9beta,11beta-Epoxy-6alpha-fluoro-16alpha-methyl-21-valeryloxy-1,4-pregnadiene-3,20-dione

Endpoint summary

Description of key information

Epoxide valerate is not irritating to the skin of rats (Kurth, 1996) and not irritating to the eyes of rabbits (Treher and Kurth, 1996).

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:

June to July 1996

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

comparable to guideline study with acceptable restrictions

Reason / purpose for cross-reference:

reference to same study

Qualifier:

according to guideline

Guideline:

other: Directive 67/548/EEC in the version of Directive 93/21/EEC

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 404 (Acute Dermal Irritation / Corrosion)

Version / remarks:

17 July 1992

Deviations:

yes

Remarks:

exposure time 24 hrs instead of 4 hrs, 6 animals instead of 3, few details in test description and reporting

Principles of method if other than guideline:

A combined study on acute dermal toxicity and on local tolerance was used to assess skin irritation/corrosion (comparable to OECD TG 402 and 404). The study design and reporting deviates from the current OECD TG 404, however, the study is considered sufficient for assessment of this endpoint. As described in ATP 96/54/EC ANNEX IV A, PART B: METHODS FOR THE DETERMINATION OF TOXICITY AND OTHER HEALTH EFFECTS, a strategy of testing for irritancy allows the non-performance of a test if an acute toxicity study by the dermal route has been conducted at the limit test dose with the substance (method B.3), and no skin irritation was observed, further testing for skin irritation (method B.4) may be unnecessary.

GLP compliance:

yes

Remarks:

- but a QA check was not performed

Species:

rat

Strain:

Wistar

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Schering AG
- Weight at study initiation: males: 105-111 g; females: 93-107 g
- Fasting period before study: ca. 19 h
- Housing: individually under conventional conditions
- Diet (e.g. ad libitum): pell. Altromin® R ad libitum
- Water (e.g. ad libitum): demineralized acidified water, pH 2-3 ad libitum
- Acclimation period: 7 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-22
- Humidity (%): 54-64
- Photoperiod (hrs dark / hrs light): 12/12

Type of coverage:

occlusive

Preparation of test site:

not specified

Vehicle:

other: 900 mg NaCl ad 100 ml bidest water

Controls:

other: the untreated skin served as control

Amount / concentration applied:

210-222 mg/male animal or 186-214 mg/female animal

Duration of treatment / exposure:

24 hours

Observation period:

14 days

Number of animals:

3 males and 3 females

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Body weight on day 1, 7, and 14.
- Necropsy of survivors performed: yes

Irritation parameter:

edema score

Basis:

animal #6

Time point:

24/48/72 h

Score:

0

Max. score:

4

Reversibility:

other: not applicable

Remarks on result:

other: The test was conducted according to Directive 67/548/EEC which requires the 24, 48 and 72h measurement timepoints. However, the exact timepoints were not reported.

Irritation parameter:

edema score

Basis:

animal #5

Time point:

24/48/72 h

Score:

0

Max. score:

4

Reversibility:

other: not applicable

Remarks on result:

other: The test was conducted according to Directive 67/548/EEC which requires the 24, 48 and 72h measurement timepoints. However, the exact timepoints were not reported.

Irritation parameter:

edema score

Basis:

animal #4

Time point:

24/48/72 h

Score:

0

Max. score:

4

Reversibility:

other: not applicable

Remarks on result:

other: The test was conducted according to Directive 67/548/EEC which requires the 24, 48 and 72h measurement timepoints. However, the exact timepoints were not reported.

Irritation parameter:

edema score

Basis:

animal #3

Time point:

24/48/72 h

Score:

0

Max. score:

4

Reversibility:

other: not applicable

Remarks on result:

other: The test was conducted according to Directive 67/548/EEC which requires the 24, 48 and 72h measurement timepoints. However, the exact timepoints were not reported.

