Reaction mass of 5-[(Disubstituted-dihydrocarbopolycyclyl)diazenyl]-6-hydroxy-4-methyl-2-substituted-1-propyl-1,2-dihydropyridine-3-carbonitrile and 1-Butyl-5-[(disubstituted-dihydrocarbopolycyclyl)diazenyl]-6-hydroxy-4-methyl-2-substituted-1,2-dihydropyridine-3-carbonitrile

Acute Toxicity: dermal

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Administrative data

Endpoint:

acute toxicity: dermal

Type of information:

experimental study

Adequacy of study:

key study

Study period:

2005

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2005

Report date:

2005

Materials and methods

Test guideline

Test guideline 1

Qualifier:

according to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

Version / remarks:

OECD Guidelines for Testing of Chemicals, Section 4, Number 402 "Acute Dermal Toxicity",
adoptedFebruary 24,1987.

Deviations:

no

Test guideline 2

Qualifier:

according to guideline

Guideline:

EU Method B.3 (Acute Toxicity (Dermal))

Version / remarks:

Directive 92/69/EEC, B.3. "Acute Toxicity-Dermal", July 31,1992.

Deviations:

no

Principles of method if other than guideline:

Guidelines followed

GLP compliance:

yes (incl. QA statement)

Test type:

standard acute method

Limit test:

yes

Test material

Reference

Name:

Unnamed

Type:

Constituent

Test material form:

solid

Details on test material:

Batch: P2/05 UL
Appearance: light orange crystalline powder
Expiration date: 31.05.2011
Storage: at room temperature

Specific details on test material used for the study:

- Identity: FAT41039/A
- Description: Light orange crystalline powder
- Batch number: P2/05 UL
- Purity / Formulation: content of organic pigments > 99 %; main components: 97 %
- Stability of test item: Stable under storage conditions.
- Expiry date: 31-MAY-2011
- Stability of test item dilution: Stable in PEG 300 for at least 7 days at room temperature.
- Storage conditions: At room temperature (range of 20 ± 5 °C), light protected.
- Safety precautions: Routine hygienic procedures were used to ensure the health and safety of the personnel.

Test animals

Species:

rat

Strain:

other: Rat, HanRcc:WIST (SPF)

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST SYSTEM
- Test system: Rat, HanRcc:WIST (SPF)
- Rationale: Recognized by the international guidelines as a recommended test system.
- Source: RCC Ltd, Laboratory Animal Services, CH-4414 Füllinsdorf / Switzerland
- Number of animals per group: 5 males and 5 females
- Total number of animals: 5 males and 5 females
- Age when treated: Males: 8 weeks, Females: 12 weeks
- Identification: By unique cage number and corresponding color-coded spots on the tail. The animals were marked at acclimatization start.
- Randomization: Selected by hand at time of delivery. No computer generated randomization program.
- Acclimatization: Under laboratory conditions, after health examination. Only animals without any visible signs of illness were used for the study.

HUSBANDRY
Conditions:
Standard Laboratory Conditions. Air-conditioned with 10-15 air changes per hour, and continuously monitored environment with ranges for room temperature 22 ± 3 °C and for relative humidity between 30-70 % (values above 70 % during cleaning process possible), automatically controlled light cycle of 12 hours light and 12 hours dark, music during the daytime light period.

Accommodation:
During acclimatization in groups of five per sex in Makrolon type-4 cages with standard softwood bedding. Individually in Makrolon type-3 cages with, standard softwood bedding ("Lignocel", Schill AG, CH-4132 Muttenz) during treatment and observation.

Diet:
Pelleted standard Provimi Kliba 3433 rat/mouse maintenance diet, batch no. 25/05 (Provimi Kliba AG, CH-4303 Kaiseraugst/ Switzerland) ad libitum. Results of analyses for contaminants are archived at RCC Ltd.

Water:
Community tap water from Füllinsdorf ad libitum. Results of bacteriological, chemical and contaminant analyses are archived at RCC Ltd.

