Registration Dossier

Administrative data

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
From the 30th March to the 2th of May, 1990
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Remarks:
Study conducted according to internationally accepted guideline

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1990
Report Date:
1990

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Qualifier:
according to
Guideline:
EU Method B.1 (Acute Toxicity (Oral))
GLP compliance:
yes (incl. certificate)
Test type:
acute toxic class method
Limit test:
yes

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
solid: particulate/powder
Details on test material:
Environmental fate/Ecotoxicological/Toxicological studies:
Storage: Room temperature, 20-24 °C, in the dark
Stability: pure, for 5 years; in solvent > 24 hours in water, DMSO, DMF, stable for at least 2 hours in aqueous medium.
Evidence of chemical instability at pH 6: none
Safety precaution: routine hygienic procedures were sufficient to assure personnel health and safety.
Toxicological studies:
Preparation: On the day of the experiment, the test article was suspended in Carboxymethylcellulose (1 %).
The vehicle was chosen to its nontoxicity for the animals. All animals received a single standard dose volume of 10 mL/kg body weight orally.

Test animals

Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals and environmental conditions:
TEST SYSTEM
Acclimatization March 30 to April 5, 1990
Observation April 6 to May 2, 1990
Source: BRL, Biological Research Laboratories Ltd, Wolferstrasse 4, CH-4414 Fullinsdorf
Mumber of animals 5 males per group 5 females
Total number of animals 20 males, 20 females
Age at start of treatment males: 9 to 10 weeks, females: 11 to 12 weeks
Body weight at start males: 200 — 290 g of treatment females: 178 — 211 g
Identification: By unique cage number and corresponding color—coded spots on the tail.
Randomization: Randomly selected at time of delivery in groups of five.
Acclimatization: One week under laboratory conditions, after veterinary examination.

HUSBANDRY
Room No.: 136
Standard Laboratory Conditions:
Air-conditioned with 10—13 air changes per hour, and hourly monitored environment with temperature 20±3 °C, relative humidity 40-70 %, 12 hours artificial fluorescent light/12 hours dark, music/light period.
Accommodation: groups of five in Nakrolon type-3 cages with standard softwood bedding (‘Lignocel’, Schill AG, CH—4132 Muttenz).
Diet: pelleted standard Kliba 343, Batches 67/90 and 68/90 rat maintenance diet (‘Kliba’, Klingentalmuehle AG, CH—4303 Kaiseraugst) available ad libUtum.
Analysis for contaminants performed.
Water: community tap water from Itingen, available ad libitum. Analyses for contaminants performed.

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
water
Details on oral exposure:
The animals received a single dose of the test article on a mg/kg body weight base by oral gavage after being fasted for 12 to 18 hours (access to water was not interrupted). Food was again presented approximately 3 hours after dosing.
The oral administration was used because this is one possible route of human exposure during manufacture, handling and use of the test article.
Doses:
10 ml at 1000 mg/kg
10 ml at 2000 mg/kg
20 ml at 3500 mg/kg
20 ml at 5000 mg/kg
No. of animals per sex per dose:
5 male
5 female
Control animals:
no
Details on study design:
OBSERVATION
Mortality, Viability: Four times during test day 1, and daily during days 2 - 15.
Body Weights: Test days 1 (pre—administration), 8 and 15.
Clinical Signs: Each animal was examined for changes in appearance and behaviour rour times during day 1, and daily during days 2-15. All abnormalities were recorded: General behaviour, Respiration, Eye, Nose, Motility, Body Posture, Motor Susceptibility, Skin, Various.

PATHOLOGY
Necropsies were perrormed by experienced prosectors.
All animals were necropsied.
All animals surviving to the end o the observation period were killed by intra peritoneal injection of sodium pentobarbitone.
Statistics:
The LOGIT—Model (COX, Analysis of Binary Data, London 1977) was applied to estimate the toxicity value. Additionally, the 90, 95 and 99 % conridence
limits for the toxicity ftr each sex and the slope of the dose response line were estimated.

