Registration Dossier

Administrative data

Description of key information

The substance is moderately toxic after single oral administration to rats (RCC 1986). The LD 50 was set at 1674 mg/kg for both sexes.

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records
Reference
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
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
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
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.
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.
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.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LD50
1 674 mg/kg bw

Acute toxicity: via inhalation route

Endpoint conclusion
Endpoint conclusion:
no study available

Acute toxicity: via dermal route

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Acute oral toxicity in rats was investigated in a study following the procedure outlined in OECD testing guideline 401 and compliant with GLP (RCC 1986). Rats were given a single dose of 1000, 2000, 3000, 5000 mg/kg bodyweight using polyethylene glycol as vehicle. One female rat died in the 1000 mg/kg dosing group (10%). At 2000 mg/kg bw, 3 males and 3 females died (60%) and in the two high dose groups all animals died (100%). Clinical symptoms observed in all treated groups included sedation, rales, dyspnea, ataxia, ventral body position (females), latero-abdominal position (female), curved body position and ruffled fur. At 3000 mg/kg chromodaccryorrhea (females) and muscle twitching was observed in addition. The surviving rats had recovered within 4 to 6 observation days. At necropsy, mottled lungs with foam excretion, reddened stomach with whitish content, mottled livers, meteorism in intestines and stomach, mucous membrane of stomach partly reddened with hard contents, intestines reddened and filled with reddish/yellowish/whitish contents, partly yellowish discolored adipose tissue, filled urinary bladder, enlarged adrenals (one animal) and partly cannibalism were observed. The LD50 was calculated at 1674 mg/kg for both sexes.

Experimental data on acute dermal toxicity and inhalation toxicity is not available. In accordance with REACh regulation EC 1907/2006 Annex XIII 8.5, acute toxicity data for these routes are not required because the test article is corrosive to the skin.


Justification for selection of acute toxicity – oral endpoint
GLP-compliant guideline study

Justification for classification or non-classification

Dangerous Substance Directive (67/548/EEC)

The available data are considered reliable and suitable for classification purposes under 67/548/EEC. As a result the substance requires classification with R22 for acute oral toxicity under Directive 67/548/EEC.

 

Classification, Labeling, and Packaging Regulation (EC) No. 1272/2008

The available experimental test data are reliable and suitable for classification purposes under Regulation 1272/2008. As a result the substance requires classification with acute oral toxicity Cat. 4 under Regulation (EC) No. 1272/2008.