Geranyl phenylacetate

Endpoint summary

Description of key information

Skin Irritation:

A skin irritation study was performed in rabbits to assess the irritation potential of geranyl phenylacetate. Undiluted geranyl phenylacetate was applied under occlusion to the intact and abraded skin in rabbits for 24 hours. The rabbits were observed for signs of irritation.Geranyl phenylacetate was not irritating to rabbit skin after 24 hours exposure.

Eye Irritation:

The ocular irritation potential of Geranyl phenylacetate was estimated using OECD QSAR toolbox v3.4 with logPow as the primary descriptor.

Geranyl phenylacetate was estimated to be not irritating to the eyes of New Zealand White rabbits.

Based on the estimated results, Geranyl phenylacetate can be considered to be not irritating to eyes and can be classified under the category “Not Classified” as per CLP regulation.

Key value for chemical safety assessment

Skin irritation / corrosion

Link to relevant study records

Reference

Endpoint:

skin irritation: in vivo

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

data from handbook or collection of data

Justification for type of information:

data is from peer reviewed journals

Qualifier:

according to guideline

Guideline:

other: as mentioned below

Principles of method if other than guideline:

To assess the dermal irritation potential of geranyl phenylacetate in rabbits

GLP compliance:

not specified

Specific details on test material used for the study:

Name of the test chemical: (2E)-3,7-dimethylocta-2,6-dien-1-yl 2-phenylacetate
Common Name: Geranyl phenylacetate
Molecular formula: C18H24O2
Molecular weight: 272.3856 g/mol
Smiles Notation: c1(CC(OC\C=C(\CC\C=C(\C)C)C)=O)ccccc1
InChI: 1S/C18H24O2/c1-15(2)8-7-9-16(3)12-13-20-18(19)14-17-10-5-4-6-11-17/h4-6,8,10-12H,7,9,13-14H2,1-3H3/b16-12+
Substance Type: Organic
Physical State: Liquid (colorless)

Species:

rabbit

Strain:

not specified

Details on test animals or test system and environmental conditions:

no data available

Type of coverage:

occlusive

Preparation of test site:

other: intact and abraded skin

Vehicle:

unchanged (no vehicle)

Controls:

not specified

Amount / concentration applied:

undiluted (full strength) test chemical

Duration of treatment / exposure:

24 hours

Observation period:

24 hours

Number of animals:

no data available

Details on study design:

no data available

Other effects / acceptance of results:

no data available

Irritation parameter:

overall irritation score

Basis:

mean

Time point:

24 h

Reversibility:

not specified

Remarks on result:

no indication of irritation

Irritant / corrosive response data:

No signs of irritation observed

Interpretation of results:

other: not irritating

Conclusions:

Geranyl phenylacetate was not irritating to rabbit skin after 24 hours exposure.

Executive summary:

A skin irritation study was performed in rabbits to assess the irritation potential of geranyl phenylacetate. Undiluted geranyl phenylacetate was applied under occlusion to the intact and abraded skin in rabbits for 24 hours. The rabbits were observed for signs of irritation.Geranyl phenylacetate was not irritating to rabbit skin after 24 hours exposure.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not irritating)

Eye irritation

Link to relevant study records

Reference

Endpoint:

eye irritation: in vivo

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:

data is from OECD QSAR toolbox v3.4 and the QMRF report has been attached

Qualifier:

according to guideline

Guideline:

other: Estimated data

Principles of method if other than guideline:

Prediction was done using OECD QSAR toolbox v3.4

GLP compliance:

not specified

Specific details on test material used for the study:

Name of the test chemical: (2E)-3,7-dimethylocta-2,6-dien-1-yl 2-phenylacetate
Common Name: Geranyl phenylacetate
Molecular formula: C18H24O2
Molecular weight: 272.3856 g/mol
Smiles Notation: c1(CC(OC\C=C(\CC\C=C(\C)C)C)=O)ccccc1
InChI: 1S/C18H24O2/c1-15(2)8-7-9-16(3)12-13-20-18(19)14-17-10-5-4-6-11-17/h4-6,8,10-12H,7,9,13-14H2,1-3H3/b16-12+
Substance Type: Organic
Physical State: Liquid (colorless)

