Phenethyl isovalerate

Endpoint summary

Description of key information

LD50 was estimated to be 2283.036865234 mg/kg bw on white rat for substance Phenethyl isovalerate. 

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Reference

Endpoint:

acute toxicity: oral

Type of information:

(Q)SAR

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Data is K2 and prediction is done using QSAR tool box version 3.3

Justification for type of information:

QSAR prediction: migrated from IUCLID 5.6

Qualifier:

according to guideline

Guideline:

other: as below

Principles of method if other than guideline:

Prediction is done using QSAR Toolbox version 3.3

GLP compliance:

not specified

Test type:

standard acute method

Species:

rat

Strain:

other: White

Route of administration:

oral: gavage

Vehicle:

other: Sunflower oil

Details on oral exposure:

MAXIMUM DOSE VOLUME APPLIED: 45 % solution in sunflower oil (5 mg/kg body weight)

Doses:

20-45 % solution in sunflower oil (2.0-5.0 mL/kg bw)

No. of animals per sex per dose:

Groups of 6 white rats

Control animals:

not specified

Details on study design:

- Duration of observation period following administration: 15 days

Statistics:

LD50 was calculated per Kerber´s method

Sex:

not specified

Dose descriptor:

LD50

Effect level:

2 283.037 mg/kg bw

Based on:

test mat.

Remarks on result:

other: 50% mortality

Mortality:

50%

Clinical signs:

other: No data available

Gross pathology:

No data available

Other findings:

No data available

The prediction was based on dataset comprised from the following descriptors: LD50
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 "o" )  )

