Registration Dossier

Administrative data

Description of key information

One read-across study on rats is available.

LD50 in female rat was in the range of 500-1000 mg/kg bw and in male was 1000-2000 mg/kg bw (Stadnicki, 1988).

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records
Reference
Endpoint:
acute toxicity: oral
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Study period:
From 29 Oct to 12 Nov 1987
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Study run to a method comparable with current guidelines and to GLP
Reference:
Composition 0
Qualifier:
according to
Guideline:
other: Acute toxicology Standard Procedure
Deviations:
no
GLP compliance:
yes
Test type:
standard acute method
Limit test:
no
Test material information:
Composition 1
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Breeding Laboratories Inc., Wilmington MA
- Age at study initiation: Six-week old
- Weight at study initiation: 164.7 to 173.0 grams for male rats, 141.1 to 150.5 grams for female rats
- Fasting period before study: overnight (i.e. for approximately 17 to 18 hours )
- Housing: Polycarbonate shoe box-type cages, males or females given the same dose were housed together (three per cage). The cage floor was covered with hardwood chip bedding (Ab-sob-dri, Lab products). All test animals were transferred into a clean cage each day.
- Diet (e.g. ad libitum): Prolab RMH-3000 pelleted rodent diet (Agway) ad libitum
- Water (e.g. ad libitum): Drinking water was obtained from a municipal water source subject to regulation by the U.S. Environmental Protection Agency. Water was suplied ad libitum from bottles that were changed two times a week.

ENVIRONMENTAL CONDITIONS
- Temperature (°F): 70±2
- Humidity (%): 50±5
- Air changes (per hr): approximately 18 times per hour with air filtered through 80-90% efficiency filters and finally through HEPA filters.
- Photoperiod (hrs dark / hrs light): illuminated by fluorescent lighting 12 hours a day (7:00 am-7:00pm).

IN-LIFE DATES: From 29 Oct to 12 Nov 1987
Route of administration:
oral: unspecified
Vehicle:
other: 0.1% (w/v) aqueous methylcellulose solution
Details on oral exposure:
VEHICLE
- Concentration in vehicle: 10%
- Amount of vehicle (if gavage):
- Justification for choice of vehicle:
- Lot/batch no. (if required): R74386-0376
- Purity:

MAXIMUM DOSE VOLUME APPLIED:

DOSAGE PREPARATION (if unusual):

