Registration Dossier

Skin irritation:

The dermal irritation potential of test chemical was estimated using OECD QSAR toolbox v3.4 with logPow as the primary descriptor.

Test chemical was estimated to be not irritating to the skin of rabbits. Based on the estimated results, test chemical can be considered not irritating to skin and can be classified under the category“Not Classified”as per CLP regulation.

Eye Irritation:

Various studies were performed on rabbits to assess the ocular irritation potential of test chemical which have been summarized as follows:

An eye irritation test was conducted in rabbits for test chemical toassess the eye irritation potential.During the study, approx. 56 mg of test chemical was instilled into the eyes of each rabbitandanimalswere observed for ocular lesions.The test chemical caused inflammation, mucous secretion, and clouding of the cornea which was reversible within40 to 64 days.

Although the effects were reversible butbased on the observed ocular lesions it was considered as irritating to eyes of the treated rabbits.

In next eye irritation study, test was conducted in rabbits for test chemical to assess the eye irritation potential.The test chemical caused slight oedema of the conjunctivae after instillation of 0.001- 0.002 mL of undiluted chemical to the eyes of 15 male rabbits.Therefore, the test chemical was considered as irritating to the rabbits’ eye.

The results obtained from these studies lead to a conclusion that Test chemical is indeed irritating to eye. Hence, comparing the above annotations with the criteria of CLP regulation, Test chemical can be classified under the category “ Category 2 (irritating to eyes)”.

Reference

Endpoint:

skin 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 predicted using OECD QSAR toolbox version 3.4 and QMRF report has been attached.

Qualifier:

according to guideline

Guideline:

other: estimated data

Principles of method if other than guideline:

Prediction was done by using OECD QSAR toolbox v3.4

GLP compliance:

not specified

Species:

rabbit

Strain:

not specified

Details on test animals or test system and environmental conditions:

No data available

Type of coverage:

semiocclusive

Preparation of test site:

not specified

Vehicle:

not specified

Controls:

not specified

Amount / concentration applied:

Not specified

Duration of treatment / exposure:

24 hrs

Observation period:

48 hrs

Number of animals:

Not specified

Details on study design:

No data available

Irritation parameter:

overall irritation score

Basis:

mean

Time point:

48 h

Reversibility:

not specified

Remarks on result:

no indication of irritation

Irritant / corrosive response data:

No skin reactions were observed.

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

((((((((((("a" and ("b" and ( not "c") ) ) and ("d" and ( not "e") ) ) and ("f" and ( not "g") ) ) and "h" ) and ("i" and ( not "j") ) ) and ("k" and ( not "l") ) ) and "m" ) and "n" ) and "o" ) and "p" ) and ("q" and "r" ) )

Domain logical expression index: "a"

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

Domain logical expression index: "b"

Referential boundary: The target chemical should be classified as No alert found by DNA binding by OASIS v.1.4

Domain logical expression index: "c"

Referential boundary: The target chemical should be classified as AN2 OR AN2 >> Michael-type addition, quinoid structures OR AN2 >> Michael-type addition, quinoid structures >> Quinone methides OR AN2 >> Michael-type conjugate addition to activated alkene derivatives OR AN2 >> Michael-type conjugate addition to activated alkene derivatives >> Alpha-Beta Conjugated Alkene Derivatives with Geminal Electron-Withdrawing Groups 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 Non-covalent interaction OR Non-covalent interaction >> DNA intercalation OR Non-covalent interaction >> DNA intercalation >> Polycyclic Aromatic Hydrocarbon and Naphthalenediimide Derivatives OR Radical OR Radical >> ROS formation after GSH depletion OR Radical >> ROS formation after GSH depletion >> Quinone methides OR SN1 OR SN1 >> Alkylation after metabolically formed carbenium ion species OR SN1 >> Alkylation after metabolically formed carbenium ion species >> Polycyclic Aromatic Hydrocarbon and Naphthalenediimide Derivatives OR SN2 OR SN2 >> Alkylation, direct acting epoxides and related after P450-mediated metabolic activation OR SN2 >> Alkylation, direct acting epoxides and related after P450-mediated metabolic activation >> Polycyclic Aromatic Hydrocarbon and Naphthalenediimide Derivatives OR SN2 >> Direct acting epoxides formed after metabolic activation OR SN2 >> Direct acting epoxides formed after metabolic activation >> Quinoline Derivatives OR SN2 >> SN2 at an activated carbon atom OR SN2 >> SN2 at an activated carbon atom >> Quinoline Derivatives by DNA binding by OASIS v.1.4

Domain logical expression index: "d"

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

Domain logical expression index: "e"

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: "f"

Referential boundary: The target chemical should be classified as No alert found by Protein binding by OASIS v1.4

Domain logical expression index: "g"

