4-[4-(3,4-Difluorophenyl)-cyclohexyl]-cyclohexanone

Endpoint summary

Description of key information

According to an OECD TG 404 compliant study in the rabbit, the test item was found to be not irritating to the skin (reference 7.3.1 -1).

According to an OECD TG 405 compliant study in the rabbit, the test item was found to be not irritating to the eye (reference 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:

January 20, 2003 - March 17, 2003

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:

July 1992

Deviations:

no

Qualifier:

according to guideline

Guideline:

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

Version / remarks:

Annex to Directive 92/69/EEC:
Annex to Commission Directive of 31st July 1992 adapting to technical progress for the seventeenth time Council Directive 67/ 548/ EEC on the approximation of the laws, regulations and administrative provisions relating to the classification, packaging and labelling of dangerous substances
Official Journal of the European Communities L383 A, Vol. 15, 29. December 1992.

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Species:

rabbit

Strain:

New Zealand White

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Wiga GmbH, Kißlegg
- Age at study initiation: about 15 weeks
- Weight at study initiation: 3.10 kg (range from 2.81 to 3.31)
- Housing: separately in special rabbit cages (manufacturer: Becker, type K99/30 KU)
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: more than 7 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19 - 20°C
- Humidity (%): 41 - 54%
- Photoperiod (hrs dark / hrs light): 12hrs dark / 12hrs light

IN-LIFE DATES: From: day 1 To: day 8

Type of coverage:

semiocclusive

Preparation of test site:

shaved

Vehicle:

unchanged (no vehicle)

Controls:

not required

Amount / concentration applied:

TEST MATERIAL
- Amount applied: 0.5 mL per animal

Duration of treatment / exposure:

4 hours

Observation period:

24, 48, 72 hours after removal of patches

Number of animals:

3 female rabbits

Details on study design:

TEST SITE
- Area of exposure: back
- Type of wrap if used: semi-occlusive

REMOVAL OF TEST SUBSTANCE
- Washing: yes
- Time after start of exposure: 4 h

OBSERVATION TIME POINTS : 1 hour after removal, after 24, 48, 72 hours, and then daily up to experimental day 8

SCORING SYSTEM:
- Method of calculation: according to the guideline and Draize:
Grading scale for evaluation:
Erythema and eschar formation: Scores
No erythema: 0
Very slight erythema (barely perceptible): 1
Well defined erythema: 2
Moderate to severe erythema:3
Severe erythema to eschar formation preventing grading of erythema: 4

Maximum possible: 4

Edema formation: Scores
No edema: 0
Very slight edema (barely perceptible): 1
Slight edema (edges of area well defined by definite raising): 2
Moderate edema (raised approx. 1 mm): 3
Severe edema (raised more than 1 mm and extending beyond area of exposure): 4

Maximum possible: 4

Total possible irritation score (maximum): 8

Mean score = Mean grading for erythema or edema of all the rabbits per time point
Mean cumulative score = Mean grading of all readings for erythema and edema per time point
Mean score per animal = Mean grading for each animal of erythema or edema (24, 48, and 72 hours after removal of the patches)

Irritation parameter:

erythema score

Basis:

animal #1

Time point:

24/48/72 h

Score:

0

Max. score:

4

Remarks on result:

no indication of irritation

Irritation parameter:

erythema score

Basis:

animal #2

Time point:

24/48/72 h

Score:

0

Max. score:

4

Remarks on result:

no indication of irritation

Irritation parameter:

erythema score

Basis:

animal #3

Time point:

24/48/72 h

Score:

0

Max. score:

4

Remarks on result:

no indication of irritation

Irritation parameter:

edema score

Basis:

animal #1

Time point:

24/48/72 h

Score:

0

Max. score:

4

Remarks on result:

no indication of irritation

Irritation parameter:

edema score

Basis:

animal #2

Time point:

24/48/72 h

Score:

0

Max. score:

4

Remarks on result:

no indication of irritation

Irritation parameter:

edema score

Basis:

animal #3

Time point:

24/48/72 h

Score:

0

Max. score:

4

Remarks on result:

no indication of irritation

Irritant / corrosive response data:

No skin irritating potential could be detected.

Other effects:

None

Clinical findings

After a single application to the intact dorsal skin of rabbits, for a 4 hours period of exposure under semiocclusive conditions, no signs of irritation were observed in the treated areas. No signs of clinical toxicity were detected.

Mortality

All animals survived the observation period.

Body weight

Body weight development of the treated rabbits was inconspicuous.

The individual local findings were:

Animal No.		Local findings on day
		1	2	3	4	5	6	7	8
		(1h)	(24h)	(48h)	(72h)
3	Erythema	0	0	0	0	0	0	0	0
	Edema	0	0	0	0	0	0	0	0
9	Erythema	0	0	0	0	0	0	0	0
	Edema	0	0	0	0	0	0	0	0
11	Erythema	0	0	0	0	0	0	0	0
	Edema	0	0	0	0	0	0	0	0

 

 

Interpretation of results:

GHS criteria not met

Conclusions:

No skin irritating potential could be detected.

