19-Norpregn-5(10)-ene-21-nitrile, 17-hydroxy-3-oxo-, (17.alpha.)-

Skin irritation / corrosion

Administrative data

Endpoint:

skin irritation: in vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

July to Nov 2006

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

comparable to guideline study with acceptable restrictions

Cross-reference

Reason / purpose for cross-reference:

reference to same study

Reference

Endpoint:

acute toxicity: dermal

Type of information:

experimental study

Adequacy of study:

key study

Study period:

July to Nov 2006

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Reason / purpose for cross-reference:

reference to same study

Qualifier:

according to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

Version / remarks:

24 February 1987

Deviations:

yes

Remarks:

- 3 instead of 5 animals/sex used

GLP compliance:

yes

Test type:

standard acute method

Limit test:

yes

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River, Sulzfeld, Germany
- Weight at study initiation: males: 283 – 290 g; females: 208 – 218 g
- Housing: individually in conventional cages
- Diet (e.g. ad libitum): pell. Ssniff® R / M - H, ad libitum, 24 hours per day
- Water (e.g. ad libitum): filtrated tap water, ad libitum, 24 hours per day
- Acclimation period: ≥ 7 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21-23
- Humidity (%): 56-59
- Photoperiod (hrs dark / hrs light): 12/12

Type of coverage:

occlusive

Vehicle:

physiological saline

Details on dermal exposure:

TEST SITE
- Area of exposure: The backs of the animals, the paste was administered on a piece of gauze the size of 4 x 9 cm
- % coverage: approximately 10% of the body surface area of a rat
- Type of wrap if used: not reported; occlusive

REMOVAL OF TEST SUBSTANCE
- Washing: Substance residues were removed with warm water.
- Time after start of exposure: 24 h

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): a paste consisting of the original compound [males: 566-580 mg ad 0.40 resp. 0.45 mL 0.9% (w/v) sodium chloride; females: 416.7-436.3 mg ad 0.30 mL 0.9% (w/v) sodium chloride]
- For solids, paste formed: yes

VEHICLE
- Amount(s) applied (volume or weight with unit): see above
- Concentration (if solution): see above

Duration of exposure:

24 hours

Doses:

2000 mg/kg bw

No. of animals per sex per dose:

3

Control animals:

no

Details on study design:

- Duration of observation period following administration: 21days
- Frequency of observations and weighing: All alterations of the baseline condition of the animals were recorded. All animals were checked four times on administration day and once daily on the following days up to day 21 of the test. All alterations of the skin at the administration sites of all animals were recorded according to the scoring system recommended by the EU. The application sites were evaluated 1, 24, 48 and 72 h after removal of the patches. Body weight was determined at the start (day 1), on days 8 and 15 and at the end of the study (day 21).
- Necropsy of survivors performed: yes

Key result

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Remarks on result:

other: test substance (technical quality including impurities)

Mortality:

No mortality was observed.

Clinical signs:

other: After administration of 2000 mg/kg of the test chemical focal to total hairless areas were found in one male animal (both fore- and hind limbs, inguinal region, abdomen) from day 15 onwards and in one female animal (both hind limbs, abdomen) on day 13 to

Gross pathology:

Autopsy revealed no compound-related findings, because the observed lesions (scab formation) in the skin are considered to be not substance related.

Conclusions:

A single dermal administration of the test substance (technical quality including impurities) to male and female rats at the limit-dose 2000 mg/kg was tolerated without mortalities and gross pathological findings. After administration of 2000 mg/kg the test item single animals showed hairless areas and thinning fur in the course of the study. These findings are suspected to be compound-related because they are known findings in rats after treatment with hormones. Additionally, a slight decrease in body weight was observed in some animals on day 8. This effect was reversible on day 15 of the test.

According to OECD TG 402 the dermal LD50 of the test item is therefore > 2000 mg/kg body weight.

Executive summary:

In an acute dermal toxicity study according to OECD TG 402 (adopted 17 December 1987), groups of young adult Wistar rats (3/sex) were dermally exposed to 5-Dehydrocyanomethylketon in physiological saline for 24 hours at a dose of 2000 mg/kg bw.  Animals then were observed for 21 days.

Dermal LD50 Combined = 2000 mg/kg bw

No mortality occurred during the conduction of this limit test.

