Benzyl propionate

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Description of key information

Toxicity to reproduction

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.

Thus, based on the above studies on Benzyl Propionate(122-63-4)and its read across substances it was considered that no adverse effects on reproductive parameter were observed. Hence NOAEL is considered to be 1000mg/kg bw . Thus, comparing this value with the criteria of CLP regulation Benzyl Propionate (122-63-4) cannot be classified as reproductive toxicant.

Link to relevant study records

Reference

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

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

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

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

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

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

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

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: oestrous cycle:

not specified

Reproductive function: sperm measures:

not specified

Reproductive performance:

not specified

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

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

Remarks on result:

not determinable

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

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.

Effect on fertility: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

1 000 mg/kg bw/day

Study duration:

subacute

Species:

rat

Quality of whole database:

K1 experimental report

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

The experimental study of Benzyl Propionate(122-63-4) summaries below

The experimental study conducted by Sustainability Support Services (Europe) AB (report no. 17871 and company study no SPL/122/004,2014) on structurally similar read across substance Benzyl Propionate(122-63-4).The reproductive toxicity of Benzyl Propionate(122-63-4) was considered on the bases of repeated dose 28-day Oral Toxicity study performed in GLP compliance 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 Behaviour, 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 were weighed 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 treated dose 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 behaviour, 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. 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 29thday 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 female Sprague-Dawley rats were treated with Benzyl Propionate(122-63-4) orally for 28 days.

It is further supported by experimental study conducted by NATIONAL TOXICOLOGY PROGRAM (NATIONAL TOXICOLOGY PROGRAM Technical Report Series No. 431,1993)on structurally similar read across substance Benzyl acetate(140-11-4).The reproductive toxicity study of Benzyl acetate(140-11-4) was performed on male and female F344/N Rates by repeated oral exposure for 13 weeks. The test material mix with feed and store for maximum 120 days after milling. All the animals provide with feed containing test material in dose concentration 0, 3130, 6250, 12500, 25000 or 50000ppm (0,230, 460, 900, 1750, or 3,900 mg/kg for male rats and 0, 240, 480, 930, 1,870, or 4,500 mg/kg for female rats ) daily for 13 weeks. Each dose group contain 10 male and 10 female. Animals were grouped by weight and assigned to cages and the cages assigned to exposure groups using tables of random numbers. Feed and water were available ad libitum. Feed consumption was, recorded daily by cage. Rats were housed five per cage and mice were housed individually. Clinical findings were recorded once weekly. The animals were weighed at the beginning of the studies, weekly, and at the end of the studies. The animals were sacrifice by carbon dioxide asphyxiation or carbon dioxide anaesthesia followed by perfusion. Necropsy was performed on all animals at age of 19 weeks; Organs weighed were brain, right kidney, liver, pancreas, prostate gland, seminal vesicle, spleen, right testis, thymus, and uterus. Complete histopathologic examinations were performedon all control,25000 and 50,000ppm rats, and on all control. In addition togrosslesions, tissue masses, and associated lymph nodes, the tissues examined included: adrenal gland, bone (including marrow), brain, esophagus, gallbladder(mice), heart, kidney, large intestine (cecum, colon, and rectum), liver, lung, mammary gland, nose, ovary, pancreas, parathyroid gland, pituitary gland, preputialorclitoral gland , prostate gland, salivary gland, skin, small intestine, spleen, stomach (forestomach and glandular), testis with epididymis and seminal vesicle, thigh muscle, thymus, thyroid gland, tongue, trachea, urinary bladder, and uterus. The testis with epididymisof6,250 and 12,500ppm male rats were also examined.Bloodwas collected from the orbital sinus (rats)orheart (mice). Pancreas samples from all control and exposed male and female rats except the50,000ppm group and all control and exposed mice were collected. Liver samples from control,25,000and50,000ppm female rats were collected.H-haematocrit, haemoglobin, erythrocytes, mean erythrocyte volume, mean erythrocyte haemoglobin, mean erythrocyte haemoglobin concentration, platelets, reticulocytes, and leukocyte count and differential leukocyte count, cholesterol and triglyceride lipase, carboxypeptidase, chymotrypsin, and ribonuclease were observed.

