Cinnamyl butyrate

Endpoint summary

Description of key information

Skin Irritation:

Erythema was the only effect observed which lasted only for 24 hours. Since the effects were reversible after 24 hours, Cinnamyl butyrate can be considered to be not irritating to rabbit skin.

Eye Irritation:

The ocular irritation potential of Cinnamyl butyrate was estimated using OECD QSAR toolbox v3.3 with logPow as the primary descriptor.

Cinnamyl butyrate was estimated to be not irritating to the eyes of New Zealand White rabbits.

Based on the estimated results, Cinnamyl butyrate 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:

The acute dermal irritation of cinnamyl butyrate was evaluated as a part of the acute dermal LD50 study.

GLP compliance:

not specified

Specific details on test material used for the study:

- Name of the test material: Cinnamyl butyrate
- IUPAC name: (2E)-3-phenylprop-2-en-1-yl butanoate
- Molecular formula: C13H16O2
- Molecular weight: 204.267 g/mol
- Substance type: Organic
- Smiles: c1(\C=C\COC(CCC)=O)ccccc1
- Physical State: Colorless liquid

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 skin

Vehicle:

unchanged (no vehicle)

Controls:

not specified

Amount / concentration applied:

5000 mg/kg

Duration of treatment / exposure:

24 hours, single dermal exposure

Observation period:

14 days

Number of animals:

4

Details on study design:

no data available

Other effects / acceptance of results:

no data available

Irritation parameter:

overall irritation score

Basis:

mean

Time point:

14 d

Reversibility:

fully reversible within: 24 hours

Remarks on result:

no indication of irritation

Irritant / corrosive response data:

Erythema was the only effect observed which lasted only for 24 hours.

Interpretation of results:

other: not irritating

Conclusions:

Erythema was the only effect observed which lasted only for 24 hours. Since the effects were reversible after 24 hours, Cinnamyl butyrate can be considered to be not irritating to rabbit skin.

Executive summary:

The acute dermal irritation of cinnamyl butyrate was evaluated as a part of the acute dermal LD50 study. 4 rabbits were received a single dermal application of 5000mg/kg of cinnamyl butyrate for 24 hours under occlusive conditions. Observations were made for 14 days.

Erythema was the only effect observed which lasted only for 24 hours. Since the effects were reversible after 24 hours, Cinnamyl butyrate can be considered to be not irritating to rabbit skin.

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 v3.3 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 v 3.3

GLP compliance:

not specified

Specific details on test material used for the study:

- Name of the test material: Cinnamyl butyrate
- IUPAC name: (2E)-3-phenylprop-2-en-1-yl butanoate
- Molecular formula: C13H16O2
- Molecular weight: 204.267 g/mol
- Substance type: Organic
- Smiles: c1(\C=C\COC(CCC)=O)ccccc1
- Physical State: Colorless liquid

Species:

rabbit

Strain:

New Zealand White

Details on test animals or tissues and environmental conditions:

no data available

Vehicle:

unchanged (no vehicle)

Controls:

not specified

Amount / concentration applied:

0.1 ml

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:

6

Details on study design:

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 signs of irritation observed

Estimation method: Takes mode value from the 5 nearest neighbours
Domain  logical expression:Result: In Domain

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

Domain logical expression index: "a"

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

Domain logical expression index: "b"

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

Domain logical expression index: "c"

Referential boundary: The target chemical should be classified as 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 ONLY

Domain logical expression index: "d"

Referential boundary: The target chemical should be classified as No alert found by DNA binding by OASIS v.1.3

Domain logical expression index: "e"

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 >> 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 >> Coumarins OR Radical 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) >> Coumarins 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) >> p-Substituted Mononitrobenzenes 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 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 >> 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, 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 >> Coumarins OR SN2 >> Direct acting epoxides formed after metabolic activation >> Quinoline Derivatives 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 >> Ring opening SN2 reaction OR SN2 >> Ring opening SN2 reaction >> Sultones 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: "f"

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

Domain logical expression index: "g"

Referential boundary: The target chemical should be classified as Acylation OR Acylation >> Isocyanates and Isothiocyanates OR Acylation >> Isocyanates and Isothiocyanates >> Isocyanates OR Michael addition OR Michael addition >> P450 Mediated Activation to Quinones and Quinone-type Chemicals OR Michael addition >> P450 Mediated Activation to Quinones and Quinone-type Chemicals >> Arenes OR Michael addition >> Polarised Alkenes-Michael addition OR Michael addition >> Polarised Alkenes-Michael addition >> Alpha, beta- unsaturated esters 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 nitro OR SN1 >> Nitrenium Ion formation >> Primary aromatic amine OR SN1 >> Nitrenium Ion formation >> Tertiary aromatic amine by DNA binding by OECD

Domain logical expression index: "h"

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

Domain logical expression index: "i"

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 by Estrogen Receptor Binding

Domain logical expression index: "j"

Referential boundary: The target chemical should be classified as SN2 AND SN2 >> SN2 Reaction at a sp3 carbon atom AND SN2 >> SN2 Reaction at a sp3 carbon atom >> Activated alkyl esters and thioesters  by Protein binding by OASIS v1.3 ONLY

Domain logical expression index: "k"

Parametric boundary:The target chemical should have a value of log Kow which is >= 3.34

Domain logical expression index: "l"

Parametric boundary:The target chemical should have a value of log Kow which is <= 4.47

Interpretation of results:

other: not irritating

Conclusions:

Cinnamyl butyrate was estimated to be not irritating to the eyes of New Zealand White rabbits.

