(2E)-2-methyl-3-phenylacrylaldehyde

Endpoint summary

Description of key information

Skin Irritation: In a reliable (Klimisch 1) study under the conditions of a Repeated Insult Patch Test (occlusive), alpha methyl cinnamaldehyde did not induce clinically meaningful irritation or show any evidence of induced allergic contact dermatitis in 75 human subjects.

Eye Irritation: In a study performed according to OECD Guideline 405, alpha methyl cinnamic aldehyde was 'Not irritating' to the eye (Frey-Tox GmbH, 1999).

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:

1 (reliable without restriction)

Qualifier:

according to guideline

Guideline:

other: This study was conducted in accordance with the intent and purpose of Good Clinical Practice regulations described in CFR 21, Part 50 (protection of Human Subjects - Informed Consent)

Principles of method if other than guideline:

Repeated Insult Patch Test (occlusive)

GLP compliance:

yes

Species:

human

Details on test animals or test system and environmental conditions:

One hundred and three (103) subjects, 73 females and 30 males, ranging in age from 18 to 69 years were empanelled for this test.

Type of coverage:

occlusive

Amount / concentration applied:

Approximately 0.3 m1 of the test articles were placed onto 25 mm Hill Top Chambers (occlusive) patch, which were applied to the back of each subject between the scapulae and waist, and to the left of the spinal mid-line.

Duration of treatment / exposure:

Induction Phase
Patches were applied every Monday, Wednesday and Friday until 9 applications of the
test article had been made.Subjects were instructed to return to the Testing Facility on Tuesday and
Thursday for supervised removal of patches applied on Monday and Wednesday. Patches applied on
Friday were removed by the test panelist approx. 24hrs after application.
The sites were scored just prior to the next patch application. Procedurally, if a
subject developed a positive reaction of 2-level (moderate) erythema or greater during the Induction phase
or, at the discretion of the Principal Investigator, if the skin response warranted a change in site, the patch
was applied to a previously unpatched, adjacent site for the next application. If a 2-level reaction (or
greater) occurred at the new site, no further applications were made. However, all reactive subjects were
subsequently Challenge patch tested
Challenge Phase
After a rest period of approx. 2 weeks (no applications of the test article), Challenge patches were
applied to previously unpatched test sites. The subjects returned to the Testing Facility 24 hours
later for supervised removal of the Challenge patches. The sites were scored 24, 48, and 72hrs after
application. A dermatologist was present at the 72-hour observation period [(except for Subj. Nos.: 26 and
30 who were unable to be seen by the dermatologist. Subj. Nos.: 81 and 98 were seen by the dermatologist
at the 48 hour evaluation due to starting the Challenge phase of the study 1 day later. In the opinion
of the Principal Investigator, the data for Subj. No.: 26, 30, 81 and 98 is considered useable for the
purposes of this study)]. All subjects were instructed to report any delayed skin reactivity that might have
occurred after the fmal Challenge patch reading. When warranted, selected test subjects were called back
to the Clinic for additional examinations and scoring to determine possible increases or deccreases in Challenge patch reactivity

Irritation parameter:

overall irritation score

Basis:

other: human subjects

Time point:

72 h

Remarks on result:

other: Test Article did not induce clinically meaningful irritation or show any evidence of induced allergic contact dermatitis in 75 human subjects.

Irritation parameter:

erythema score

Basis:

mean

Time point:

24/48/72 h

Remarks on result:

other: 24, 48, & 72 hour scores not specified

Irritation parameter:

edema score

Basis:

mean

Time point:

24/48/72 h

Remarks on result:

other: 24, 48, & 72 hour scores not specified

Seventy-five (75) subjects satisfactorily completed the test procedure. Twenty-seven (27) test panelists [Subj. Nos.: 7, 20, 21, 24, 25, 31, 34, 45, 47, 49,51,54,55,58,62,70,71,72,73,76,77,87,92,93, 100, 102 and 103] were discontinued for reasons unrelated to the conduct of the study. One (I) test panelist [Subj. No.: 64] was discontinued due to technician error. Discontinued panelists data are shown, up to the point of discontinuation, but are not used in the Results and Discussion or Conclusions sections of this final report.

Transient and non-transient, barely perceptible (+) to mild (I-level) non-specific patch test patch test irritant (non-cumulative) responses (occasionally accompanied by mild to moderate dryness, mild edema and scab formation) were observed on twenty-six (34.7% of the test population) test panelists [Subj. Nos.: 4, 8,11,15,17,18,19,29,36,37,39,40,41,43,50,69,79,80, 84, 86, 88, 91, 94, 96, 97 and 101] during the Induction and/or Challenge phases of the study. One test panelist [Subj. No.: 29] exhibited mild dryness with no observed erythema during the Challenge phase of the study. One test panelist [Subj. No.: 59] exhibited a mild papular response with no observed erythema during the Challenge phase of the study.

None of these responses were considered evidence of clinically meaningful irritation. Nor were they considered allergic in nature.

