Cinnamonitrile

Endpoint summary

Description of key information

Skin irritation :

Cinnamyl nitrile was used as a test material to evaluate its skin irritation potential on human subjects by closed patch test.

It was applied in the concentration of 4% in petrolatum for 48 hrs in a closed patch test produced no skin reaction.

 Cinnamyl nitrile did not resulted any skin reaction when tested on human subjects. Hence, Cinnamyl nitrile can be considered as not irritation on human skin.

Eye irritation:

 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 forCinnamyl nitrile. It was estimated thatCinnamyl nitrilewas not irritating to eye of rabbits.

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:

To evaluate skin irritation potential of Cinnamonitrile on human subjects.

GLP compliance:

not specified

Specific details on test material used for the study:

IUPAC: Cinnamonitrile
CAS No:1885-38-7
EC No: 217-552-5
Commen name: Cinnamyl Nitrile
Molecular formula : C9H7N
Molecular weight : 129.161 g/mol
substance type: organic
InChI: 1S/C9H7N/c10-8-4-7-9-5-2-1-3-6-9/h1-7H/b7-4+
Smiles :N#C\C=C\c1ccccc1
Physical state: colorless- yellow liquid

Details on test system:

No data available

Species:

other: Human

Strain:

not specified

Details on test animals or test system and environmental conditions:

No data available

Type of coverage:

occlusive

Preparation of test site:

not specified

Vehicle:

other: petrolatum

Controls:

not specified

Amount / concentration applied:

4% in petrolatum

Duration of treatment / exposure:

48 hrs

Observation period:

48 hrs

Number of animals:

Not specified

Details on study design:

Not specified

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 dermal reaction was observed on human skin

Interpretation of results:

other: Not irritant

Conclusions:

Cinnamyl nitrile did not resulted any skin reaction when tested on human subjects. Hence, Cinnamyl nitrile can be considered as not irritation on human skin.

Executive summary:

Cinnamyl nitrile was used as a test material to evaluate its skin irritation potential on human subjects by closed patch test.

It was applied in the concentration of 4% in petrolatum for 48 hrs in a closed patch test produced no skin reaction.

 Cinnamyl nitrile did not resulted any skin reaction when tested on human subjects. Hence, Cinnamyl nitrile can be considered to be not irritation on human skin.

 

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 predicted using OECD QSAR toolbox version 3.3 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 v3.3

GLP compliance:

not specified

Specific details on test material used for the study:

- Name of the test material: (E)-3-phenylprop-2-enenitrile
- IUPAC name: (E)-3-phenylprop-2-enenitrile
- Molecular formula: C9H7N
- Molecular weight: 129.161 g/mol
- Substance type: Organic
- Smiles: N#C\C=C\c1ccccc1
Physical state: colorless- yellow liquid

Species:

rabbit

Strain:

not specified

Details on test animals or tissues and environmental conditions:

no data available

Vehicle:

not specified

Controls:

not specified

Amount / concentration applied:

not specified

Duration of treatment / exposure:

not specified

Observation period (in vivo):

not specified

Details on study design:

No data available

Irritation parameter:

overall irritation score

Basis:

mean

Reversibility:

not specified

Remarks on result:

no indication of irritation

Irritant / corrosive response data:

no indication of irritation.

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 ( not "f") )  )  and ("g" and ( not "h") )  )  and "i" )  and "j" )  and "k" )  and ("l" and ( not "m") )  )  and "n" )  and ("o" and ( not "p") )  )  and ("q" and ( not "r") )  )  and ("s" and ( not "t") )  )  and ("u" and ( not "v") )  )  and ("w" and ( not "x") )  )  and ("y" and ( not "z") )  )  and ("aa" and ( not "ab") )  )  and ("ac" and ( not "ad") )  )  and ("ae" and ( not "af") )  )  and ("ag" and ( not "ah") )  )  and ("ai" and ( not "aj") )  )  and ("ak" and "al" )  )

Domain logical expression index: "a"

Referential boundary: The target chemical should be classified as Alkene AND Aryl AND Nitrile by Organic Functional groups

Domain logical expression index: "b"

Referential boundary: The target chemical should be classified as Alkene AND Aryl AND Nitrile AND Overlapping groups by Organic Functional groups (nested)

