methyl 2-ethoxy-3-[[4-[2-(2H-tetrazol-5-yl)phenyl]phenyl]methyl]benzimidazole-4-carboxylate

Acute Toxicity: dermal

Administrative data

Endpoint:

acute toxicity: dermal

Type of information:

experimental study

Adequacy of study:

key study

Study period:

Date of start of the experimental period: 27 May 2004 - Date of end of the experimental period: 10 June 2004.

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Justification for type of information:

Experimental study is been performed according to guideline (OECD 402).

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2004

Report date:

2004

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

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:

methyl 2-ethoxy-3-[[4-[2-(2H-tetrazol-5-yl)phenyl]phenyl]methyl]benzimidazole-4-carboxylate

EC Number:

604-139-3

Cas Number:

139481-69-9

Molecular formula:

C25H22N6O3

IUPAC Name:

methyl 2-ethoxy-3-[[4-[2-(2H-tetrazol-5-yl)phenyl]phenyl]methyl]benzimidazole-4-carboxylate

Test material form:

solid: particulate/powder

Details on test material:

batch No. February 2004

Specific details on test material used for the study:

On 20 April 2004, one sample of CAN 5, batch No. February 2004, was received. Immediately upon receipt, CAN 5 was registered, then stored at ambient temperature and protected from light in accordance with the Sponsor's instructions. The complete description of the chemical and physical properties of the CAN 5 including stability, is the responsibility of the Sponsor.

Appearance: White powder.

Test animals

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Origin: Charles River Laboratoires France, Domaine cles Oncins, 69592 L'Arbresle Cedex, France.
- Identification: Animals were identified individually by marking the tail with a felt-tip marker.
- Age: 8-12 weeks at the time of administration.
- Number: Limit test: 5 males, 5 females.

- Acclimatization: Minimum of five days before the treatment in the laboratory animal house where
the experiment took place.

- Housing: Daily observations were performed at the time of delivery of the animals and during the
period of acclimatization. Animals were housed in cages of standard dimensions with sawdust bedding
(or equivalent). Cages were cleaned at least once per week.The animals were placed in an air-conditioned (19-23 "C) animal house kept at relative humidity between 45% and 65% in which non-recycled fìltered air was changed approximately 10 times per hour. The artificial day/night cycle involved 12 hours light and 12 hours darkness with light on at 7.30 a.m.

Feeding: RM1 (E)-SQC SDS/DIETEX (quality controlled/radiation sterilised) was available ad libitum. The criteria for acceptable levels of contaminants in the feed supply were within the limits of the analytical specifìcations established by the diet manufacturer.

- Drinking water: Drinking water was available ad libitum in polycarbonate feeder bottles with a stainless steel nipple. A specimen of water is obtained every 6 months and sent to the Laboratoire Départemental d'Analyse du Cher- 216, Rue Louis Mallet- 18014 Bourges Cedex, France, for analysis. The criteria for acceptable levels of contaminants in the water supply were within the limits of the analytical specifìcations.

Administration / exposure

Type of coverage:

other: CAN 5 was applied to each animal on a piece of absorbant gauze measuring 30 cm2 (6 cm x 5 cm).

Vehicle:

other: CAN 5 was moistened with sterile water in order to ensure good contact with the skin.

Details on dermal exposure:

Timing, frequency and duration of administration
CAN 5 was applied to the back of the animal on a previously shaved area. The absorbent gauze was
held in piace for 24 hours using an elastic band. At the end of the exposure period, no remaining CAN
5 was noted.

Application of the test substance
CAN 5 was applied to the skin in the dorsal region of each animal without prior fasting. For this purpose, on the day prior to application, the dorsal region of each rat was carefully clipped on an area of approximately 50 cm2 using an electric clipper, avoiding damage to the skin. Any animal found to have damage skin at the time of application was removed from the study. On the day of study, test substance was applied to the prepared area to expose at least 10% of the total body surface. CAN 5 was applied to each animal on a piece of absorbant gauze measuring 30 cm2 (6 cm x 5 cm).

Duration of exposure:

24 hours

Doses:

2000 mg/kg body weight

No. of animals per sex per dose:

Single group often animals (5 males and 5 females) was dosed at the dose of2000 mg/kg body weight.

Control animals:

not required

Details on study design:

General clinical examination
Animals were examined clinically twice on the day of treatment (between 30 and 90 minutes after administration and then again between 3 and 4 hours post-dose). Thereafter they were examined clinically at least once daily far 14 days.

Full clinical examination
On D1 between 30 and 90 minutes after administration and on 07 the animals were submitted to a full clinical examination outside the housing cage, including functional and neurobehavioural tests.

Examination performed
-Skin lesion evaluation
-Necropsy
-Mortality
-Body weight

Results and discussion

Preliminary study:

Dermal application of the test substance CAN 5 (batch No. February 2004) at a dose of 2000 mg/kg caused no mortality and no dermal reactions during a 14-day period, in the male and female Sprague-Dawley rats.

Effect levels

Key result

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Mortality:

No mortality occurred during the study.

Clinical signs:

No clinical signs were observed during the course of the study.

Body weight:

Mean weight gain in treated animals was normal when compared with values usually found in our Centre.

Gross pathology:

No organ or tissue gross findings were seen at necropsy.

Other findings:

No dermal reactions were observed during the course of the study.

Any other information on results incl. tables

Body weight and clinical signs are reported in the illustration attached below.

Applicant's summary and conclusion

Interpretation of results:

GHS criteria not met

Conclusions:

Under the experimental conditions adopted, dermal application of the test substance CAN 5 (batch No. February 2004) at a dose of 2000 mg/kg caused no mortality and no dermal reactions during a 14-day period, in the male and female Sprague-Dawley rats.

Under the experimental conditions adopted, the LD50 of the test substance CAN 5 (batch No. February 2004) administered by the dermal route was higher than 2000 mg/kg body weight
in the male and female Sprague-Dawley rats.

Executive summary:

Under the experimental conditions adopted, dermal application of the test substance CAN 5 (batch No. February 2004) at a dose of 2000 mg/kg caused no mortality and no dermal reactions during a 14-day period, in the male and female Sprague-Dawley rats.

Under the experimental conditions adopted, the LD50 of the test substance CAN 5 (batch No. February 2004) administered by the dermal route was higher than 2000 mg/kg body weight in the male and female Sprague-Dawley rats.