Methyl abietate

Endpoint summary

Description of key information

Skin Irritation

Methyl abietate was applied full strength to intact or abraded rabbit skin for 24 hours under occlusion and observed for signs of irritation.Methyl abietate was moderately irritating to rabbit skin after 24 hours of exposure.

Eye Irritation:

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

Methyl abietate was estimated to be not irritating to the eyes of rabbits.

Based on the estimated results, Methyl abietate 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 methyl abietate in rabbits

GLP compliance:

not specified

Specific details on test material used for the study:

- Name of test material: methyl (1R,4aR,4bR,10aR)-1,4a-dimethyl-7-(propan-2-yl)-1,2,3,4,4a,4b,5,6,10,10a-decahydrophenanthrene-1-carboxylate
- Molecular formula: C21H32O2
- Molecular weight: 316.4818 g/mol
- Smiles notation: COC(=O)[C@]1(C)CCC[C@]2(C)[C@H]3CCC(=CC3=CC[C@@H]12)C(C)C
- InChl: 1S/C21H32O2/c1-14(2)15-7-9-17-16(13-15)8-10-18-20(17,3)11-6-12-21(18,4)19(22)23-5/h8,13-14,17-18H,6-7,9-12H2,1-5H3/t17-,18+,20+,21+/m0/s1
- 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 skin

Vehicle:

unchanged (no vehicle)

Controls:

not specified

Amount / concentration applied:

full strentgh

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 moderate irritation

Irritant / corrosive response data:

Moderate irritation was observed

Interpretation of results:

Category 2 (irritant) based on GHS criteria

Conclusions:

Methyl abietate was moderately irritating to rabbit skin after 24 hours of exposure.

Executive summary:

A skin irritation study was performed in rabbits to assess the irritation potential of Methyl abietate.Methyl abietate was applied full strength to intact or abraded rabbit skin for 24 hours under occlusion and observed for signs of irritation.Methyl abietate was moderately irritating to rabbit skin after 24 hours of exposure.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed (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 v 3.3 and the QMRF report has been attached

Guideline:

OECD Guideline 405 (Acute Eye Irritation / Corrosion)

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: methyl (1R,4aR,4bR,10aR)-1,4a-dimethyl-7-(propan-2-yl)-1,2,3,4,4a,4b,5,6,10,10a-decahydrophenanthrene-1-carboxylate
- Common Name: Methyl abietate
- Molecular formula: C21H32O2
- Molecular weight: 316.4818 g/mol
- Smiles notation: COC(=O)[C@]1(C)CCC[C@]2(C)[C@H]3CCC(=CC3=CC[C@@H]12)C(C)C
- InChl: 1S/C21H32O2/c1-14(2)15-7-9-17-16(13-15)8-10-18-20(17,3)11-6-12-21(18,4)19(22)23-5/h8,13-14,17-18H,6-7,9-12H2,1-5H3/t17-,18+,20+,21+/m0/s1
- Substance type: Organic
- Physical state: Liquid

Species:

rabbit

Strain:

not specified

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:

aingle exposure

Observation period (in vivo):

72 hours

Duration of post- treatment incubation (in vitro):

no data available

Number of animals or in vitro replicates:

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:

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

Domain logical expression index: "a"

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

Domain logical expression index: "b"

Referential boundary: The target chemical should be classified as Alkane, branched with tertiary carbon OR Allyl OR Carboxylic acid ester OR Cyclo conjugated system OR Cycloalkane OR Cycloalkene OR Fused unsaturated carbocycles OR Isopropyl OR Rosins by Organic Functional groups ONLY

Domain logical expression index: "c"

Referential boundary: The target chemical should be classified as Alkane, branched with tertiary carbon OR Allyl OR Carboxylic acid ester OR Isopropyl OR Overlapping groups OR Rosins by Organic Functional groups (nested) ONLY

Domain logical expression index: "d"

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

Domain logical expression index: "e"