 Clinical findings related to toxicity observed in the50,000 ppm rats included tremors, ataxia, and urine stains. These findings were first observed on day 15 of the study in nine males and six females and continued until the end of the study. Nine male and nine female rats in dose group 50,000ppm died or were killed moribund between weeks 2 and 8 , one female in dose group 12,500 ppm died under anaesthesia during blood collection at the end of study. The mean body weight gain and the final mean body weight of 25000ppm male rats were significantly lower than those of the control. The final mean body weight of 25000ppm male was 10% lower than that of the control group, whereas the final body weights of surviving 50000ppm male and female were less than half those of the control. Final mean body weights of male and female of other exposed group were similar to or slightly lower than those of the control. Feed consumption by exposed rats was similar to control in all group expect 25000ppm and 50,000ppm male and 50000ppm female. The reduced feed consumption by 25,000 and50,000 ppm males and50000ppm females may have been due to decreased palatability and/or toxicity. Slight differences in organ weights were observed and were considered secondary to the reduced body weights .Excluding the data from the50,000ppm males and females (only one survivor in each group), Haematology values for all exposed groups was similar to those of the control groups. The clinical chemistry evaluations showed significantly lower cholesterol levels in 12,500 and 25,000 ppm female rats than in the controls. No chemical-related differences occurred in the cholesterol or triglyceride levels in exposed males.

 Testicular changes related to chemical exposure occurred in male rats receiving 12,500, 25,000, and 50000ppm dosed feed. The lesions were characterized by mild or moderate aspermatogenesis in two50,000ppm male rats and atrophy of seminiferous tubules intwo25,000 ppm and one 12,500 ppm rats. In one25,000ppm rat, the seminiferous tubule atrophy was marked in severity and included atypical cells (enlarged, degenerated spermatozoa) in the corresponding epididymis and mild interstitial cell hyperplasia. The seminiferous tubule atrophy was minimal in severity in one 12,500 ppm rat. No testicular lesions occurred in the6,250ppm or lower exposure levels. Several changes in50,000ppm rats were considered indirectly related to chemical exposure. These changes included depletion of the cellular components of the bone marrow, thymus (atrophy), and splenic lymphoid follicles, zymogengranule depletion and increased basophilia of the pancreatic acinar cells (Cytoplasmic alteration), minimal to mild erosions of the glandular stomach, secretory depletion of the seminal vesicles, and immature hypoplastic uterus. These changes are frequently observed in rodents and are usually caused by debilitation, stress, age, or poor nutrition. Hence No Observed Adverse Effect Level (NOAEL)was considered to be 25000ppm i.e 1750mg/kg bw/day in male and1870mg/kg bw/day in female on the as no effects on reproductive organ .when male and female F344/N Rats were treated with Benzyl acetate(140-11-4)by repeated oral exposure for 13 weeks

 Thus, based on the above studies and predictions on Benzyl Propionate(122-63-4)and its read across substances it was considered that no adverse effects on reproductive parameter were observed. Hence NOAEL is considered to be 1000mg/kg bw . Thus, comparing this value with the criteria of CLP regulation Benzyl Propionate (122-63-4) cannot be classified as reproductive toxicant.

Effects on developmental toxicity

Description of key information

Developmental toxicity/ Teratogenecity: In a prediction done by SSS (2014) using the OECD QSAR toolbox v 3.1with log kow as the primary descriptor, the developmental toxicity was estimated benzyl propionate (CAS No.: 122-63-4) NOAEL was estimated to be 710.0mg/kg bw. When male and female wistar rats were exposed with benzyl propionate (CAS No.: 122-63-4) orally.

Thus, based on the above studies and predictions on Benzyl Propionate(122-63-4)and its read across substances it was considered that no adverse effects on reproductive and developmental parameter were observed. Hence NOAEL is considered to be 710.0mg/kg bw . Thus, comparing this value with the criteria of CLP regulation Benzyl Propionate (122-63-4) cannot be classified as developmental toxicant.

