Anisyl formate

Endpoint summary

Description of key information

Skin irritation:

Skin irritation tests of Anisyl Formate (CAS No: 122-91-8) was performed in rabbits to assess the degree of irritancy caused by the chemical.In this test, each rabbit received undiluted Anisyl Formate dermally on intact or abraded skin for 24 hours and later observed for skin reactions.No known signs of skin irritation were observed. HencechemicalAnisyl Formate (CAS No: 122-91-8) was considered to be not irritating to the skin of rabbit.

Eye irritation:

The ocular irritation potential of Anisyl Formate (CAS No: 122-91-8) was estimated using OECD QSAR toolbox version 3.3 with logPow as the primary descriptor. The substance is Anisyl Formate (CAS No: 122-91-8) is estimated to be not irritating to the eye of rabbits. Based on the estimated result N-benzyl-N-ethylaniline (CAS No: 92-59-1) can be considered as non-irritant to eye 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 journal

Qualifier:

according to guideline

Guideline:

other: as mentioned below

Principles of method if other than guideline:

Skin irritation tests of Anisyl Formate (CAS No: 122-91-8) was performed in rabbits to assess the degree of irritancy caused by the chemical.

GLP compliance:

not specified

Specific details on test material used for the study:

- Name of test material: (4-methoxyphenyl)methyl formate/ Anisyl Formate
- Molecular formula: C9H10O3
- Molecular weight: 166.175 g/mol
- Smiles notation: c1(ccc(OC)cc1)COC=O
- InChl: 1S/C9H10O3/c1-11-9-4-2-8(3-5-9)6-12-7-10/h2-5,7H,6H2,1H3
- Substance type: Organic
- Physical state: 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 or abraded rabbit skin

Vehicle:

unchanged (no vehicle)

Controls:

not specified

Amount / concentration applied:

100%

Duration of treatment / exposure:

24 hours

Observation period:

24 hours

Number of animals:

No data available

Details on study design:

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 skin irritation were observed.

Interpretation of results:

other: Not irritating

Conclusions:

The test chemical Anisyl Formate (CAS No: 122-91-8) was considered to be not irritating on intact or abraded skin of rabbits when applied in full strength.

Executive summary:

Skin irritation tests of Anisyl Formate (CAS No: 122-91-8) was performed in rabbits to assess the degree of irritancy caused by the chemical.

 

In this test, each rabbit received undiluted Anisyl Formate dermally on intact or abraded skin for 24 hours and later observed for skin reactions.

 

No known signs of skin irritation were observed. HencechemicalAnisyl Formate (CAS No: 122-91-8) was considered to be not irritating to the skin of rabbit.

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 v3.3

GLP compliance:

not specified

Specific details on test material used for the study:

- Name of test material: (4-methoxyphenyl)methyl formate
- Molecular formula: C9H10O3
- Molecular weight: 166.175 g/mol
- Smiles notation: c1(ccc(OC)cc1)COC=O
- InChl: 1S/C9H10O3/c1-11-9-4-2-8(3-5-9)6-12-7-10/h2-5,7H,6H2,1H3
- Substance type: Organic
- Physical state: 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:

0.1ml

Duration of treatment / exposure:

24 hours

Observation period (in vivo):

72 hours

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

Irritation parameter:

overall irritation score

Basis:

mean

Time point:

72 h

Reversibility:

not specified

Remarks on result:

no indication of irritation

Irritant / corrosive response data:

No irritation observed

Estimation method: Takes mode value from the 6 nearest neighbours
Domain  logical expression:Result: In Domain

((((((((((((("a" or "b" or "c" or "d" )  and "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 ( not "q") )  )  and ("r" and ( not "s") )  )  and "t" )  and ("u" and ( not "v") )  )  and ("w" and ( not "x") )  )  and ("y" and "z" )  )

Domain logical expression index: "a"

Referential boundary: The target chemical should be classified as Alkylarylether AND Aromatic compound AND Carboxylic acid derivative AND Carboxylic acid ester AND Ether by Organic functional groups, Norbert Haider (checkmol)

Domain logical expression index: "b"

Referential boundary: The target chemical should be classified as Alkylarylether OR Aromatic compound OR Carboxylic acid derivative OR Carboxylic acid ester OR Ether by Organic functional groups, Norbert Haider (checkmol) ONLY