Species:

rabbit

Strain:

New Zealand White

Details on test animals or tissues and environmental conditions:

no data available

Vehicle:

not specified

Controls:

not specified

Amount / concentration applied:

0.1ml

Duration of treatment / exposure:

single exposure

Observation period (in vivo):

7 days

Duration of post- treatment incubation (in vitro):

no data available

Number of animals or in vitro replicates:

3

Details on study design:

no data available

Other effects / acceptance of results:

no data available

Irritation parameter:

overall irritation score

Basis:

mean

Time point:

7 d

Reversibility:

not specified

Remarks on result:

no indication of irritation

Irritant / corrosive response data:

No irritation observed

Estimation method: Takes mode value from the 8 nearest neighbours
Domain  logical expression:Result: In Domain

((((((("a" or "b" or "c" or "d") and("e" and(not "f")) ) and "g") and "h") and "i") and "j") and("k" and "l") )

Domain logical expression index: "a"

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

Domain logical expression index: "b"

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: "c"

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: "d"

Referential boundary:The target chemical should be classified as Esters AND Vinyl/Allyl Esters by Aquatic toxicity classification by ECOSAR

Domain logical expression index: "e"

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

Domain logical expression index: "f"

Referential boundary:The target chemical should be classified as 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 Very strong binder, OH group by Estrogen Receptor Binding

Domain logical expression index: "g"

Referential boundary:The target chemical should be classified as No superfragment by Superfragments ONLY

Domain logical expression index: "h"

Referential boundary:The target chemical should be classified as Low (Class I) by Toxic hazard classification by Cramer (extension) ONLY

Domain logical expression index: "i"

Referential boundary:The target chemical should be classified as Not bioavailable by Lipinski Rule Oasis ONLY

Domain logical expression index: "j"

Similarity boundary:Target: CC(C)=CCCC(C)=CCOC(=O)Cc1ccccc1
Threshold=30%,
Dice(Atom centered fragments)
Atom type; Count H attached; Hybridization

Domain logical expression index: "k"

Parametric boundary:The target chemical should have a value of log Kow which is >= 5.13

Domain logical expression index: "l"

Parametric boundary:The target chemical should have a value of log Kow which is <= 7.23

Interpretation of results:

other: not irritating

Conclusions:

Geranyl phenylacetate was estimated to be not irritating to the eyes of New Zealand White rabbits.

Executive summary:

The ocular irritation potential of Geranyl phenylacetate was estimated using OECD QSAR toolbox v3.4 with logPow as the primary descriptor.

Geranyl phenylacetate was estimated to be not irritating to the eyes of New Zealand White rabbits.

Based on the estimated results, Geranyl phenylacetate can be considered to be not irritating to eyes and can be classified under the category “Not Classified” as per CLP regulation.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not irritating)

Respiratory irritation

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Skin Irritation:

In different studies, Geranyl phenylacetate has been investigated for potential for dermal irritation to a greater or lesser extent. The studies are based on in vivo experiments in rabbits along with human data for target chemical and its structurally similar read across substances, Benzyl propionate [CAS: 122-63-4] and Phenethyl phenyl acetate [CAS: 102-20-5]. The predicted data using the OECD QSAR toolbox has also been compared with the experimental data.

Various studies for Geranyl phenylacetate were summarized in Food and Cosmetics Toxicology Volume 12, Issues 7–8, December 1974, Page 895; to assess the dermal irritation potential in humans and rabbits.

Geranyl phenylacetate applied at full strength to intact or abraded rabbit underocclusion was not irritating. Also, when tested on human subjects at 4% in petrolatum in a 48-hr closed-patch test,Geranyl phenylacetateproduced no irritation.

 

Both the experimental results are in agreement with each indicating a possibility of Geranyl phenylacetate being not irritating.

 

In a prediction done by SSS (2017) using the OECD QSAR toolbox with log kow as the primary descriptor, the skin irritation potential was estimated forGeranyl phenylacetate. Geranyl phenylacetatewas not irritating to New Zealand White rabbit skin.