Link to relevant study records

Reference

Endpoint:

developmental toxicity

Type of information:

(Q)SAR

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

results derived from a valid (Q)SAR model and falling into its applicability domain, with limited documentation / justification

Justification for type of information:

QSAR prediction: migrated from IUCLID 5.6

Guideline:

OECD Guideline 414 (Prenatal Developmental Toxicity Study)

Principles of method if other than guideline:

The prediction is done using QSAR Toolbox version 3.1

GLP compliance:

not specified

Limit test:

no

Specific details on test material used for the study:

- Name of test material: benzyl propionate
- Molecular formula: C10H12O2
- Molecular weight: 164.20
- Substance type: Organic
- Physical state: Liquid
- SMILES:c1(COC(=O)CC)ccccc1

Species:

rat

Strain:

Wistar

Route of administration:

oral: gavage

Vehicle:

olive oil

Analytical verification of doses or concentrations:

not specified

Details on mating procedure:

no data

Duration of treatment / exposure:

10 days

Frequency of treatment:

Once each day from days 6 to 15 of pregnancy

Duration of test:

10 days

Dose / conc.:

710 mg/kg bw/day (nominal)

No. of animals per sex per dose:

no data

Control animals:

yes, concurrent no treatment

Details on study design:

No data available

Maternal examinations:

No data available

Ovaries and uterine content:

No data available

Fetal examinations:

No data available

Statistics:

No data available

Indices:

No data available

Historical control data:

No data available

Clinical signs:

not specified

Dermal irritation (if dermal study):

not specified

Mortality:

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

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:

not specified

Histopathological findings: neoplastic:

not specified

Other effects:

not specified

Number of abortions:

not specified

Pre- and post-implantation loss:

not specified

Total litter losses by resorption:

not specified

Early or late resorptions:

not specified

Dead fetuses:

not specified

Changes in pregnancy duration:

not specified

Description (incidence and severity):

Migrated Data from removed field(s)
Field "Effects on pregnancy duration" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsMaternalAnimals.MaternalDevelopmentalToxicity.EffectsOnPregnancyDuration): not specified

Changes in number of pregnant:

not specified

Other effects:

not specified

Details on maternal toxic effects:

Maternal toxic effects:no effects

Dose descriptor:

NOAEL

Effect level:

710 mg/kg bw/day (nominal)

Based on:

test mat.

Basis for effect level:

other: maternal toxicity

Remarks on result:

other: overall no reproductive toxic effects observed

Abnormalities:

not specified

Fetal body weight changes:

no effects observed

Description (incidence and severity):

Migrated Data from removed field(s)
Field "Fetal/pup body weight changes" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.FetalPupBodyWeightChanges): not specified

Reduction in number of live offspring:

not specified

Changes in sex ratio:

not specified

Changes in litter size and weights:

not specified

Changes in postnatal survival:

not specified

External malformations:

no effects observed

Skeletal malformations:

not specified

Visceral malformations:

not specified

Other effects:

not specified

Details on embryotoxic / teratogenic effects:

Embryotoxic / teratogenic effects:no effects

Dose descriptor:

NOAEL

Effect level:

710 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

not specified

Basis for effect level:

external malformations

other: overall no teratogenic effects observed

Remarks on result:

other: overall no teratogenic effects observed

Abnormalities:

not specified

Localisation:

other: not specified

Developmental effects observed:

not specified

Treatment related:

not specified

Relation to maternal toxicity:

not specified

Dose response relationship:

not specified

Relevant for humans:

not specified

The prediction was based on dataset comprised from the following descriptors: NOAEL
Estimation method: Takes average value from the 5 nearest neighbours
Domain  logical expression:Result: In Domain

(((("a" or "b" or "c" or "d" or "e" )  and ("f" and ( not "g") )  )  and (("h" or "i" or "j" or "k" or "l" )  and ("m" and ( not "n") )  )  and (("o" or "p" or "q" or "r" or "s" )  and ("t" and ( not "u") )  )  )  and ("v" and "w" )  )

Domain logical expression index: "a"

Referential boundary: The target chemical should be classified as Esters (Acute toxicity) by US-EPA New Chemical Categories

Domain logical expression index: "b"

Referential boundary: The target chemical should be classified as Aryl AND Benzyl AND Carboxylic acid ester by Organic functional groups

Domain logical expression index: "c"

Referential boundary: The target chemical should be classified as Benzyl AND Carboxylic acid ester AND Overlapping groups by Organic functional groups (nested)