Domain logical expression index: "c"

Referential boundary: The target chemical should be classified as Aliphatic Carbon [CH] OR Aliphatic Carbon [-CH2-] OR Aliphatic Carbon [-CH3] OR Aromatic Carbon [C] OR Ester, aromatic attach [-C(=O)O] OR Miscellaneous sulfide (=S) or oxide (=O) OR Olefinic carbon [=CH- or =C<] OR Oxygen, one aromatic attach [-O-] OR Oxygen, two olefinic attach [-O-] by Organic functional groups (US EPA) ONLY

Domain logical expression index: "d"

Referential boundary: The target chemical should be classified as Aryl OR Carboxylic acid ester OR Ether by Organic Functional groups ONLY

Domain logical expression index: "e"

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

Domain logical expression index: "f"

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

Domain logical expression index: "g"

Referential boundary: The target chemical should be classified as Alkali Earth OR Alkaline Earth OR Halogens OR Metalloids OR Rare Earth OR Transition Metals by Groups of elements

Domain logical expression index: "h"

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: "i"

Referential boundary: The target chemical should be classified as Group 15 - Nitrogen N OR Group 15 - Phosphorus P OR Group 16 - Sulfur S by Chemical elements

Domain logical expression index: "j"

Referential boundary: The target chemical should be classified as Aryl AND Carboxylic acid ester AND Ether AND Overlapping groups by Organic Functional groups (nested)

Domain logical expression index: "k"

Referential boundary: The target chemical should be classified as Alkene OR Alkoxy OR Alkyl arenes OR Allyl OR Alpha,beta unsaturated aldehyde OR Anthracene  OR Benzyl OR Carbonate OR Cyclo conjugated system OR Cycloalkane OR Cycloalkene OR Cycloketone OR Dihydropyran OR Epoxide OR Furanone/ Furanondione OR Fused carbocyclic aromatic OR Fused unsaturated heterocycles OR Inden OR Isopropyl OR Ketone OR Naphtalene OR No functional group found OR Phenanthrene OR Saturated heterocyclic fragment OR Tetralin OR Unsaturated heterocyclic fragment by Organic Functional groups (nested)

Domain logical expression index: "l"

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

Domain logical expression index: "m"

Referential boundary: The target chemical should be classified as 3-Methylcholantrene (Hepatotoxicity) Alert OR Amineptine (Hepatotoxicity) Alert OR Aromatic hydrocarbons (Liver enzyme induction) Rank C OR Phthalate esters (Testicular toxicity) Rank C OR Tamoxifen (Hepatotoxicity) Alert by Repeated dose (HESS)

Domain logical expression index: "n"

Referential boundary: The target chemical should be classified as (!Undefined)Group All Lipid Solubility < 0.01 g/kg AND (!Undefined)Group C Surface Tension > 62 mN/m by Skin irritation/corrosion Exclusion rules by BfR

Domain logical expression index: "o"

Referential boundary: The target chemical should be classified as Group C Melting Point > 55 C OR Group C Vapour Pressure < 0.0001 Pa by Skin irritation/corrosion Exclusion rules by BfR

Domain logical expression index: "p"

Referential boundary: The target chemical should be classified as H-acceptor-path3-H-acceptor by in vivo mutagenicity (Micronucleus) alerts by ISS

Domain logical expression index: "q"

Referential boundary: The target chemical should be classified as No alert found by in vivo mutagenicity (Micronucleus) alerts by ISS

Domain logical expression index: "r"

Referential boundary: The target chemical should be classified as Not known precedent reproductive and developmental toxic potential by DART scheme v.1.0

Domain logical expression index: "s"

Referential boundary: The target chemical should be classified as Di-carboxylic acid derivatives (adipates) (22d) OR Di-substituted hydrocarbons (24b) OR Known precedent reproductive and developmental toxic potential by DART scheme v.1.0

Domain logical expression index: "t"

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

Domain logical expression index: "u"

Referential boundary: The target chemical should be classified as Basic [0,10) AND No pKa value by Ionization at pH = 9

Domain logical expression index: "v"

Referential boundary: The target chemical should be classified as Acidic [0,10) by Ionization at pH = 9

Domain logical expression index: "w"

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

Domain logical expression index: "x"

Referential boundary: The target chemical should be classified as 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 >> P450 Mediated Activation to Quinones and Quinone-type Chemicals >> Hydroquinones by DNA binding by OECD

Domain logical expression index: "y"

Parametric boundary:The target chemical should have a value of log Kow which is >= -0.173

Domain logical expression index: "z"

Parametric boundary:The target chemical should have a value of log Kow which is <= 2.83

Interpretation of results:

other: not irritating

Conclusions:

(4-methoxyphenyl)methyl formate (CAS No: 122-91-8) was estimated to be not irritating to the eyes of New Zealand White rabbits.