 

Skin irritation effects were also estimated by four different models i.e, Battery, Leadscope, SciQSAR and CASE Ultra used within Danish QSAR database for Geranyl phenylacetate. Based on estimation, No severe skin irritation effects were known when Geranyl phenylacetate was exposed to rabbit skin.

The results from the experimental studies are ably supported by both the estimated results, thereby increasing the possibility of Geranyl phenylacetate being not irritating to skin.

Also these results are further supported by the experimental study conductedin an OECD GLP laboratory (Sustainability Support Services (Europe) AB has the letter of access) for the structurally similar read across substance,Benzyl propionate [CAS: 122-63-4]. This study was performed as per OECD guideline No. 404. Three healthy young adult female rabbits were used for conducting acute dermal irritation study. Body weights were re­corded on day 0 (prior to application) and at termination. Rabbits with good intact skin were selected for the study. The hairs of all the rabbits were clipped at contralateral sites, approximately 24 hours prior to treatment. A dose of0.5 ml of test item (as such) was applied to the skin, over an area of approximately 6 x 6 cm clipped of hair on one side of rabbits. The other untreated side was kept as control area and 0.5 ml of distilled water was applied at this site. At the end of 4 hours, the gauze patch was removed and test item application site was wiped with water without altering the integrity of the epidermis. Initially, the test item was applied to the clipped area of skin of one rabbit. The test site was covered with gauze patch. After 4 hours of exposure in Animal No. 1, there was no erythema and oedema observed at 1, 24, 48 and 72 hours observation. Hence the confirmatory test was conducted on additional two rabbits (No. 2 and 3)to confirm the non irritant nature of the test item. In Animals No. 2 and 3 after post patch removal, revealed no erythema and oedema at 1, 24, 48 and 72 hours observation. The patch was removed after 4 hours and rabbits were observed for erythema and oedema at 1, 24, 48 and 72 hours after patch removal, evaluated and graded as per Draize method. The individual mean score at 24, 48 and 72 hours for Animal Nos. 1, 2 and 3 were 0.00, 0.00, 0.00 and 0.00, 0.00, 0.00, for erythema and oedema formation, respectively.  

Hence, it was concluded that “Benzyl propionate (CAS No. - 122 -63-4)” was Non-Irritating to the skin of Female New Zealand White rabbits under the experimental conditions tested and Classified as “Category- Not Classified” as per CLP Regulation.

These experimental studies are further supported by study performed in an OECD GLP laboratory (Sustainability Support Services (Europe) AB has the letter of access) for the structurallysimilar read across substance,Phenethyl phenyl acetate [CAS: 102-20-5]. The study was conducted as per OECD guideline No. 404. Three healthy young adult female rabbits were used for conducting acute dermal irritation/corrosion study. Body weights were re­corded on day 0 (prior to application) and at termination. Rabbits with good intact skin were selected for the study. The hairs of all the rabbits were clipped at contralateral sites, approximately 24 hours prior to treatment. A dose of 0.5 ml test item was applied to the skin, over an area of approximately 6 x 6 cm clipped of hair on one side of rabbits. The other untreated side was kept as control area and 0.5 ml of distilled water was applied at this site. At the end of 4 hours, the gauze patch was removed and test item application site was wiped with water without altering the integrity of the epidermis. 

Initially, the test item was applied to the clipped area of skin of one rabbit. The test site was covered with gauze patch. After 4 hours of exposure in animal no.1, no erythema and oedema was observed at 1 hour of observation. At 24, 48 and 72 hours observation no erythema and no oedema was observed. Hence the confirmatory test was conducted on additional two rabbits (No. 2 and 3) to confirm the non irritant nature of the test item. The patch was removed after 4 hours and rabbits were observed for erythema and oedemaat 1, 24, 48 and 72 hours after patch removal, evaluatedand graded as per Draize method. In animal no. 2, at 1 hour observation post patch removal, revealed very slight erythema (barely perceptible) and no oedema whereas animal no. 3 showed no erythema and oedema. At 24, 48 and 72 hours, animal nos. 2 and 3 showed no erythema and no oedema. The other untreated side revealed no erythema and no oedema and was found to be normal throughout the experimental period. The individual mean score at 24, 48 and 72 hours for treated site for animal nos. 1, 2 and 3 were 0.00, 0.00, 0.00 and 0.00, 0.00, 0.00, for erythema and oedema formation, respectively. No erythema and no oedema (skin irritation) were found at the end of 72 hour observation period after patch removal. Hence, it was concluded that Phenethyl phenyl acetate (CAS No. – 102-20-5) was Non-Irritating to the skin of Female New Zealand White rabbits

under the experimental conditions tested and is Classified as “Category- Not Classified as Skin Irritant” as per CLP criteria for Classification.

