Registration Dossier

Administrative data

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
From 21. Sep. 1987 to 12. Oct. 1987
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1987
Report Date:
1987

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Version / remarks:
1987
Deviations:
no
Qualifier:
according to
Guideline:
EU Method B.1 (Acute Toxicity (Oral))
Version / remarks:
1984
Deviations:
no
GLP compliance:
yes
Test type:
standard acute method
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
solid: particulate/powder

Test animals

Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Kleintierfarm Madörin AG, 4414 Füllinsdorf, CH
- Age at study initiation: 9 to 11 weeks
- Weight at study initiation: males: 193 to 250 g; females: 156 to 211 g
- Fasting period before study: 12 to 18 hours
- Housing: standard laboratory conditions. Groups of five in Makrolon type-3 cages with standard softwood bedding ("lignocel", Schill AG, 4132 Muttenz, CH)
- Diet: ad libitum; palleted standard Kliba 343, Batch 77/87 and 79/87 rat maintenance diet ("Kliba", Klingentalmühle AG,.4303 Kaiseraugst, CH) (analytical test report demonstrates suitability)
- Water: ad libitum; community tap water from Itingen (bacteriological assay and chemical water analysis demonstrated suitability)
- Acclimation period: at least one week

ENVIRONMENTAL CONDITIONS
- Temperature: 22 °C ± 3 degrees
- Humidity: 40 to 70 %
- Air changes: 10 to 15 per hour
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
polyethylene glycol
Details on oral exposure:
TEST ITEM PREPARATION
- The test item was placed into a glass beaker on a tared Mettler PK 300 balance, and the vehicle polyethylene glycol (PEG 400) was added. A weight by volume dilution was prepared using a homogeniser.
- Homogeneity of the test item in the vehicle was maintained during treatment using a magnetic stirrer.
- The preparation was made immediately prior to dosing.

TREATMENT
The animals received the test item on a mg/kg bw base by oral gavage after fasting for 12 to 18 hours (access to water was not interrupted). Food was again presented approximately one hour after dosing.
Application Volume/kg b.w.:
Group 1: 10 mL at 2000 mg/kg bw
Group 2: 20 mL at 5000 mg/kg bw
Doses:
2000 mg/kg bw
5000 mg/kg bw
No. of animals per sex per dose:
5 females and 5 males per dose
Control animals:
no
Details on study design:
- Duration of observation period following administration: 15 days
- Frequency of observations: four times during test day 1, then daily during days 2-15
- Frequency of weighing: test days 1 (pre-administration), 8 and 15
- Necropsy of survivors performed: all animals were killed by intraperitoneal injection of sodium pentobarbitone
- Observations recorded: signs and symptoms, mortality, body weights, macroscopic findings
- Specific signs and symptoms observed:
General behaviour: aggressiveness, vocalisation, restlessness / excitation, nervousness, fear, sedation, somnolence, sleep, coma
Respiration: apnoea, dyspnea, rales
Eye: chromodacryorrhea, exophthalmos, miosis, mydriasis, whitish discharge, lid adhesion, lacrimation
Nose: rhinorrhoea, epistaxis
Motility: akinesia, ataxia, dropped head, hyperkInesia, hypokinesia, paralysis (flaccid), paralysis (spastic), paddling movements, stiff movements, rolling movements
Body posture: ventral body position, latero-abdominal position, hunched posture
Motor susceptibility: spasms, tonic muscle spasms, clonic muscle spasms, opisthotonus, saltatory spasms, trismus, retching, "Straub" phenomenon, tremor, muscle-twitching, muscle-twitching (generalised)
Skin: erythema, oedema, necrosis
Various: loss of weight, emaciation, negative corneal reflex, diarrhoea, ruffled fur, salivation, pallor, cyanosis
Statistics:
The LOGIT-model could not be applied to the observed rates of death. The toxicity was estimated without use of a statistical model.

Results and discussion

Effect levels
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 5 000 mg/kg bw
Based on:
test mat.
Mortality:
0 % at 2000 mg/kg bw
20 % at 5000 mg/kg bw
Clinical signs:
2000 mg/kg bw: sedation, dyspnoea, hunched posture, ruffled fur
5000 mg/kg bw: sedation, dyspnoea, ataxia, hunched posture, diarrhoea, ruffled fur
All surviving rats had recovered within 4 to 6 observation days
Body weight:
The body weight gain of all rats was similar.
Gross pathology:
All animals were subjected to necropsy by experienced prosectors. All animals surviving to the end of the observation period were killed by intraperitoneal injection of sodium pentobarbitone.

2000 mg/kg bw:
sacrificed: - no pathologic changes (10)
5000 mg/kg bw:
dead: - lung: several dark-red foci, partly black (2),
Black (2)
- liver,
- stomach
- intestines
- kldneys,
- adrenal glands,
- spleen
sacrificed: - no pathologic changes (8)

Applicant's summary and conclusion

Interpretation of results:
other: not classified according to the CLP Regulation (EC) No.1272/2008
Conclusions:
The LD50 (oral, rat) of test item was found to be greater than 5000 mg/kg bw
Executive summary:

Acute oral toxicity of the substance was evaluated in an experimental study performed according to the OECD Guideline 401 (1987) and EU method B.1 (1984).

No mortality was observed at 2000 mg/kg bw, and 20 % mortality was observed at the higher dose of 5000 mg/kg bw. Toxic symptoms of sedation, dyspnoea, hunched posture and ruffled fur were observed in one male and one female animal administered 2000 mg/kg bw until day 4 and 5, respectively at 2000 mg/kg bw; toxic symptoms of sedation, dyspnoea, ataxia, hunched posture, diarrhoea and ruffled fur were observed in 1 - 2 male and 1 - 2 female animals until day 3 at 5000 mg/kg bw. Body weights of all animals remained constant. No gross pathological changes were observed among animals administered at 2000 mg/kg bw or the surviving animals administered at 5000 mg/kg bw; the two animals of the higher dose who died during the study period were found to have several dark red foci, partly black, of the lungs and black liver, stomach, intestines, kidneys, adrenal glands and spleen. The LOGIT-Model could not be applied to these data. Based on these findings, the acute oral toxicity of the test item in rats of both sexes, observed over a period of 15 days, was estimated to be greater than 5000 mg/kg bw Therefore, it can be extrapolated that the LD50 is greater than 5000 mg/kg bw.