Interpretation of results:

not irritating

Remarks:

Criteria used for interpretation of results: expert judgment

Conclusions:

In a reliable (Klimisch 1) study under the conditions of a Repeated Insult Patch Test (occlusive), the Test Article did not induce clinically meaningful irritation or show any evidence of induced allergic contact dermatitis in 75 human subjects.
The test article Alpha methyl cinnamic aldehyde should not be labelled as R38 irritating to 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:

experimental study

Adequacy of study:

key study

Study period:

1999-08-30 to 1999-09-03

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 405 (Acute Eye Irritation / Corrosion)

Qualifier:

according to guideline

Guideline:

EU Method B.5 (Acute Toxicity: Eye Irritation / Corrosion)

GLP compliance:

yes (incl. QA statement)

Specific details on test material used for the study:

Test material was described with the generic name "methyl cinnamic aldehyde alpha". As manufactured by Innospec, the product met the criteria of > 80% trans-isomer, supporting that the test material was the isomer better described as CAS 15174-47-7.

Product Name: METHYLZIMTALDEHYD ALPHA
Batch No.: 8100051
Purity: 98.9%
Description of test article: slight yellowish, liquid
Stability: at least 1 year
Storage of test article: cool and dry

Species:

rabbit

Strain:

New Zealand White

Details on test animals or tissues and environmental conditions:

Four female SPF albino rabbits (2A - 2.6 kg b.w.)
The study took place in animal room No. 5 provided with filtered air at a temperature of 20°C ± 3°C, relative humidity of 55% + 15% and air changes 10 times/hour. The room was illuminated to give a cycle of 12 hours light and 12 hours darkness. Light was on from 06 to 18 h.

During a pre-period of at least one week and throughout the experiment the rabbits were caged individually in PPO cages (floor area: 2576 cm-) with perforated floor.

Diet: A pelleted complete rabbit diet "Mirnmin 2123" from Altromin, D-32791 Lage, Lippe, was available ad libitum. Analyses for major nutritive components and relevant possible contaminants are performed regularly on the diet.

Drinking Water: The animals had free access to bottles with domestic quality drinking watet acidified with hydrochloric acid to pH 2.5 in order to prevent microbial growth. Analyses for relevant possible contaminants are performed regularly.

Vehicle:

unchanged (no vehicle)

Controls:

yes, concurrent no treatment

Amount / concentration applied:

0.1 mL

Duration of treatment / exposure:

24 hours

Observation period (in vivo):

72 hours

Number of animals or in vitro replicates:

4

Details on study design:

The day before testing both eyes of the anirnals were examined with a hand held inspection lamp fitted with White and. UV-light and magnifying glass with 2 x magnification to ensure there were na defects or irritation. The examination was performed before and after instillation of Fluorescein.

Only the left eye was treated. The right eye remained untreated and served as control.

0.1 ml of the test article was placed in the left eye of the rabbits by gently pulling the lower lid away from the eyeball to form a cup into which the test article was dropped. The lids were then gently held together for 1 second.

The eyes were examined and the grade of ocular reaction was recorded one hour and 24 hours later. After the first 24 hour reading Fluorescein was instilled. After rinsing with 20 ml 0.9% sodiurn chloride solution the eyes were examined again using LTV-light to detect possible corneal damage. The eyes were also examined 48 and 72 hours after the treatment.

Irritation parameter:

cornea opacity score

Basis:

mean

Time point:

24/48/72 h

Score:

0

Max. score:

4

Irritation parameter:

iris score

Basis:

mean

Time point:

24/48/72 h

Score:

0.1

Max. score:

2

Reversibility:

fully reversible within: 72hours

Irritation parameter:

conjunctivae score

Basis:

mean

Time point:

24/48/72 h

Score:

0.3

Max. score:

3

Reversibility:

fully reversible within: 72hours

Irritation parameter:

chemosis score

Basis:

mean

Time point:

24/48/72 h

Score:

0

Max. score:

4

Irritant / corrosive response data:

One hour after application of the test article animal. No. 1543 and No. 1559 showed crimson red conjuctiva with individual vessels not easily discernible, some swelling of the conjunctiva above normal and some amount of discharge different from normal. Animal No. 1539 and No. 1544 showed conjunctival vessels definitely injected and some amount of discharge different from normal.

After 24 hours animal No. 1543 showed conjunctival vessels definitely injected, congestion and swelling of iris. Conjunctival vessels definitely injected were observed in animal No. 1559. Animal No. 1539 and No. 1544 were free of any signs of eye irritation.
After 48 hours animal No. 1559 showed conjunctival vessels definitely injected. Animal No. 1543 was free of any signs of eye irritation. It is possible that the reaction of the iris seen in animal No. 1543 24 hours after the application is due to wounding by the animal itself
After 72 hours animal No. 1559 was free of any signs of eye irritation.