Domain logical expression index: "c"

Referential boundary: The target chemical should be classified as Acetylenic Carbon [#C] AND Aromatic Carbon [C] AND Olefinic carbon [=CH- or =C<] by Organic functional groups (US EPA)

Domain logical expression index: "d"

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

Domain logical expression index: "e"

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

Domain logical expression index: "f"

Referential boundary: The target chemical should be classified as Acylation OR Acylation >> Direct Addition of an Acyl Halide OR Acylation >> Direct Addition of an Acyl Halide >> Acyl halide 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 Acylation >> P450 Mediated Activation to Isocyanates or Isothiocyanates >> Thioureas OR Michael addition OR Michael addition >> P450 Mediated Activation of Heterocyclic Ring Systems OR Michael addition >> P450 Mediated Activation of Heterocyclic Ring Systems >> Furans 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 >> P450 Mediated Activation to Quinones and Quinone-type Chemicals >> Methylenedioxyphenyl OR Michael addition >> P450 Mediated Activation to Quinones and Quinone-type Chemicals >> Polycyclic (PAHs) and heterocyclic (HACs) aromatic hydrocarbons-Michael addition OR Michael addition >> Polarised Alkenes-Michael addition 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 >> Chemicals Activated by P450 to Mono-aldehydes OR Schiff base formers >> Chemicals Activated by P450 to Mono-aldehydes >> Benzylamines-Schiff base OR Schiff base formers >> Direct Acting Schiff Base Formers OR Schiff base formers >> Direct Acting Schiff Base Formers >> Mono aldehydes OR SN1 OR SN1 >> Carbenium Ion Formation OR SN1 >> Carbenium Ion Formation >> Allyl benzenes OR SN1 >> Carbenium Ion Formation >> Polycyclic (PAHs) and heterocyclic (HACs) aromatic hydrocarbons-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 >> Primary aromatic amine OR SN1 >> Nitrenium Ion formation >> Secondary aromatic amine OR SN1 >> Nitrenium Ion formation >> Tertiary (unsaturated) heterocyclic amine  OR SN1 >> Nitrenium Ion formation >> Tertiary aromatic amine OR SN1 >> Nitrenium Ion formation >> Unsaturated heterocyclic azo OR SN2 OR SN2 >> Direct Acting Epoxides and related OR SN2 >> Direct Acting Epoxides and related >> Epoxides OR SN2 >> Episulfonium Ion Formation OR SN2 >> Episulfonium Ion Formation >> 1,2-Dihaloalkanes OR SN2 >> Episulfonium Ion Formation >> Mustards OR SN2 >> P450 Mediated Epoxidation OR SN2 >> P450 Mediated Epoxidation >> Coumarins OR SN2 >> P450 Mediated Epoxidation >> Thiophenes-SN2 OR SN2 >> P450 Mediated Sulfoxidation OR SN2 >> P450 Mediated Sulfoxidation >> Thioureas-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: "g"

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

Domain logical expression index: "h"

Referential boundary: The target chemical should be classified as Moderate binder, NH2 group OR Moderate binder, OH grooup OR Non binder, impaired OH or NH2 group OR Non binder, MW>500 OR Non binder, non cyclic structure OR Strong binder, NH2 group OR Strong binder, OH group OR Very strong binder, OH group OR Weak binder, NH2 group OR Weak binder, OH group by Estrogen Receptor Binding

Domain logical expression index: "i"

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

Domain logical expression index: "j"

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

Domain logical expression index: "k"

Similarity boundary:Target: N#CC=Cc1ccccc1
Threshold=20%,
Dice(Atom centered fragments)
Atom type; Count H attached; Hybridization

Domain logical expression index: "l"

Referential boundary: The target chemical should be classified as Alkene AND Aryl AND Nitrile by Organic Functional groups

Domain logical expression index: "m"

Referential boundary: The target chemical should be classified as Acetoxy OR Acid anhydride OR Acridone/ Acridinimine OR Acrylamide OR Acrylate OR Alcohol OR Aldehyde OR Aliphatic Amine, primary OR Aliphatic Amine, secondary OR Alkane, branched with tertiary carbon by Organic Functional groups

Domain logical expression index: "n"