Administration / exposure

Type of coverage:

semiocclusive

Vehicle:

other: Polyethylene glycol 300 (PEG 300)

Details on dermal exposure:

REMOVAL OF TEST SUBSTANCE
- Washing (if done): After removal of the dressing, the skin was flushed with lukewarm tap water and dried with disposable paper towels.
- Time after start of exposure: 24 h

TEST MATERIAL
- Application volume/kg body weight: 6 mL

VEHICLE
- Identification: Polyethylene glycol 300 (PEG 300)
- Description: Colorless viscous liquid
- Lot number: 1157790 51105271
- Source: FLUKA Chemie GmbH, CH-9471 Buchs
- Stability of vehicle: Stable under storage conditions;
- Expiration date: 19-JUL-2006
- Storage conditions: At room temperature (range of 20 ± 5 °C), light protected.
- Safety precautions: Routine hygienic procedures were used to ensure the health and safety of the personnel.
The vehicle was chosen after a non-GLP solubility trial which was performed before the study initiation date. This formulation trial is excluded from the GLP statement of compliance.

Duration of exposure:

24 h

Doses:

2000 mg/kg bw

No. of animals per sex per dose:

5

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Mortality / Viability: Daily during the acclimatization period, during the first 30 minutes and at approximately 1, 2, 3 and 5 hours after administration on test day 1 (with the clinical signs) and twice daily during days 2-15.
- Body weights: On test days 1 (prior to administration), 8 and 15.
- Clinical signs: Daily during the acclimatization period, during the first 30 minutes and at approximately 1 , 2 , 3 and 5 hours after administration on test day 1. Once daily during days 2-15.
- Local signs: Once daily during days 2-15. All abnormalities were recorded.
- Necropsy of survivors performed: yes All animals were killed at the end of the observation period by an intraperitoneal injection of Vetanarcol at a dose of at least 2.0 mL/kg body weight (equivalent to at least 324 mg sodium pentobarbitone/kg body weight) and discarded after macroscopic examinations were performed. No organs or tissues were retained.

Statistics:

No statistical analysis was used.

Results and discussion

Effect levels

Key result

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Mortality:

No deaths occurred during the study.

Clinical signs:

No clinical signs were observed during the course of the study. Orange discoloration of the treated skin area produced by the test item prevent the assessment of a possible erythema in all animals on test day 2 and in one male animal on test day 3.

Body weight:

The body weight of the animals was within the range commonly recorded for this strain and age.

Gross pathology:

No macroscopic findings were observed at necropsy.

Any other information on results incl. tables

None

Applicant's summary and conclusion

Interpretation of results:

GHS criteria not met

Conclusions:

The median lethal dose (LD50) of FAT 41039/A after single dermal administration to rats of both sexes, observed over a period of 14 days was >2000 mg/kg body weight.

Executive summary:

FAT 41039/A was evaluated for acute dermal toxicity in a study conducted according to OECD Guideline 402 and EU Method B.3. Five male and five female HanRcc.WIST (SPF) rats were treated with FAT 41039/A at 2000 mg/kg by dermal application. The test item was diluted in vehicle (PEG 300) at a concentration of 0.33 g/mL and administered at a volume dosage of 6 mL/kg. The application period was 24 hours. The animals were examined daily during the acclimatization period and mortality, viability and clinical signs were recorded. All animals were examined for clinical signs at approximately 30 minutes, 1, 2, 3 and 5 hours after treatment on day 1 and once daily during test days 2-15. Local signs were noted once daily from test day 2 to 15. Mortality/viability was recorded at approximately 30 minutes, 1,2,3 and 5 hours after administration on test day 1 (with the clinical signs) and twice daily during days 2-15. Body weights were recorded on day 1 (prior to administration) and on days 8 and 15. All animals were necropsied and examined macroscopically.

No deaths or clinical signs were observed during the course of the study. The body weight of the animals was within the range commonly recorded for this strain and age. No macroscopic findings were observed at necropsy. Hence, based on the findings of the study, the median lethal dose (LD50) of FAT 41039/A after single dermal administration to rats of both sexes, observed over a period of 14 days was >2000 mg/kg body weight.