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

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 >> 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 >> Shiff base formation after aldehyde release OR AN2 >> Shiff base formation after aldehyde release >> Specific Acetate Esters OR Radical OR Radical >> Generation of reactive oxygen species OR Radical >> Generation of reactive oxygen species >> Thiols OR Radical >> Radical mechanism by ROS formation (indirect) or direct radical attack on DNA OR Radical >> Radical mechanism by ROS formation (indirect) or direct radical attack on DNA >> Organic Peroxy Compounds 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 >> 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 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 >> P450 Mediated Activation to Isocyanates or Isothiocyanates OR Acylation >> P450 Mediated Activation to Isocyanates or Isothiocyanates >> Formamides OR Michael addition OR Michael addition >> Polarised Alkenes-Michael addition OR Michael addition >> Polarised Alkenes-Michael addition >> Alpha, beta- unsaturated amides 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 by DNA binding by OECD

Domain logical expression index: "j"

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

Domain logical expression index: "k"

Referential boundary: The target chemical should be classified as Non binder, MW>500 OR Non binder, non cyclic structure by Estrogen Receptor Binding

Domain logical expression index: "l"

Referential boundary: The target chemical should be classified as (!Undefined)Group All Lipid Solubility < 0.01 g/kg AND Group All Aqueous Solubility < 0.00002 g/L AND Group C Aqueous Solubility < 0.0001 g/L AND Group C Aqueous Solubility < 0.0005 g/L AND Group C Melting Point > 55 C by Eye irritation/corrosion Exclusion rules by BfR

Domain logical expression index: "m"

Referential boundary: The target chemical should be classified as (!Undefined)Group CN Lipid Solubility < 0.4 g/kg OR Group All Aqueous Solubility < 0.000005 g/L OR Group All log Kow > 9 OR Group All Melting Point > 200 C OR Group C Molecular Weight > 380 g/mol OR Group CN Aqueous Solubility < 0.1 g/L by Eye irritation/corrosion Exclusion rules by BfR

Domain logical expression index: "n"

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

Domain logical expression index: "o"

Referential boundary: The target chemical should be classified as alpha,beta-unsaturated carbonyls by in vitro mutagenicity (Ames test) alerts by ISS

Domain logical expression index: "p"

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

Domain logical expression index: "q"

Parametric boundary:The target chemical should have a value of log Kow which is >= 5.05

Domain logical expression index: "r"

Parametric boundary:The target chemical should have a value of log Kow which is <= 6.92

Interpretation of results:

other: not irritating

Conclusions:

Methyl abietate was estimated to be not irritating to the eyes of rabbits.

Executive summary:

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

Methyl abietate was estimated to be not irritating to the eyes of rabbits.

Based on the estimated results, Methyl abietate 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, methyl abietate has been investigated for potential for dermal irritation to a greater or lesser extent. The studies are based on in vivo experiments in rabbits and guinea pigs for target chemical and its structurally similar read across substances, Abietic acid [CAS: 514-10-3] and Pentaerythrityl Rosinate [CAS: 8050-26-8].

A skin irritation study was performed (Food and Cosmetics Toxicology, Volume 12, Issues 7–8, December 1974, Page 931) in rabbits to assess the irritation potential of Methyl abietate. Methyl abietate was applied full strength to intact or abraded rabbit skin for 24 hours under occlusion and observed for signs of irritation. Methyl abietate was moderately irritating to rabbit skin after 24 hours of exposure.

This study is supported by the experimental study conducted by B. M. HAUSEN et.al (Contact Dermatitis, 1989: 20: 41-50) in guinea pigs as a part of the Guinea Pig Maximization assay. 10 female Pirbright White guinea pigs were applied different concentrations of methyl abietate (10% and 1%) to the right flank 1 day prior to the Challenge exposure. The reactions were scored and rated after 24 hours. The intensity of reactions were scored according to the following scale:

0 –no reaction = 0.0; (+) –discrete erythema covering more than half of the test area and considered as a very weak but positive reaction = 0.5; + - distinct confluent erythema covering the whole test area = 1.0; ++ - erythema and swelling restricted to test area = 2.0; +++ - erythema with intense swelling, infiltration and exudation spreading over the test area = 3.0

A (+) reaction was considered to be the threshold of irritancy. 10% methyl abietate was slightly irritating to female Pirbright White guinea pigs skin. Hence, methyl abietate can be considered to be irritating to skin.

Both the experimental studies are in agreement with each other, indicating the possibility of methyl abietate being irritating to skin.

