2-benzylideneheptanal

Endpoint summary

Description of key information

Skin irritation:

A primary skin test of alpha-Amyl cinnamaldehyde (CAS No: 122-40-7) was carried out by mean of closed patch to examine the degree of skin irritancy caused by the chemical on 108 human subject. In this test, alpha-Amyl cinnamaldehydewas applied to the back, forearm and upper arm of 108 male/female humans in Japan under occlusive condition at a concentration of 0.05-0.5% 24–48 h and the sites evaluated 30 min after the patches were removed. Cream base or ethyl alcohol was used as a vehicle. Only 1 subject showed positive erythema while negative results were observed in remaining subjects (1/108). Thereforealpha-Amyl cinnamaldehyde (CAS No: 122-40-7)was considered to be non-irritant to the skin.

 

Eye irritation

The ocular irritation potential of alpha-Amyl cinnamaldehyde (CAS No: 122-40-7) was estimated using OECD QSAR toolbox version 3.3 with logPow as the primary descriptor. The test substance Alpha-Amyl cinnamaldehyde (CAS No: 122-40-7) was estimated to be not irritating into the eyes of Vienna White rabbits. Based on the estimated result alpha-Amyl cinnamaldehyde (CAS No: 122-40-7) can be considered to be not irritating to eye and can be classified under the category ˋ 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:

key study

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:

A primary skin test of alpha-Amyl cinnamaldehyde (CAS No: 122-40-7) was carried out by mean of closed patch to examine the degree of skin irritancy caused by the chemical on 108 human subjects.

GLP compliance:

not specified

Specific details on test material used for the study:

- Name of test material: (2E)-2-(phenylmethylidene)heptanal
- Molecular formula: C14H18O
- Molecular weight: 202.2952 g/mol
- Smiles notation: c1(\C=C(\CCCCC)C=O)ccccc1
- InChl: 1S/C14H18O/c1-2-3-5-10-14(12-15)11-13-8-6-4-7-9-13/h4,6-9,11-12H,2-3,5,10H2,1H3/b14-11-
- Substance type: Organic
- Physical state: Liquid

Species:

other: human

Strain:

other: not applicable

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Tokyo, Osaka
- Age at study initiation:16-45 yrs of age
- Weight at study initiation: No data available
- Fasting period before study: No data available
- Housing: No data available
- Diet (e.g. ad libitum): No data available
- Water (e.g. ad libitum): No data available
- Acclimation period: No data available


ENVIRONMENTAL CONDITIONS
- Temperature (°C): No data available
- Humidity (%): No data available
- Air changes (per hr): No data available
- Photoperiod (hrs dark / hrs light): No data available

IN-LIFE DATES: From: To: September 1963- December 1967

Type of coverage:

occlusive

Preparation of test site:

not specified

Vehicle:

other: Cream base or 99% ethyl alcohol

Controls:

yes

Amount / concentration applied:

0.05-0.5 %

Duration of treatment / exposure:

24-48 hrs

Observation period:

30mins after patch removal

Number of animals:

108 humans

Details on study design:

- Area of exposure: back, forearm (flexor) and upperarm (inside flexion side)
- % coverage: No data available
- Type of wrap if used: No data available

REMOVAL OF TEST SUBSTANCE
- Washing (if done): No data available
- Time after start of exposure: No data available

Irritation parameter:

overall irritation score

Basis:

mean

Time point:

24/48 h

Score:

1

Max. score:

108

Reversibility:

not specified

Remarks on result:

no indication of irritation

Remarks:

Only 1 subject showed positive erythema while negative results were observed in remaining subjects.

Irritant / corrosive response data:

Only 1 subject showed positive erythema while negative results were observed in remaining subjects.

Interpretation of results:

other: not irritating

Conclusions:

The test material alpha-Amyl cinnamaldehyde (CAS No: 122-40-7) when applied as a patch did not show any reaction.

This suggests alpha-Amyl cinnamaldehyde (CAS No: 122-40-7) to be non irritant to the skin.

Executive summary:

A primary skin test of alpha-Amyl cinnamaldehyde (CAS No: 122-40-7) was carried out by mean of closed patch to examine the degree of skin irritancy caused by the chemical on 108 human subject.

 

alpha-Amyl cinnamaldehydewas applied to the back, forearm and upper arm of 108 male/female humans in Japan under occlusive condition at a concentration of 0.05-0.5% 24–48 h and the sites evaluated 30 min after the patches were removed. Cream base or ethyl alcohol was used as a vehicle.