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 >> Michael-type addition on alpha, beta-unsaturated carbonyl compounds OR AN2 >> Michael-type addition on alpha, beta-unsaturated carbonyl compounds >> Four- and Five-Membered Lactones OR AN2 >> Nucleophilic addition to alpha, beta-unsaturated carbonyl compounds OR AN2 >> Nucleophilic addition to alpha, beta-unsaturated carbonyl compounds >> alpha, beta-Unsaturated Aldehydes OR AN2 >> Schiff base formation OR AN2 >> Schiff base formation >> alpha, beta-Unsaturated Aldehydes OR AN2 >> Schiff base formation by aldehyde formed after metabolic activation OR AN2 >> Schiff base formation by aldehyde formed after metabolic activation >> Geminal Polyhaloalkane Derivatives OR AN2 >> Shiff base formation after aldehyde release OR AN2 >> Shiff base formation after aldehyde release >> Specific Acetate Esters OR AN2 >> Shiff base formation for aldehydes OR AN2 >> Shiff base formation for aldehydes >> Geminal Polyhaloalkane Derivatives OR AN2 >> Shiff base formation for aldehydes >> Haloalkane Derivatives with Labile Halogen OR Non-covalent interaction OR Non-covalent interaction >> DNA intercalation OR Non-covalent interaction >> DNA intercalation >> DNA Intercalators with Carboxamide Side Chain OR Radical OR Radical >> Generation of reactive oxygen species OR Radical >> Generation of reactive oxygen species >> Thiols OR Radical >> Generation of ROS by glutathione depletion (indirect) OR Radical >> Generation of ROS by glutathione depletion (indirect) >> Haloalkanes Containing Heteroatom OR Radical >> Radical mechanism via ROS formation (indirect) OR Radical >> Radical mechanism via ROS formation (indirect) >> Geminal Polyhaloalkane Derivatives OR Radical >> Radical mechanism via ROS formation (indirect) >> Nitroarenes with Other Active Groups OR Radical >> Radical mechanism via ROS formation (indirect) >> Nitrophenols, Nitrophenyl Ethers and Nitrobenzoic Acids OR Radical >> Radical mechanism via ROS formation (indirect) >> p-Substituted Mononitrobenzenes OR Radical >> Radical mechanism via ROS formation (indirect) >> Single-Ring Substituted Primary Aromatic Amines OR SN1 OR SN1 >> Carbenium ion formation OR SN1 >> Carbenium ion formation >> Alpha-Haloethers OR SN1 >> Nucleophilic attack after carbenium ion formation OR SN1 >> Nucleophilic attack after carbenium ion formation >> Specific Acetate Esters OR SN1 >> Nucleophilic attack after diazonium or carbenium ion formation OR SN1 >> Nucleophilic attack after diazonium or carbenium ion formation >> Nitroarenes with Other Active Groups OR SN1 >> Nucleophilic attack after metabolic nitrenium ion formation OR SN1 >> Nucleophilic attack after metabolic nitrenium ion formation >> Single-Ring Substituted Primary Aromatic Amines OR SN1 >> Nucleophilic attack after reduction and nitrenium ion formation OR SN1 >> Nucleophilic attack after reduction and nitrenium ion formation >> Nitroarenes with Other Active Groups OR SN1 >> Nucleophilic attack after reduction and nitrenium ion formation >> Nitrophenols, Nitrophenyl Ethers and Nitrobenzoic Acids OR SN1 >> Nucleophilic attack after reduction and nitrenium ion formation >> p-Substituted Mononitrobenzenes OR SN2 OR SN2 >> Acylation OR SN2 >> Acylation >> Specific Acetate Esters OR SN2 >> Acylation involving a leaving group  OR SN2 >> Acylation involving a leaving group  >> Geminal Polyhaloalkane Derivatives OR SN2 >> Acylation involving a leaving group  >> Haloalkane Derivatives with Labile Halogen OR SN2 >> Acylation involving a leaving group after metabolic activation OR SN2 >> Acylation involving a leaving group after metabolic activation >> Geminal Polyhaloalkane Derivatives OR SN2 >> Alkylation, direct acting epoxides and related OR SN2 >> Alkylation, direct acting epoxides and related >> Epoxides and Aziridines OR SN2 >> Alkylation, nucleophilic substitution at sp3-carbon atom OR SN2 >> Alkylation, nucleophilic substitution at sp3-carbon atom >> Haloalkane Derivatives with Labile Halogen OR SN2 >> Alkylation, nucleophilic substitution at sp3-carbon atom >> Sulfonates and Sulfates OR SN2 >> Alkylation, ring opening SN2 reaction OR SN2 >> Alkylation, ring opening SN2 reaction >> Four- and Five-Membered Lactones OR SN2 >> Direct acting epoxides formed after metabolic activation OR SN2 >> Direct acting epoxides formed after metabolic activation >> Quinoline Derivatives OR SN2 >> DNA alkylation OR SN2 >> DNA alkylation >> Alkylphosphates, Alkylthiophosphates and Alkylphosphonates OR SN2 >> DNA alkylation >> Vicinal Dihaloalkanes OR SN2 >> Internal SN2 reaction with aziridinium and/or cyclic sulfonium ion formation (enzymatic) OR SN2 >> Internal SN2 reaction with aziridinium and/or cyclic sulfonium ion formation (enzymatic) >> Vicinal Dihaloalkanes OR SN2 >> Nucleophilic substitution at sp3 Carbon atom OR SN2 >> Nucleophilic substitution at sp3 Carbon atom >> Haloalkanes Containing Heteroatom OR SN2 >> Nucleophilic substitution at sp3 Carbon atom >> Specific Acetate Esters OR SN2 >> Nucleophilic substitution at sp3 carbon atom after thiol (glutathione) conjugation OR SN2 >> Nucleophilic substitution at sp3 carbon atom after thiol (glutathione) conjugation >> Geminal Polyhaloalkane Derivatives OR SN2 >> SN2 at an activated carbon atom OR SN2 >> SN2 at an activated carbon atom >> Quinoline Derivatives OR SN2 >> SN2 at sp3-carbon atom OR SN2 >> SN2 at sp3-carbon atom >> Alpha-Haloethers OR SN2 >> SN2 attack on activated carbon Csp3 or Csp2 OR SN2 >> SN2 attack on activated carbon Csp3 or Csp2 >> Nitroarenes with Other Active Groups by DNA binding by OASIS v.1.3

Domain logical expression index: "h"

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: "i"

