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Diss Factsheets

Administrative data

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2012
Report date:
2012

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to guideline
Guideline:
OECD Guideline 425 (Acute Oral Toxicity: Up-and-Down Procedure)
Deviations:
no
Qualifier:
according to guideline
Guideline:
EPA OPPTS 870.1100 (Acute Oral Toxicity)
Deviations:
no
GLP compliance:
yes
Test type:
up-and-down procedure
Limit test:
no

Test material

Constituent 1
Test material form:
solid
Details on test material:
- Purity: 99.9%

Test animals

Species:
rat
Strain:
other: Crl:CD(SD)
Sex:
female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Age at study initiation: 10-12 weeks old
- Fasting period before study: The rats were fasted approximately 16.5-19.5 hours prior to dosing, with food being returned to the rats approximately 3.5-4 hours after dosing.
- Housing: All animals were housed singly in polycarbonate pans that contained bedding with enrichment
- Diet: PMI® Nutrition International, LLC Certified Rodent LabDiet® 5002 was available ad libitum except before dosing.
- Water: ad libitum
- Acclimation period: 6-day quarantine period

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-26ºC
- Humidity (%): 30-70%
- Photoperiod (hrs dark / hrs light): an approximate 12-hour light/dark cycle

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
other: mixed with 0.1% Tween-80 (V/V) in 0.5% methycellulose
Doses:
175, 550, 1750, or 5000 mg/kg
No. of animals per sex per dose:
175 mg/kg - 1
550 mg/kg - 1
1750 mg/kg - 3
5000 mg/kg - 3
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations: Observations for mortality and signs of illness, injury, or abnormal behaviour were made daily throughout the study. The rats were observed for clinical signs at the beginning of fasting, just before dosing (test day 0), once during the first 30 minutes after dosing and 2 more times on the day of dosing, and once each day thereafter. Rats were weighed on test days –1, 0, 7, and 14. On test day 14, the surviving rats were euthanized and necropsied to detect grossly observable evidence of organ or tissue damage.

Results and discussion

Effect levels
Key result
Sex:
female
Dose descriptor:
LD50
Effect level:
3 129 mg/kg bw
Based on:
test mat.
95% CL:
>= 1 750 - <= 5 000
Mortality:
175 mg/kg - 0 of 1 died
550 mg/kg - 0 of 1 died
1750 mg/kg - 0 of 3 died
5000 mg/kg - 3 of 3 died
Clinical signs:
No clinical signs were observed in the rat dosed at 175 mg/kg. Ataxia, decreased muscle tone, and high posture were observed on the day of dosing in the rat dosed at 550 mg/kg. One rat dosed at 1750 mg/kg exhibited ataxia, decreased muscle tone, and high posture on the day of dosing. Another rat dosed at 1750 mg/kg exhibited ataxia, eyelid ptosis, decreased muscle tone, and high posture on the day of dosing. The remaining rat dosed at 1750 mg/kg exhibited ataxia, decreased muscle tone, low posture, and splayed forelimbs and hindlimbs on the day of dosing. Ataxia, laboured breathing, cold to touch, clear ocular discharge, decreased muscle tone, and prostrate posture were observed on the day of dosing and/or the day after dosing in a rat dosed at 5000 mg/kg. This rat was moribund and underwent unscheduled sacrifice for humane reasons on the day after dosing. Another rat dosed at 5000 mg/kg exhibited ataxia, fast or slow breathing, cold to touch, clear ocular discharge, decreased muscle tone, and prostate posture on the day of dosing. This rat was moribund and underwent unscheduled sacrifice for humane reasons on the day of dosing. The remaining rat dosed at 5000 mg/kg exhibited ataxia, fast breathing, clear ocular discharge, low or prostate posture, and decreased muscle tone on the day of dosing. This rat was moribund and underwent unscheduled sacrifice for humane reasons on the day of dosing.

A rat that was supposed to be dosed at 1750 mg/kg but was dosed at 5000 mg/kg exhibited ataxia and decreased muscle tone and survived until scheduled sacrifice. No body weight loss occurred in this rat after dosing. No gross lesions were observed in this rat at necropsy.
Body weight:
No body weight loss occurred in surviving rats after dosing.
Gross pathology:
No test substance-related gross lesions were found in the study. The only gross lesion observed, urinary bladder distended with fluid (dark) in a rat dosed at 5000 mg/kg, was nonspecific, occurred in a single incidence, and is a common finding in rats of this strain and age.

Applicant's summary and conclusion

Interpretation of results:
GHS criteria not met
Conclusions:
LD50 (female rats): 3129 mg/kg
Executive summary:

A single dose of the test substance was administered by oral gavage to fasted female rats at a dose of 175, 550, 1750, or 5000 mg/kg. The rats were dosed one at a time at a minimum of 48-hour intervals. The rats were observed for mortality, body weight effects, and clinical signs for up to 14 days after dosing. All rats were necropsied to detect grossly observable evidence of organ or tissue damage.

Three rats dosed at 5000 mg/kg were moribund and underwent unscheduled sacrifice for humane reasons on test day 0 or 1. These rats exhibited ataxia; laboured, fast, or slow breathing; cold to touch; clear ocular discharge; prostrate or low posture; and/or decreased muscle tone. One rat, which was supposed to be dosed at 1750 mg/kg, was dosed at 5000 mg/kg. This rat exhibited ataxia and decreased muscle tone and survived until scheduled sacrifice. No clinical signs were observed in the rat dosed at 175 mg/kg. The rat dosed at 550 mg/kg exhibited ataxia, decreased muscle tone, and high posture on the day of dosing. The 3 rats dosed at 1750 mg/kg exhibited ataxia, decreased muscle tone, high or low posture, splayed limbs, and/or eyelid ptosis on the day of dosing. No body weight losses occurred in surviving rats. No test substance-related gross lesions were found in the study.

Under the conditions of this study, the estimated oral LD50 for the test substance was 3129 mg/kg for female rats.

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