Irritation parameter:

edema score

Basis:

animal #2

Time point:

24/48/72 h

Score:

0

Max. score:

4

Reversibility:

other: not applicable

Remarks on result:

other: The test was conducted according to Directive 67/548/EEC which requires the 24, 48 and 72h measurement timepoints. However, the exact timepoints were not reported.

Irritation parameter:

erythema score

Basis:

animal #6

Time point:

24/48/72 h

Score:

0

Max. score:

4

Reversibility:

other: not applicable

Remarks on result:

other: The test was conducted according to Directive 67/548/EEC which requires the 24, 48 and 72h measurement timepoints. However, the exact timepoints were not reported.

Irritation parameter:

erythema score

Basis:

animal #5

Time point:

24/48/72 h

Score:

0

Max. score:

4

Reversibility:

other: not applicable

Remarks on result:

other: The test was conducted according to Directive 67/548/EEC which requires the 24, 48 and 72h measurement timepoints. However, the exact timepoints were not reported.

Irritation parameter:

erythema score

Basis:

animal #4

Time point:

24/48/72 h

Score:

0

Max. score:

4

Reversibility:

other: not applicable

Remarks on result:

other: The test was conducted according to Directive 67/548/EEC which requires the 24, 48 and 72h measurement timepoints. However, the exact timepoints were not reported.

Irritation parameter:

erythema score

Basis:

animal #3

Time point:

24/48/72 h

Score:

0

Max. score:

4

Reversibility:

other: not applicable

Remarks on result:

other: The test was conducted according to Directive 67/548/EEC which requires the 24, 48 and 72h measurement timepoints. However, the exact timepoints were not reported.

Irritation parameter:

erythema score

Basis:

animal #2

Time point:

24/48/72 h

Score:

0

Max. score:

4

Reversibility:

other: not applicable

Remarks on result:

other: The test was conducted according to Directive 67/548/EEC which requires the 24, 48 and 72h measurement timepoints. However, the exact timepoints were not reported.

Irritation parameter:

erythema score

Basis:

animal #1

Time point:

24/48/72 h

Score:

0

Max. score:

4

Reversibility:

other: not applicable

Remarks on result:

other: The test was conducted according to Directive 67/548/EEC which requires the 24, 48 and 72h measurement timepoints. However, the exact timepoints were not reported.

Irritation parameter:

edema score

Basis:

animal #1

Time point:

24/48/72 h

Score:

0

Max. score:

4

Reversibility:

other: not applicable

Remarks on result:

other: The test was conducted according to Directive 67/548/EEC which requires the 24, 48 and 72h measurement timepoints. However, the exact timepoints were not reported.

Other effects:

none

Conclusions:

A single dermal administration of the test substance for 24 hours to male and female rats at a dose of 2000 mg/kg bw (210-222 mg/male and 186-214 mg/female applied as a paste) was tolerated without any local irritations. The mean values of findings relevant for classification (reddening, scab formation and swelling of the skin) during the observation period of 14 days were 0. Therefore, local application of the test item was tolerated without irritation of the skin.

Executive summary:

In a primary dermal irritation study similar to OECD TG 404 (adopted 17 July 1992), (3/sex) female and male Wistar rats were dermally exposed to 186-214 mg females and 210-222 mg males of Epoxide-Valerate (100% a.i). in physiological saline. Test sites were covered with an occlusive dressing for 24 hours. Animals were then observed for 14 days. Evaluation of skin reactions (reddening, scab formation and swelling of the skin) was done according to the system recommended in Directive 67/548/EEC.

A single dermal administration of the test item for 24 h was tolerated without any local irritations. In this study, the test item is not a dermal irritant.