Similarity boundary:Target: N#CC=Cc1ccccc1
Threshold=80%,
Dice(Atom centered fragments)
Atom type; Count H attached; Hybridization

Domain logical expression index: "o"

Referential boundary: The target chemical should be classified as No alert found by Respiratory sensitisation

Domain logical expression index: "p"

Referential boundary: The target chemical should be classified as Michael Addition OR Michael Addition >> Polarised alkenes OR Michael Addition >> Polarised alkenes >> Indigotine and related OR Pro-Michael Addition OR Pro-Michael Addition >> Pro-quinone and related OR Pro-Michael Addition >> Pro-quinone and related >> Phenylenediamines OR Pro-SN2 OR Pro-SN2 >> Pro-ring opening SN2 OR Pro-SN2 >> Pro-ring opening SN2 >> Vinyl benzenes OR Pro-SN2 >> Pro-SN2 at chlorine OR Pro-SN2 >> Pro-SN2 at chlorine >> N-Phenylacetamides by Respiratory sensitisation

Domain logical expression index: "q"

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

Domain logical expression index: "r"

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

Domain logical expression index: "s"

Referential boundary: The target chemical should be classified as Stable form by Tautomers unstable

Domain logical expression index: "t"

Referential boundary: The target chemical should be classified as Conjugated ketoamine(scy) - 1,5-H shift OR Imine - amine form(5-membered ring) - 1,3-H shift OR Imine form - 1,3-H shift OR Thiolactim form by Tautomers unstable

Domain logical expression index: "u"

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

Domain logical expression index: "v"

Referential boundary: The target chemical should be classified as 3-Methylcholantrene (Hepatotoxicity) Alert OR Aliphatic amines (Mucous membrane irritation) Rank C OR Allyl esters (Hepatotoxicity) Rank A OR Amineptine (Hepatotoxicity) Alert OR Aromatic hydrocarbons (Liver enzyme induction) Rank C OR Benzene/ Naphthalene sulfonic acids (Less susceptible) Rank C OR Benzenesulfonamides (Toxicity to urinary system) Rank B OR Organophosphates (Neurotoxicity) Rank A OR Phenyl phoshates (Lipodosis of adrenocortial) Rank C OR Phthalate esters (Testicular toxicity) Rank C OR Tamoxifen (Hepatotoxicity) Alert OR Thiocarbamates/Sulfides (Hepatotoxicity) No rank by Repeated dose (HESS)

Domain logical expression index: "w"

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

Domain logical expression index: "x"

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

Domain logical expression index: "y"

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

Domain logical expression index: "z"

Referential boundary: The target chemical should be classified as CO2 derivative (general) OR Cyanate OR Dialkylether by Organic functional groups, Norbert Haider (checkmol)

Domain logical expression index: "aa"

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

Domain logical expression index: "ab"

Referential boundary: The target chemical should be classified as Alkylarylether OR Amine OR Anion by Organic functional groups, Norbert Haider (checkmol)

Domain logical expression index: "ac"

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

Domain logical expression index: "ad"

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

Domain logical expression index: "ae"

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

Domain logical expression index: "af"

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

Domain logical expression index: "ag"

Referential boundary: The target chemical should be classified as Acetylenic Carbon [#C] AND Aromatic Carbon [C] AND Olefinic carbon [=CH- or =C<] by Organic functional groups (US EPA)

Domain logical expression index: "ah"

Referential boundary: The target chemical should be classified as Aliphatic Nitrogen, one aromatic attach [-N] by Organic functional groups (US EPA)

Domain logical expression index: "ai"

Referential boundary: The target chemical should be classified as Acetylenic Carbon [#C] AND Aromatic Carbon [C] AND Olefinic carbon [=CH- or =C<] by Organic functional groups (US EPA)

Domain logical expression index: "aj"

Referential boundary: The target chemical should be classified as Aromatic Nitrogen by Organic functional groups (US EPA)

Domain logical expression index: "ak"

Parametric boundary:The target chemical should have a value of log Kow which is >= 1.49

Domain logical expression index: "al"

Parametric boundary:The target chemical should have a value of log Kow which is <= 2.95

Interpretation of results:

other: Not irritating

Conclusions:

Cinnamyl nitrile is considered to be non irritant to rabbit eye.