 

Only 1 subject showed positive erythema while negative results were observed in remaining subjects (1/108). Thereforealpha-Amyl cinnamaldehyde (CAS No: 122-40-7)was considered to be non-irritant to the 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 from 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 is done using QSAR Toolbox version 3.3

GLP compliance:

not specified

Specific details on test material used for the study:

- Name of test material: (2E)-2-(phenylmethylidene)heptanal
- Molecular formula: C14H18O
- Molecular weight: 202.2952 g/mol
- Smiles notation: c1(\C=C(\CCCCC)C=O)ccccc1
- InChl: 1S/C14H18O/c1-2-3-5-10-14(12-15)11-13-8-6-4-7-9-13/h4,6-9,11-12H,2-3,5,10H2,1H3/b14-11-
- Substance type: Organic
- Physical state: Liquid

Species:

rabbit

Strain:

Vienna White

Details on test animals or tissues and environmental conditions:

no data available

Vehicle:

not specified

Controls:

not specified

Amount / concentration applied:

0.1ml

Duration of treatment / exposure:

72 hours

Observation period (in vivo):

72 hours

Number of animals or in vitro replicates:

3

Details on study design:

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 eye irritation was observed in treated rabbits.

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 "n" )  )

Domain logical expression index: "a"

Referential boundary: The target chemical should be classified as Aldehydes (Acute toxicity) by US-EPA New Chemical Categories

Domain logical expression index: "b"

Referential boundary: The target chemical should be classified as AN2 AND AN2 >> Nucleophilic addition to alpha, beta-unsaturated carbonyl compounds AND AN2 >> Nucleophilic addition to alpha, beta-unsaturated carbonyl compounds >> alpha, beta-Unsaturated Aldehydes AND AN2 >> Schiff base formation AND AN2 >> Schiff base formation >> alpha, beta-Unsaturated Aldehydes by DNA binding by OASIS v.1.3

Domain logical expression index: "c"

Referential boundary: The target chemical should be classified as Low reactive AND Low reactive >> alpha-alkyl cinnamaldehyde derivatives by DPRA Cysteine peptide depletion

Domain logical expression index: "d"

Referential boundary: The target chemical should be classified as Michael Addition AND Michael Addition >> alpha,beta-Unsaturated carbonyl compounds AND Michael Addition >> alpha,beta-Unsaturated carbonyl compounds >> alpha,beta-Aldehydes  AND Schiff base formation AND Schiff base formation >> Schiff base formation with carbonyl compounds AND Schiff base formation >> Schiff base formation with carbonyl compounds >> Aldehydes by Protein binding by OASIS v1.3

Domain logical expression index: "e"

Referential boundary: The target chemical should be classified as Michael addition AND Michael addition >> Polarised Alkenes AND Michael addition >> Polarised Alkenes >> Polarised alkene - aldehydes AND Schiff Base Formers AND Schiff Base Formers >> Direct Acting Schiff Base Formers AND Schiff Base Formers >> Direct Acting Schiff Base Formers >> Mono-carbonyls by Protein binding by OECD

Domain logical expression index: "f"

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

Domain logical expression index: "g"

Referential boundary: The target chemical should be classified as Non binder, non cyclic structure OR Weak binder, OH group by Estrogen Receptor Binding

Domain logical expression index: "h"

Referential boundary: The target chemical should be classified as Michael Addition AND Michael Addition >> alpha,beta-Unsaturated carbonyl compounds AND Michael Addition >> alpha,beta-Unsaturated carbonyl compounds >> alpha,beta-Aldehydes  AND Schiff base formation AND Schiff base formation >> Schiff base formation with carbonyl compounds AND Schiff base formation >> Schiff base formation with carbonyl compounds >> Aldehydes by Protein binding by OASIS v1.3

Domain logical expression index: "i"

Referential boundary: The target chemical should be classified as No alert found OR SN2 OR SN2 >> Nucleophilic substitution at sp3 carbon atom OR SN2 >> Nucleophilic substitution at sp3 carbon atom >> Alkyl halides  by Protein binding by OASIS v1.3

Domain logical expression index: "j"

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

Domain logical expression index: "k"

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

Domain logical expression index: "l"

Similarity boundary:Target: CCCCCC(=Cc1ccccc1)C=O
Threshold=80%,
Dice(Atom centered fragments)
Atom type; Count H attached; Hybridization

Domain logical expression index: "m"

Parametric boundary:The target chemical should have a value of log Kow which is >= 3.28

Domain logical expression index: "n"

Parametric boundary:The target chemical should have a value of log Kow which is <= 4.83

Interpretation of results:

other: not irritating

Conclusions:

The test substance Alpha-Amyl cinnamaldehyde (CAS No: 122-40-7) was estimated to be not irritating into the eyes of Vienna White rabbits. Based on the estimated result alpha-Amyl cinnamaldehyde (CAS No: 122-40-7) can be considered to be not irritating to eye.

