1,1-diethoxy-3,7-dimethylocta-2,6-diene

Endpoint summary

Description of key information

Skin Irritation:

Citral diethyl acetal was moderately irritating to rabbit skin after 24 hours exposure.

Eye Irritation:

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

Citral diethyl acetal was estimated to be not irritating to the eyes of Himalayan rabbits.

Based on the estimated results, citral diethyl acetal can be considered 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 skin irritation potential of citral diethyl acetal in rabbits

GLP compliance:

not specified

Specific details on test material used for the study:

- Name of test material: 1,1-diethoxy-3,7-dimethylocta-2,6-diene
- Common name: Citral diethyl acetal
- Molecular formula: C14H26O2
- Molecular weight: 226.357 g/mol
- Smiles notation: C(\C=C(\CC\C=C(/C)C)C)(OCC)OCC
- InChl: 1S/C14H26O2/c1-6-15-14(16-7-2)11-13(5)10-8-9-12(3)4/h9,11,14H,6-8,10H2,1-5H3/b13-11+
- 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 strenth, undiluted 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

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:

Moderately irritating to rabbit skin

Interpretation of results:

Category 2 (irritant) based on GHS criteria

Conclusions:

Citral diethyl acetal was moderately irritating to rabbit skin after 24 hours exposure.

Executive summary:

A study was performed to assess the dermal irritation potential of citral diethyl acetal in rabbits.Undiluted citral diethyl acetal was applied under occlusion to intact and abraded skin of rabbits. The rabbits were observed for signs of irritation for 24 hours.Citral diethyl acetal was moderately 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 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: 1,1-diethoxy-3,7-dimethylocta-2,6-diene
- Common name: Citral diethyl acetal
- Molecular formula: C14H26O2
- Molecular weight: 226.357 g/mol
- Smiles notation: C(\C=C(\CC\C=C(/C)C)C)(OCC)OCC
- InChl: 1S/C14H26O2/c1-6-15-14(16-7-2)11-13(5)10-8-9-12(3)4/h9,11,14H,6-8,10H2,1-5H3/b13-11+
- Substance type: Organic
- Physical state: Liquid

Species:

rabbit

Strain:

Himalayan

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:

single exposure

Observation period (in vivo):

1,24,48 and 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

Other effects / acceptance of results:

no data available

Irritation parameter:

overall irritation score

Basis:

mean

Time point:

other: 1,24,48 and 72 hours

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 ("m" and ( not "n") )  )  and ("o" and ( not "p") )  )  and ("q" and ( not "r") )  )  and ("s" and ( not "t") )  )  and ("u" and "v" )  )

Domain logical expression index: "a"

Referential boundary: The target chemical should be classified as Neutral Organics by US-EPA New Chemical Categories

Domain logical expression index: "b"

Referential boundary: The target chemical should be classified as Acetal AND Alkene AND Alkoxy AND Allyl AND Ether by Organic Functional groups

Domain logical expression index: "c"

Referential boundary: The target chemical should be classified as Acetal AND Alkoxy AND Allyl 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 Alpha-diether [C-O-C-O-C] AND Olefinic carbon [=CH- or =C<] AND Oxygen, aliphatic attach [-O-] by Organic functional groups (US EPA)

Domain logical expression index: "e"

Referential boundary: The target chemical should be classified as Dialkylether AND Ether 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, quinoid structures OR AN2 >>  Michael-type addition, quinoid structures >> Quinones 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 Non-covalent interaction OR Non-covalent interaction >> DNA intercalation OR Non-covalent interaction >> DNA intercalation >> Acridone, Thioxanthone, Xanthone and Phenazine Derivatives OR Non-covalent interaction >> DNA intercalation >> DNA Intercalators with Carboxamide Side Chain OR Non-covalent interaction >> DNA intercalation >> Quinones 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 by ROS formation OR Radical >> Radical mechanism by ROS formation >> Acridone, Thioxanthone, Xanthone and Phenazine Derivatives 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) >> Hydrazine Derivatives OR Radical >> Radical mechanism via ROS formation (indirect) >> Nitro Azoarenes 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) >> Quinones 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 >> Nitro Azoarenes 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 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 after metabolic activation OR SN2 >> Acylation involving a leaving group after metabolic activation >> Geminal Polyhaloalkane Derivatives OR SN2 >> Alkylation by epoxide metabolically formed after E2 reaction OR SN2 >> Alkylation by epoxide metabolically formed after E2 reaction >> Monohaloalkanes 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 >> Monohaloalkanes 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 acylation involving a leaving group OR SN2 >> Direct acylation involving a leaving group >> Acyl Halides OR SN2 >> DNA alkylation OR SN2 >> DNA alkylation >> Alkylphosphates, Alkylthiophosphates and Alkylphosphonates OR SN2 >> DNA alkylation >> Vicinal Dihaloalkanes OR SN2 >> Internal SN2 reaction with aziridinium and/or cyclic sulfonium ion formation (enzymatic) OR SN2 >> Internal SN2 reaction with aziridinium and/or cyclic sulfonium ion formation (enzymatic) >> Vicinal Dihaloalkanes OR SN2 >> Nucleophilic substitution after carbenium ion formation OR SN2 >> Nucleophilic substitution after carbenium ion formation >> Monohaloalkanes 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 >> 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: "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 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 >> P450 Mediated Activation to Quinones and Quinone-type Chemicals >> Hydroquinones 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 Michael addition >> Polarised Alkenes-Michael addition >> Alpha, beta- unsaturated ketones OR Schiff base formers OR Schiff base formers >> Chemicals Activated by P450 to Glyoxal  OR Schiff base formers >> Chemicals Activated by P450 to Glyoxal  >> Ethanolamines (including morpholine) 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 >> Aromatic phenylureas OR SN1 >> Nitrenium Ion formation >> Primary (unsaturated) heterocyclic amine OR SN1 >> Nitrenium Ion formation >> Tertiary aromatic amine OR SN1 >> Nitrenium Ion formation >> Unsaturated heterocyclic azo OR SN2 OR SN2 >> P450 Mediated Epoxidation OR SN2 >> P450 Mediated Epoxidation >> Thiophenes-SN2 OR SN2 >> SN2 at an sp3 Carbon atom OR SN2 >> SN2 at an sp3 Carbon atom >> Aliphatic halides OR SN2 >> SN2 at an sp3 Carbon atom >> Phosphates 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 Non binder, impaired OH or NH2 group OR Non binder, MW>500 OR Non binder, without OH or NH2 group OR Weak binder, OH group by Estrogen Receptor Binding