Executive summary:

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 Cinnamyl nitrile. It was estimated that Cinnamyl nitrile was not irritating to eye of rabbits.

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, Cinnamonitrile 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 Cinnamonitrile and its structurally similar read across substance Cinnamyl formate (104-65-4).

Various studies forCinnamonitrilewere summarized in Food and Cosmetics Toxicology, Volume 12, Issues 7–8, December 1974, Page 897; to assess the dermal irritation potential in humans and rabbits.

Cinnamonitrileapplied at full strength to intact or abraded rabbit underocclusion caused slight o moderate irritation. Also, when tested on human subjects at 4% in petrolatum in a 48-hr closed-patch test,Cinnamonitrileproduced no irritation.

 

Even though rabbit study indicates thatCinnamyl nitrile  is slightly to moderately irritating to rabbit skin but human data concludes that it is not irritating to human skin. Since, in the rabbit study skin was exposed to higher concentration ofCinnamyl nitrilethan the normal use, there exists a possibility ofCinnamyl nitrilebeing of not irritating to rabbit skin at lower concentrations. So,Cinnamyl nitrilecan be considered to be not irritating to skin.

These experimental studies are also supported by the estimated data.

In a prediction done by SSS (2017) using the OECD QSAR toolbox with log kow as the primary descriptor, the dermal irritation potential was estimated for Cinnamyl nitrile. It was estimated that Cinnamyl nitrile was not irritating to skin of rabbits.

Skin irritation effects were also estimated by four different models i.e, Battery, Leadscope, SciQSAR and CASE Ultra used within Danish QSAR database forCinnamyl nitrile. Based on estimation, No severe skin irritation effects were known whenCinnamyl nitrilewas exposed to rabbit skin.

The experimental and estimated data are in agreement with each other; substantiate the claim thatCinnamyl nitrileis indeed not irritating to skin.

These results are further supported by the experimental study summarized inFood and Chemical Toxicology 45 (2007) S1–S23 for the structurally similar read across substance Cinnamyl formate (104-65-4). Cinnamyl formate was used as a test material for maximization pre-test to evaluate it’s skin irritation potential on 5 male volunteers . The test material was used in the concentration of 4% in petrolatum ,

No skin reactions were observed. Cinnamyl formate was considered to be not irritating 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 Cinnamyl nitrilewas not irritating to skin. Itcan be classified under the category “Not Classified” as per CLP regulation

 

 Eye irritation :

In different studies, Cinnamonitrile 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 human data for target chemical Cinnamonitrile and its structurally similar read across substances Cinnamyl formate (104-65-4) and Methyl cinnamate (103-26-4).

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 Cinnamyl nitrile. It was estimated that Cinnamyl nitrile was not irritating to eye of rabbits.

The above predicted data was supported by experimental study conducted by Food and Chemical Toxicology, 50 (2012) S402-S406 for the structurally similar read across substance Benzyl formate (104-57-4).

Benzyl formate (undiluted) was evaluated for eye irritation in four female SPF alibino rabbits. A dose volume of 0.1 ml was instilled into one eye. The untreated eye of each animal served as a control. 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 conjunctivawere diffuse, crimson red with individual vessels not easily discernible, swelling was 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 diffusely red; the individual vessels were not easily discernible and abnormal swelling was present. At 72 h after dosing, the conjunctival vessels were 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

 Benzyl formate when applied on the eye of SPF albino rabbits and observed for 7 days gave ocular reactions which were cleared by day 7. Hence , Benzyl formate is considered to be non eye irritant.

The above experimental data was further supported by study conducted by Food and Chemical Toxicology 45 (2007) S1–S23 for structurally similar read across substanceMethyl cinnamate (103-26-4).

Methyl cinnamate was used as test material for evaluating its eye irritation potential on rabbits

The test material was applied ocularly in the concentration 100% ,

No ocular reaction were observed . Hence, Methyl cinnamate can be considered non eye irritant on rabbit eye.

 Based on the available data for the target as well as it read across substances and applying weight of evidences,it can be concluded that Cinnamyl nitrile  was not irritating to eye; and itcan be classified under the category “Not Classified” as per CLP regulation.

Justification for classification or non-classification

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