Registration Dossier

Skin Irritation:

Geranyl isobutyrate was applied full strength under occlusion to intact and abraded rabbit skin. The rabbits were exposed for 24 hours and signs of irritation were observed. Mild irritation occurred after 24 hours.

Hence,Geranyl isobutyrate (2345-26-8) was considered to bemildly irritating to rabbit skin.

Eye Irritation:

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

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

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

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 isobutyrate in rabbits

GLP compliance:

not specified

Specific details on test material used for the study:

- Name of test material: 3,7-dimethylocta-2,6-dien-1-yl 2-methylpropanoate
- Common Name: Geranyl isobutyrate
- Molecular formula: C14H24O2
- Molecular weight: 224.342 g/mol
- Smiles notation: C(OC\C=C(\CC\C=C(/C)C)C)(C(C)C)=O
- InChl: 1S/C14H24O2/c1-11(2)7-6-8-13(5)9-10-16-14(15)12(3)4/h7,9,12H,6,8,10H2,1-5H3/b13-9+
- 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 and abraded

Vehicle:

unchanged (no vehicle)

Controls:

not specified

Amount / concentration applied:

full strength

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:

probability of mild irritation

Irritant / corrosive response data:

mild irritation observed

Interpretation of results:

Category 3 (mild irritant) based on GHS criteria

Conclusions:

Mild irritation occurred after 24 hours.
Hence, Geranyl isobutyrate (2345-26-8) was considered to be mildly irritating to rabbit skin.

Executive summary:

A skin irritation study was performed in rabbits to assess the irritation potential of Geranyl isobutyrate.

Geranyl isobutyrate was applied full strength under occlusion to intact and abraded rabbit skin. The rabbits were exposed for 24 hours and signs of irritation were observed. Mild irritation occurred after 24 hours.

Hence,Geranyl isobutyrate (2345-26-8) was considered to bemildly irritating to rabbit skin.

Endpoint conclusion:

no adverse effect observed (not irritating)

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: 3,7-dimethylocta-2,6-dien-1-yl 2-methylpropanoate
- Common Name: Geranyl isobutyrate
- Molecular formula: C14H24O2
- Molecular weight: 224.342 g/mol
- Smiles notation: C(OC\C=C(\CC\C=C(/C)C)C)(C(C)C)=O
- InChl: 1S/C14H24O2/c1-11(2)7-6-8-13(5)9-10-16-14(15)12(3)4/h7,9,12H,6,8,10H2,1-5H3/b13-9+
- 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:

100 microliters

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:

2

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 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" and ( not "p") ) ) and "q" ) and ("r" and "s" ) )

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 Alkene AND Allyl AND Carboxylic acid ester AND Isopropyl by Organic Functional groups

Domain logical expression index: "c"

Referential boundary: The target chemical should be classified as Allyl AND Carboxylic acid ester AND Isopropyl AND Overlapping groups 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 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 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 >> 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 >> 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 >> Nucleophilic substitution at sp3 Carbon atom 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 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 No alert found 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 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 OR Michael addition >> P450 Mediated Activation to Quinones and Quinone-type Chemicals >> Alkyl phenols 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 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 Non binder, non cyclic structure by Estrogen Receptor Binding

Domain logical expression index: "k"

Referential boundary: The target chemical should be classified as Moderate binder, OH grooup OR Non binder, impaired OH or NH2 group OR Non binder, MW>500 OR Non binder, without OH or NH2 group OR Strong binder, OH group OR Weak binder, OH group by Estrogen Receptor Binding

Domain logical expression index: "l"

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: "m"

Referential boundary: The target chemical should be classified as Highly reactive (GSH) OR Highly reactive (GSH) >> Dialkyl chloromalonates (SN2) OR Highly reactive (GSH) >> Miscellaneous Alkyl 2-halo alkenoates (SN2) OR Moderately reactive (GSH) OR Moderately reactive (GSH) >> Alkyl 2-bromoalkanoates (SN2) by Protein binding potency

Domain logical expression index: "n"

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

Domain logical expression index: "o"

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: "p"

Referential boundary: The target chemical should be classified as (!Undefined)Group CN Lipid Solubility < 0.4 g/kg OR Group All log Kow > 9 OR Group All Melting Point > 200 C OR Group C Aqueous Solubility < 0.0001 g/L OR Group C Melting Point > 55 C OR Group C Molecular Weight > 350 g/mol OR Group C Vapour Pressure < 0.0001 Pa OR Group CN Aqueous Solubility < 0.1 g/L OR Group CN Melting Point > 180 C OR Group CN Molecular Weight > 290 g/mol OR Group CN Vapour Pressure < 0.001 Pa by Skin irritation/corrosion Exclusion rules by BfR