These results are further supported by the experimental study conducted by B. M. HAUSEN et.al (Contact Dermatitis, 1989: 20: 41-50) in guinea pigs as a part of the Guinea Pig Maximization assay for the structurally similar read across substance, Abietic acid [CAS: 514-10-3]. 10 female Pirbright White guinea pigs were applied different concentrations of abietic acid (10% and 1%) to the right flank 1 day prior to the Challenge exposure. The reactions were scored and rated after 24 hours. The intensity of reactions were scored according to the following scale:

0 –no reaction = 0.0; (+) – discrete erythema covering more than half of the test area and considered as a very weak but positive reaction = 0.5; + - distinct confluent erythema covering the whole test area = 1.0; ++ - erythema and swelling restricted to test area = 2.0; +++ - erythema with intense swelling, infiltration and exudation spreading over the test area = 3.0. A (+) reaction was considered to be the threshold of irritancy. 10% abietic acid was slightly irritating to female Pirbright White guinea pigs skin.

Hence, abietic acid can be considered to be irritating to skin.

These results are also supported by the experimental study summarized in International Journal of Toxicology, Vol 17, Issue 4_suppl, pp. 83 - 94, 1998; for the structurally similar read across substance, Pentaerythrityl Rosinate [CAS: 8050-26-8]. Pentaerythrityl Rosinate 25% in mineral oil was applied to the skin of 9 rabbits in a single occlusive patch test. The test sites were observed and rated for signs of irritation 2 and 24 hours post application of test chemical. The maximum attainable score for Primary Irritation Index (PII) was 8. The Primary Irritation Index for Pentaerythrityl Rosinate was 0.78/8.

Based on the scores, Pentaerythrityl Rosinate was considered to be a minimal irritant to rabbit skin.

Based on the available data for the target as well as read across chemicals and applying the weight of evidence approach, methyl abietate can be considered irritating to skin.Comparing the above annotations with the criteria of CLP regulation, test chemical can be classified under the category “Category 2”.

 

Eye Irritation:

In different studies, methyl abietate has been investigated for potential for ocular irritation to a greater or lesser extent. The studies are based on in vivo experiments in rabbits and predicted data for target chemical and its closely related read across substances, Cyclododecane [CAS:294-62-2] and 1,5,9-cyclododecatriene [CAS: 4904-61-4]. 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 with log kow as the primary descriptor, the ocular irritation potential was estimated for methyl abietate. Methyl abietate was estimated to be not irritating to the eyes of New Zealand White rabbits.

This result is supported by the experimental study summarized in GESTIS SUBSTANCE Database (information system in hazardous substance of the Berufsgenossenscheftn),2017 ; for the closely related read across substance, Cyclododecane [CAS:294-62-2]. The study was performed as per OECD 405 Guidelines. Cyclododecane was instilled into rabbit eyes and observed for signs of irritation (dose and duration not specified). The Primary Irritation Index for cyclododecane was 5/110.

Hence, it was considered to be not irritating to rabbit eyes.              

These results are also supported by the experimental study summarized in Hazardous Substance DataBank (HSDB), U.S National Library of Medicine, last updated 2009; for the closely related read across substance, 1,5,9-cyclododecatriene [CAS: 4904-61-4]. 0.1 ml 1,5,9-cyclododecatriene was instilled into the eyes of rabbits and observed for signs of irritation. The reactions observed were scored at1, 24, 48, 72 hours, and 1 week. The test chemical produced erythema of the palpebral conjunctiva, obvious swelling of the lids and nictitating membrane, and lacrimation in the treated eyes of rabbits within 1 hour of instillation. The effects were completely reversible in 1 week. The Average values at the end of 1, 24, 48, 72 hours, and 1 week were 6.6, 2.3, 1.0, 1.0, and 0, respectively, with 110.0 the maximum score attainable.

Based on the scores and observations, 1,5,9-cyclododecatriene can be considered not irritating to rabbit eyes.

Based on the available data for the target as well as read across chemicals and applying the weight of evidence approach, methyl abietate can be considered 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 studies for methyl abietate indicate that it is likely to cause irritation to skin but does not cause any irritation to eyes.

Hence, methyl abietate can be classified under the category “CATEGORY 2” for skin irritation and “Not Classified” for eye irritation as per CLP regulation.