Executive summary:

The ocular irritation potential of Cinnamyl butyrate was estimated using OECD QSAR toolbox v3.3 with logPow as the primary descriptor.

Cinnamyl butyrate was estimated to be not irritating to the eyes of New Zealand White rabbits.

Based on the estimated results, Cinnamyl butyrate 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,Cinnamyl butyrate hasbeen 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 substance,Citronellyl isobutyrate [CAS: 97-89-2]. The predicted data using the OECD QSAR toolbox has also been compared with the experimental data.

Various studies for Cinnamyl butyrate were summarized in Food and Chemical Toxicology, 45, (2007), S62–S65 to assess the dermal irritation potential in humans and rabbits.

The acute dermal irritation of cinnamyl butyrate was evaluated as a part of the acute dermal LD50 study. 4 rabbits were received a single dermal application of 5000mg/kg of cinnamyl butyrate for 24 hours under occlusive conditions. Observations were made for 14 days.

Erythema was the only effect observed which lasted only for 24 hours. Since the effects were reversible after 24 hours, Cinnamyl butyrate can be considered to be not irritating to rabbit skin.

As a part of pre-test for human maximization study, 4% (2760µg/cm2) cinnamyl butyrate in petrolatum was applied on the forearms of 29 healthy, male volunteers for 48 hours under occlusion and observed for effects.

No signs of irritation observed after 48 hours. Hence, Cinnamyl butyrate can be considered to be not irritating to human skin.

Similarly various studies for the target chemical were summarized in Food and Cosmetics Toxicology,Volume 16, Supplement 1, 1978, Page 691, to assess the dermal irritation potential in humans and rabbits.

Cinnamyl butyrate applied at full strength to intact or abraded rabbit underocclusion was considered to be irritating. Also, when tested on human subjects at 4% in petrolatum in a 48-hr closed-patch test,Cinnamyl butyrate produced no irritation.

 

Even though rabbit study indicates that Cinnamyl butyrate is moderately irritating to rabbit skin but human data concludes that it is not irritating to human skin. Since, in the rabbit study skin was exposed to higher concentration of Cinnamyl butyrate than the normal use; there exists a possibility of Cinnamyl butyrate being of not irritating to rabbit skin at lower concentrations. So, Cinnamyl butyrate can be considered to be not irritating to skin.

These experimental studies for the target are further supported by the following estimated results.

In a prediction done by SSS (2017) using the OECD QSAR toolbox v3.3 with log kow as the primary descriptor, the dermal irritation potential was estimated forCinnamyl butyrate. Cinnamyl butyrate was estimated to be not irritating to the skin of New Zealand White rabbits.

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

The experimental and estimated data are in mutual agreement with each other, indicating a very strong possibility of Cinnamyl butyrate being not irritating to skin.

The above studies are ably supported by the results summarized in Food and Cosmetics Toxicology Volume 16, Supplement 1, 1978, Pages 693; for the structurally similar substance, Citronellyl isobutyrate (CAS No: 97 -89-2). Citronellyl isobutyrate 4% in petrolatum was applied to human skin in a closed-patch for 48 hours and observed for signs of irritation.

There was no irritation seen in any of the subjects after 48 hours of exposure. Hence, Citronellyl isobutyrate(CAS No: 97 -89-2) was considered to be not irritating on skin of humans.

Based on the available data for the target as well as read across substances and applying the weight of evidence approach,Cinnamyl butyrate was not irritating to skin.Comparing the above annotations with the criteria of CLP regulation, test chemical can be classified under the category “Not Classified”.

Eye Irritation:

In different studies,Cinnamyl butyrate hasbeen 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 substance,Benzyl propionate[CAS: 122-63-4] and Methyl cinnamate[CAS: 103-26-4].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 v3.3 with log kow as the primary descriptor, the ocular irritation potential was estimated forCinnamyl butyrate. Cinnamyl butyrate was estimated to be not irritating to the eyes of New Zealand White rabbits.

This result is supported by the experimental study performed in 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. 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 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 3 at 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. 

These results are supported by the experimental study summarized in Food and Chemical Toxicology, 45 (2007), S113–S119, for the structurally similar substance, Methyl cinnamate[CAS: 103-26-4]. 0.1ml methyl cinnamate was instilled in one eye of 6 New Zealand White rabbits and observed for signs of irritation. The untreated eyes served as controls. Observations were made at 1, 4, 24, 48, 72 and 96 h and daily thereafter for a total of 7 days. Conjunctival irritation was observed in 1/6 rabbits for 24-h.Under the conditions of this study, methyl cinnamate was considered to be not irritating.

Based on the available data for the target as well as read across substances and applying the weight of evidence approach,Cinnamyl butyrate was not irritating to eyes.Comparing the above annotations with the criteria of CLP regulation, test chemical can be classified under the category “Not Classified”.

Justification for classification or non-classification

Available data for Cinnamyl butyrate indicates that it is not likely to cause any irritation to skin and eyes.

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