Phenethyl isovalerate

Endpoint summary

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Reference

Endpoint:

short-term repeated dose toxicity: oral

Type of information:

(Q)SAR

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Justification for type of information:

QSAR prediction: migrated from IUCLID 5.6

Qualifier:

according to guideline

Guideline:

other:

Principles of method if other than guideline:

Prediction is done using QSAR Toolbox version 3.3

GLP compliance:

not specified

Limit test:

no

Species:

rat

Strain:

not specified

Sex:

not specified

Details on test animals or test system and environmental conditions:

No data

Route of administration:

oral: unspecified

Vehicle:

not specified

Details on oral exposure:

No data

Analytical verification of doses or concentrations:

not specified

Details on analytical verification of doses or concentrations:

No data

Duration of treatment / exposure:

10-11 days

Frequency of treatment:

Daily

No. of animals per sex per dose:

No data

Control animals:

not specified

Details on study design:

No data

Positive control:

No data

Observations and examinations performed and frequency:

The rats were observed for abnormal behaviour and weight gain/loss.

Sacrifice and pathology:

No data

Other examinations:

No data

Statistics:

There was no statistical analysis performed.

Clinical signs:

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

Organ weight findings including organ / body weight ratios:

not specified

Gross pathological findings:

not specified

Histopathological findings: non-neoplastic:

not specified

Histopathological findings: neoplastic:

not specified

Details on results:

No data

Dose descriptor:

NOAEL

Effect level:

870 mg/kg bw/day (nominal)

Based on:

test mat.

Remarks on result:

other: estimated results

Critical effects observed:

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" and ( not "i") )  )  and ("j" and ( not "k") )  )  and ("l" and ( not "m") )  )  and ("n" and ( not "o") )  )  and ("p" and "q" )  )

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 Carboxylic acid ester AND Isopropyl by Organic Functional groups

Domain logical expression index: "c"

Referential boundary: The target chemical should be classified as Aryl AND Carboxylic acid ester AND Isopropyl 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<] AND Tertiary Carbon 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 No alert found by DNA binding by OASIS v.1.3

Domain logical expression index: "g"

Referential boundary: The target chemical should be classified as AN2 OR AN2 >> Shiff base formation after aldehyde release OR AN2 >> Shiff base formation after aldehyde release >> Specific Acetate Esters OR Radical OR Radical >> Generation of reactive oxygen species OR Radical >> Generation of reactive oxygen species >> Thiols OR SN1 OR SN1 >> Nucleophilic attack after carbenium ion formation OR SN1 >> Nucleophilic attack after carbenium ion formation >> Specific Acetate Esters OR SN2 OR SN2 >> Acylation OR SN2 >> Acylation >> Specific Acetate Esters OR SN2 >> Alkylation, direct acting epoxides and related OR SN2 >> Alkylation, direct acting epoxides and related >> Epoxides and Aziridines OR SN2 >> Nucleophilic substitution at sp3 Carbon atom OR SN2 >> Nucleophilic substitution at sp3 Carbon atom >> Specific Acetate Esters by DNA binding by OASIS v.1.3

Domain logical expression index: "h"

Referential boundary: The target chemical should be classified as No alert found by Protein binding by OASIS v1.3

Domain logical expression index: "i"

Referential boundary: The target chemical should be classified as Michael Addition OR Michael Addition >> Michael addition on conjugated systems with electron withdrawing group OR Michael Addition >> Michael addition on conjugated systems with electron withdrawing group >> alpha,beta-Carbonyl compounds with polarized double bonds  OR Nucleophilic addition OR Nucleophilic addition >> Addition to carbon-hetero double bonds OR Nucleophilic addition >> Addition to carbon-hetero double bonds >> Ketones OR SN2 OR SN2 >> SN2 Reaction at a sp3 carbon atom OR SN2 >> SN2 Reaction at a sp3 carbon atom >> Activated alkyl esters and thioesters  by Protein binding by OASIS v1.3

Domain logical expression index: "j"

Referential boundary: The target chemical should be classified as No alert found by Protein binding alerts for Chromosomal aberration by OASIS v1.1

Domain logical expression index: "k"

Referential boundary: The target chemical should be classified as Ac-SN2 OR Ac-SN2 >> Acylation involving an activated (glucuronidated) ester group OR Ac-SN2 >> Acylation involving an activated (glucuronidated) ester group >> Arenecarboxylic Acid Esters by Protein binding alerts for Chromosomal aberration by OASIS v1.1

Domain logical expression index: "l"

Referential boundary: The target chemical should be classified as Non-Metals by Groups of elements

Domain logical expression index: "m"

Referential boundary: The target chemical should be classified as Alkali Earth by Groups of elements

Domain logical expression index: "n"

Referential boundary: The target chemical should be classified as Not categorized by Repeated dose (HESS)

Domain logical expression index: "o"

Referential boundary: The target chemical should be classified as Phthalate esters (Testicular toxicity) Rank C by Repeated dose (HESS)

Domain logical expression index: "p"

Parametric boundary:The target chemical should have a value of log Kow which is >= 1.66

Domain logical expression index: "q"

Parametric boundary:The target chemical should have a value of log Kow which is <= 5.97

Conclusions:

The No Observed Adverse Effect Level (NOAEL) as predicted by SSS QSAR (2016) is likely found to be 870 mg/Kg bw (nominal).