Table 1. Scores for ocular lesions
Rabbit No./ Weight per Kg		1h	24 h	24 h F	48 h	72 h	Individual Mean Score*
1539 / 2.4	Cornea opacity, degree	0	0	0	0	0	0.00
	Cornea opacity, area	0	0	0	0	0
	Iris	0	0		0	0	0.00
	Conjunctiva Redness	1	0		0	0	0.00
	Conjunctiva Chemosis	0	0		0	0	0.00
	Conjunctiva Discharge	1	0		0	0
1543 / 2.1	Cornea opacity, degree	0	0	0	0	0	0.00
	Cornea opacity, area	0	0	0	0	0
	Iris	0	1		0	0	0.33
	Conjunctiva Redness	2	1		0	0	0.33
	Conjunctiva Chemosis	1	0		0	0	0.00
	Conjunctiva Discharge	1	0		0	0
1544 / 2.6	Cornea opacity, degree	0	0	0	0	0	0.00
	Cornea opacity, area	0	0	0	0	0
	Iris	0	0		0	0	0.00
	Conjunctiva Redness	1	0		0	0	0.00
	Conjunctiva Chemosis	0	0		0	0	0.00
	Conjunctiva Discharge	1	0		0	0
1559 / 2.2	Cornea opacity, degree	0	0	0	0	0	0.00
	Cornea opacity, area	0	0	0	0	0
	Iris	0	0		0	0	0.00
	Conjunctiva Redness	2	1		1	0	0.67
	Conjunctiva Chemosis	1	0		0	0	0.00
	Conjunctiva Discharge	1	0		0	0

F Reading after instillation of Fluorescein.

* Only the scores from the readings after 24, 48 and 72 hours are included in the calculation of the individual mean scores.

Interpretation of results:

other: Not irritating

Remarks:

Regulation (EC) No 1272/2008 on classification, labelling and packaging (CLP) of substances and mixtures

Conclusions:

Based on the results observed, methyl cinnamic aldehyde alpha is not considered to be an ocular irritant under EU Regulation (EC) No 1272/2008 on classification, labelling and packaging (CLP) of substances and mixtures.

Executive summary:

In a key Guideline (OECD 405) ocular irritation study, the eye irritant effect of the test material (Methyl cinnamic aldehyde alpha; CAS# 101-39-3) was investigated according to the method recommended in OECD Guideline No. 405, "Acute Eye Irritation/Corrosion", Feb. 1987, and EEC Guideline B5 "Acute Toxicity (Eye Irritation)", Jan. 1997.

 

Four female albino rabbits were exposed to 0,1 ml of the test material in the left eye. The eyes were examined and the changes were graded according to a numerical scale one hour, 24, 48 and 72 hours after dosing,

 

Slight signs of irritation were observed in the treated eyes. The mean 24-, 48-, and 72-hour readings for corneal opacity, iris lesion, redness of conjunctiva, and oedema were 0.0, 0.1, 0.3, and 0.0, respectively.

 

Based on the results observed, methyl cinnamic aldehyde alpha is not considered to be an ocular irritant under EU Regulation (EC) No 1272/2008 on classification, labelling and packaging (CLP) of substances and mixtures.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not irritating)

Respiratory irritation

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Skin Irritation

In a reliable (Klimisch 1) study under the conditions of a Repeated Insult Patch Test (occlusive), alpha methyl cinnamaldehyde did not induce clinically meaningful irritation or show any evidence of induced allergic contact dermatitis in 75 human subjects (RIFM, 2004).

Eye Irritation

In a key Guideline (OECD 405) ocular irritation study (Frey-Tox GmbH, 1999), the eye irritant effect of the test material (Methyl cinnamic aldehyde alpha; CAS# 101-39-3) was investigated according to the method recommended in OECD Guideline No. 405, "Acute Eye Irritation/Corrosion", Feb. 1987, and EEC Guideline B5 "Acute Toxicity (Eye Irritation)", Jan. 1997.

 

Four female albino rabbits were exposed to 0,1 ml of the test material in the left eye. The eyes were examined and the changes were graded according to a numerical scale one hour, 24, 48 and 72 hours after dosing,

 

Slight signs of irritation were observed in the treated eyes. The mean 24-, 48-, and 72-hour readings for corneal opacity, iris lesion, redness of conjunctiva, and oedema were 0.0, 0.1, 0.3, and 0.0, respectively.

 

Based on the results observed, methyl cinnamic aldehyde alpha is not considered to be an ocular irritant under EU Regulation (EC) No 1272/2008 on classification, labelling and packaging (CLP) of substances and mixtures.

Respiratory Irritation

There is no data in relation to respiratory tract irritation in humans or laboratory animals. However, due to its low skin and eye irritation potential, it is unlikely that alpha methylcinnamaldehyde would cause such an effect

Justification for classification or non-classification

Skin Irritation: Based on the results attained, according to the classification and labelling directives of the EEC commission, alpha methyl cinnamaldehyde, shall not be classified as irritating to the skin

Eye Irritation: Methyl cinnamic aldehyde alpha is not considered to be an ocular irritant under EU Regulation (EC) No 1272/2008 on classification, labelling and packaging (CLP) of substances and mixtures.