Phenethyl isovalerate

Endpoint summary

Description of key information

Skin irritation:

The dermal irritation potential of test article was determined according to the OECD 439 In Vitro Skin Irritation: Reconstructed Human Epidermis Test Method”. The MatTek EpiDerm™ model was used to assess the potential dermal irritation of the test article by determining the viability of the tissues following exposure to the test article via MTT. The objective of this study was to assess the dermal irritation potential of test article Tissues were exposed to test article and controls for ~one hour, followed by a 42 hour post-exposure recovery period. The viability of each tissue was determined by MTT assay. 

The MTT data shows that the assay quality controls were met. The mean tissue viabilities for the Positive control, Methyl acetate were 6.5%, 10.7% respectively in the first and second run, whereas the tissue viabilities of the negative control, Tissue culture water remained at 100% in the both the runs.

The Mean % tissue viability compared to negative control (n=3) of the test substance Phenethyl isovalerate, CAS No. 140-26-1 was determined to be 108.7%.

Hence, under the experimental test conditions it was concluded that test substance Phenethyl isovalerate, CAS No. 140-26-1 was considered to be not irritating to the human skin and being classified as “Not Classified'' as per CLP Regulation.

Eye irritation:

Eye irritation study was predicted to evaluate the irritation potential of the test compound Phenethyl isovalerate. The study performed indicates that the test material is likely not be an eye irritant.

Key value for chemical safety assessment

Skin irritation / corrosion

Link to relevant study records

Reference

Endpoint:

skin irritation: in vivo

Type of information:

calculation (if not (Q)SAR)

Remarks:

Migrated phrase: estimated by calculation

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Data is from modelling database developed by the National Food Institute, Technical University of Denmark.

Principles of method if other than guideline:

The data predicted using the Danish (Q)SAR Database

GLP compliance:

no

Species:

rabbit

Strain:

not specified

Details on test animals or test system and environmental conditions:

No data

Type of coverage:

not specified

Preparation of test site:

not specified

Vehicle:

not specified

Controls:

not specified

Amount / concentration applied:

No data

Duration of treatment / exposure:

No data

Observation period:

No data

Number of animals:

No data

Details on study design:

No data

Irritation parameter:

overall irritation score

Remarks on result:

other: Model predicted negative result

Irritant / corrosive response data:

No data

Other effects:

No data

Interpretation of results:

not irritating

Remarks:

Migrated informationCriteria used for interpretation of results: EU

Conclusions:

Based on the QSAR prediction done using the Danish (Q)SAR Database, the skin irritation was estimated to be negative on rabbits .Thus it can be concluded that the substance Phenethyl isovalerate has negative skin irritation effects and based on the CLP criteria for classification it can be classified as non skin irritant.

Executive summary:

Based on the QSAR prediction done using the Danish (Q)SAR Database, the skin irritation was estimated to be negative on rabbits .Thus it can be concluded that the substance Phenethyl isovalerate has negative skin irritation effects and based on the CLP criteria for classification it can be classified as non skin irritant.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not irritating)

Eye irritation

Link to relevant study records

Reference

Endpoint:

eye irritation: in vitro / ex vivo

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

Species:

other: Reconstituted Corneal Epithelium

Strain:

not specified

Vehicle:

unchanged (no vehicle)

Controls:

other:

Amount / concentration applied:

- Amount applied: Tissues were treated with 30 µL of the test material.

Duration of treatment / exposure:

Cultures were exposed for 10 minutes to the test material.

Observation period (in vivo):

Skin cultures were examined after three hours.