Domain logical expression index: "d"

Referential boundary: The target chemical should be classified as Aliphatic Carbon [CH] AND Aliphatic Carbon [-CH2-] AND Aliphatic Carbon [-CH3] AND Aromatic Carbon [C] AND Carbonyl, aliphatic attach [-C(=O)-] AND Ester, aliphatic attach [-C(=O)O] AND Miscellaneous sulfide (=S) or oxide (=O) AND Olefinic carbon [=CH- or =C<] by Organic functional groups (US EPA)

Domain logical expression index: "e"

Referential boundary: The target chemical should be classified as Aromatic compound AND Carbonic acid derivative AND Carboxylic acid derivative AND Carboxylic acid ester by Organic functional groups, Norbert Haider (checkmol)

Domain logical expression index: "f"

Referential boundary: The target chemical should be classified as Michael addition AND Michael addition >> P450 Mediated Activation to Quinones and Quinone-type Chemicals AND Michael addition >> P450 Mediated Activation to Quinones and Quinone-type Chemicals >> Arenes by DNA binding by OECD

Domain logical expression index: "g"

Referential boundary: The target chemical should be classified as Acylation OR Acylation >> Direct Addition of an Acyl Halide OR Acylation >> Direct Addition of an Acyl Halide >> Acyl halide OR Acylation >> Isocyanates and Isothiocyanates OR Acylation >> Isocyanates and Isothiocyanates >> Isothiocyanates OR Acylation >> P450 Mediated Activation to Acyl Halides OR Acylation >> P450 Mediated Activation to Acyl Halides >> 1,1-Dihaloalkanes OR Acylation >> P450 Mediated Activation to Isocyanates or Isothiocyanates OR Acylation >> P450 Mediated Activation to Isocyanates or Isothiocyanates >> Benzylamines-Acylation OR Acylation >> P450 Mediated Activation to Isocyanates or Isothiocyanates >> Formamides OR Acylation >> P450 Mediated Activation to Isocyanates or Isothiocyanates >> Sulfonylureas OR Michael addition >> P450 Mediated Activation of Heterocyclic Ring Systems OR Michael addition >> P450 Mediated Activation of Heterocyclic Ring Systems >> Furans OR Michael addition >> P450 Mediated Activation of Heterocyclic Ring Systems >> Thiophenes-Michael addition OR Michael addition >> P450 Mediated Activation to Quinones and Quinone-type Chemicals >> 5-alkoxyindoles OR Michael addition >> P450 Mediated Activation to Quinones and Quinone-type Chemicals >> Alkyl phenols OR Michael addition >> P450 Mediated Activation to Quinones and Quinone-type Chemicals >> Hydroquinones OR Michael addition >> P450 Mediated Activation to Quinones and Quinone-type Chemicals >> Methylenedioxyphenyl OR Michael addition >> P450 Mediated Activation to Quinones and Quinone-type Chemicals >> Polycyclic (PAHs) and heterocyclic (HACs) aromatic hydrocarbons-Michael addition OR Michael addition >> Polarised Alkenes-Michael addition OR Michael addition >> Polarised Alkenes-Michael addition >> Alpha, beta- unsaturated aldehydes OR Michael addition >> Polarised Alkenes-Michael addition >> Alpha, beta- unsaturated amides OR Michael addition >> Polarised Alkenes-Michael addition >> Alpha, beta- unsaturated esters OR Michael addition >> Polarised Alkenes-Michael addition >> Alpha, beta- unsaturated ketones OR Michael addition >> Quinones and Quinone-type Chemicals OR Michael addition >> Quinones and Quinone-type Chemicals >> Quinones OR No alert found OR Schiff base formers OR Schiff base formers >> Chemicals Activated by P450 to Glyoxal  OR Schiff base formers >> Chemicals Activated by P450 to Glyoxal  >> Ethanolamines (including morpholine) OR Schiff base formers >> Chemicals Activated by P450 to Mono-aldehydes OR Schiff base formers >> Chemicals Activated by P450 to Mono-aldehydes >> Benzylamines-Schiff base OR Schiff base formers >> Direct Acting Schiff Base Formers OR Schiff base formers >> Direct Acting Schiff Base Formers >> Alpha-beta-dicarbonyl OR Schiff base formers >> Direct Acting Schiff Base Formers >> Mono aldehydes OR SN1 OR SN1 >> Carbenium Ion Formation OR SN1 >> Carbenium Ion Formation >> Aliphatic N-Nitro OR SN1 >> Carbenium Ion Formation >> Allyl benzenes OR SN1 >> Carbenium Ion Formation >> Alpha halo ethers (including alpha halo thioethers) OR SN1 >> Carbenium Ion Formation >> Diazoalkanes OR SN1 >> Carbenium Ion Formation >> Hydrazine OR SN1 >> Carbenium Ion Formation >> N-Nitroso (alkylation) OR SN1 >> Carbenium Ion Formation >> Polycyclic (PAHs) and heterocyclic (HACs) aromatic hydrocarbons-SN1 OR SN1 >> Iminium Ion Formation OR SN1 >> Iminium Ion Formation >> Aliphatic tertiary amines OR SN1 >> Nitrenium Ion formation OR SN1 >> Nitrenium Ion formation >> Aromatic azo OR SN1 >> Nitrenium Ion formation >> Aromatic nitro OR SN1 >> Nitrenium Ion formation >> Aromatic phenylureas OR SN1 >> Nitrenium Ion formation >> Primary (unsaturated) heterocyclic amine OR SN1 >> Nitrenium Ion formation >> Primary aromatic amine OR SN1 >> Nitrenium Ion formation >> Secondary (unsaturated) heterocyclic amine OR SN1 >> Nitrenium Ion formation >> Secondary aromatic amine OR SN1 >> Nitrenium Ion formation >> Tertiary (unsaturated) heterocyclic amine  OR SN1 >> Nitrenium Ion formation >> Tertiary aromatic amine OR SN1 >> Nitrenium Ion formation >> Unsaturated heterocyclic azo OR SN1 >> Nitrenium Ion formation >> Unsaturated heterocyclic ester hydroxylamine OR SN1 >> Nitrenium Ion formation >> Unsaturated heterocyclic N-hydroxylamines OR SN1 >> Nitrenium Ion formation >> Unsaturated heterocyclic nitro OR SN2 OR SN2 >> Direct Acting Epoxides and related OR SN2 >> Direct Acting Epoxides and related >> Aziridines OR SN2 >> Direct Acting Epoxides and related >> Epoxides OR SN2 >> Episulfonium Ion Formation OR SN2 >> Episulfonium Ion Formation >> 1,2-Dihaloalkanes OR SN2 >> Episulfonium Ion Formation >> Mustards OR SN2 >> Epoxidation of Aliphatic Alkenes OR SN2 >> Epoxidation of Aliphatic Alkenes >> Phenoxy polarised alkenes OR SN2 >> Nitrosation-SN2 OR SN2 >> Nitrosation-SN2 >> Nitroso-SN2 OR SN2 >> P450 Mediated Epoxidation OR SN2 >> P450 Mediated Epoxidation >> Thiophenes-SN2 OR SN2 >> Ring opening SN2 Reaction OR SN2 >> Ring opening SN2 Reaction >> Lactones OR SN2 >> SN2 at an sp3 Carbon atom OR SN2 >> SN2 at an sp3 Carbon atom >> Aliphatic halides OR SN2 >> SN2 at an sp3 Carbon atom >> Alkyl carbamates OR SN2 >> SN2 at an sp3 Carbon atom >> Phosphonic esters OR SN2 >> SN2 at an sp3 Carbon atom >> Sulfonates by DNA binding by OECD

Domain logical expression index: "h"

Referential boundary: The target chemical should be classified as Esters (Acute toxicity) by US-EPA New Chemical Categories

Domain logical expression index: "i"

Referential boundary: The target chemical should be classified as Aryl AND Benzyl AND Carboxylic acid ester by Organic functional groups

Domain logical expression index: "j"

Referential boundary: The target chemical should be classified as Benzyl AND Carboxylic acid ester AND Overlapping groups by Organic functional groups (nested)

Domain logical expression index: "k"