Based on the available data for the target and read across substances and applying the weight of evidence approach, Geranyl phenylacetate can be considered to be not irritating to skin. Comparing the above annotations with the criteria of CLP regulation, it can be classified under the category “Not Classified”.

Eye Irritation:

In different studies,Geranyl phenylacetate  has been investigated for potential for ocular irritation to a greater or lesser extent. The studies are based on in vivo experiments in rabbits along with predicted data for target chemical and its structurally similar read across substances,Benzyl propionate [CAS: 122-63-4], Methyl phenylacetate [CAS: 101-41-7].The predicted data using the OECD QSAR toolbox has also been compared with the experimental data.

In a prediction done by SSS (2017) using the OECD QSAR toolbox with log kow as the primary descriptor, the ocular irritation potential was estimated forgeranyl phenylacetate. Geranyl phenylacetate was estimated to be not irritating to eyes of New Zealand White rabbits.

This result is supported by the experimental study conductedin an OECD GLP laboratory (Sustainability Support Services (Europe) AB has the letter of access) for the structurallysimilar read across substance,Benzyl propionate [CAS: 122-63-4]. The study was performed according to OECD 405 Guidelines.

Rabbits free from injury of eye were selected for the study. The eyes of all the rabbits were examined 24 hours prior to treatment. One eye of each rabbit served as control and other as treated. Control eye was left untreated whereas;0.1 ml of test item (as such)was instilled in the other (treated) eye of rabbits. The eye was observed at 1, 24, 48, 72 hours after test item instillation. Ophthalmoscope was used for scoring of eye lesions. In the initial test, 0.1 ml of test item was applied into the conjunctival sac of the right eye of Animal No.1. The left eye of the rabbit served as the control. Animal No. 1 presented ocular lesions at 1 hour observation period. Hence the confirmatory test was conducted on additional two rabbits (Animal No. 2 and 3);0.1 ml of test item was instilled into the conjunctival sac of right eye and left eye served as the control. Ocular lesions were observed at 1, 24 and 48 hour in Animal Number 2 whereas in Animal Number 3 ocular lesions presented only at 1 hour observation period. Untreated eye of the treated rabbits was normal throughout the experimental period of 72 hours.

The following grading scores were observed in treated eye of tested rabbits.

Observation at 1 hour after instillation of test item revealed: Cornea-No ulceration or opacity in all 3 animals; Area of Opacity-Zero in all the animals; Iris: Normal in all the animals. Conjunctivae -Some blood vessels definitely hyperaemic (injected) in all the animals; Chemosis:Some swelling above normal (includes nictating membranes) were observed in animal number 1 and 3 whereas animal number 2 was normal. Observation at 24 hours after instillation of test item revealed: Cornea-No ulceration or opacity in all the animals; Area of Opacity-Zero in all the animals; Iris:Normal in all the animals. Conjunctivae -Some blood vessels definitely hyperaemic (injected) was observed in animal no. 2. Animal no. 1 and 3 recovered to normal; Chemosis:No swelling was observed in all the Animals. At 24 hours observation the rabbits were examined for corneal epithelium cell damage using sodium fluorescein strips and noticed 0 % damage in Animal Nos 1, 2 and 3, respectively. Observation at 48 and 72 hours after instillation of test item revealed: Cornea-No ulceration or opacity in all the animals; Area of Opacity-Zero in all the animals; Iris: Normal in all the animals. Conjunctivae -Some blood vessels definitely hyperaemic (injected) was observed in animal no. 3 at 48 hours which was recovered to normal at 72 hours observation whereas blood vessels were normal in Animal Numbers 1 and 3 at 48 and 72 hours observation; Chemosis: No swelling was observed in all the animals. The individual mean score for Animal Nos. 1, 2 and 3at 24, 48, 72 hours for Corneal opacity, iris, conjunctiva, chemosis were found 0.00, 0.00, 0.00, 0.00; 0.00, 0.00, 0.67, 0.00 and 0.00, 0.00, 0.00, 0.00, respectively.