Domain logical expression index: "q"

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

Domain logical expression index: "r"

Parametric boundary:The target chemical should have a value of log Kow which is >= 5.17

Domain logical expression index: "s"

Parametric boundary:The target chemical should have a value of log Kow which is <= 6.73

Interpretation of results:

other: not irritating

Conclusions:

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

Executive summary:

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

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

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

Endpoint conclusion:

no adverse effect observed (not irritating)

Endpoint conclusion:

no study available

Skin Irritation:

In different studies, Geranyl isobutyrate 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, Geranyl butyrate [CAS: 106-29-6] and Citronellyl butyrate [CAS: 97-89-2]. The predicted data using the OECD QSAR toolbox has also been compared with the experimental data.

Various studies for Geranyl isobutyrate were summarized in Fd Cosmet. Toxicol, Vol. 13, pp. 449-457, 1975, to assess the irritation in humans and rabbits.

Geranyl isobutyrate applied at full strength to intact or abraded rabbit underocclusion was mildly irritating. Also, when tested on human subjects at 10% in petrolatum in a 48-hr closed-patch test, geranyl isobutyrateproduced no irritation.

Even though rabbit study indicates that geranyl isobutyrate is mildly irritating to rabbit skin but human data concludes that it is not irritating to human skin. Hence, Geranyl isobutyrate was considered to be not irritating to skin.

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 isobutyrate. Geranyl isobutyrate was estimated to be not irritating to the eyes 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 geranyl isobutyrate. Based on estimation, No severe skin irritation effects were known when geranyl isobutyrate was exposed to rabbit skin.

The experimental and estimated data are in agreement with each other, suggesting that geranyl isobutyrate is not irritating to skin.

These results are further supported by the experimental study summarized in Food and Cosmetics Toxicology Volume 12, Issues 7–8, December 1974, Pages 889, for thestructurally similar read across substance, Geranyl butyrate [CAS: 106-29-6].Geranyl butyrate was applied full strength under occlusion to intact and abraded skin of rabbits. The rabbits were exposed for 24 hours and signs of irritation were observed. No irritation occurred after 24 hours.

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

The above results are also supported by the experimental study summarized in Food and Cosmetics Toxicology Volume 16, Supplement 1, 1978, Pages 693, for thestructurally similar read across substance, Citronellyl butyrate [CAS: 97-89-2].Citronellyl isobutyrate was tested 4% in petrolatum on human volunteers in a 48 hours closed patch test.

Citronellyl sobutyrate was not irritating to human skin after 48 hours exposure.

Based on the available data for the target as well as read across substances and applying the weight of evidence approach,geranyl isobutyrate 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, Geranyl isobutyrate 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, Diisopropyl sebacate [CAS: 7491-02-3] and methyl laurate [CAS: 111-82-0]. 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 isobutyrate. Geranyl isobutyrate was estimated to be not irritating to the eyes of New Zealand White rabbits.

This result is supported by the experimental study summarized in International Journal of Toxicology; 31(Suppl 1):5-76, 2012, for thestructurally similar read across substance, Diisopropyl sebacate [CAS: 7491-02-3].A volume of 0.1 ml diisopropyl sebacate was instilled in to the eyes of 6 New Zealand White rabbits, which remained unwashed. The other (untreated) eye of each rabbit served as control. The ocular reactions were scored according to Draize method. The average Draize scores were 2.0 at 24 and 48 hours, 0.3 at 72 hours and 0.0 at 4 days.

Based on the scores after 4 days, diisopropyl sebacate can be considered as not irritating to New Zealand White rabbit eyes.

These results are also supported by the experimental study summarized in CoCAM 4, 16-18 April 2013,for thestructurally similar read across substance, methyl laurate [CAS: 111-82-0].Methyl laurate was instilled into the eyes of rabbits and observed for signs of irritation (dose and duration not mentioned). No abnormality was found when methyl laurate was instilled into rabbit eyes. Hence, methyl laurate can be considered not irritating to rabbit eyes.

Based on the available data for the target as well as read across substances and applying the weight of evidence approach,geranyl isobutyrate 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”.

Available studies forGeranyl isobutyrate indicate that it is not likely to any cause irritation to skin and eyes.

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