for phenethyl butyrate (CAS no 103-38-8) (as provided in section 7.2.3) is >2000 mg/kg body weight. Considering this, the end point for repeated dermal toxicity is considered as waiver.

Based on the observations made, the test chemical is not likely to be toxic upon repeated exposure by oral, inhalation and dermal route of exposure. Hence the test chemical is not likely to classify as a toxicant as per the criteria mentioned in CLP regulation.

Justification for classification or non-classification

Based on the observations made, the test chemical is not likely to be toxic upon repeated exposure by oral, inhalation and dermal route of exposure. Hence the test chemical is not likely to classify as a toxicant as per the criteria mentioned in CLP regulation.