4-trans-(4-trans-Propylcyclohexyl)-cyclohexancarbonic acid

Endpoint summary

Description of key information

The test item did not induce significant or irreversible damage to the rabbit skin and eye and is considered to be "not irritating" to rabbit skin and eye (reference 7.3.1-1 and 7.3.2-1).

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

Study period:

2002-01-22 to 2002-02-04

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 404 (Acute Dermal Irritation / Corrosion)

Version / remarks:

07-1992

Deviations:

no

Qualifier:

according to guideline

Guideline:

EU Method B.4 (Acute Toxicity: Dermal Irritation / Corrosion)

Version / remarks:

07-1992

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Species:

rabbit

Strain:

New Zealand White

Remarks:

SPF

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Elevage Scientifique des Dombes, F-01400 Chatillon sur Chalaronne, France
- Age at study initiation: 12 weeks (males) and 10-11 weeks (females)
- Weight at study initiation: 2.16 - 2.4 kg
- Housing: Individually in stainless steel cages equipped with feed hoppers, drinking water bowls, with wood, and haysticks for gnawing
- Diet: ad libitum
- Water: ad libitum

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 17 - 23
- Humidity (%): 30 - 70
- Photoperiod (hrs dark / hrs light): 12 / 12

IN-LIFE DATES: Days 1 to 7

Type of coverage:

semiocclusive

Preparation of test site:

clipped

Vehicle:

water

Remarks:

Before application, the test material was moistened with 0.1 mL of purified water

Controls:

not required

Amount / concentration applied:

TEST MATERIAL
- Amount applied: 500 mg

VEHICLE
Name: purified water

Duration of treatment / exposure:

4 hours

Observation period:

7 days

Number of animals:

2 females and 1 male

Details on study design:

TEST SITE
Four days before treatment, one flank was clipped. The skin of the animals was examined one day before treatment, and regrown fur of all animals was again clipped. Animals with overt signs of skin injury or marked irritation which may have interfered with the interpretation of the results were not used in the test. On the day of treatment, 500 mg of the test item was placed on a surgical gauze patch, which was applied to the intact skin of the clipped area. The patch was covered with a semi-occlusive dressing. The dressing was wrapped around the abdomen and anchored with tape.

REMOVAL OF TEST SUBSTANCE
The duration of treatment was 4 hours. Then the dressing was removed and the skin was flushed with lukewarm tap water to clean the application site so that any reactions (erythema) were clearly visible at that time.

OBSERVATION TIME POINTS
1 hour after removal, after 24, 48, 72 hours, and then daily up to experimental day 7.
Viability/Mortality/Clinical signs: Daily from delivery of the animals to the termination of test.
Body weights: At start of acclimatization, on the day of application and at termination of observation.
Necropsy: Not performed as animals were sacrificed at termination of observation.

SCORING SYSTEM: The skin reaction was assessed according to the numerical scoring system
(Erythema: 0= no erythema, 1= very slight erythema, 2= well defined erythema, 3= moderate to severe erythema, 4= severe erythema. Edema: 0= no edema, 1= very slight edema, 2= slight edema, 3= moderate edema, 4= severe erythema) listed in the EU Regulation (EC) No 1272/2008 (CLP), as amended for fifteenth time in Regulation (EU) No 2020/217, approximately 1, 24, 48 and 72 hours, as well as 7 days after the removal of the dressing, gauze patch and test item.

Irritation parameter:

erythema score

Basis:

mean

Time point:

24/48/72 h

Score:

0

Max. score:

4

Reversibility:

other: no effect

Remarks on result:

no indication of irritation

Irritation parameter:

edema score

Basis:

mean

Time point:

24/48/72 h

Score:

0

Max. score:

4

Reversibility:

other: no effect

Remarks on result:

no indication of irritation

Irritant / corrosive response data:

No skin irritating potential could be detected.

Other effects:

- pH measurements: Prior to the application, the pH of the test item was determined at a concentration of 1% in water with a pH test strip (E. Merck, D-64271 Darmstadt / Germany). The pH was found to be 5.

- Other adverse local effects: Very slight erythema was observed at the test site of two animals 1 hour after treatment (table 1). The test item did not, however, elicit any signs of irritation at the application site of any animal at the 24-, 48-, 72-hour or 7-day readings. The mean values from 24 to 72 hours were, therefore, 0 for erythema and 0 for edema (table 2).

