Guanidine, N-methyl-N'-nitro-

Acute Toxicity: dermal

Administrative data

Endpoint:

acute toxicity: dermal

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1996-07-05 till 1996-08-16

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Guideline conform study without deviations

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1996

Report date:

1996

Materials and methods

Test guideline

Test guideline 1

Qualifier:

according to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

Deviations:

no

Test guideline 2

Qualifier:

according to guideline

Guideline:

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

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Test type:

fixed dose procedure

Limit test:

yes

Test material

Test material information

Constituent 1

Reference substance name:

-

EC Number:

433-400-2

EC Name:

-

Cas Number:

4245-76-5

Molecular formula:

C2H6N4O2

IUPAC Name:

1-Methyl-3-nitro-guanidine

Constituent 2

Reference substance name:

N-methyl-N'-nitro-guanidine

IUPAC Name:

N-methyl-N'-nitro-guanidine

Details on test material:

- Name of test material (as cited in study report): CA 2342 A (~ntermediate of CGA 293343)
- Substance type: intermediate
- Physical state: solid
- Analytical purity: 98%
- Purity test date: reanakysis on December 1997
- Lot/batch No.: P.601014
- Expiration date of the lot/batch: no data
- Stability under test conditions: no data
- Storage condition of test material: room temperature

Test animals

Species:

rat

Strain:

other: Tif: RAI f (SPF)

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: CIBA-GEIGY Limited Laboratory Animal Breeding Pharma Division, Stein / Switzerland
- Age at study initiation: young adult
- Weight at study initiation: 210 to 245 g
- Fasting period before study: no data
- Housing: Animals were individually housed in Macrolon cages type 3, with standardized soft wood bedding
- Diet (e.g. ad libitum): Rat diet - NAFAG 890, ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: at least 5 days before exposure


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 +/- 2°C
- Humidity (%): 55 +/- 10%
- Air changes (per hr): approximately 15 air changes per hour
- Photoperiod (hrs dark / hrs light): 12 hour/day light cycle

Administration / exposure

Type of coverage:

semiocclusive

Vehicle:

CMC (carboxymethyl cellulose)

Details on dermal exposure:

TEST SITE
- Area of exposure: The test article was evenly dispersed on the skin at the back of the rat.
- % coverage: at least 10% of the body surface
- Type of wrap if used: Test article was covered with a gauze-lined semiocclusive dressing fastened around the trunk with an adhesive elastic
bandage.

REMOVAL OF TEST SUBSTANCE
- Washing (if done): The skin was cleaned with lukewarm water.
- Time after start of exposure: 24 hours after instillation

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 2000 mg/kg body weight
- Concentration (if solution): 500 mg/ml
- Constant concentration used: yes (500 mg/ml)

VEHICLE
- Amount(s) applied (volume or weight with unit): 4 ml/kg body weight
- Concentration (if solution): 0.5 % (w/v) carboxymethylcellulose in 0.1 % (w/v) aqueous polysorbate 80

Duration of exposure:

24 hours

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
- Frequency weighing: immediately before application and on days 7 and 14
- Frequency of observations: daily for 14 days
- Necropsy of survivors performed: The animals were submitted to a gross necropsy at the end of the observation period.

Results and discussion

Preliminary study:

The dose level was selected according to OECD 402 (limit test; single application of at least 2000 mg/kg body weight).

Effect levels

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Mortality:

All animals survived to the scheduled sacrifice

Clinical signs:

other: Observation of dyspnea and piloerection 1 day after application in 2 of 5 males. No skin irritation at application site.

Gross pathology:

At necropsy, no deviations from normal morphology were found

Applicant's summary and conclusion

Interpretation of results:

practically nontoxic

Remarks:

Migrated information Criteria used for interpretation of results: OECD GHS

Conclusions:

The substance is not classified as acute dermal toxic by EU-GHS (CLP), since LD50 > 2000 mg/ kg body weight, which is the cut-off in the EU's GHS
classification system. UN-GHS has a Category 5 for acute oral toxicity for the dose range 2000 mg/kg bw < LD50 < 500 mg/kg bw, a concentration range which has not been tested. However acute toxicity Category 5 is applied by some authorities only. Furthermore, acc. to GHS 3.1.2.5 testing
animals in the Category 5 range is discouraged unless "there is a strong likelyhood that results of such testing would have a direct relevance to the
protection of human health", which is not the case.

Executive summary:

Upon single dose, dermal administration of 2000 mg/kg to male and female rats (limit test) and a 14 day post-treatment observation period, the following LD50 was determined for CA 2342 A (Intermediate of CGA 293343):

- LD50 in male rats: greater than 2000 mg/kg body weight

- LD50 in female rats: greater than 2000 mg/kg body weight

- LD50 in rats of both sexes: greater than 2000 mg/kg body weight

Observations In-life observations indicating treatment related effects included dyspnea and piloerection 1 day after application in 2 of 5 males. There were no remarkable findings at the skin application site of all animals. All animals survived to the scheduled sacrifice. Body weights were not affected by the treatment. At autopsy, no deviations from normal morphology were found.

The substance is not classified as acutedermal toxic by EU-GHS (CLP), since LD50 > 2000 mg/ kg body weight, which is the cut-off in the EU's GHS classification system. UN-GHS has a Category 5 for acute oral toxicity for the dose range 2000 mg/kg bw < LD50 < 5000 mg/kg bw, a concentration range which has not been tested. However acute toxicity Category 5 is applied by some authorities only. Furthermore, acc. to GHS 3.1.2.5 testing animals in the Category 5 range is discouraged unless "there is a strong likelyhood that results of such testing would have a direct relevance to the protection of human health", which is not the case.