Referential boundary: The target chemical should be classified as Acylation OR Acylation >> Isocyanates and Isothiocyanates OR Acylation >> Isocyanates and Isothiocyanates >> Isocyanates OR Acylation >> P450 Mediated Activation to Isocyanates or Isothiocyanates OR Acylation >> P450 Mediated Activation to Isocyanates or Isothiocyanates >> Benzylamines-Acylation OR Michael addition >> P450 Mediated Activation of Heterocyclic Ring Systems 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 >> Polarised Alkenes-Michael addition OR Michael addition >> Polarised Alkenes-Michael addition >> Alpha, beta- unsaturated esters 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 >> Mono aldehydes OR 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 >> Primary (unsaturated) heterocyclic amine OR SN1 >> Nitrenium Ion formation >> Primary aromatic amine OR SN1 >> Nitrenium Ion formation >> Tertiary (unsaturated) heterocyclic amine  OR SN1 >> Nitrenium Ion formation >> Tertiary aromatic amine OR SN2 OR SN2 >> P450 Mediated Epoxidation OR SN2 >> P450 Mediated Epoxidation >> Thiophenes-SN2 by DNA binding by OECD

Domain logical expression index: "j"

Referential boundary: The target chemical should be classified as Not possible to classify according to these rules (GSH) by Protein binding potency

Domain logical expression index: "k"

Referential boundary: The target chemical should be classified as Moderately reactive (GSH) OR Moderately reactive (GSH) >> Alkyl 2-alkenoates (MA) by Protein binding potency

Domain logical expression index: "l"

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

Domain logical expression index: "m"

Referential boundary: The target chemical should be classified as Acylation OR Acylation >> Ester aminolysis or thiolysis OR Acylation >> Ester aminolysis or thiolysis >> Activated aryl esters  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 alerts for skin sensitization by OASIS v1.3

Domain logical expression index: "n"

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

Domain logical expression index: "o"

Parametric boundary:The target chemical should have a value of log Kow which is <= 4.84

Interpretation of results:

practically nontoxic

Remarks:

Migrated informationCriteria used for interpretation of results: EU

Conclusions:

The acute median lethal dose (LD50) value for the test chemical Phenethyl isovalerate in white rats is estimated to be 2283.036865234 mg/kg bw.

Executive summary:

Acute oral toxicity study was conducted on white rats to predict the acute oral toxic nature of the test compound Phenethyl isovalerate (CAS no 140 -26 -1). The acute median lethal dose (LD50) value for the test chemical Phenethyl isovalerate in white rats is estimated to be 2283.036865234 mg/kg bw.

As per the CLP classification, the test material is not likely to be classified as an acute oral toxicant.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

2 283.037 mg/kg bw

Quality of whole database:

Prediction model based estimation

Acute toxicity: via dermal route

Link to relevant study records

Reference

Endpoint:

acute toxicity: dermal

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Qualifier:

according to guideline

Guideline:

other:

Principles of method if other than guideline:

Acute dermal toxicity study was performed to determine the dermal toxic nature of the test compound Phenethyl isovalerate

GLP compliance:

not specified

Species:

rabbit

Strain:

not specified

Sex:

not specified

Details on test animals or test system and environmental conditions:

No data available.

Type of coverage:

open

Vehicle:

not specified

Details on dermal exposure:

No data

Duration of exposure:

No data

Doses:

No data

No. of animals per sex per dose:

No data

Control animals:

not specified

Details on study design:

No data

Statistics:

No data

Preliminary study:

No data

Sex:

not specified

Dose descriptor:

LD50

Effect level:

> 5 000 mg/kg bw

Based on:

test mat.

Mortality:

No mortality wasn noted at 5000 mg/Kg bw

Clinical signs:

other: No data

Gross pathology:

No data

Other findings:

No data

Interpretation of results:

not classified

Remarks:

Migrated informationCriteria used for interpretation of results: EU

Conclusions:

The LD50 for phenethyl isovalerate was found to be greater than 5000mg/kg in rabbits.

Executive summary:

In a acute dermal toxicity study, rabbits were treated with Phenethyl isovalerate in the concentration of 5000 mg/kg bw. No mortality was observed in treated rabbits. Therefore, LD50 was considered to be > 5000 mg/kg bw when rabbit were treated with Phenethyl isovalerate dermally.

Based on the above value ,the test material does not classify as an acute dermal irritent.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

5 000 mg/kg bw

Quality of whole database:

Data is Klimish 2 and from peer reviewed journal

Additional information

Acute oral toxicity:

Based on the QSAR prediction done using version 3.3 (2016),Acute oral toxicity was evaluated on white rats by using Phenethyl isovalerate. The acute median lethal dose (LD50) value was estimated to be 2283.036865234 mg/kg bw when white ratstreated withPhenethyl isovalerate orally.