Table 1: Skin irritation scores – individual values

Animal Number	Sex	Evaluation Interval	Erythema	Edema
55	M	1 hour	1	0
56	F		1	0
57	F		0	0
55	M	24 hours	0	0
56	F		0	0
57	F		0	0
55	M	48 hours	0	0
56	F		0	0
57	F		0	0
55	M	72 hours	0	0
56	F		0	0
57	F		0	0
55	M	7 days	0	0
56	F		0	0
57	F		0	0

M= Male

F=Female

 

Table 2: Skin irritation scores – individual mean values after 24, 48 and 72 hours

Animal Number	Sex	Erythema	n	Edema	n
55	M	0	3	0	3
56	F	0	3	0	3
57	F	0	3	0	3

n= number of available data points

Interpretation of results:

GHS criteria not met

Conclusions:

The test item did not induce significant or irreversible damage to the rabbit skin and is considered to be "not irritating" to rabbit skin.

Executive summary:

The primary skin irritation potential of the test item was investigated by topical semi-occlusive application of 0.5 g to the intact left flank of each of three young adult New Zealand White rabbits. The duration of treatment was four hours. The scoring of skin reactions was performed 1, 24, 48, 72 as well as 7 days after removal of the dressing. The application of the test item caused very slight erythema at the test site of two animals 1 hour after treatment. The test item did not, however, elicit any signs of irritation at the application site of any animal at the 24-, 48-, 72- hour or 7-day readings. The mean values from 24 to 72 hours were, therefore, 0 for erythema and 0 for edema. The test item caused no staining of the treated skin. No corrosive effects were noted on the treated skin of any animal at any measuring interval. Thus, the test item did not induce significant or irreversible damage to the rabbit skin. Based upon the referred classification criteria (EU Regulation (EC) No 1272/2008 (CLP), as amended for fifteenth time in Regulation (EU) No 2020/217), the test item is considered to be "not irritating" to rabbit 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:

2002-02-12 to 2002-02-25

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 405 (Acute Eye Irritation / Corrosion)

Version / remarks:

02-1987

Deviations:

no

Qualifier:

according to guideline

Guideline:

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

Version / remarks:

07-1992

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Species:

rabbit

Strain:

New Zealand White

Remarks:

SPF

Details on test animals or tissues and environmental conditions:

TEST ANIMALS
- Source: Elevage Scientifique des Dombes, F-01400 Chatillon sur Chalaronne, France
- Age at study initiation: 11 weeks (male) and 8-9 weeks (female)
- Weight at study initiation: 2.21 - 2.47 kg
- Housing: Individually in stainless steel cages equipped with feed hoppers, drinking water bowls, with wood, and haysticks for gnawing
- Diet: ad libitum
- Water: ad libitum

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 17 - 23
- Humidity (%): 30 - 70
- Photoperiod (hrs dark / hrs light): 12 / 12

IN-LIFE DATES: Days 1 to 7

Vehicle:

unchanged (no vehicle)

Controls:

yes, concurrent no treatment

Amount / concentration applied:

A single application of 100 mg into the conjunctival sac of the left eye

Duration of treatment / exposure:

Single exposure

Observation period (in vivo):

7 days;

Viability/mortality: daily from delivery of the animals to the termination of the test;

Clinical signs: Daily from delivery of the animals to the termination of the test;

Body weights: At start of acclimatization, on the day of application and at termination of observation;

Irritation scores: 1, 24, 48, and 72 hours, as well as 7 days after treatment

Number of animals or in vitro replicates:

2 females and 1 male

Details on study design:

REMOVAL OF TEST SUBSTANCE
- Washing: The treated eyes were not rinsed after instillation
- Time after start of exposure: 7 days

SCORING SYSTEM: The occular reaction was assessed according to the numerical scoring system listed in the EU Regulation (EC) No 1272/2008 (CLP), as amended for fifteenth time in Regulation (EU) No 2020/217, at approximately 1, 24, 48 and 72 hours as well as 7 days after application. When present, corrosion and/or staining of sclera and cornea by the test item were recorded and reported.

TOOL USED TO ASSESS SCORE: Eye examinations were made with a Varta Cliptrix diagnostic-lamp (A. Riegger, Basel/ Switzerland)

Irritation parameter:

chemosis score

Basis:

animal #1

Time point:

24/48/72 h

Score:

0

Max. score:

4

Reversibility:

fully reversible within:

Remarks:

24 hours

Irritation parameter:

chemosis score

Basis:

animal #2

Time point:

24/48/72 h

Score:

1

Max. score:

4

Reversibility:

fully reversible within:

Remarks:

72 hours

Irritation parameter:

chemosis score

Basis:

animal #3

Time point:

24/48/72 h

Score:

0

Max. score:

4

Reversibility:

fully reversible within:

Remarks:

24 hours

Irritation parameter:

chemosis score

Basis:

mean

Time point:

