Benzyl butyrate

Endpoint summary

Description of key information

Repeated Dose Oral Toxicity

Repeated dose oral toxicity study was performed using rats to determine the toxic nature of the test chemical. The test chemical was incorporated into the diet of 24 (12/sex) rats for 12 weeks as part of a blend with five other aromatic esters. The total intake was 2229.9 (males) and 1815.9 mg (females); The test chemical alone was not measured. Observations were made on physical appearance, behavior, and food utilization.  Urine samples were collected at the end of the 12 weeks. Liver and kidney weights were obtained. The no observed adverse effect level (NOAEL) is considered to be 2229.9 mg/Kg (males) and 1815.9 mg/Kg (females) when rats were exposed to the test chemical for 12 weeks.

Repeated dose inhalation toxicity

A short-term toxicity study need not be conducted because exposure of humans via inhalation route in production/use is highly unlikely based on the provided thorough and rigorous risk assessment. The test chemical has very low vapour pressure (6.5061 Pa.= 0.0487997562 mmHg),So the potential for the generation of inhalable vapours is very low. Also the normal conditions of use of this substance will not result in aerosols, particles or droplets of an inhalable size, so exposure to humans via the inhalatory route will be highly unlikely and therefore the short term inhalation toxicity end point was considered for waiver.

Repeated dose dermal toxicity

A short-term toxicity study need not be conducted because exposure of humans via dermal route in production/use is highly unlikely based on the provided thorough and rigorous risk assessment. he acute dermal toxicity value for Benzyl butyrate (CAS no 103-37-7) (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:

sub-chronic toxicity: oral

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 journals

Qualifier:

according to guideline

Guideline:

other: Refer below principle

Principles of method if other than guideline:

Subchronic oral toxicity test of the test chemical was conducted on rats

GLP compliance:

not specified

Limit test:

no

Species:

rat

Strain:

not specified

Sex:

male/female

Details on test animals or test system and environmental conditions:

No data available

Route of administration:

oral: feed

Vehicle:

other: Diet

Details on oral exposure:

No data

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

12 weeks

Frequency of treatment:

No data available

Remarks:

2229.9 (males) and 1815.9 mg/Kg (females) - Total intake

No. of animals per sex per dose:

12/sex

Control animals:

not specified

Details on study design:

No data available

Positive control:

No data available

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes, Physical appearance and behaviour was observed

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: No data available

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

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

FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: No data

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

OPHTHALMOSCOPIC EXAMINATION: No data
- Time schedule for examinations:
- Dose groups that were examined: No data available

HAEMATOLOGY: No data
- Time schedule for collection of blood: No data available
- Anaesthetic used for blood collection: No data
- Animals fasted: No data
- How many animals: No data available
- Parameters checked in table [No.?] were examined.

CLINICAL CHEMISTRY: No data
- Time schedule for collection of blood:
- Animals fasted: No data
- How many animals: No data available
- Parameters checked in table [No.?] were examined.

URINALYSIS: Yes
- Time schedule for collection of urine: at the end of 12 weeks
- Metabolism cages used for collection of urine: No data
- Animals fasted: No data
- Parameters checked in table [No.?] were examined.

NEUROBEHAVIOURAL EXAMINATION: No data
- 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: No data available

OTHER: No data

Sacrifice and pathology:

GROSS PATHOLOGY: Yes, liver and kidney weights were taken
HISTOPATHOLOGY: No

Other examinations:

No data

Statistics:

No data available

Clinical signs:

no effects observed

Description (incidence and severity):

No signs of clinical toxicity were observed.

Mortality:

no mortality observed

Body weight and weight changes:

not specified

Food consumption and compound intake (if feeding study):

not specified

Food efficiency:

no effects observed

Description (incidence and severity):

No abnormalities were observed

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:

no effects observed

Description (incidence and severity):

No abnormalities were observed

Behaviour (functional findings):

not specified

Immunological findings:

not specified

Organ weight findings including organ / body weight ratios:

not specified

Gross pathological findings:

not specified

Neuropathological findings:

not specified

Histopathological findings: non-neoplastic:

no effects observed

Histopathological findings: neoplastic:

not specified

Other effects:

not specified

Dose descriptor:

NOAEL

Effect level:

2 229.9 mg/kg diet

Based on:

test mat.

Sex:

male

Basis for effect level:

other: Physical appearance, behavior, food utilization, Liver and kidney weights

Dose descriptor:

NOAEL

Effect level:

1 815.9 mg/kg diet

Based on:

test mat.

Sex:

female

Basis for effect level:

other: Physical appearance, behavior, food utilization, Liver and kidney weights

Critical effects observed:

not specified

Conclusions:

The no observed adverse effect level (NOAEL) is considered to be 2229.9 mg/Kg (males) and 1815.9 mg/Kg (females) when rats were exposed to the test chemical for 12 weeks.