Number of animals or in vitro replicates:

All test substances were tested in triplicate (including controls)

Irritation parameter:

other: relative mean tissue viability

Basis:

mean

Time point:

other: 10 min

Remarks on result:

other: Not irritating

Estimation method: Takes mode value from the 6 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 ("k" and ( not "l") )  )  and ("m" and ( not "n") )  )  and ("o" and ( not "p") )  )  and ("q" and ( not "r") )  )  and "s" )  and ("t" and "u" )  )

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 Non-covalent interaction OR Non-covalent interaction >> DNA intercalation OR Non-covalent interaction >> DNA intercalation >> DNA Intercalators with Carboxamide Side Chain 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 >> Alkylation, nucleophilic substitution at sp3-carbon atom OR SN2 >> Alkylation, nucleophilic substitution at sp3-carbon atom >> Sulfonates and Sulfates OR SN2 >> DNA alkylation 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 >> 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 Inclusion rules not met by Eye irritation/corrosion Inclusion rules by BfR

Domain logical expression index: "i"

Referential boundary: The target chemical should be classified as Substituted indoles by Eye irritation/corrosion Inclusion rules by BfR

Domain logical expression index: "j"

Referential boundary: The target chemical should be classified as Bioavailable by Lipinski Rule Oasis ONLY

Domain logical expression index: "k"

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

Domain logical expression index: "l"

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

Domain logical expression index: "m"

Referential boundary: The target chemical should be classified as Group 14 - Carbon C AND Group 16 - Oxygen O by Chemical elements

Domain logical expression index: "n"

Referential boundary: The target chemical should be classified as Group 15 - Nitrogen N by Chemical elements

Domain logical expression index: "o"

Referential boundary: The target chemical should be classified as (!Undefined)Group All Lipid Solubility < 0.01 g/kg by Eye irritation/corrosion Exclusion rules by BfR

Domain logical expression index: "p"

Referential boundary: The target chemical should be classified as Group C Melting Point > 55 C OR Group C Molecular Weight > 380 g/mol by Eye irritation/corrosion Exclusion rules by BfR

Domain logical expression index: "q"

Referential boundary: The target chemical should be classified as No alert found by Protein binding by OECD

Domain logical expression index: "r"

Referential boundary: The target chemical should be classified as Michael addition OR Michael addition >> Polarised Alkenes OR Michael addition >> Polarised Alkenes >> Polarised alkene - esters by Protein binding by OECD

Domain logical expression index: "s"

Referential boundary: The target chemical should be classified as Biodegrades Fast by Biodeg probability (Biowin 1) ONLY

Domain logical expression index: "t"

Parametric boundary:The target chemical should have a value of log Kow which is >= 3.01

Domain logical expression index: "u"

Parametric boundary:The target chemical should have a value of log Kow which is <= 4.61

Interpretation of results:

not irritating

Remarks:

Migrated informationCriteria used for interpretation of results: EU

Conclusions:

The test compound Phenethyl isovalerate is not an eye irritant.

Executive summary:

Eye irritation study was predicted to evaluate the irritation potential of the test compound Phenethyl isovalerate. The study performed indicates that the test material is likely not be an eye irritant.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not irritating)

Additional information

Skin irritation:

The dermal irritation potential of test article was determined according to the OECD 439 In Vitro Skin Irritation: Reconstructed Human Epidermis Test Method”. The MatTek EpiDerm™ model was used to assess the potential dermal irritation of the test article by determining the viability of the tissues following exposure to the test article via MTT. The objective of this study was to assess the dermal irritation potential of test article Tissues were exposed to test article and controls for ~one hour, followed by a 42 hour post-exposure recovery period. The viability of each tissue was determined by MTT assay. 

The MTT data shows that the assay quality controls were met. The mean tissue viabilities for the Positive control, Methyl acetate were 6.5%, 10.7% respectively in the first and second run, whereas the tissue viabilities of the negative control, Tissue culture water remained at 100% in the both the runs.

The Mean % tissue viability compared to negative control (n=3) of the test substance Phenethyl isovalerate, CAS No. 140-26-1 was determined to be 108.7%.

Hence, under the experimental test conditions it was concluded that test substance Phenethyl isovalerate, CAS No. 140-26-1 was considered to be not irritating to the human skin and being classified as “Not Classified'' as per CLP Regulation.