Executive summary:

Repeated dose oral toxicity prediction was done using SSS QSAR prediction model, 2013. Subacute toxicity study was performed using rats and the dosing of the test chemical was done daily. The No Observed Adverse Effect Level (NOAEL) as predicted by SSS QSAR (2016) is likely found to be 870 mg/Kg bw (nominal).

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

870 mg/kg bw/day

Study duration:

subacute

Species:

rat

Quality of whole database:

Prediction model based estimation

Additional information

Prediction model based estimation and data from the read across chemicals have been used to determine the toxic nature of the test compound Phenethyl isovalerate (CAS no 140 -26 -1) upon repeated exposure. The summary is as below:

Repeated dose toxicity: Oral

SSS QSAR Prediction model was used to predict the repeated dose oral toxic nature of the test compound Phenethyl isovalerate (CAS no 140 -26 -1). The study was considered to be performed using rats. The test chemical was given orally, daily for 10 -11 days. The No Observed Adverse Effect Level (NOAEL) for the test compound Phenethyl isovalerate is found to be 870 mg/Kg bw/day (nominal.)

A subacute study was conducted (Sustainability Support Services, 2014) to evaluate the toxic effects of repeated administration of Benzyl Propionate (RA CAS no 122-63-4) in male and female Sprague-Dawley rats by gavage. Benzyl Propionate was administered to 6 animals/sex/species in 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, Benzyl Propionate have no effect on mortality. Blood samples for Clinical Biochemistry and Haematology were collected. No abnormalities occurred that could be directly attributed to Benzyl Propionate 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 Benzyl Propionate related gross pathological or histological changes were seen and findings were not Benzyl Propionate dependent and hence considered to be of no toxicological importance. Therefore NOEAL for repeated dose toxicity study was considered to be 1000 mg/kg/bw/day in male and female Sprague-Dawley rats when exposed to Benzyl Propionate by oral route for 28 days.

The purpose of this study conducted by Abdo et al (1986) was to evaluate toxicity and carcinogenicity of benzyl acetate (RA CAS no 140-11-4).Benzyl acetate was administered to group of 5 male and femaleF344/N rats for 14 concecutive days by gavage route in corn oil at dose conccentration of 0, 250, 500, 1,000, 2,000 or 4,000 mg/kg body weight. Animals were observed daily for mortalities and clinical signs.Necropsies were performed on all animals.Mortalities were observed in last two groups of rats in first 5 days of treatment. Increase body weight was observed . Hence theNo Observed Adverse Effect Level (NOAEL) was considered to be 500 mg/kg bw/day.

Similar study was performed on mice (Abdo et al, 1986).Benzyl acetate was administered to group of 5 male and female B6C3F1mice for 14 concecutive days by gavage route in corn oil at dose conccentration of 0,125, 250, 500, 1,000, or 2,000mg/kg body weight. Animals were observed daily for mortalities and clinical signs.Necropsies were performed on all animals.Mortalities were observed in last groups of mice within 3 days of treatment.Compound-related clinical signs were observed in high-dose males and females.No stastically significant difference was observed in body weight in treated and control. Hence the No Observed Adverse Effect Level (NOAEL) was considered to be 1000 mg/kg bw/day.

Benzyl butyrate (CAS no 103 -37 -7) 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 (Oser, 1985). Average daily intake of 0 or 100 times the assumed human intake, calculated to be 130 mg/kg bw per day. The agents were incorporated into the diet in the ratio of their use in foods: ethyl benzoate, 0.15 mg/kg; isobutyl benzoate, 25 mg/kg: benzyl acetate, 19 mg/kg; benzyl butyrate, 25 mg/kg; ethyl methylphenylglycidate, 25 mg/kg; and glycidate M116, 25 mg/kg. The group receiving the ester blend had normal bodyweight 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 treatmentrelated abnormalities were observed, and the weights of the livers and kidneys were within normal limits for both groups. No histopathological examination was performed .Hence,the NOEL was found to be 25 mg/kg in repeated dose oral toxicity of chemical benzyl butyrate administered to rat for 12 weeks through diet.

Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
SSS QSAR Prediction model was used to predict the repeated dose oral toxic nature of the test compound Phenethyl isovalerate. The study was considered to be performed using rats. The test chemical was given orally, daily for 10 -11 days. The No Observed Adverse Effect Level (NOAEL) for the test compound Phenethyl isovalerate is found to be 870 mg/Kg bw/day (nominal.)

Justification for classification or non-classification

Weight of evidence used suggest that the chemical Phenethyl isovalerate (CAS no 140 -26 -1) is not toxic upon repeated oral exposure via the oral route.

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