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Toxicological information

Acute Toxicity: oral

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Administrative data

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Meets generally accepted scientific standards, well documented and acceptable for assessment

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1982
Report Date:
1982

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
other: No data
Principles of method if other than guideline:
Species: Fischer 344
Exposure: Five dosage levels (0, 560, 1000, 1800, and 3600 mg/kg) were tested in groups of ten (5 male and 5 female) fasted rats.
Examinations: Mortalities, sublethal effects and necropsy
GLP compliance:
no
Test type:
other:
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
solid: crystalline

Test animals

Species:
rat
Strain:
Fischer 344
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Breeding Laboratories, Portage, Michigan.
- Age at study initiation: No data
- Weight at study initiation:
Male: 250.7 +/- 3.1 - 249.1 +/- 3.8
Female: 172.8 +/- 3.1 - 168.1 +/- 2.9
- Fasting period before study: Fasted overnight.
- Housing: Caged individually in polycarbonate wire-mesh cages.
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: 14 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): Average temperature 22.1 (18.9-22.2)°C
- Humidity (%): Average relative humidity 39.4 (22-54)%.
- Air changes (per hr): No data
- Photoperiod (hrs dark / hrs light): A light cycle of 12 hours on (6 a.m. -6 p.m.) and 12 hours off was maintained throughout the study.

Administration / exposure

Route of administration:
other: oral: administered using a ball-tipped intubating needle-syringe assembly.
Vehicle:
other: 1% aqueous methyl cellulose (METHOCEL(R))
Details on oral exposure:
VEHICLE
- Concentration in vehicle: 5.6, 10.0 and 18.0% w/v
- Amount of vehicle (if gavage): A constant dose volume of 10 mL/kg was used for all treatments except for the 3600 mg/kg dose level where the dose volume
used was 20 mL/kg.
- Justification for choice of vehicle: No data
- Lot/batch no. (if required): No data
- Purity: No data

MAXIMUM DOSE VOLUME APPLIED: 3600 mg/kg as a 18% concentration (20 mL/kg)

Doses:
A constant dose volume of 10 mL/kg was used for all treatments except for the 3600 mg/kg dose level where the dose volume used was 20 mL/kg.

Dose (mg/kg) Dose Concentration (%)
3600 18.0
1800 18.0
1000 10.0
560 5.6
No. of animals per sex per dose:
50 animals in total
5 males and 5 females per dose (10 per dose, 4 doses)
5 males and 5 females as control
Control animals:
yes
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Body weights were obtained on days -1, 0, 7 and 14.
- Necropsy of survivors performed: yes, surviving animals on day 14 were necropsied following euthanasia with carbon dioxide.
- Other examinations performed: Observations for clinical signs of toxicity were made hourly for a six hour period, at 24 hours, and twice daily (a.m. and p.m.) thereafter until termination of the study on day 14. All animals dying during the study were necropsied.
Statistics:
Statistical analysis of body weights included the calculation of mean (x) and standard error (S.E.). Determination of the significance of body weight changes at day 7 and 14 compared to controls was made by an independent T-test. The lethal dose (LD50 and 95% confidence limits) was determined by a computerized log-probit method of Finney. A probability level of 0.05 was used as criterion for significance.

Results and discussion

Effect levels
Sex:
male/female
Dose descriptor:
LD50
Effect level:
850 mg/kg bw
Based on:
test mat.
95% CL:
612 - 1 114
Remarks on result:
other: mg/kg
Mortality:
All rats at the 3600 mg/kg dose level died 2-3 hours following dosing. In the lower dose groups. the majority of deaths occurred overnight between 6
and 24 hours post-dosing.
Clinical signs:
One control animal, 65-60, was observed to have diarrhea at the fourth hourly observation; no other toxic effects were seen in control animals. Surviving rats generally recovered within 48 hours after dosing.
Prominent signs of toxicity included: polyuria, lacrimation, loss of pain reflex, ataxia, hypoactivity. emprosthotonus, tremors, diminished or blocked myotactic plaoing reflex, loss of righting reflex, clonic convulsions, and prostration. Other less prominent effects observed were diarrhea, soft stool, salivation, ptosis, hypotonus, respiratory dysfunction-hypopnea, hyperpnea, dyspnea and rales, hypothermia, and cyanosis. Rapid rigor was observed following cessation of respiration.
Body weight:
A significant decrease in mean body weight gain was observed on days 7 and 14 in female rats treated with 560 mg/kg Crude Catalyst 32899.
Gross pathology:
Principal findings in rats dying during the study were related to the gastro-intestinal tract: distention with fluid, enlarged caecum and hemorrhagic areas in
the stomach. Incidental findings were: yellow or white discharge around the mouth, yellow urogenital staining and brown watery anal staining.
No remarkable necropsy findings were found in surviving rats.

Any other information on results incl. tables

Table 1. Incidence of Lethality in Rats Orally Administered Crude Catalyst 32899

Crude Catalyst

32899 (mg/kg)

Male

Female

Total

No. Tested

No. Dead

No. Tested

No. Dead

No. Tested

No. Dead

3600

5

5

5

5

10

10

1800

5

4

5

5

10

9

1000

5

3

5

5

10

8

560

5

0

5

1

10

1

-a)

5

0

5

0

10

0

LD50(mg/kg)

1082 (651 – 1794)b)

850 (612 – 1114)

Slope +/- S.E.

2.30 +/- 0.89

2.29 +/- 0.68

a) control animals administered 10 mL/kg of 1% aqueous methyl cellulose/ kg body weight.

b) figures in parenthesis represent 95% confidence limits. 5

Applicant's summary and conclusion

Interpretation of results:
harmful
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
An acute oral toxicity study was conducted in the rat on Crude Catalyst 32899. Five dosage levels (0, 560, 1000, 1800, and 3600 mg/kg) were tested in groups of ten (5 male and 5 female) fasted rats. The acute oral LD50 was calculated to be 850 mg Crude Catalyst 32899/kg body weight with 95% confidence limits of 612-1114 mg/kg.
Executive summary:

An acute oral toxicity study was conducted in the rat on Crude Catalyst 32899. Five dosage levels (0, 560, 1000, 1800, and 3600 mg/kg) were tested in groups of ten (5 male and 5 female) fasted rats. The acute oral LD50 was calculated to be 850 mg Crude Catalyst 32899/kg body weight with 95% confidence limits of 612-1114 mg/kg. Lethalities generally occurred within 24 hours after dosing. The onset of clinical signs of toxicity occurred within one hour. Survivors generally recovered from observable clinical signs of toxicity within 48 hours after dosing. Body weight gain of survivors was decreased in the 560 mg/kg female dosage group at days 7 and 14. Prominent clinical signs of toxicity included: polyuria, lacrimation, loss of pain reflex, ataxia, hypoactivity, emprosthotonus, diminished myotactic placing reflex, loss of righting reflex, clonic convulsions, and prostration. Necropsy findings in animals dying over the first 24 hours involved primarily the gastro-intestinal tract (distension with fluid and hemorrhagic areas in the stomach). Necropsy findings in survivors were not remarkable.