CLASS METHOD (if applicable)
- Rationale for the selection of the starting dose
Doses:
500, 1000 and 2000 mg/kg
No. of animals per sex per dose:
3
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: All rats were observed for clinical signs and mortality for 14 days after dosing. The individual body weights of the animals was obtained at least six times during the study, i.e. on the day of dosing (day 0) and on the day 1, 4, 7, 10, and prior to the sacrifice on day 14.
- Necropsy of survivors performed: Animals that died during the study and those that survived to sacrifice were necropsied for gross pathological changes.
- Other examinations performed: Changes were apparent on the gastric mucosa of one male rat given the low oral dose of 500 mg/kg. Therefore, the stomach of this animal was submitted to Pathology for microscopic evaluation. Following fixation in 10% neutral buffered formalin, the tissue was trimmed, embedded in paraffin, cut at 5 to 6 microns, and stained with hematoxylin and eosin.
Statistics:
None stated
Sex:
female
Dose descriptor:
approximate LD50
Effect level:
500 - 1 000 mg/kg bw
Based on:
test mat.
Sex:
male
Dose descriptor:
approximate LD50
Effect level:
1 000 - 2 000 mg/kg bw
Based on:
test mat.
Mortality:
No mortality was produced by an oral dose of 500 mg/kg in animals of either sex or by a dose of 1000 mg/kg in males. Two of three females given 1000 mg/kg and all rats given the high dose of 2000 mg/kg died.
Clinical signs:
In animals given the low dose of 500 mg/kg, no clinical signs were noted on the day of dosing (day 0), and one rat of either sex was asymptomatic throught the 14-day observation period. Within about 5 to 7 hours of dosing, the activity of animals given 1000 or 2000 mg/kg was decreased. Females at these doses, as well as the high dose males, also tended to remain in stationary, hunched position and their respiration was decreased, and, the females exihibited slow placement of the feet when walking.
By day 1, clinical signs were evident in two of the three low dose male and female rats. Most animals were markedly weak and remained in stationary, prone position, and they tened to hold their mouth open. The respiration of the animals was decreased and often shallow, slight pilomotor reaction was noted, and many rats appeared shaky, particularly when attempting to move. In addition, some animals at the higher doses were nearly prostrate, barely able to move, and slightly limp; a few animals also appeared flushed.
All mortality occurred within 2 to 6 days of dosing. Prior to death, the animals were often prostrate, barely breathing, and felt cool. Several rats appeared thin and unkempt, and a reddish staining was noted generally around their nose and mouth.
Body weight:
With the exception of the two low dose animals that remained asymptomatic, all rats lost weight within 1 or 2 days of dosing, and their food consumption and/or fecal output were usually decreased. The general condition of most survivors remianed essentially unchanged for several days, and a continued weight loss was often evident. The low dose males recovered by day 3 or day 4, but clinical signs persisted in the other survivors for 5 to 8 days after dosing. A progressive body weight gain was apparent in the survivors from day 4,5 or 6 until sacrifice; howener, the overall body weight gain of animals given 1000 mg/kg and that of the two low dose females that exhibited clinical signs was less than that expected for rats of this age.
Gross pathology:
In the animals found dead on day 2 or day 3, the liver was dark, a yellowish material was apparent on the mucosa of the stomach near the pylorus, and portions of the small intestine were rendened and contained a yellow material. In the rats found dead on day 4 or 6, the lungs were reddened and mottled, the liver was dark, and the pancreas appeared white. The stomach contained a considerable amount of food, but the intestines were essentially empty. The kidneys were dark in situ and reddened throughout when cross-sectioned, the spleen was small, and a lack of body fat was noted.
At sacrifice on day 14, no gross pathological changes were apperent in any of the surviving rats with the exception of one low dose male which had been asyptomatic throught the study period. In this animal, white focal areas, measuring 1 to 2 mm in diameter, were visible on the aglandular portion the stomach when viewed in situ. When the stomach was excised and oppened, six raised areas, ranging in size from 1 to 8 mm in diameter, were apperent on the aglandular mucosa. At the three larger areas, there was a very narrow band of whitish, thichened, and rounded tissue at the perimeter of the rained edge. The center of these areas was depressed and often contained a small amount oof white material that was firmly adhered to the underlying mucosa. No gross changes were noted on the glandular portion of the stomach, and all other internal organs of this animal appeared essentially normal.
Other findings:
Microscopically, the raised white areas that were seen grossly on the mucosa of the aglandular stomach are keratinaceous cysts with associated mucosal dysplasia. These structures appear to be developmental defects rather than treatment-related lesions. The mucosal projections consist of submucosal, keratin-filled cysts opening to the interior of the stomach via small pores surrounded by narrow rims of glandular mucosa consisting of many pits lined by simple cilumnar epithelium and scattered goblet cells. These are overlain by mucus, keratin, and cell debris and in turn are surrounded by rims of thickly keratinized, stratified squamous epithelium that becomes less keratinized where it extends down onto the stalk of each projection.
Interpretation of results:
Toxicity Category IV
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
The approximate acute oral median lethal dose (LD50) of the test item in the female rat was estimated to be in the range of 500 - 1000 mg/kg body weight, and the approximate LD50 for males was between 1000 and 2000 mg/kg bw.
Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LD50
500 mg/kg bw
Quality of whole database:
1 (reliable without restriction)

Additional information

Oral:

One read-across study on rats is available.

The approximate acute oral median lethal dose (LD50) of the test item in the female rat was estimated to be in the range of 500 -1000 mg/kg body weight, and the approximate LD50 for males was between 1000 and 2000 mg/kg bw (Stadnicki, 1988). See read-across justification document attached in section 13.

Justification for selection of acute toxicity – oral endpoint

Read-across study run to a method comparable with current guidelines and to GLP

Justification for classification or non-classification

300 < Oral LD50 <= 2000 mg/kg bw (actual value: F 500 - 1000 mg/kg bw, M 1000 - 2000 mg/kg bw); no significant toxic effects observed.

Therefore in accordance with Regulation (EC) No. 1272/2008 (as amended by Regulation (EC) No. 286/2011) Table 3.1.1, this substance should be classified as Category 4 for acute oral toxicity.

In accordance with Regulation (EC) No. 1272/2008 Table 3.8.1, this substance should not be classified for STOT SE endpoint.