Under the experimental conditions tested, eye irritation and reversibility of effects on eyes of rabbits was observed at 72 hours. Hence under the experimental test conditions, Benzyl propionate (CAS: 122-63-4) is “Non Irritant” to New Zealand White Male rabbit eyes and is being classified as “Not Classified” as per the CLP regulation.

These results are also supported by the experimental studyconductedin an OECD GLP laboratory (Sustainability Support Services (Europe) AB has the letter of access) for the structurally similar read across substance,Methyl phenylacetate [CAS: 101-41-7].This study was performed as per OECD guideline No. 405.

Rabbits free from injury of eye were selected for the study. The eyes of all the rabbits were examined 24 hours prior to treatment. One eye of each rabbit served as control and other as treated. Control eye was left untreated whereas; 0.1 ml of as such test item was instilled in the other (treated) eye of each rabbit. The eye was observed at 1, 24, 48 and 72 hour after test item instillation. Ophthalmoscope was used for scoring of eye lesions. In the initial test, 0.1 ml of as such test item was instilled into the conjunctival sac of the right eye of animal no.1 whereas the left eye of the rabbit served as the control. As animal no. 1 showed no severe ocular lesions hence a confirmatory test was conducted on additional two rabbits (animal no. 2 and 3);0.1 ml of as such test item was instilled into the conjunctival sac of right eye of both the rabbits and left eye served as the control. Untreated eye of all the three rabbits was normal throughout the experimental period of 72 hours. The following grading scores were observed in treated eye of tested rabbits.

Observation at 1 hour after instillation of test item revealed: Cornea- No ulceration or opacity in all the animals; Area of Opacity-Zero in all the animals;Iris: Normal in all the animals. Conjunctivae - Some blood vessels definitely hyperaemic (injected) was observed in all the animals; Chemosis: Some swelling above normal (includes nictitating membranes) was observed in all the animals. Observation at 24 hours after instillation of test item revealed: Cornea- No ulceration or opacity in all the animals; Area of Opacity-Zero in all the animals; Iris: Normal in all the animals. Conjunctivae - Some blood vessels definitely hyperaemic (injected) was observed in all the animals; Chemosis: No swelling (normal) was observed in all the animals. At 24 hours observation the rabbits were examined for corneal epithelium cell damage using sodium fluorescein strips and noticed 0% damage in all the animals. Observation at 48 and 72 hours after instillation of test item revealed: Cornea- No ulceration or opacity in all the animals; Area of Opacity-Zero in all the animals; Iris: Normal in all the animals. Conjunctivae - Blood vessels normal in all the animals; Chemosis: No swelling (normal) was observed in all the animals. The individual mean score for animal nos. 1, 2 and 3 at 24, 48, 72 hours (at treated site)for corneal opacity, iris, conjunctiva and chemosis were determined to be 0.00, 0.00, 0.33, 0.00; 0.00, 0.00, 0.33, 0.00 and 0.00, 0.00, 0.33, 0.00 respectively.

Under the experimental conditions tested, eye irritation and reversibility of effects on eyes of rabbits was observed within 72 hours.  Hence, it was concluded that Methyl phenyl acetate (CAS: 101-41-7) was Non-Irritating to the eyes of Male New Zealand White rabbits under the experimental conditions tested and is Classified as “Category- Not Classified" as per CLP criteria for Classification.

Based on the available data for the target and read across substances and applying the weight of evidence approach, geranyl phenylacetate can be considered to be not irritating to eyes. Comparing the above annotations with the criteria of CLP regulation, it can be classified under the category “Not Classified”.

Justification for classification or non-classification

Based on the available information, Geranyl phenylacetate is not likely to cause any irritation to eyes and skin.

Hence, Geranyl phenylacetate can be classified under the category “Not Classified” as per CLP regulation.