Referential boundary: The target chemical should be classified as Acylation OR Acylation >> Acylation involving an activated (glucuronidated) carboxamide group OR Acylation >> Acylation involving an activated (glucuronidated) carboxamide group >> Carboxylic Acid Amides OR Acylation >> Direct acylation involving a leaving group OR Acylation >> Direct acylation involving a leaving group >> Carboxylic Acid Amides OR Acylation >> Ester aminolysis OR Acylation >> Ester aminolysis >> Amides OR AN2 OR AN2 >> Michael addition to activated double bonds OR AN2 >> Michael addition to activated double bonds >> alpha,beta-Unsaturated Carbonyls and Related Compounds OR AN2 >> Michael addition to alpha, beta-unsaturated acids and esters OR AN2 >> Michael addition to alpha, beta-unsaturated acids and esters >> alpha,beta-Unsaturated Carboxylic Acids and Esters OR AN2 >> Michael-type addition to activated double bonds in vinyl pyridines OR AN2 >> Michael-type addition to activated double bonds in vinyl pyridines >> Ethenyl Pyridines OR AN2 >> Michael-type addition to quinoid structures OR AN2 >> Michael-type addition to quinoid structures >> Carboxylic Acid Amides OR AN2 >> Nucleophilic addition to pyridonimine tautomer of aminopyridoindoles or aminopyridoimidazoles (hypothesized) OR AN2 >> Nucleophilic addition to pyridonimine tautomer of aminopyridoindoles or aminopyridoimidazoles (hypothesized) >> Heterocyclic Aromatic Amines OR Michael addition OR Michael addition >> Michael addition on alpha,beta-Unsaturated carbonyl compounds OR Michael addition >> Michael addition on alpha,beta-Unsaturated carbonyl compounds >> alpha,beta-Aldehydes OR Michael addition >> Michael addition on conjugated systems with electron withdrawing group OR Michael addition >> Michael addition on conjugated systems with electron withdrawing group >> alpha,beta-Carbonyl compounds with polarized double bonds OR Michael addition >> Michael addition on conjugated systems with electron withdrawing group >> Conjugated systems with electron withdrawing groups OR Michael addition >> Michael addition on conjugated systems with electron withdrawing group >> Cyanoalkenes OR Michael addition >> Michael addition on polarised Alkenes OR Michael addition >> Michael addition on polarised Alkenes >> Polarised Alkene - alkenyl pyridines, pyrazines, pyrimidines or triazines OR Nucleophilic addition OR Nucleophilic addition >> Addition to carbon-hetero double bonds OR Nucleophilic addition >> Addition to carbon-hetero double bonds >> Ketones OR Radical reactions OR Radical reactions >> ROS generation and direct attack of hydroxyl radical to the C8 position of nucleoside base OR Radical reactions >> ROS generation and direct attack of hydroxyl radical to the C8 position of nucleoside base >> Heterocyclic Aromatic Amines OR Schiff base formation OR Schiff base formation >> Schiff base formation with carbonyl compounds OR Schiff base formation >> Schiff base formation with carbonyl compounds >> Aldehydes OR SE reaction (CYP450-activated heterocyclic amines) OR SE reaction (CYP450-activated heterocyclic amines) >> Direct attack of arylnitrenium cation to the C8 position of nucleoside base OR SE reaction (CYP450-activated heterocyclic amines) >> Direct attack of arylnitrenium cation to the C8 position of nucleoside base >> Heterocyclic Aromatic Amines OR SN2 OR SN2 >> SN2 Reaction at a sp3 carbon atom OR SN2 >> SN2 Reaction at a sp3 carbon atom >> Activated alkyl esters and thioesters OR SR reaction (peroxidase-activated heterocyclic amines) OR SR reaction (peroxidase-activated heterocyclic amines) >> Direct attack of arylnitrenium radical to the C8 position of nucleoside base OR SR reaction (peroxidase-activated heterocyclic amines) >> Direct attack of arylnitrenium radical to the C8 position of nucleoside base >> Heterocyclic Aromatic Amines by Protein binding by OASIS v1.4

Domain logical expression index: "h"

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

Domain logical expression index: "i"

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

Domain logical expression index: "j"

Referential boundary: The target chemical should be classified as Halogens OR Metalloids by Groups of elements

Domain logical expression index: "k"

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

Domain logical expression index: "l"

Referential boundary: The target chemical should be classified as 3-Methylcholantrene (Hepatotoxicity) Alert OR Aliphatic amines (Mucous membrane irritation) Rank C OR Amineptine (Hepatotoxicity) Alert OR Aromatic hydrocarbons (Liver enzyme induction) Rank C OR Chlorphentermine (Hepatotoxicity) Alert OR Tamoxifen (Hepatotoxicity) Alert OR Thiocarbamates/Sulfides (Hepatotoxicity) No rank by Repeated dose (HESS)

Domain logical expression index: "m"