 

Based on the QSAR prediction done using the Danish (Q) SAR Database, the LD50 was estimated to be 4500 mg/kg on rat for substance Phenethyl isovalerate.

In a study conducted by Levensteinet al, (2016), acute oral toxicity was evaluated in rats by using phenethyl isovalerate. LD50 was found to be > 5000mg/kg when rats treated with phenethyl isovalerate.

In a Safety Assessment report given by Burdock Group (2003), acute oral toxicity was evaluated in rabbits by using phenethyl isovalerate orally. No morality was observed at 5000 mg/kg. Therefore, LD50 was considered to be > 5000 mg/kg when rats were treated with phenethyl isovalerate.

In a RTECS database (2016), acute oral toxicity to rats, mouse and guinea pig by using phenethyl isovalerate was found to be6220 mg/kg. Therefore, LD50 was considered to be 6220 mg/kg whenrats, mouse and guinea pigwere treated withphenethyl isovalerate orally.

In a study conducted by McGintyet al, (2012) and by Baret al, (1967) for read across benzyl butyrate, acute oral toxicity was evaluated in Osborne-Mendel male and female rats by using benzyl butyrate orally in the concentration of 2330 mg/kg bw. Depression and tremors were observed in 2330 mg/kg bw treated rats. Therefore, LD50 was found to be 2330 mg/kg body weight (with 95 % confidence limit of 1940 –2800 mg/kg bw) when Osborne-Mendel male and female rats were treated with benzyl butyrate orally. 

In a study conducted by Jenneret al, (1964) and in Sax's Handbook of Dangerous Industrial Materials by Richardet al, (2007) for read across phenethyl phenylacetate, acute oral toxicity was evaluated in Osborne-Mendel male and female rats by using phenethyl phenylacetate orally in the concentration of 15390 mg/kg bw (with 95 % confidence limit of 12830 -18470 mg/kg bw). Mortality was observed within 4 hours to 5 days in treated rats.Depression was observed soon after treatment and scrawny for several days were observed in treated rats. Therefore, LD50 was found to be 15390 mg/kg body weight (with 95 % confidence limit of 12830 -18470 mg/kg bw) Osborne-Mendel male and female rats were treated with phenethyl phenylacetate orally.

In a study mentioned by McGintyet al, (2012), rats were treated with benzyl propionate in the concentration of 2050, 2560, 3200, 4000 or 5000 mg/kg orally by gavage and observed for 14 days. All the treated rats were died within two days of treatment. Piloerection, lethargy, tremors and chromodacryorrhea were observed in 2560, 3200, 4000 or 5000 mg/kg treated rats. Therefore, LD50 was considered to be 3300 mg/kg when rats were treated with benzyl propionate orally.

Based on the studies reviewed for the target Phenethyl isovalerate (CAS no 140-26-1) and its Structurally similar read across chemical benzyl butyrate (CAS no 103-37-7), phenethyl phenylacetate (CAS no 102-20-5) and benzyl propionate (CAS no 122-63-4) is not likely to be classified as an acute oral toxicant. Acute dermal toxicity:

In a study conducted by Opdykeet al(1979), acute dermal toxicity was evaluated in rabbit by using Phenethyl isovalerate in the concentration of 5000 mg/kg bw. No mortality was observed in treated rabbits. Therefore, LD50 was considered to be > 5000 mg/kg bw when rabbit were treated with Phenethyl isovalerate dermally.

Based on the above reviewed study for the target Phenethyl isovalerate (CAS no 140-26-1) as per the CLP regulation is likely to be non hazardous by dermal route to rabbits.

Justification for selection of acute toxicity – oral endpoint
Acute oral toxicity study was conducted on white rats to predict the acute oral toxic nature of the test compound Phenethyl isovalerate (CAS no 140 -26 -1). The acute median lethal dose (LD50) value for the test chemical Phenethyl isovalerate in white rats is estimated to be 2283.036865234 mg/kg bw.

Justification for selection of acute toxicity – dermal endpoint
LD50 was considered to be > 5000 mg/kg bw when rabbit were treated with Phenethyl isovalerate dermally.

Justification for classification or non-classification

The test material is not likely to classify as an acute oral and dermal toxicant.

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