2,6-Benzothiazolediamine, 4,5,6,7-tetrahydro-, (6S)-, (2R,3R)-2,3-dihydroxybutanedioate, hydrate (1:1:3)

Acute Toxicity: oral

Administrative data

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

05 October - 02 November 1994

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1995

Report date:

1995

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

Deviations:

no

GLP compliance:

yes

Test type:

fixed dose procedure

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

(6S)-4,5,6,7-tetrahydro-1,3-benzothiazole-2,6-diamine 2,3-dihydroxybutanedioic acid trihydrate

EC Number:

928-472-1

Cas Number:

1184301-52-7

Molecular formula:

C11-H17-N3-O6-S x 3H2O

IUPAC Name:

(6S)-4,5,6,7-tetrahydro-1,3-benzothiazole-2,6-diamine 2,3-dihydroxybutanedioic acid trihydrate

Test material form:

solid: particulate/powder

Specific details on test material used for the study:

In the study report is mentioned that a dihydrate was used for testing, this statement is not correct. After further evaluation of the substances it was found out that it is a trihydrate. The batch for testing was a typical production batch.

Test animals

Species:

rat

Strain:

other: Chbb: THOM

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Male and female Albino rats, Chbb:THOM strain were obtained from Experimental Animal Breeding Centre of Dr. Karl Thomae GmBH, Biberach
- The rats were in the body weight range of the following on Day 1:
Male - 231.3 g +/- 32.4, Female - 188.7 g +/- 17.0

CONDITIONS
- Filtered, demineralized water, adjusted to pH = 2.6 +/- 0.2 with hydrochloric acid, was freely availbale to the animals in bottles.
- Pelleted feed for rats and mice, type R 8013, from Altromin, Lage, was offered to the animals ad libitum throughout the study duration, with the exception of a period of 16 to 20 hours before and up to 2 hours after administration.
- Conventional accomodation in the Room No. 218 of the small animal house I; individual accomodation in type III Makrolon cages with softwood granulate bedding. The target temperature and relative humidity ranges were 21deg. Celsius to 25deg. Celsius and 50% to 65%, respectively.
- Light/darkness Rythm: 12 hours (light 6.00 to 18.00)

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

other: 0.1% Tween 80 solution

Details on oral exposure:

Doses were administered orally, by gavage, the single peroral administration was performed with a Ultra asept syringe and a stomach tube. The day of the administration counted as day 1 for each treated animal.

Doses:

280 - 1100 mg/kg

No. of animals per sex per dose:

5 males per 280 mg/kg
5 males per 400 mg/kg
5 males and 5 females per 560 mg/kg
5 males and 5 females per 800 mg/kg
5 females per 1100 mg/kg

Control animals:

no

Details on study design:

On the day of the administration (day 1 = day of the treatment) the animals were observed throughout the working day. Thereafter, up to the 14th day, they were observed twice daily (in the morning and in the afternoon). On weekends and holidays they were observed once daily (in the morning). Behaviour changes and toxic symptoms were recorded in group protocols.

All study animals were weighed one day before the study start (day -1=fasting day) and before treatment. The surviving animals were weighed on the 8th and 15th study day.
The increase of the body weight per group was calculated for each study week.

Results and discussion

Effect levels

Effect levels 1

Sex:

female

Dose descriptor:

approximate LD50

Effect level:

> 1 100 mg/kg bw

Based on:

test mat.

Effect levels 2

Sex:

male

Dose descriptor:

approximate LD50

Effect level:

675.2 mg/kg bw

Based on:

test mat.

Mortality:

9 of 35 treated animals died. Death occurred within 10 days after administration.

Clinical signs:

other: Males: 280 mg/kg: reduced motility, tachypnea, exophthalmia, piloerection, cyanosis, salvation, discoloured yellow urine, and incrusted snout and eyes. 400 mg/kg: in addition breathing noises but no cyanosis. 560 mg/kg: in addition prone position, tremor

Gross pathology:

Macroscopic organ or tissue findings at the autopsy of died animals and the surviving animals at the end of the study were: congestion of lung and liver, emphysema of the lung, hemorrhages of the stomach moucosa, meteorism of the stomach and intestine, reddening of the stomach moucosa, hemorrahges in the cecum moucosa, dilatation of the colon with soft contents, small spleen, tip of the tail necrotic (automutilation), and tip of the tail absent (automutilation).

Applicant's summary and conclusion

Interpretation of results:

Category 4 based on GHS criteria

Conclusions:

With an approximate LD50 of 675.2 mg/kg b.w. for males and >1100 mg/kg b.w. for females after oral administration in rats the precursor 3 of SND 919 CL2 Y could be classified as Category 4/H302.