24/48/72 h

Score:

0.33

Max. score:

4

Reversibility:

fully reversible within: 72 hours

Irritation parameter:

conjunctivae score

Basis:

animal #1

Time point:

24/48/72 h

Score:

0.67

Max. score:

3

Reversibility:

fully reversible within:

Remarks:

72 hours

Irritation parameter:

conjunctivae score

Basis:

animal #2

Time point:

24/48/72 h

Score:

1

Max. score:

3

Reversibility:

fully reversible within:

Remarks:

7 days

Irritation parameter:

conjunctivae score

Basis:

animal #3

Time point:

24/48/72 h

Score:

0.33

Max. score:

3

Reversibility:

fully reversible within:

Remarks:

48 hours

Irritation parameter:

conjunctivae score

Basis:

mean

Time point:

24/48/72 h

Score:

0.67

Max. score:

3

Reversibility:

fully reversible within: 7 days

Irritation parameter:

cornea opacity score

Basis:

mean

Time point:

24/48/72 h

Score:

0

Max. score:

4

Reversibility:

other: no effects observed

Remarks on result:

no indication of irritation

Irritation parameter:

iris score

Basis:

mean

Time point:

24/48/72 h

Score:

0

Max. score:

2

Reversibility:

other: no effects observed

Remarks on result:

no indication of irritation

Irritant / corrosive response data:

Application of the test item to healthy rabbit conjunctivae resulted in a primary eye irritation score of 1. No abnormal findings were observed in the cornea or iris of any animal at any of the measuring intervals (table 1). Slight to moderate reddening of the conjunctivae was observed in all animals 1 hour after treatment. Slight reddening continued to be observed in all animals but gradually diminished to clear at the 7-day reading (table 1). Swelling of the conjunctivae (slight with partial eversion of lids or with lids about half-closed) was apparent in all animals at the 1-hour reading. Swelling persisted in one animal up to 48 hours after treatment (table 1). Assessment of the sclera was not possible in one animal at the 1-hour reading due to swelling of the conjunctiva. Moderate reddening was, however, subsequently observed in this animal at the 24- and 48-hour readings but diminished to clear 7 days after treatment. Moderate reddening was similarly observed in the remaining two animals 1 hour after treatment but cleared in one animal at the 24-hour reading and in the other animal at the 48-hour reading (table 1). A slight to moderate waterly discharge was present in all animals 1 hour after treatment and a slight waterly discharge was still evident in one animal at the 24-hour reading. No abnormal findings were observed in the treated eye of any animal 7 days after treatment, the end of the observation period for all animals. No corrosion of the cornea was observed at any of the reading times.

Other effects:

- Lesions and clinical observations: no clinical signs of systemic toxicty were observed in the animals during the study and no mortality occured
- white remnants of the test item were observed in the eye or conjunctival sac of all animals 1 hour after treatment and continued to be observed in one animal up to the 24-hour reading

Table 1: Eye irritation scores – individual values

Animal Number	Sex	Evaluation Interval	Corneal Opacity	Iris	Conjunctivae		Cumulative		Sclera
					Redness	Chemosis	Score	Mean
4	M	1 hour	0	0	2	1	3	3.33	2
5	F		0	0	1	3	4		n.a.
6	F		0	0	1	2	3		2
4	M	24 hours	0	0	1	0	1	1.67	1
5	F		0	0	1	2	3		2
6	F		0	0	1	0	1		0
4	M	48 hours	0	0	1	0	1	1	0
5	F		0	0	1	1	2		2
6	F		0	0	0	0	0		0
4	M	72 hours	0	0	0	0	0	0.33	0
5	F		0	0	1	0	1		1
6	F		0	0	0	0	0		0
4	M	7 days	0	0	0	0	0	0.00	0
5	F		0	0	0	0	0		0
6	F		0	0	0	0	0		0

n.a.= not assessable due to swelling of the conjunctivae

F= female

M=male

 

 

Table 2. Eye irritation scores – mean values after 24, 48 and 72 hours

Animal Number	Sex	Corneal Opacity	n	iris	n	Conjunctivae				Primary Eye Irritation Score
						redness	n	chemosis	n
4	M	0	3	0	3	0.67	3	0	3	1
5	F	0	3	0	3	1	3	1	3
6	F	0	3	0	3	0.33	3	0	3
Mean score		0		0		0.67		0.33

n= number of available data points

 

 

Table 3. Eye irritation scores – assessment according to EEC guidelines

Evaluated intervals	Corneal Opacity	Iris	Conjunctivae
			redness	chemosis
24 hours	Not irritating	Not irritating	Not irritating
48 hours
72 hours

Interpretation of results:

GHS criteria not met

Conclusions:

The test item did not induce significant or irreversible damage to the rabbit eye and is considered to be "not irritating" to the rabbit eye.