Executive summary:

The ocular irritation potential of alpha-Amyl cinnamaldehyde (CAS No: 122-40-7) was estimated using OECD QSAR toolbox version 3.3 with logPow as the primary descriptor. The test substance Alpha-Amyl cinnamaldehyde (CAS No: 122-40-7) was estimated to be not irritating into the eyes of Vienna White rabbits. Based on the estimated result alpha-Amyl cinnamaldehyde (CAS No: 122-40-7) can be considered to be not irritating to eye and can be classified under the category ˋ 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:

Various studieshas been investigated for the test chemicalalpha-Amyl cinnamaldehyde (CAS No: 122-40-7)to observe the potential for dermal irritation to a greater or lesser extent. The studies are based on in vivo experiments in rabbits, guinea pigs,miniature swineand humans for target chemical-Amyl cinnamaldehyde (CAS No: 122-40-7).The predicted data using the OECD QSAR toolbox has also been compared with the experimental data and summarized as below;

 

 

A primary skin test of alpha-Amyl cinnamaldehyde (CAS No: 122-40-7) was carried out by Toshio Takenaka, Eiko Hasegawa, Umeko Takenaka, Fumio Saito M. D. and Tazuko Odaka M. D. (1968)by mean of closed patch to examine the degree of skin irritancy caused by the chemical on 108 human subject. In this test, alpha-Amyl cinnamaldehydewas applied to the back, forearm and upper arm of 108 male/female humans in Japan under occlusive condition at a concentration of 0.05-0.5% 24–48 h and the sites evaluated 30 min after the patches were removed. Cream base or ethyl alcohol was used as a vehicle. Only 1 subject showed positive erythema while negative results were observed in remaining subjects (1/108). Thereforealpha-Amyl cinnamaldehyde (CAS No: 122-40-7)was considered to be non-irritant to the skin.

 

 

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 chemicalalpha-Amyl cinnamaldehyde (CAS No: 122-40-7).The chemical alpha-Amyl cinnamaldehyde (CAS No: 122-40-7) is estimated to be not irritating tothe skin of Japanese white strain rabbits.

 

The MAK Collection for Occupational Health and Safety (2014) carried out skin irritation studies on miniature swineand humans as follows;

The undiluted alpha -amylcinnamaldehyde did not lead to irritation in the miniature swine when applied under occlusive application for 48 hours.

The human study of alpha-Amyl cinnamaldehyde (CAS No: 122-40-7) was conducted on 50 volunteers.In this study, the test chemical was applied to the skin of each subject for the 48 hours under occlusion and then observed for skin reactions.None of the 50 subjects showed known signs of skin irritation. Hence thealpha-Amyl cinnamaldehyde (CAS No: 122-40-7)was considered to be non irritant to the skin of50 volunteers.

 

 

Another skin irritation study of alpha-Amyl cinnamaldehyde (CAS No: 122-40-7) was reported by NTRL (1991) to determine the degree of irritation the material may produce when applied to the clipped intact and abraded skin of rabbits. On the day prior to the experiment 10% of the total body area or the rabbits was carefully dipped free of hair. Small animal clippers were used since these left the skin undisturbed. On the posterior of the clipped area several minor abrasions were made so as to penetrate the stratum corneum but Dot disturb the derma. This was to prevent bleeding. About 0.5 ml of the chemical was applied to the intact and abraded skin over the 2 x 2 patch area covered with Webril patches and the entire experimental area was covered with surgical tape for 24 hours. Skin reactions were evaluated at 48 and 72 hours according to Draize method. Since the chemical did not induce skin irritating effects when applied to the clipped intact and abraded skin of rabbits. Hencethe test materialalpha-Amyl cinnamaldehyde (CAS No: 122-40-7) was considered as not irritating.

 

The MAK Collection for Occupational Health and Safety (2014) carried out another skin irritation studies onrabbits and guinea pigs.The undiluted alpha -amylcinnamaldehyde was observed to be strongly and moderately irritative in rabbits and guinea pigs, respectively, after repeated occlusive application for 24 hours.

 

The last study of alpha-Amyl cinnamaldehyde (CAS No: 122-40-7) was again reported by NTRL (1991) which followed the similar procedure as mentioned in previous NTRL REPORT but the chemical induce mild skin irritating effects. Hencethe test materialalpha-Amyl cinnamaldehyde (CAS No: 122-40-7) was considered as mild primary irritant when applied to the clipped intact and abraded skin of rabbits.