Referential boundary: The target chemical should be classified as Aliphatic Carbon [CH] AND Aliphatic Carbon [-CH2-] AND Aliphatic Carbon [-CH3] AND Aromatic Carbon [C] AND Carbonyl, aliphatic attach [-C(=O)-] AND Ester, aliphatic attach [-C(=O)O] AND Miscellaneous sulfide (=S) or oxide (=O) AND Olefinic carbon [=CH- or =C<] by Organic functional groups (US EPA)

Domain logical expression index: "l"

Referential boundary: The target chemical should be classified as Aromatic compound AND Carbonic acid derivative AND Carboxylic acid derivative AND Carboxylic acid ester by Organic functional groups, Norbert Haider (checkmol)

Domain logical expression index: "m"

Referential boundary: The target chemical should be classified as Non binder, without OH or NH2 group by Estrogen Receptor Binding

Domain logical expression index: "n"

Referential boundary: The target chemical should be classified as Moderate binder, NH2 group OR Moderate binder, OH grooup OR Non binder, impaired OH or NH2 group OR Non binder, MW>500 OR Non binder, non cyclic structure OR Strong binder, NH2 group OR Strong binder, OH group OR Weak binder, NH2 group OR Weak binder, OH group OR Very strong binder, OH group by Estrogen Receptor Binding

Domain logical expression index: "o"

Referential boundary: The target chemical should be classified as Esters (Acute toxicity) by US-EPA New Chemical Categories

Domain logical expression index: "p"

Referential boundary: The target chemical should be classified as Aryl AND Benzyl AND Carboxylic acid ester by Organic functional groups

Domain logical expression index: "q"

Referential boundary: The target chemical should be classified as Benzyl AND Carboxylic acid ester AND Overlapping groups by Organic functional groups (nested)

Domain logical expression index: "r"

Referential boundary: The target chemical should be classified as Aliphatic Carbon [CH] AND Aliphatic Carbon [-CH2-] AND Aliphatic Carbon [-CH3] AND Aromatic Carbon [C] AND Carbonyl, aliphatic attach [-C(=O)-] AND Ester, aliphatic attach [-C(=O)O] AND Miscellaneous sulfide (=S) or oxide (=O) AND Olefinic carbon [=CH- or =C<] by Organic functional groups (US EPA)

Domain logical expression index: "s"

Referential boundary: The target chemical should be classified as Aromatic compound AND Carbonic acid derivative AND Carboxylic acid derivative AND Carboxylic acid ester by Organic functional groups, Norbert Haider (checkmol)

Domain logical expression index: "t"

Referential boundary: The target chemical should be classified as SN2 AND SN2 >> SN2 reaction at sp3 carbon atom AND SN2 >> SN2 reaction at sp3 carbon atom >> Allyl acetates and related chemicals by Protein binding by OECD

Domain logical expression index: "u"

