Registration Dossier

Administrative data

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
January 23, 1986 - February 13, 1986
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP-compliant guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1986
Report Date:
1986

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Version / remarks:
(1981)
Qualifier:
according to
Guideline:
EU Method B.1 (Acute Toxicity (Oral))
GLP compliance:
yes
Remarks:
Research & Consulting Company AG, CH 4452 Itingen / Switzerland
Test type:
standard acute method
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Physical state: oily liquid
- Analytical purity: commercial grade
- Stability of test article dilution: stable for at least 2 hours

Test animals

Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Kleintierfarm Madoerin AG, CH 4414 Fuellinsdorf / Switzerland
- Age at study initiation: 10 to 12 weeks
- Weight at study initiation: Males: 236 - 291 g, Females: 191 - 213 g
- Fasting period before study: 12 to 13 hours
- Housing: Groups of five in Makrolon type-3 cages with standard softwood bedding ("Lignocel", Schill AG, 4132 Muttenz, Switzerland).
- Diet: Pelleted standard Kliba 343, Batch 36/85 rat maintenance diet ("Kliba", Klingentalmuehle AG, 4303 Kaiseraugst, Switzerland) available ad libitum
- Water: Community tap water from Itingen, available ad libitum
- Acclimation period: 1 week

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

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
polyethylene glycol
Remarks:
PEG 400
Details on oral exposure:
VEHICLE
- Amount of vehicle (if gavage): 10 ml/kg bw (group 1 and 2), 20 ml/kg (group 3 and 4)

MAXIMUM DOSE VOLUME APPLIED: 20 ml/kg bw

DOSAGE PREPARATION (if unusual):
The test article was placed into a glass beaker on a tared Mettler PK 4800 balance, and the vehicle was added. A weight by volume dilution was prepared using a homogenizer (Ultra-Turrax, Janke and Kunkel, Staufen, FRG). Homogeneity of the test article in the vehicle was maintained during treatment using a magnetic stirrer (Auer-Bittmann, Switzerland). The preparation was made immediately prior to dosing.
Doses:
1000, 2000, 3000, 5000 mg/kg bodyweight
No. of animals per sex per dose:
5
Control animals:
no
Details on study design:
- Duration of observation period following administration: 15 days
- Frequency of observations: Four times during test day 1, and daily during days 2-15.
- Frequency of and weighing: Test days 1 (pre-administration) , 8 and 15.
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, eye observations
Statistics:
The LOGIT-Model (COX, Analysis of Binary Data, London 1977) was applied to estimate the LD50 value. Additionally, the 90, 95 and 99 % confidence intervals for the LD50 for each sex and the slope of the concentration response line were estimated.

Results and discussion

Effect levelsopen allclose all
Sex:
male/female
Dose descriptor:
LD50
Effect level:
1 674 mg/kg bw
95% CL:
1 264 - 2 145
Sex:
male
Dose descriptor:
LD50
Effect level:
1 790 mg/kg bw
95% CL:
1 191 - 2 511
Sex:
female
Dose descriptor:
LD50
Effect level:
1 554 mg/kg bw
95% CL:
501.9 - 2 663
Mortality:
At 1000 mg/kg bw 1 female died (10%)
At 2000 mg/kg bw 3 males and 3 females died (60%)
At 3000 and 5000 mg/bw all animals died (100%)
Clinical signs:
In all treated groups sedation, rales, dyspnea, ataxia, ventral body position (females), latero-abdominal position (female), curved body position and ruffled fur were observed. At 3000 mg/kg chromodaccryorrhea (females) and muscle twitching was observed in addition. The surviving rats had recovered within 4 to 6 observation days
Body weight:
group 1 showed normal weight gain, group 2 displayed retarded weight gains, group 3 and 4 could not be assessed because all animals were dead prior to day (day of scheduled weighing)
Gross pathology:
At necropsy, the following observations were reported in the deceased animals:
-1000 mg/kg: mottled lungs with foam excretion, reddened stomach with whitish content
-2000 mg/kg: mottled lungs with foam excretion, mottled liver, meteorism in stomach/intestines, totally filled with yellowish contents, reddened intestines, filled with whitish or yellowish contents, severely filled urinary bladder and partly yellowish discolored adipose tissue
-3000 mg/kg: mottled lungs with foam excretion, mucous membrane partly reddened, reddened stomach filled with hard or reddish contents, reddened intestine with reddish, whitish, orange or yellow-white content, totally filled urinary bladder, enlarged adrenals (one animal) and partly cannibalism
-5000 mg/kg: mottled lungs with foam excretion, mucous membrane partly reddened, reddened stomach/intestine filled severely yellow-red content, reddened intestines with orange-red content, totally filled urinary bladder.

Applicant's summary and conclusion

Conclusions:
The acute oral LD50 of the test item in rats observed over a period of 14 days is 1674 mg/kg bodyweight.
Executive summary:

In a oral acute toxicity study performed according to OECD guideline 401 and in compliance with GLP, the test article was administered to groups of 5 male and 5 female Wistar rats by gavage at dose levels of 1000, 2000, 3000 and 5000 mg/kg bodyweight. All animals of the two high dose groups died within 6 days. In the low dose group one female died and in the intermediate dose group (2000 mg/kg) 60% of all animals died. The LD50 was set by calculation with the LOGIT-Model for female/male rats at 1674 mg/kg bodyweight. Based on the result of this study, the test article is considered to be moderately toxic after single ingestion.