 

Based on the QSAR prediction done using the Danish (Q)SAR Database (2016), the skin irritation was estimated to be negative on rabbits .Thus it can be concluded that the substance Phenethyl isovalerate (CAS no 140-26-1) has negative skin irritation effects and based on the CLP criteria for classification it can be classified as non skin irritant.

Skin irritation test for Phenylethyl isovalerate was conducted in rabbit. Phenylethyl Isovalerate was applied in full strength to intact or abraded rabbit skin. It was observed for 24 hour under occlusion. It was not irritating. Therefore it was concluded that the test substance Phenylethyl Isovalerate is

not irritating to rabbit skin. Based on the above value, the test material does not classify as a skin irritant ,in accordance with CLP criteria.

 

The primary dermal irritation index (PDII) score of Phenethyl phenylacetate (RA CAS no 102-20-5) in New Zealand white rabbits was calculated to be 0 from the test result using OECD method (Sustainability Support Services, 2016). From this it is concluded that the test substance Phenethyl phenylacetate can be classified under non irritant category at the dose level of 0.5 ml.

The test compound Phenethyl phenylacetate (CAS No-102-20-5) was tested for its dermal irritation potential in New Zealand White Rabbits (Sustainability Support Services, 2016). The study was conducted according to OECD guideline 404. In the initial test one healthy rabbit of body weight 2.10kg selected for study after acclimatization. The test compound in the amount of 0.5 ml (as it was in the liquid form) was applied at the three different sites on the shaven back skin of animal. The hairs of back sides were removed (approximately 6 cm2) one day earlier before the treatment with the help of electric clipper. The site of application was covered with impervious dressing secured in position with adhesive tape. The first patch was applied on the shaven back skin of rabbit and removed after three minutes. No serious reaction was observed at the site of application. The second patch was applied on the different shaven back side and removed after one hour. There were no signs of skin reaction observed at this site of application. Finally, a third patch was applied at a different site and was removed after four hour.No skin reactionwas observed after four hours patch removal.Finally, the animal was observed for 14 days, for any irritation and corrosion. Because of there was no corrosive effect observed in the initial test, a confirmatory test was done to confirm the negative or irritant response of the test substance using two additional animals. Two healthy rabbit of body weight 1.80kg±200 gm selected for study after acclimatization. The test compound in the amount of 0.5 ml (as it was in the liquid form) was applied at the three different sites on the shaven back skin of animal. The hairs of back sides were removed (approximately 6 cm2) one day earlier before the treatment with the help of electric clipper. After four hours the patch was removed and the skin reactions were graded according to Draize’s method. The test compound Phenethyl phenylacetate applied dermally to New Zealand White rabbit in the amount of 0.5 ml did not produce any clinical sign of dermal irritation after 4 hours patch removal. Finally both the animals observed for 14 days for any irritation or clinical signs which did not reveal any dermal irritation as well as clinical signs of toxicity. The dermal irritation index of New Zealand white rabbits is calculated as 0.00 and test compound can be classified under non irritant categories at the dose level of 0.5 ml.

Benzyl butyrate (RA CAS no 103-37-7) was tested at a concentration of 4 % in petrolatum and produced no irritation in a 48-hr closed-patch test in 25 human subjects (Opdyke, 1974)

On the basis of available information for the target as well as read across substance, the test substance Phenylethyl isovalerate can be considered as not irritating to the skin, inaccordance with the CLP criteria.

Eye irritation:

Prediction model based estimation and data from the read across cas nos is used to predict the eye irritation potential of the test compound Phenethyl isovalerate (CAS no 140 -26 -1). The summary is as below:

Eye irritation study was predicted using SSS QSAR (2016) to evaluate the irritation potential of the test compound Phenethyl isovalerate. The study performed indicates that the test material is likely not be an eye irritant.