Dehydrocyanomethylketon is of low Toxicity based on the LD50 males and females.

After administration of 2000 mg/kg the test item single animals showed hairless areas and thinning fur in the course of the study. These findings are suspected to be compound-related because they are known findings in rats after treatment with hormones. Additionally, a slight decrease in body weight was observed in some animals on day 8. This effect was reversible on day 15 of the test.

No other effects were observed.

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2009

Report date:

2009

Materials and methods

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 404 (Acute Dermal Irritation / Corrosion)

Version / remarks:

24 April 2002

Deviations:

yes

Remarks:

- exposure time 24 hrs instead of 4 hrs, 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

Test material

Test material information

Constituent 1

Reference substance name:

17 alpha-Cyanomethyl-17 beta-hydroxy-5(10)-estren-3-one

EC Number:

613-855-5

Cas Number:

65928-65-6

Molecular formula:

C20 H27 N O2

IUPAC Name:

17 alpha-Cyanomethyl-17 beta-hydroxy-5(10)-estren-3-one

Constituent 2

Reference substance name:

612-855-5

IUPAC Name:

612-855-5

Details on test material:

Purity not specified

Test animals

Species:

rat

Strain:

Wistar

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River, Sulzfeld, Germany
- Weight at study initiation: males: 283 – 290 g; females: 208 – 218 g
- Housing: individually in conventional cages
- Diet (e.g. ad libitum): pell. Ssniff® R / M - H, ad libitum, 24 hours per day
- Water (e.g. ad libitum): filtrated tap water, ad libitum, 24 hours per day
- Acclimation period: ≥ 7 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21-23
- Humidity (%): 56-59
- Photoperiod (hrs dark / hrs light): 12/12

Test system

Type of coverage:

occlusive

Preparation of test site:

clipped

Vehicle:

physiological saline

Controls:

other: the untreated skin served as control

Amount / concentration applied:

566-580 mg / male animal or 417-436 mg / female animal (= 2000 mg/kg bw)

Duration of treatment / exposure:

24 hours

Observation period:

21 days

Number of animals:

3 males and 3 females

Details on study design:

- Duration of observation period following administration: 21days
- Frequency of observations and weighing: All alterations of the baseline condition of the animals were recorded. All animals were checked four times on administration day and once daily on the following days up to day 21 of the test. All alterations of the skin at the administration sites of all animals were recorded according to the scoring system recommended by the EU. The application sites were evaluated 1, 24, 48 and 72 h after removal of the patches. Body weight was determined at the start (day 1), on days 8 and 15 and at the end of the study (day 21).
- Necropsy of survivors performed: yes

Results and discussion

In vivo

Results

Results 1

Irritation parameter:

erythema score

Basis:

mean

Time point:

24/48/72 h

Score:

0

Max. score:

4

Reversibility:

other: no irritation observed

Results 2

Irritation parameter:

edema score

Basis:

mean

Time point:

24/48/72 h

Score:

0

Max. score:

4

Reversibility:

other: No irritation observed

Any other information on results incl. tables

No compound-related findings were observed at the dose of 2000 mg/kg. The mean values of findings relevant for classification (reddening, scab formation and swelling of the skin) at the time-points 24, 48 and 72 hours after the end of administration were 0 for swelling, reddening and scab formation.

Applicant's summary and conclusion

Conclusions:

A single dermal administration of the test substance for 24 hours to male and female rats at a dose of 2000 mg/kg (566-580 mg/male or 417-436 mg/ female) was tolerated without any local irritations. The mean values of findings relevant for classification (reddening, scab formation and swelling of the skin) at the time-points 24, 48 and 72 hours after the end of administration were 0 for swelling, reddening and scab formation.

Executive summary:

In a primary dermal irritation study similar to OECD TG 404 (adopted 24 April 2002), young adult Wistar rats (3/sex) were dermally exposed to 566-580 mg (males) and 417-436 mg (females) of 5-Dehydrocyanomethylketon in physiological saline for 24 hours). Animals then were observed for 21 days.  Irritation was scored by the method described in the guideline.

The mean values of findings relevant for classification (reddening, scab formation and swelling of the skin) at the time-points 24, 48 and 72 hours after the end of administration were 0 for swelling, reddening and scab formation.. In this study, 5-Dehydrocyanomethylketon is not a dermal irritant.