Referential boundary: The target chemical should be classified as 2-Alkoxy-2-propenoic acid deriv. [C=C(COOH)-O-C] AND Alcohol, olefinic attach [-OH] AND Aromatic Oxygen AND Carbonyl, olefinic attach [-C(=O)-] AND Miscellaneous sulfide (=S) or oxide (=O) AND Olefinic carbon [=CH- or =C<] AND Oxygen, two olefinic attach [-O-] by Organic functional groups (US EPA) ONLY

Domain logical expression index: "n"

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

Domain logical expression index: "o"

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

Domain logical expression index: "p"

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

Domain logical expression index: "q"

Parametric boundary:The target chemical should have a value of log Kow which is >= 0.639

Domain logical expression index: "r"

Parametric boundary:The target chemical should have a value of log Kow which is <= 1.17

Interpretation of results:

other: Not irritating

Conclusions:

Test chemical was considerd to be not irritating on rabbit skin.

Executive summary:

The dermal irritation potential of test chemical was estimated using OECD QSAR toolbox v3.4 with logPow as the primary descriptor.

Test chemical was estimated to be not irritating to the skin of rabbits. Based on the estimated results, test chemical can be considered not irritating to skin and can be classified under the category “Not Classified” as per CLP regulation.

Endpoint conclusion:

no adverse effect observed (not irritating)

Endpoint conclusion:

adverse effect observed (irritating)

Endpoint conclusion:

no study available

Skin irritation:

In different studies, test chemical has been investigated for potential for dermal irritation to a greater or lesser extent. The studies are based on in vivo and in vitro experiments in rabbits along with human data for target chemical and for its functionally similar read across substances with logKow as the primary descriptor. 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 skin irritation potential was estimated for test chemical. It was estimated that test chemical was not irritating to skin of New Zealand White rabbits.

The above data was supported by another study.In a preliminary study to a maximization test, a 10% concentration of test chemical in petrolatum was applied under occlusion for 48 h to the back of 5 healthy male patients. There was no irritation observed.

The above results are further supported by the experimental data in which occluded patch test was conducted on 4737 human volunteers to assess the irritation of test chemical (in a non perfumed base cream).The total number of Japanese human volunteers for the study were 4737 (2341 male, 2396 females).The test chemical was applied in a non perfumed base cream under occlusion and effects were observed (concentration and duration not specified). No visible reactions to the test substance were observed.

Hence, Test chemical can be considered not irritating to skin.

The dermal irritation potential of test article was determined according to the OECD 439 test guideline for this study. The MatTek EpiDerm™ model was used to assess the potential dermal irritation of the test article by determining the viability of the tissues following exposure to the test article via MTT. Tissues were exposed to the test article and controls for ~one hour, followed by a 42 hour post-exposure recovery period. The viability of each tissue was determined by MTT assay.The MTT data show the assay quality controls were met and passed the acceptance of criteria.The mean of OD for test chemical was determined to be 1.880 and 0.159 for 3 min. enpoint and 1 hour endpoint,respectively. The Mean % tissue viability compared to negative control (n=3) of the test chemical was determined to be 99.1% and 8.8% for 3 min. enpoint and 1 hour endpoint,respectively.Hence, under the current experimental test conditions it was concluded that test chemical was considered to be corrosive to human skin.

Based on the available data for the target as well as it read across substances and applying the weight of evidence approach,it can be concluded that test chemical was not irritating to skin and it can be classified under the category “Not Classified” as per CLP regulation.

Eye Irritation:

Various studies were performed on rabbits to assess the ocular irritation potential of test chemical which have been summarized as follows:

An eye irritation test was conducted in rabbits for test chemical toassess the eye irritation potential.During the study, approx. 56 mg of test chemical was instilled into the eyes of each rabbit and animals were observed for ocular lesions.The test chemical caused inflammation, mucous secretion, and clouding of the cornea which was reversible within40 to 64 days.Although the effects were reversible but based on the observed ocular lesions it was considered as irritating to eyes of the treated rabbits.

In next eye irritation study, test was conducted in rabbits for test chemical to assess the eye irritation potential.The test chemical caused slight oedema of the conjunctivae after instillation of 0.001- 0.002 mL of undiluted chemical to the eyes of 15 male rabbits.Therefore, the test chemical was considered as irritating to the rabbits’ eye.

The results obtained from these studies lead to a conclusion that Test chemical is indeed irritating to eye. Hence, comparing the above annotations with the criteria of CLP regulation, Test chemical can be classified under the category “ Category 2 (irritating to eyes)”.

On the basis of available information,test chemical is not likely to cause irritation to skin while likely to cause irritation to eyes. Hence, test chemical can be evaluated as Not Irritating to skin while irritating to eyes and can be classified under the category “Not Classified” as for skin irritation and "Category 2 (irritating to eyes)" for eye irritation as per CLP regulation.