Results and discussion

Effect levelsopen allclose all
Sex:
male/female
Dose descriptor:
approximate LD50
Effect level:
2 717 mg/kg bw
Based on:
test mat.
95% CL:
>= 1 984 - <= 3 719
Sex:
male
Dose descriptor:
approximate LD50
Effect level:
2 432 mg/kg bw
Based on:
test mat.
95% CL:
>= 1 642 - <= 3 602
Sex:
female
Dose descriptor:
approximate LD50
Effect level:
2 655 mg/kg bw
Based on:
test mat.
95% CL:
>= 785 - <= 8 973
Mortality:
The following death rate was observed:
0% at 1000 mg/kg
20 % at 2000 mg/kg
100 % at 3500 mg/kg
80 % at 5000 mg/kg
the LOGIT-ESTIMATION for the acute oral toxicity of in rats of bot6 sexes observed for a period of 15 days is 2717 mg/kg.
For Males: 2432 mg/kg
For Females: 2655 mg/kg
WITH A 95 % CONFIDENCE LIMITS OF:
males/females: 1984- 3719 mg/kg
males 1642 - 3602 mg/kg
females 785 - 8973 mg/kg
Clinical signs:
The following clinical signs were observed:
1000 mg/kg: males/females - diarrhea; no clinical signs noted.
The animals showed diarrhea only on day 1 (from hour 5). Afterwards they had no changes in behaviour and appearence during the whole observation period.

2000 mg/kg: males/females: slightly ruffled fur, diarrhea;
2000 mg/kg: females: slight sedation, hunched posture.
recovering after 4 observation days

3500 mg/kg: males/females: sliqht to moderate sedation, hunched posture, sliqhtly to moderately ruffled rur, sllqht dyspnea, diarrhea, ventral, recumbency;
3500 mg/kg: females: lateral recumbency.

5000 mg/kg: males/females: slight to severe sedation, slightly ruffled fur, hunched posture
5000 mg/kg: males: ventral recumbency
5000 mg/kg: females: diarrhea, slight dyspnea, lateral recumbency
recovering after 7 observation days
Body weight:
The body weight gain of the surviving animals was not arfected by the test article treatment. Animal no. 32 of the 3500 mg/kg group showed loss of weight between days 1 to 8.
Gross pathology:
The following macroscopical organ rindings were observed:
1000 mg/kg sacrificed, no macroscopical findings noted
2000 mg/kg: sacrificed, no macroscopical rindings noted
2000 mg/kg: dead lungs: not collapsed, reddened .
3500 mg/kg: dead, general observations: emaciated
stomach : contents black—brown
duodenum: contents black—brown
jejunum : contents black—brown
ileum : contents black—brown
caecum : contents black—brown
colon : contents black—brown
general observations: discoloration yellowish.
5000 mg/kg: sacrificed, lungs: discoloration, dark red
5000 mg/kg: dead, general observations: discoloration yellowish

Applicant's summary and conclusion

Interpretation of results:
not classified
Remarks:
Migrated information according to CLP Regulation Criteria used for interpretation of results: EU
Conclusions:
The LD50 oral toxicity of the substance in rats of both sexes observed for a period of 15 days is:
2717 mg/kg
For Males: 2432 mg/kg
For Females: 2655 mg/kg
Executive summary:

Materials and method

The acute oral toxicity was determinated in the substance according to the OECD Guideline 401 (Acute Oral Toxicity) and EU Method B.1 (Acute Toxicity (Oral), in GLP.

The test article was administered to rats of both sexes by oral gavage at single doses from 1000 to 5000 mg/kg.

Observation:

The following death rate was observed:

0 % at 1000 mg/kg

20 % at 2000 mg/kg

100 % at 3500 mg/kg

80 % at 5000 mg/kg

Results

the LOGIT-estimation for the acute oral toxicity of in rats of both sexes observed for a period of 15 days is 2717 mg/kg (LD50).

(Males: 2432 mg/kg-Females: 2655 mg/kg). Several recovered clinical signs were observed.