 

Although positive skin reactions observed in few references but on the basis of available dataand majority of results obtained in various studies, the chemical alpha-Amyl cinnamaldehyde (CAS No: 122-40-7) can considered as not irritating.Comparing the above annotations with the criteria of CLP regulation, it can be classified under the category “Not Classified”.

 

 

Eye irritation:

In different studies,the test chemicalalpha-Amyl cinnamaldehyde (CAS No: 122-40-7) has been investigated for potential for ocular irritationto a greater or lesser extent. The studies are based on in vivo experiments in rabbits for target chemicalalpha-Amyl cinnamaldehyde (CAS No: 122-40-7)its structurally similar read across substancesLilial (CAS No: 80-54-6)andHexyl cinnamic aldehyde (CAS No: 101-86-0).The predicted data using the OECD QSAR toolbox has also been compared with the experimental data and summarized as below;

 

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 test chemical alpha-Amyl cinnamaldehyde (CAS No: 122-40-7).The chemicalalpha-Amyl cinnamaldehyde (CAS No: 122-40-7)is estimated to be not irritating to eyeof Vienna White rabbits.

 

NTRL (1991) reported two eye irritation studies of alpha-Amyl cinnamaldehyde (CAS No: 122-40-7) to determine if the test material produces any irritation when instilled into rabbits' eyes.

In the first study, about 0.1ml ml of chemical was installed into the right of each albino rabbits while the other untreated eye served as control. The eyes were evaluated every twenty-four hours for tour days and then again on the seventh day. The Installation of chemical did not produce any ocular lesions. Hence the chemical alpha-Amyl cinnamaldehyde (CAS No: 122-40-7) was considered as not irritating to the eyes of each rabbits.

The next study followed the similar procedure as mentioned in above test. The Installation of chemical produced a conjunctival irritation with corneal involvement which did not clear on the seventh day of observation period. Hence the chemical alpha-Amyl cinnamaldehyde (CAS No: 122-40-7) was considered as considered as irritating to the eyes of each rabbits.

 

The above results were further supported by experimental studies conducted by INVENTORY MULTITIERED ASSESSMENT AND PRIORITISATION (IMAP) NICNAS (2017) on twostructurally similar read across substancesLilial (CAS No: 80-54-6)andHexyl cinnamic aldehyde (CAS No: 101-86-0).

An eye irritation study of chemical Lilial (CAS No: 80-54-6) was conducted in three Vienna white rabbits. Each rabbit received undiluted chemical into one of the eye and then observed for ocular lesions. Slight redness in all animals was observed within 24 hours. Redness persisted in one rabbit 48 hours after instillation and disappeared by 72 hours after exposure. No other effects were observed (mean scores for cornea, iris and chemosis were 0).Hence the chemicala Lilial (CAS No: 80-54-6) was considered as not irritating to the eye of each of three Vienna White rabbits.

In case of chemical Hexyl cinnamic aldehyde (CAS No: 101-86-0) an ocular test was performed in three male New Zealand White rabbits according to the EU Method B.5. The undiluted (0.1ml) of chemical was installed into the conjunctival sac of left eye of each rabbit. Observations were made for seven days. Slight conjunctival redness was observed and was reversed in two days. ThereforeTheHexyl cinnamic aldehyde (CAS No: 101-86-0) was considered as not irritating to the eye of each of three New Zealand White rabbits.

 

 

Although positive eye reaction was observed in one study but on the basis of available data fortarget chemicalalpha-Amyl cinnamaldehyde (CAS No: 122-40-7)its structurally similar read across substancesLilial (CAS No: 80-54-6)andHexyl cinnamic aldehyde (CAS No: 101-86-0),it can be concluded thatchemical alpha-Amyl cinnamaldehyde (CAS No: 122-40-7) is unable to cause skin irritation and considered as not irritating.Comparing the above annotations with the criteria of CLP regulation, it can be classified under the category “Not Classified”.

Justification for classification or non-classification

The skin and eye irritation potential of test chemicalalpha-Amyl cinnamaldehyde (CAS No: 122-40-7)were observed in various studies. The results obtained from these studies indicate that the chemicalalpha-Amyl cinnamaldehydeis unlikely to cause skin and eye irritation. Hencealpha-Amyl cinnamaldehyde (CAS No: 122-40-7)can be classified under the category “Not Classified” for skin and eye as per CLP.