Executive summary:

The ocular irritation potential of (4-methoxyphenyl)methyl formate  (CAS No: 122-91-8) was estimated using OECD QSAR toolbox v3.3 with logPow as the primary descriptor. (4-methoxyphenyl)methyl formate was estimated to be not irritating to the eyes of New Zealand White rabbits. Based on the estimated results, (4-methoxyphenyl)methyl formate (CAS No: 122-91-8) 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:

Various studieshas been investigated for the test chemicalAnisyl Formate (CAS No: 122-91-8)to observe the potential for dermal irritation to a greater or lesser extent. The studies are based on in vivo experiments in rabbits, guinea pigs and humans for target chemicalAnisyl Formate (CAS No: 122-91-8) and its structurally similar read across substancesBenzyl formate (CAS No: 104-57-4)and p-anisyl acetate (CAS No: 104-21-2).The predicted data using the OECD QSAR toolbox has also been compared with the experimental data and summarized as below;

The two skin irritation studies were conducted by D.L.J. Opdyke (1976) for target chemical Anisyl Formate (CAS No: 122-91-8) in rabbits and humans to assess the degree of irritancy caused by the chemical as follows;

In the first study, each rabbit received undiluted Anisyl Formate dermally on intact or abraded skin for 24 hours and later observed for skin reactions.No known signs of skin irritation were observed.

In next study, a closed patch test of Anisyl Formate (CAS No: 122-91-8) was performed in 22 humans. Anisyl formate was applied at concentration of 4% in petrolatum on skin of each subject under occlusive condition for 48 hours. None of the subjects showed any cutaneous reaction within the 48 hour.

In both the studies, thechemicalAnisyl Formate (CAS No: 122-91-8) did not induce any skin reactions and hence it was considered to be not irritating to the skin.

 

 

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 for test chemicalAnisyl Formate (CAS No: 122-91-8).The chemical Anisyl Formate (CAS No: 122-91-8) is estimated to be not irritating to skin of rabbits.

 

 

The above results were supported by thePreliminary irritation testconducted by D.W. SHARP (1978)inHartley albinoguineapigs of same sex forstructurally similar read across substanceBenzyl formate (CAS No: 104-57-4)to determine the concentration suitableforthe sensitization study[injection challenge concentration (ICC) and application challenge concentration(ACC)].In the preliminary test, the guinea pigs were treated intradermally and dermally. 4 guinea pigs were injected intradermally in the clipped and shaved flanks with 0.1ml aliquots of a range of concentration of test substance in a suitable solvent. 24 hours later, the skin was examined for erythema and edema.The concentration giving slight but perceptible irritation with no oedema was selected as the injection challenge concentration (ICC).Aliquots of 0.1ml using a range of concentration of the test substancein a suitable solventwere applied in small circular areas to the shaved flanks of 4 previously untreated guinea pigs.24 hours later, the skin was examined for erythema and the highest concentration which caused no irritation was selected as the application challenge concentration (ACC).As a result of preliminary studies, the concentrations of Benzyl formate at which no irritation was observed were 0.25% for the ICC and 20% for ACC.Since the test chemical did not induce any cutaneous effects at these concentrations (0.25% for the ICC and 20% for ACC), the chemical Benzyl formate (CAS No: 104-57-4) was considered to be not irritating to the skin of guinea pigs.

 

 

Toshio Takenaka, Eiko Hasegawa, Umeko Takenaka, Fumio Saito M. D. and Tazuko Odaka M. D. (1968) and D. McGinty, C.S. Letizia,A.M. Api (2012) reporteda patch test onstructurally similar read across substancep-anisyl acetate (CAS No: 104-21-2) on 80 patients. In this patch test, Anisyl acetate was applied as a closed patch to the back, forearm and upperarm of 80 male/female humans in Japan. The test material was applied at a concentration of 0.05-0.5%. Cream base or ethyl alcohol was used as a vehicle. The patches were applied for 24–48 h and the sites evaluated 30 min after the patches were removed. No irritation was noted in any of the human (0/80). Therefore Anisyl acetate(CAS No: 104-21-2) was considered to be non-irritant to the skin.