Referential boundary: The target chemical should be classified as Acylation OR Acylation >> Direct Acylation Involving a Leaving group OR Acylation >> Direct Acylation Involving a Leaving group >> Acetates OR Acylation >> Direct Acylation Involving a Leaving group >> Acyl halides (including benzyl and carbamoyl deriv.) OR Acylation >> Direct Acylation Involving a Leaving group >> Anhydrides OR Acylation >> Direct Acylation Involving a Leaving group >> Azlactone OR Acylation >> Isocyanates and Related Chemicals OR Acylation >> Isocyanates and Related Chemicals >> Isothiocyanates OR Acylation >> Isocyanates and Related Chemicals >> Thiocyanates-Acylation OR Acylation >> Ring Opening Acylation OR Acylation >> Ring Opening Acylation >> alpha-Lactams OR Acylation >> Ring Opening Acylation >> beta-Lactones-Acylation OR Michael addition OR Michael addition >> Acid imides OR Michael addition >> Acid imides >> Acid imides-MA OR Michael addition >> Polarised Alkenes OR Michael addition >> Polarised Alkenes >> Polarised alkene - aldehydes OR Michael addition >> Polarised Alkenes >> Polarised alkene - amides OR Michael addition >> Polarised Alkenes >> Polarised alkene - cyano OR Michael addition >> Polarised Alkenes >> Polarised alkene - esters OR Michael addition >> Polarised Alkenes >> Polarised alkene - ketones OR Michael addition >> Polarised Alkenes >> Polarised alkene - nitro OR Michael addition >> Polarised Alkynes OR Michael addition >> Polarised Alkynes >> Polarised alkyne - ester OR Michael addition >> Quinones and Quinone-type Chemicals OR Michael addition >> Quinones and Quinone-type Chemicals >> Benzoquinones OR Michael addition >> Quinones and Quinone-type Chemicals >> Pyranones (and related nitrogen chemicals) OR Michael addition >> Quinones and Quinone-type Chemicals >> Quinone-diimine OR Michael addition >> Quinones and Quinone-type Chemicals >> Quinone-imine OR Michael addition >> Quinones and Quinone-type Chemicals >> Quinone-methides OR No alert found OR Schiff Base Formers OR Schiff Base Formers >> Direct Acting Schiff Base Formers OR Schiff Base Formers >> Direct Acting Schiff Base Formers >> 1-2-Dicarbonyls OR Schiff Base Formers >> Direct Acting Schiff Base Formers >> 1-3-Dicarbonyls OR Schiff Base Formers >> Direct Acting Schiff Base Formers >> Di-substituted alpha, beta-unsaturated aldehydes OR Schiff Base Formers >> Direct Acting Schiff Base Formers >> Mono-carbonyls OR SN2 >> Episulfonium Ion Formation OR SN2 >> Episulfonium Ion Formation >> 1,2-Dihaloalkane OR SN2 >> Episulfonium Ion Formation >> Mustards OR SN2 >> Epoxides and Related Chemicals OR SN2 >> Epoxides and Related Chemicals >> Epoxides OR SN2 >> Ring Opening SN2 Reaction OR SN2 >> Ring Opening SN2 Reaction >> beta-Lactones-SN2 OR SN2 >> SN2 reaction at a nitrogen atom OR SN2 >> SN2 reaction at a nitrogen atom >> N-Acetoxy-N-acetyl-phenyl OR SN2 >> SN2 reaction at a nitrogen atom >> Nitrosoureas (nitrogen) OR SN2 >> SN2 reaction at a sp2 carbon atom OR SN2 >> SN2 reaction at a sp2 carbon atom >> Polarised alkenes with a halogen leaving group OR SN2 >> SN2 reaction at a sp2 carbon atom >> Polarised alkenes with a phosphate leaving group OR SN2 >> SN2 reaction at a sp2 carbon atom >> Polarised alkenes with a tiophosphate leaving group OR SN2 >> SN2 reaction at a sulphur atom OR SN2 >> SN2 reaction at a sulphur atom >> Disulfides OR SN2 >> SN2 reaction at a sulphur atom >> Thiocyanates-SN2 OR SN2 >> SN2 reaction at a sulphur atom >> Thiols OR SN2 >> SN2 reaction at sp3 carbon atom >> Alkyl halides OR SN2 >> SN2 reaction at sp3 carbon atom >> alpha-Halo ethers OR SN2 >> SN2 reaction at sp3 carbon atom >> alpha-Haloalkenes (and related cyano, sulfate and sulfonate subs. chem.) OR SN2 >> SN2 reaction at sp3 carbon atom >> alpha-Haloalkynes (and related cyano, sulfate, sulphpnate subs. chem.) OR SN2 >> SN2 reaction at sp3 carbon atom >> alpha-Halobenzyls (and related cyano, sulfate and sulphonate subs. chem.) OR SN2 >> SN2 reaction at sp3 carbon atom >> alpha-Halocarbonyls OR SN2 >> SN2 reaction at sp3 carbon atom >> beta-Halo ethers OR SN2 >> SN2 reaction at sp3 carbon atom >> Nitrosoureas (carbon) OR SN2 >> SN2 reaction at sp3 carbon atom >> Phosphates OR SN2 >> SN2 reaction at sp3 carbon atom >> Phosphonates OR SN2 >> SN2 reaction at sp3 carbon atom >> Sulfonates OR SN2 >> SN2 reaction at sp3 carbon atom >> Thiophosphates OR SNAr OR SNAr >> Nucleophilic aromatic substitution OR SNAr >> Nucleophilic aromatic substitution >> Activated halo-benzenes OR SNAr >> Nucleophilic aromatic substitution >> Activated halo-pyridines OR SNAr >> Nucleophilic aromatic substitution >> Halo-pyrimidines OR SNAr >> Nucleophilic aromatic substitution >> Halo-triazines by Protein binding by OECD