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:

Aug 1996

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:

24 February 1987

Deviations:

yes

Remarks:

4 instead of 3 animals

GLP compliance:

yes

Remarks:

- but a QA check was not performed

Species:

rabbit

Strain:

New Zealand White

Details on test animals or tissues and environmental conditions:

TEST ANIMALS
- Source: Schriever
- Weight at study initiation: males: 2.8-3.3 kg; females: 2.6-3.3 kg
- Housing: Individually in conventional metal cages
- Diet (e.g. ad libitum): pell. Altromin® K ad libitum
- Water (e.g. ad libitum): demineralized water ad libitum
- Acclimation period: > 14 days; during this period a diet containing 0.03%
sulfaquinoxaline was offered for 7 consecutive days as coccidiosis prophylaxis; the animals received Jacutin® emulsion into the meatus acusticus externus for prophylaxis against mite infection of the ear and were vaccinated against rabbit haemorrhagic disease (Arvilap®)

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22-23
- Humidity (%): 56-60
- Photoperiod (hrs dark / hrs light): 12/12

Vehicle:

unchanged (no vehicle)

Controls:

other: the left eye, which remained untreated, served as control.

Amount / concentration applied:

0.1 mL

Duration of treatment / exposure:

test substance remained in the eye (eye was not rinsed)

Observation period (in vivo):

7 days

Number of animals or in vitro replicates:

2 males and 2 females

Details on study design:

SCORING SYSTEM: Evaluation of the local tolerance on the conjunctiva of the rabbit after a single application was performed according to the score system recommended for the EU.

Irritation parameter:

cornea opacity score

Basis:

animal: #1-#4

Time point:

24/48/72 h

Score:

0

Max. score:

4

Reversibility:

other: not applicable

Irritation parameter:

iris score

Basis:

animal #4

Time point:

24/48/72 h

Score:

0

Max. score:

2

Reversibility:

other: not applicable

Irritation parameter:

iris score

Basis:

animal #3

Time point:

24/48/72 h

Score:

0

Max. score:

2

Reversibility:

other: not applicable

Irritation parameter:

iris score

Basis:

animal #2

Time point:

24/48/72 h

Score:

0

Max. score:

2

Reversibility:

other: not applicable

Irritation parameter:

iris score

Basis:

animal #1

Time point:

24/48/72 h

Score:

0

Max. score:

2

Reversibility:

other: not applicable

Irritation parameter:

conjunctivae score

Remarks:

reddening

Basis:

animal #4

Time point:

24/48/72 h

Score:

1.67

Max. score:

3

Reversibility:

fully reversible within: 6 d

Irritation parameter:

conjunctivae score

Remarks:

reddening

Basis:

animal #3

Time point:

24/48/72 h

Score:

1.33

Max. score:

3

Reversibility:

fully reversible within: 6 d

Irritation parameter:

conjunctivae score

Remarks:

reddening

Basis:

animal #2

Time point:

24/48/72 h

Score:

1.33

Max. score:

3

Reversibility:

fully reversible within: 6 d

Irritation parameter:

conjunctivae score

Remarks:

reddening

Basis:

animal #1

Time point:

24/48/72 h

Score:

0.66

Max. score:

3

Reversibility:

fully reversible within: 48 h

Irritation parameter:

conjunctivae score

Remarks:

swelling

Basis:

animal #4

Time point:

24/48/72 h

Score:

0

Max. score:

4

Reversibility:

other: not applicable

Irritation parameter:

conjunctivae score

Remarks:

swelling

Basis:

animal #3

Time point:

24/48/72 h

Score:

0

Max. score:

4

Reversibility:

other: not applicable

Irritation parameter:

conjunctivae score

Remarks:

swelling

Basis:

animal #2

Time point:

24/48/72 h

Score:

0

Max. score:

4

Reversibility:

other: not applicable

Irritation parameter:

conjunctivae score

Remarks:

swelling

Basis:

animal #1

Time point:

24/48/72 h

Score:

1

Max. score:

4

Reversibility:

fully reversible within: 48 h

Irritation parameter:

chemosis score

Basis:

mean

Time point:

24/48/72 h

Max. score:

4

Remarks on result:

not measured/tested

Remarks:

In the present study only swelling of the conjunctivae was measured, swelling of eye lids and nictating membranes was not reported

Table 1: Results of the study

 