Executive summary:

Repeated dose oral toxicity study was performed using rats to determine the toxic nature of the test chemical. The test chemical was incorporated into the diet of 24 (12/sex) rats for 12 weeks as part of a blend with five other aromatic esters. The total intake was 2229.9 (males) and 1815.9 mg (females); The test chemical alone was not measured. Observations were made on physical appearance, behavior, and food utilization.  Urine samples were collected at the end of the 12 weeks. Liver and kidney weights were obtained. The no observed adverse effect level (NOAEL) is considered to be 2229.9 mg/Kg (males) and 1815.9 mg/Kg (females) when rats were exposed to the test chemical for 12 weeks.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

2 220 mg/kg bw/day

Study duration:

subchronic

Experimental exposure time per week (hours/week):

168

Species:

rat

Quality of whole database:

KLIMISCH RATING 2

Repeated dose toxicity: inhalation - systemic effects

Link to relevant study records

Reference

Endpoint:

short-term repeated dose toxicity: inhalation

Data waiving:

exposure considerations

Justification for data waiving:

a short-term toxicity study does not need to be conducted because exposure of humans via inhalation in production and/or use is not likely as based on the provided thorough and rigorous exposure assessment

Endpoint conclusion

Endpoint conclusion:

no study available

Quality of whole database:

waiver

Repeated dose toxicity: dermal - systemic effects

Link to relevant study records

Reference

Endpoint:

short-term repeated dose toxicity: dermal

Data waiving:

exposure considerations

Justification for data waiving:

a short-term toxicity study does not need to be conducted because exposure of humans via the dermal route in production and/or use is not likely as based on the provided thorough and rigorous exposure assessment

Endpoint conclusion

Quality of whole database:

waiver

Additional information

Repeated Dose Oral Toxicity

Various studies have been reviewed to evaluate the repeated dose oral toxicity of the test chemical. These studies include in vivo experimental studies performed on rats for the test chemical. The results are mentioned below:

Repeated dose oral toxicity study was performed using rats to determine the toxic nature of the test chemical. The test chemical was incorporated into the diet of 24 (12/sex) rats for 12 weeks as part of a blend with five other aromatic esters. The total intake was 2229.9 (males) and 1815.9 mg (females); The test chemical alone was not measured. Observations were made on physical appearance, behavior, and food utilization.  Urine samples were collected at the end of the 12 weeks. Liver and kidney weights were obtained. The no observed adverse effect level (NOAEL) is considered to be 2229.9 mg/Kg (males) and 1815.9 mg/Kg (females) when rats were exposed to the test chemical for 12 weeks.

This result is supported by another subchronic repeated dose oral toxicity study performed to determine the toxic nature of the test chemical. The test chemical was incorporated into the diet of 12 weanling rats of each sex for 12 weeks as part of a blend with five other aromatic esters. average daily intake of 0 or 100 times the assumed human intake, calculated to be 130 mg/kg bw per day. The test chemical was incorporated in the diet at dose level of 25 mg/kg. The group receiving the ester blend had normal body weight gain, food consumption, efficiency of food use, appearance, and behaviour. The blood haemoglobin and urine glucose concentrations did not differ significantly between test and control groups. Traces of albumin present in urine specimens from both control and test groups were regarded as not significant. At autopsy, no treatment related abnormalities were observed, and the weights of the livers and kidneys were within normal limits for both groups. No histopathological examination was performed. Based on the observations made, the no observed adverse effect level (NOAEL) for the test chemical is considered to be 25 mg/Kg/day when male and female rats were treated for 12 weeks.

These results are further supported by a subacute repeated dose oral toxicity study 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.

 

All of the above results are further supported by another 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 10000ppm) 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 available results the test chemical can be considered to be non-toxic when exposed repeatedly via oral route of exposure. Hence, it can be classified under the category “Not Classified” as per CLP Regulation.

Repeated dose inhalation toxicity

A short-term toxicity study need not be conducted because exposure of humans via inhalation route in production/use is highly unlikely based on the provided thorough and rigorous risk assessment. The test chemical has very low vapour pressure (6.5061 Pa.= 0.0487997562 mmHg),So the potential for the generation of inhalable vapours is very low. Also the normal conditions of use of this substance will not result in aerosols, particles or droplets of an inhalable size, so exposure to humans via the inhalatory route will be highly unlikely and therefore the short term inhalation toxicity end point was considered for waiver.

Repeated dose dermal toxicity

A short-term toxicity study need not be conducted because exposure of humans via dermal route in production/use is highly unlikely based on the provided thorough and rigorous risk assessment. he acute dermal toxicity value for Benzyl butyrate (CAS no 103-37-7) (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

 

Justification for classification or non-classification

Based on the available results the test chemical can be considered to be non-toxic when exposed repeatedly via oral,dermal or inhalation route of exposure. Hence, it can be classified under the category “Not Classified” as per CLP Regulation.