 

 

Thus on the basis of available data for the target chemical Anisyl Formate (CAS No: 122-91-8) and its structurally similar read across substancesBenzyl formate (CAS No: 104-57-4)andp-anisyl acetate (CAS No: 104-21-2),it can be concluded thatchemical Anisyl Formate (CAS No: 122-91-8) is unable to cause skin irritation and considered as not irritating.Comparing the above annotations with the criteria of CLP regulation, it can be classified under the category “Not Classified”.

 

 

Eye irritation:

In different studies,the test chemicalAnisyl Formate (CAS No: 122-91-8) has been investigated for potential for ocular irritationto a greater or lesser extent. The studies are based on in vivo experiments in rabbits for target chemicalAnisyl Formate (CAS No: 122-91-8) and its structurally similar read across substancesBenzyl formate (CAS No: 104-57-4)andp-anisyl acetate (CAS No: 104-21-2).The predicted data using the OECD QSAR toolbox has also been compared with the experimental data and summarized as below;

 

 

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 for test chemicalAnisyl Formate (CAS No: 122-91-8).The chemical Anisyl Formate (CAS No: 122-91-8) is estimated to be not irritating to eye ofNew Zealand Whiterabbits.

 

 

The above result was supported by the experimental studies reported by D. McGinty, C.S. Letizia,A.M. Api (2012) on twostructurally similar read across substances Benzyl formate (CAS No: 104-57-4)and p-anisyl acetate (CAS No: 104-21-2) in four female SPF alibino rabbits in order to assess their eye irritation potential as follows;

In case of Benzyl formate (CAS No: 104-57-4), about 0.1ml of undiluted Benzyl formate was installed into the one of each animal while the other untreated eye served as control. The observations were made at 1, 48, 72 h and 7 days after treatment. At 24 h after dosing, corneal opacity was scattered or diffuse on more than one quarter but less than one half of the cornea. Application of fluorescein confirmed this finding. The conjunctiva were still diffuse, crimson red with individual vessels not easily discernible, swelling was still noted as well as an abnormal discharge. At 48 h after dosing, the scattered or diffuse area of opacity was still noted on one quarter or less of the cornea, even after instillation of fluorescein. The conjunctiva was still diffusely red; the individual vessels were not easily discernible and abnormal swelling still present. At 72 h after dosing, the conjunctival vessels were still injected and following the instillation of fluorescein a scattered or diffuse area of opacity on one quarter or less of the cornea was noted. By 7 days after dosing the animals were free of any signs of eye irritation.

In case of p-anisyl acetate (CAS No: 104-21-2), 0.1 ml aliquot of undiluted p-anisyl acetate was instilled into the left eye then gently closed for 1 s. The untreated right eye of each animal served as a control. Observations were made at 1, 24, 48 and 72 h. Slight to moderate conjunctive irritation (4/4) was observed 1 hour after application. All effects were reversible within 48 h.

As all the observed effects were cleared in the cases, the chemicalsBenzyl formate(CAS No 104-57-4) and p-anisyl acetate (CAS No: 104-21-2) was considered to be non-irritant to the eyes of SPF alibino rabbits.

 

 

Thus on the basis of available data for the target chemical Anisyl Formate (CAS No: 122-91-8) and its structurally similar read across substancesBenzyl formate (CAS No: 104-57-4)andp-anisyl acetate (CAS No: 104-21-2),it can be concluded that chemical Anisyl Formate (CAS No: 122-91-8) is unable to cause eye irritation and considered as not irritating.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

The skin and eye irritation potential of test chemicaltarget chemical Anisyl Formate (CAS No: 122-91-8) and its structurally similar read across substancesBenzyl formate (CAS No: 104-57-4)andp-anisyl acetate (CAS No: 104-21-2)were observed in various studies. The results obtained from these studies indicate that the chemica lAnisyl Formate is unlikely to cause skin and eye irritation. HenceAnisyl Formate (CAS No: 122-91-8) can be classified under the category “Not Classified” for skin and eye as per CLP.