The MMAS ( Modified Maximum Average Draizes test ) score of Phenethyl phenylacetate in New Zealand white rabbits was calculated to be 0 from the test result using OECD method(Sustainability Support Services, 2012). From this, it is concluded that the test substance Phenethyl phenylacetate can be classified under non irritant categories at the dose level of 0.1 ml.

The acute eye irritation study (Sustainability Support Services, 2012) of Phenethyl phenylacetate (CAS No 102-20-5) was conducted in New Zealand White Rabbits as per the OECD- 405 Guideline. One healthy rabbits of body weight 2.13kg was selected for study after acclimatization. Rabbit was examined for any abnormal discharge such as eye irritation, ocular defects or pre-existing corneal injury from eye 24 hours prior to application of test compound.The test compound was applied in the conjunctival sac of rabbit after gently pulling the lower lid away from the eyeball at the dose rate of0.1ml.The other eye which remain untreated, served as a control. The acute irritation to eye conjunctiva, cornea and iris was evaluated at 1, 24, 48 and 72 hoursafter the treatment. The grades of ocular reaction (conjunctiva, cornea and iris) were recorded at each observation. To determine the reversibility of the effect the animal was observed normally for 21 days. Any other lesions in the eye viz pannus, staining were observed and scored accordingly. Examination of reactions was facilitated by use of biomicroscope and hand slit lamp. Individual animal weight before and during the study was observed. The test compound Phenethyl phenylacetate (102-20-5)when applied to conjunctival sac of rabbit in the amount of0.1mldid not produce any clinical sign eye irritation throughout the observation period of 21 days. Furthermore, no other clinical signs such as cage side activity, pain etc. were recorded after application of test compound. The result obtained from the initial test was confirmed in additional two animal of same sex and same dose level (OECD-405, paragraph-21). The confirmatory test was also helpful to determine the irritation and any negative response of the test compound.In the confirmatory test the test compound Phenethyl phenylacetate (102-20-5)was applied in the amount of 0.1 ml in the conjunctival sac of rabbit after gently pulling the lower lid away from the eyeball. The other eye which remain untreated, served as a control. The acute irritation to eye conjunctiva, cornea and iris was evaluated at 1, 24, 48 and 72 hoursafter the treatment. The grades of ocular reaction (conjunctiva, cornea and iris) were recorded at each observation. To determine the reversibility of the effect the animals were observed normally for 21 days. Any other lesions in the eye viz pannus, staining were observed and scored accordingly. Examination of reactions was facilitated by use of biomicroscope and hand slit lamp. Individual animal weight before and during the study was observed. In the confirmatory test, the test compound Phenethyl phenylacetate (102-20-5) when applied to the conjunctival sac of the rabbits did not produce any clinical sign of eye irritation during observation period of 21 days. Furthermore, no other clinical signs of toxicity were observed throughout the observation period of 21 days. Based on above findings, it can be concluded that the test compound Phenethyl phenylacetate (102-20-5)is non irritant when applied in the amount of 0.1 ml in the conjunctival sac of the rabbits.

On the basis of available information for the target as well as read across substance and applying weight of evidence approach, the test substance Phenylethyl isovalerate can be considered as not irritating to the eye, in accordance with the CLP criteria

 

Justification for selection of skin irritation / corrosion endpoint:
The dermal irritation potential of test article was determined according to the OECD 439 test guideline followed for this study. The Mean % tissue viability compared to negative control (n=3) of the test substance Phenethyl isovalerate, CAS No. 140-26-1 was determined to be 108.7%. Thus, Phenethyl isovalerate was considered to be not irritating to the human skin.

Justification for selection of eye irritation endpoint:
Eye irritation study was predicted to evaluate the irritation potential of the test compound Phenethyl isovalerate. The study performed indicates that the test material is likely not be an eye irritant.

Justification for classification or non-classification

The substance Phenylethyl isovalerate is estimated to be " not irritating" to both skin and eye.