Benzenecarboximidamide, 4-amino-N-hydroxy-

Acute Toxicity: oral

Administrative data

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: GLP- and Guideline study with no or minor deviations.

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2006

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)

Deviations:

no

GLP compliance:

yes

Test type:

acute toxic class method

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

4-amino-N-hydroxybenzene-1-carboximidamide

EC Number:

664-406-5

Cas Number:

277319-62-7

Molecular formula:

C7 H9 N3 O

IUPAC Name:

4-amino-N-hydroxybenzene-1-carboximidamide

Test material form:

solid: particulate/powder

Remarks:

migrated information: powder

Test animals

Species:

rat

Strain:

other: CrlGlxBrlHan:WI (SPF quality)

Sex:

male/female

Details on test animals or test system and environmental conditions:

According to the revised version of OECD Guideline 423 (Acute Oral Toxicity - Acute Toxic Class Method, October 2000), the rat is the preferred rodent species in acute toxicity testing.

Species, number of animals: 12 rats, 3 males (M) and 9 females (F)
Strain: CrlGlxBrlHan:WI (SPF quality)
Supplier: Charles River Deutschland GmbH, 97633 Sulzfeld,
Germany
Age (Day 1): approximately 8 - 10 weeks
Body weight range (Day 1): males 200 - 228 g, females 124 - 152 g

Housing conditions:

Temperature: 22 ± 2°C
Relative humidity: 45 - 75%
Light/darkness cycle: 12/12 hours
Illumination period: 06:00 h - 18:00 h
Average illumination: approximately 60 lx (depending on the cage position;
during work in the room the intensity is raised to
approximately 450 lx)
Air change: minimum of 10 air changes per hour

Diet and water:

pelleted dry food ad libitum, withdrawn at Day -1
Municipal tap drinking water ad libitum

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

other: 0.5% aqueous hydroxyethylcellulose (Natrosol® 250 HX)

Doses:

100, 200 and 2000 mg/kg. In the absence of prior experience, 100 mg/kg body weight was chosen as the initial dose.
The second dose was selected based on the animals’ response to 100 mg/kg.

No. of animals per sex per dose:

100 mg/kg 3 Female
200 mg/kg 3 Female, 3 Male
2000 mg/kg 3 Female

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing:
Clinical observations: twice a day
Body weight: Day 1, 2, 8, 15
- Necropsy of survivors performed: yes
- Other examinations performed:

clinical signs:
The health status of the animals was checked at arrival. The overall appearance and behavior of each animal was inspected once or twice daily. On weekends, on non-working days ..., this inspection was performed only once daily. Any abnormality was recorded with regard to onset, duration and, if possible, intensity.

body weight:
The body weight of all animals was recorded manually within 24 h after arrival. These data were used to monitor body weight compliance with
weight ranges defined in the study plan. They are not reported, but filed in the raw data. During the pretest period, the body weight was recorded one day
before administration (Day -1). During the observation period, the body weight of all animals was recorded on Day 1, 2, 8 and 15, respectively.

Pathology: Necropsy was performed on all animals. Rats were anaesthetized by intraperitoneal injection of sodium pentobarbital and exsanguinated via the abdominal aorta. All gross macroscopical changes were recorded.

Results and discussion

Effect levels

Sex:

male/female

Dose descriptor:

LD50

Effect level:

>= 200 - <= 2 000 mg/kg bw

Based on:

test mat.

Mortality:

100 mg/kg: No mortality occurred in the three females treated.
200 mg/kg: Female No. 252 was found dead on Day 1 (0.5 h). All three males survived the entire 14-day observation period.
2000 mg/kg: All three female rats treated had to be sacrificed on Day 1 (0.5 h).

Clinical signs:

other: 100 mg/kg: In all three females treated, piloerection (0.25 h to 7.75 h), reduced motor activity (0.25 h to 5.0 h) and hunched posture (2.25 h only) were observed. Rats returned to normal on Day-2 and no further clinical signs were seen throughout the r

Gross pathology:

Macroscopic observations at necropsy:

100 mg/kg
No gross macroscopic alterations were seen at necropsy of the three female rats treated.

200 mg/kg
All males survived the observation period and, except enlarged kidneys in No. 301, no changes were observed at necropsy.
Female No. 252 died on Day 1. Necropsy revealed generalized congestion as well as alterations in the lungs (discoloration),
small intestine (aqueous content), jejunum (hyperemia), spleen (discoloration) and adrenal glands (enlargement). No changes were
observed in the two other female rats which survived the entire study period.

2000 mg/kg
All females had to be sacrificed for reasons of animal welfare on Day 1. At necropsy, alteration in the lungs (discolorations)
and the intestinal tract were noted (discoloration and altered luminal content in the small intestine).

Applicant's summary and conclusion

Interpretation of results:

harmful

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

Under the conditions of the present study, no mortality was seen in rats subsequent to a single oral administration of BIBR 1048 ABA at 100 mg/kg. At 200 mg/kg, all three males survived, but one out of three females died. Subsequent to 2000 mg/kg, all three females had to be sacrificed.
The approximate lethal dose (ALD) for BIBR 1048 ABA is between 200 mg/kg and 2000 mg/kg for male and female rats.