Domain logical expression index: "v"

Parametric boundary:The target chemical should have a value of log Kow which is >= 2.08

Domain logical expression index: "w"

Parametric boundary:The target chemical should have a value of log Kow which is <= 4.85

Conclusions:

In a prediction done by SSS (2014) using the OECD QSAR toolbox v 3.1with log kow as the primary descriptor, the developmental toxicity was estimated benzyl propionate (CAS No.: 122-63-4) NOAEL was estimated to be 710.0mg/kg bw. When male and femalewistar rats were exposed with benzyl propionate (CAS No.: 122-63-4) orally.

Executive summary:

In a prediction done by SSS (2014) using the OECD QSAR toolbox v 3.1with log kow as the primary descriptor, the developmental toxicity was estimated benzyl propionate (CAS No.: 122-63-4) NOAEL was estimated to be 710.0mg/kg bw. When male and femalewistar rats were exposed with benzyl propionate (CAS No.: 122-63-4) orally.

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

710 mg/kg bw/day

Study duration:

subacute

Species:

rat

Quality of whole database:

Data is Klimicsh 2 and from QSAR Toolbox 3.1. (2014)

Effect on developmental toxicity: via inhalation route

Endpoint conclusion:

no study available

Effect on developmental toxicity: via dermal route

Endpoint conclusion:

no study available

Additional information

Developmental toxicity

In different studies, Benzyl Propionate (122-63-4) has been investigated for developmental toxicity to a greater or lesser extent. Often are the studies based on in vivo experiments and estimated data in rodents, i.e. most commonly in rats for Benzyl Propionate (122-63-4)also been compared with the experimental studies performed on structurally similar read across substance.

In a prediction done by SSS (2014) using the OECD QSAR toolbox v 3.1with log kow as the primary descriptor, the developmental toxicity was estimated benzyl propionate (CAS No.: 122-63-4) NOAEL was estimated to be 710.0mg/kg bw. When male and female wistar rats were exposed with benzyl propionate (CAS No.: 122-63-4) orally.

It is further supported by experimental study conducted by U.S. Environmental Protection Agency (U.S. Environmental Protection Agency Hazard Characterization Document, September, 2010)on structurally similar read across substance Benzyl acetate(140-11-4).In developmental toxicity study of benzyl acetate (140-11-4) was performed in Pregnant Wistar rats. The test material in dose concentration 0, 10, 100, 500 or 1000 mg/kg/day was administered via gavage for 10 days (GD 6-15).20 animals in each dose group were used. All the animals were observed Up to gestation days 20. fetuses were examined for intrauterine death and internal, external and skeletal changes. There were no indications of maternal toxicity in any dose group. Fetal body weight was significantly decreased (p < 0.05) at 1000 mg/kg/day. Fetuses at 500 and 1000 mg/kg/day exhibited increased combined incidence of organ variations (slight dilatation of the lateral ventricle and renal pelvis and presence of levo-umbilical artery) and the high-dose group exhibited increased skeletal variations including wavy ribs, dumb-bell shaped vertebrae, absence/splitting of thoracic vertebrae, presence of lumbar ribs and degree of ossification. Hence The NOAEL value of benzyl acetate is considered to be 1000 mg/kg/day for maternal toxicity and 100 mg/kg/day for developmental toxicity whereas the LOAEL value for developmental toxicity is considered to be 500 mg/kg/day based on increased combined incidence of organ and skeletal variations. When Pregnant Wistar rats were treated with benzyl acetate (140-11-4) orally.

 Thus, based on the above studies and predictions on Benzyl Propionate(122-63-4)and its read across substances it was considered that no adverse effects on reproductive and developmental parameter were observed. Hence NOAEL is considered to be 710.0mg/kg bw . Thus, comparing this value with the criteria of CLP regulation Benzyl Propionate (122-63-4) cannot be classified as developmental toxicant.

Justification for classification or non-classification

On the basis of the available studies, it is concluded that the chemical benzyl propionate does not exhibit toxicity to the reproductive system and developmental toxicity.