		Irritant effects (score)
Animal no. (sex)	Irritation parameter	24 h	48 h	72 h	Mean scores
1 (M)	Cornea	0	0	0	0.0
	Iris	0	0	0	0.0
	Conjunctiva (reddening)	2	0	0	0.67
	Conjunctiva (swelling)	3	0	0	1.0
2 (M)	Cornea	0	0	0	0.0
	Iris	0	0	0	0.0
	Conjunctiva (reddening)	2	1	1	1.33
	Conjunctiva (swelling)	0	0	0	0.0
3 (F)	Cornea	0	0	0	0.0
	Iris	0	0	0	0.0
	Conjunctiva (reddening)	2	1	1	1.33
	Conjunctiva (swelling)	0	0	0	0.0
4 (F)	Cornea	0	0	0	0.0
	Iris	0	0	0	0.0
	Conjunctiva (reddening)	2	2	1	1.67
	Conjunctiva (swelling)	0	0	0	0.0

 

The control eyes were without findings.

 

The single application of 0.1 mL ZK 50992 (corresponding to 61-71 mg) into the conjunctival sac of the right eye led to moderate to severe reddening and vascular injection and slight to moderate swelling of the conjunctivae on the administration day 1. Slight to moderate reddening and/or swelling, which gradually subsided were observed up to day 6.

Conclusions:

In a local tolerance test on the rabbit eye according to OECD TG 405 a single application of the test substance into the conjunctival sac provoked slight to moderate reddening and/or swelling, which gradually subsided up to day 6. On day 7 all animals were without findings. The mean values of findings relevant for classification at the time-points 24, 48 and 72 hours after application were 0.0 for the parameters cornea and iris, 1.25 for conjunctival reddening as well as 0.25 for conjunctival swelling. Thus, the test item is not considered as an eye irritant.

Executive summary:

In a primary eye irritation study according to OECD TG 405 (adopted 24 February 1987), 0.1 mL corresponding to 61-71 mg of Epoxide-Valerate was instilled into the conjunctival sac of the right eye of young adult female and male New Zealand White rabbits (2/sex) and the animals were observed for 7 days. The eyes were not washed. Irritation was scored by the method described in the guideline.

 

The single application of 0.1 mL of the test item (corresponding to 61-71 mg) into the conjunctival sac of the right eye led to moderate to severe reddening and vascular injection and slight to moderate swelling of the conjunctivae on the administration day 1. Slight to moderate reddening and/or swelling, which gradually subsided were observed up to day 6. In this study, the test item is not an eye irritant.

 

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not irritating)

Respiratory irritation

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

In a primary dermal irritation study similar to OECD TG 404 (adopted 17 July 1992), (3/sex) female and male Wistar rats were dermally exposed to 186-214 mg females and 210-222 mg males of Epoxide-Valerate (100% a.i). in physiological saline. Test sites were covered with an occlusive dressing for 24 hours. Animals were then observed for 14 days. Evaluation of skin reactions (reddening, scab formation and swelling of the skin) was done according to the system recommended in Directive 67/548/EEC.

A single dermal administration of the test item for 24 h was tolerated without any local irritations. In this study, the test item is not a dermal irritant.

 

In a primary eye irritation study according to OECD TG 405 (adopted 24 February 1987), 0.1 mL corresponding to 61-71 mg of Epoxide-Valerate was instilled into the conjunctival sac of the right eye of young adult female and male New Zealand White rabbits (2/sex) and the animals were observed for 7 days. The eyes were not washed. Irritation was scored by the method described in the guideline.

 

The single application of 0.1 mL of the test item (corresponding to 61-71 mg) into the conjunctival sac of the right eye led to moderate to severe reddening and vascular injection and slight to moderate swelling of the conjunctivae on the administration day 1. Slight to moderate reddening and/or swelling, which gradually subsided were observed up to day 6. In this study, the test item is not an eye irritant.

 

Justification for classification or non-classification

Based on the study results a classification according to Regulation (EC) No. 1272/2008 (CLP) is not required.