Executive summary:

The purpose of this assay was to identify the skin irritation/corrosion potential of the test item when applied to the intact skin of previously shaven rabbits for a 4 hours period under semiocclusive conditions. This study should provide a rational basis for risk assessment to the irritating potential of the test item in man. The test material was spread onto patches and applied to the intact skin of three previously shaven rabbits for a 4 hours period under semiocclusive conditions. The first examination of the treated skin sites followed 1 hour after removal of the patches. Then, examinations were performed daily for further 7 days. Under the conditions of the present study no signs of irritation were seen. The evaluation of all animals yields a zero mean score. The test item was not irritating to the skin in this assay.

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:

January 23, 2003 - June 12, 2003

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:

adopted, April 24th, 2002

Deviations:

no

Qualifier:

according to guideline

Guideline:

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

Version / remarks:

Annex to Directive 92/69/EEC:
Annex to Commission Directive of 31st July 1992 adapting to technical progress for the seventeenth time Council Directive 67/ 548/ EEC on the approximation of the laws, regulations and administrative provisions relating to the classification, packaging and labeling of dangerous substances.
Official Journal of the European Communities L383 A, Vol. 15, 29. December 1992.

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Species:

rabbit

Strain:

New Zealand White

Details on test animals or tissues and environmental conditions:

TEST ANIMALS
- Source: Charles River Wiga GmbH, Kißlegg
- Age at study initiation: approx. 16 weeks
- Weight at study initiation: 3.37 kg (range from 3.17 to 3.48 kg)
- Housing: separately in special rabbit cages (manufacturer: Becker; type K99/30 KU)
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: 7 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18 to 20 °C
- Humidity (%): 39 to 54 %.
- Air changes (per hr): not specified
- Photoperiod: 12 / 12 hrs dark / hrs light

IN-LIFE DATES: From: day 1 To: day 8

Vehicle:

unchanged (no vehicle)

Controls:

not required

Amount / concentration applied:

0.1 g test material was instilled into the conjunctival sac of the left eye of each animal by gently pulling the lower lid away from the eyeball to form a cup into which the test material was placed. The right eye remained untreated and served as control. After instillation, the eyelids were closed for about 30 seconds.

Observation period (in vivo):

1 hour after treatment, after 24, 48, and 72 hours, then daily up to day 8

Number of animals or in vitro replicates:

3 female rabbits

Details on study design:

REMOVAL OF TEST SUBSTANCE
- Washing: not done

TOOL USED TO ASSESS SCORE: fluorescein & ophthalmoscope

SCORING SYSTEM: according to the guideline and Draize scoring system:

Evaluation of eye reactions

Cornea Scores

A) Opacity-degree of density (area most dense taken for reading)No ulceration or opacity 0
Scattered or diffuse areas of opacity (other than slight dullingof normal lustre), details of iris clearly visible 1
Easily discernible translucent area, details of iris slightly obscured 2
Nacrous area, no details of iris visible, size of pupil barely discernible 3
Opaque cornea, iris not discernible through the opacity 4

B) Area of cornea involved not evaluated (Rating according to the DRAIZE method)


Iris

Normal 0
Markedly deepened rugae, congestion, swelling, moderate circumcorneal hyperemia, or injection,
any of these or combination of any thereof, iris still reacting to light (sluggish reaction is positive) 1
No reaction to light, hemorrhage, gross destruction (any or all of these) 2

Conjunctivae

A) Redness (refers to palpebral and bulbar conjunctivae, cornea and iris)Blood vessels normal 0
Some blood vessels definitely hyperemic (injected) 1
Diffuse, crimson color, individual vessels not easily discernible 2
Diffuse beefy red 3

B) Chemosis: lids and/or nictating membranesNo swelling 0
Any swelling above normal (includes nictating membranes) 1
Obvious swelling with partial eversion of lids 2
Swelling with lids about half closed 3
Swelling with lids more than half closed 4

C) Discharge (Rating according to the DRAIZE method )
No discharge 0
Any amount different from normal (does not include small amounts observed in inner canthus of normal animals) 1
Discharge with moistening of the lids and hairs just adjacent to lids 2
Discharge with moistening of the lids and hairs, and of a considerable area around the eye 3

Mean score of all animals = Mean grading for irritations of cornea, iris, and conjunctivae per time point
Mean score per animal = Mean grading for each animal of irritations of cornea, iris, and conjunctivae (1, 24, 48, and 72 hours after application)
Maximum value = Maximum grading of a sign of irritation within a period

Irritation parameter:

cornea opacity score

Basis:

animal #1

Time point:

24/48/72 h

Score:

0

Max. score:

4

Remarks on result:

no indication of irritation

Irritation parameter:

cornea opacity score

Basis:

animal #2

Time point:

24/48/72 h

Score:

0

Max. score:

4

Remarks on result:

no indication of irritation

Irritation parameter:

cornea opacity score

Basis:

animal #3

Time point:

24/48/72 h

Score:

0

Max. score:

4

Remarks on result:

no indication of irritation

Irritation parameter:

iris score

Basis:

animal #1

Time point:

24/48/72 h

Score:

0

Max. score:

2

Remarks on result:

no indication of irritation

Irritation parameter:

iris score

Basis:

animal #2

Time point:

24/48/72 h

Score:

0

Max. score:

2

Remarks on result:

no indication of irritation

Irritation parameter:

iris score

Basis:

animal #3

Time point:

24/48/72 h

Score:

0

Max. score:

2

Remarks on result:

no indication of irritation

Irritation parameter:

conjunctivae score

Remarks:

redness

Basis:

animal #1

Time point:

24/48/72 h

Score:

0

Max. score:

3

Remarks on result:

no indication of irritation

Irritation parameter:

conjunctivae score

Remarks:

redness

Basis:

animal #3

Time point:

24/48/72 h

Score:

0

Max. score:

3

Remarks on result:

no indication of irritation

Irritation parameter:

chemosis score

Basis:

animal #1

Time point:

24/48/72 h

Score:

0

Max. score:

4

Remarks on result:

no indication of irritation

Irritation parameter:

chemosis score

Basis:

animal #2

Time point:

24/48/72 h

Score:

0

Max. score:

4

Remarks on result:

no indication of irritation

Irritation parameter:

chemosis score

Basis:

animal #3

Time point:

24/48/72 h

Score:

0

Max. score:

4

Remarks on result:

no indication of irritation

Irritant / corrosive response data:

No signs of irritation were observed at the cornea or iris. The conjunctivae showed only discharge (score 2) in all animals at the first reading. Thereafter no signs of irritation were observed. The untreated eyes were unchanged.

Other effects:

none

Eye alterations

No signs of irritation were observed at the cornea or iris. The conjunctivae showed only discharge (score 2) in all animals at the first reading (1h). Thereafter no signs of irritation were observed. The untreated eyes were unchanged.

Clinical findings

No signs of irritation were observed at the cornea and iris. The untreated eyes were unchanged. No signs of clinical toxicity were detected.

Mortality

All animals survived the observation period.

Body weight

Body weight development of the treated rabbits was inconspicuous.

Interpretation of results:

GHS criteria not met

Conclusions:

The test material is not regarded as an irritant for the eyes.

Executive summary:

The purpose of this primary eye irritation assay was to provide information on possible health hazards in case of acute eye contact with a test material and serve as a rational basis for risk assessment to the eye irritating potential of the test item in man. The test material was tested for its toxicological properties. For the test of primary eye irritation, 0.1 g of the ground test material was applied into the conjunctival sac of rabbits. The first examination of the eyes followed 1 hour after instillation. The examinations were performed daily for further 7 days. No signs of irritation were observed at the cornea and iris. The conjunctivae showed only discharge (score 2) in all animals at the first reading. Thereafter no signs of irritation were observed. The untreated eyes were unchanged. The test material is not regarded as an irritant for the eyes.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not irritating)

Respiratory irritation

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Skin irritation:

The purpose of this assay was to identify the skin irritation/corrosion potential of the test item when applied to the intact skin of previously shaven rabbits for a 4 hours period under semiocclusive conditions. This study should provide a rational basis for risk assessment to the irritating potential of the test item in man. The test material was spread onto patches and applied to the intact skin of three previously shaven rabbits for a 4 hours period under semiocclusive conditions. The first examination of the treated skin sites followed 1 hour after removal of the patches. Then, examinations were performed daily for further 7 days. Under the conditions of the present study no signs of irritation were seen. The evaluation of all animals yields a zero mean score. The test item was not irritating to the skin in this assay.

Eye irritation

The purpose of this primary eye irritation assay was to provide information on possible health hazards in case of acute eye contact with a test material and serve as a rational basis for risk assessment to the eye irritating potential of the test item in man. The test material was tested for its toxicological properties. For the test of primary eye irritation, 0.1 g of the ground test material was applied into the conjunctival sac of rabbits. The first examination of the eyes followed 1 hour after instillation. The examinations were performed daily for further 7 days. No signs of irritation were observed at the cornea and iris. The conjunctivae showed only discharge (score 2) in all animals at the first reading. Thereafter no signs of irritation were observed. The untreated eyes were unchanged. The test material is not regarded as an irritant for the eyes.

Justification for classification or non-classification

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

The available data for skin irritation and eye irritation are reliable and suitable for classification purposes under Regulation (EC) No 1272/2008. Based on this data, the substance is neither considered to be classified for skin irritation nor for eye irritation under Regulation (EC) No 1272/2008, as amended for the twelfth time in Regulation (EU) No 2019/521.