Executive summary:

The primary eye irritation of the test item was investigated by instillation of 0.1 g into one eye of each of three young adult New Zealand White rabbits. Scoring of irritation effects was performed approximately 1, 24, 48 and 72 hours, as well as 7 days after test item application. The scores of each animal at the following reading times (24, 48 and 72 hours) were used in calculating the respective mean values for each type of lesion. The primary eye irritation score was calculated by totaling the mean cumulative scores at 24, 48 and 73 hours and then dividing the resulting total by the number of data points. The primary eye irritation score was 1.00 (max 13). The eye reactions (mean values from 24 to 72 hours) consisted of grade 0.00 corneal opacity, grade 0.00 iris lesions, grade 0.67 redness of the conjunctivae and grade 0.33 chemosis of the conjunctivae. The instillation of the test item into the eye resulted in mild, early-onset and transient ocular changes, such as reddening of the conjunctivae and sclerae, discharge and swelling. These effects were reversible and were no longer evident 7 days after treatment, the end of the observation period for all animals. No abnormal findings were observed in the cornea or iris of any animal at any reading. No corrosion was observed at any of the measuring intervals. No staining of the treated eyes by the test item was observed. Thus, the test item did not induce significant or irreversible damage to the rabbit eye. Based upon the referred classification criteria (EU Regulation (EC) No 1272/2008 (CLP), as amended for fifteenth time in Regulation (EU) No 2020/217), the test item is considered to be "not irritating" to the rabbit eye.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not irritating)

Respiratory irritation

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Skin irritation/corrosion

The primary skin irritation potential of the test item was investigated by topical semi-occlusive application of 0.5 g to the intact left flank of each of three young adult New Zealand White rabbits. The duration of treatment was four hours. The scoring of skin reactions was performed 1, 24, 48, 72 as well as 7 days after removal of the dressing. The application of the test item caused very slight erythema at the test site of two animals 1 hour after treatment. The test item did not, however, elicit any signs of irritation at the application site of any animal at the 24-, 48-, 72- hour or 7-day readings. The mean values from 24 to 72 hours were, therefore, 0 for erythema and 0 for edema. The test item caused no staining of the treated skin. No corrosive effects were noted on the treated skin of any animal at any measuring interval. Thus, the test item did not induce significant or irreversible damage to the rabbit skin. Based upon the referred classification criteria (EU Regulation (EC) No 1272/2008 (CLP), as amended for fifteenth time in Regulation (EU) No 2020/217), the test item is considered to be "not irritating" to rabbit skin.

Eye irritation/corrosion

The primary eye irritation of the test item was investigated by instillation of 0.1 g into one eye of each of three young adult New Zealand White rabbits. Scoring of irritation effects was performed approximately 1, 24, 48 and 72 hours, as well as 7 days after test item application. The scores of each animal at the following reading times (24, 48 and 72 hours) were used in calculating the respective mean values for each type of lesion. The primary eye irritation score was calculated by totaling the mean cumulative scores at 24, 48 and 73 hours and then dividing the resulting total by the number of data points. The primary eye irritation score was 1.00 (max 13). The eye reactions (mean values from 24 to 72 hours) consisted of grade 0.00 corneal opacity, grade 0.00 iris lesions, grade 0.67 redness of the conjunctivae and grade 0.33 chemosis of the conjunctivae. The instillation of the test item into the eye resulted in mild, early-onset and transient ocular changes, such as reddening of the conjunctivae and sclerae, discharge and swelling. These effects were reversible and were no longer evident 7 days after treatment, the end of the observation period for all animals. No abnormal findings were observed in the cornea or iris of any animal at any reading. No corrosion was observed at any of the measuring intervals. No staining of the treated eyes by the test item was observed. Thus, the test item did not induce significant or irreversible damage to the rabbit eye. Based upon the referred classification criteria (EU Regulation (EC) No 1272/2008 (CLP), as amended for fifteenth time in Regulation (EU) No 2020/217), the test item is considered to be "not irritating" to the rabbit eye.

Justification for classification or non-classification

Classification, Labeling, and Packaging Regulation (EC) No 1272/2008

The available data for skin and eye irritation are reliable and suitable for classification purposes under Regulation (EC) No 1272/2008. The test item is not considered to be classified for skin and eye irritation/corrosion according to EU Regulation (EC) No 1272/2008 (CLP), as amended for fifteenth time in Regulation (EU) No 2020/217.