Domain logical expression index: "l"

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

Domain logical expression index: "m"

Referential boundary: The target chemical should be classified as Inclusion rules not met by Skin irritation/corrosion Inclusion rules by BfR

Domain logical expression index: "n"

Referential boundary: The target chemical should be classified as Ethylenglycolethers OR Ketones by Skin irritation/corrosion Inclusion rules by BfR

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 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 by Skin irritation/corrosion Exclusion rules by BfR

Domain logical expression index: "q"

Referential boundary: The target chemical should be classified as Acetal AND Alkene AND Alkoxy AND Allyl AND Ether by Organic Functional groups

Domain logical expression index: "r"

Referential boundary: The target chemical should be classified as Alcohol OR Alkane, branched with tertiary carbon OR Carbonate OR Carboxylic acid ester OR Isopropyl by Organic Functional groups

Domain logical expression index: "s"

Referential boundary: The target chemical should be classified as Dialkylether AND Ether by Organic functional groups, Norbert Haider (checkmol)

Domain logical expression index: "t"

Referential boundary: The target chemical should be classified as Acetal OR Carboxylic acid orthoester OR Enolether OR Orthocarboxylic acid derivative by Organic functional groups, Norbert Haider (checkmol)

Domain logical expression index: "u"

Parametric boundary:The target chemical should have a value of log Kow which is >= 1.05

Domain logical expression index: "v"

Parametric boundary:The target chemical should have a value of log Kow which is <= 5.4

Interpretation of results:

other: not irritating

Conclusions:

Citral diethyl acetal was estimated to be not irritating to the eyes of Himalayan rabbits.

Executive summary:

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

Citral diethyl acetal was estimated to be not irritating to the eyes of Himalayan rabbits.

Based on the estimated results, citral diethyl acetal can be considered 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, citral diethyl acetal 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, Citral dimethyl acetal [CAS: 7549-37-3]and Diethyl acetal [CAS: 105-57-7].

 

Various studies for Citral diethyl acetal were summarized in Food and Chemical Toxicology, Volume 21, Issue 5, October 1983, Page 667 to assess the irritation in humans and rabbits.

Citral diethyl acetal was applied at full strength to intact or abraded to rabbits under occlusion was moderately irritating. Also, when tested on human subjects at 4% in petrolatum in a 48-hr closed-patch test, citral diethyl acetal produced no irritation.

 

Even though rabbit study indicates that citral diethyl acetal is moderately irritating to rabbit skin but human data concludes that it is not irritating to human skin. Hence, citral dieithyl acetal was considered to be not irritating to 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 citral diethyl acetal. Based on estimation, No severe skin irritation effects were known when citral diethyl acetal was exposed to rabbit skin.

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

These results are further supported by the experimental study summarized in Food and Cosmetics Toxicology, 1979, Pages 230, for thestructurally similar read across substance, Citral dimethyl acetal [CAS: 7549-37-3].Citral dimethyl acetal was tested 4% in petrolatum in 25 human volunteers in 48 hours closed patch test. Citral dimethyl acetal was not irritating to human skin after 48 hours exposure.

The above results are also supported by the experimental study summarized in Food and Cosmetics Toxicology, Volume 13, Issue 6, 1975, Pages 685-686,diethyl acetal 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. Hence, diethyl acetal was considered not irritating to skin.

Based on the available data for the target as well as read across substances and applying the weight of evidence approach,citral diethyl acetal 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, citral diethyl acetal 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 closely related read across substances, diethyl ether [CAS: 60-29-7] and 6-methylhept-5-en-2-one [CAS: 110-93-0]. 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 for citral diethyl acetal.Citral diethyl acetalwas estimated to be not irritating to the eyes of Himalayan rabbits.

This result is supported by the experimental study summarized inThe MAK Collection for Occupational Health and Safety,150–160,2012; for the closely related read across substance, diethyl ether [CAS: 60-29-7].Rabbits were exposed to either liquid diethyl ether or its vapours and observed for signs of irritation (dose and duration not specified).Mild reversible irritation of the rabbit eye was observed after exposure to liquid diethyl ether or its vapour. Since the effects were reversible in nature, diethyl ether can be considered not irritating to rabbit eyes.

 

These results are further supported by the experimental study summarized in IUCLID DATASET, European Chemicals Bureau, last updated 2000; for the closely related read across substance, 6-methylhept-5-en-2-one [CAS: 110-93-0].6-methylhept-5-en-2-one was instilled into rabbit eyes and were observed for signs of irritation (dose and duration not specified).6 -methylhept-5-en-2-one was 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,citral diethyl acetal 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 citral diethyl acetal suggests that it is not likely to cause any irritation to skin and eyes.

Hence,citral diethyl acetal can be classified under the category “Not Classified” as per CLP regulation.