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Acute Toxicity: oral

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Administrative data

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
20 November - 4 December 2001
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP/Guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2002
Report Date:
2002

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
EPA OPPTS 870.1100 (Acute Oral Toxicity)
Deviations:
not specified
GLP compliance:
yes
Test type:
standard acute method
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
other: Pale yellow liquid
Details on test material:
Kordek 573F, Lot #8001J123 (TD01-119)

Test animals

Species:
rat
Strain:
other: CD (BR)
Sex:
male/female
Details on test animals and environmental conditions:
Animals were received from Charles River Laboratories, Stoneridge, NY on 11/13/01. Following a quarantine period of at least five days, eighteen healthy male and eighteen healthy, nonpregnant and nulliparous female CD (BR) rats were randomly assigned to the treatment group using computer generated numbers.

The animals were born 9/10 and 9/24/01. The pretest body weight range was 218 - 236 grams for males and 202 - 228 grams for females. The weight variation of the animals used did not exceed +/- 20% of the mean weight.

The animals were identified by cage notation and indelible body marks, and housed 1/cage in suspended wire cages. Bedding was placed beneath the cages and changed at least three times/week. Fresh Purina Rat Chow (Diet #5012) was freely available except for 16-20 hours prior to dosing. Water was freely available at all times. The animal room, reserved exclusively for rats on acute tests, was temperature controlled, had a 12 hour light/dark cycle, and was kept clean and vermin free.

The temperature range of the animal room was 19.44 to 21.11C and the relative humidity was 21 to 72%. Although the relative humidity range was slightly outside of the acceptable range, this minor deviation was not considered to have had any adverse effect on the conduct or results of this study.

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
water
Details on oral exposure:
The test article was diluted with distilled water to the appropriate concentration for each dose. All rats received their treatment in a single dose at a constant volume of 10 ml/kg. The dose was administered orally by syringe and dosing needle and all doses were administered as mg of active ingredient per kg of body weight.
Doses:
150, 180, 225 and 300 mg a.i./kg
No. of animals per sex per dose:
6 females at 150, 6 males and 6 females at 180 and 225 and 6 males at 300 mg a.i./kg (total of 18 males and 18 females)
Control animals:
not specified
Details on study design:
In Vivo - Animals were observed 1, 2 and 4 hours postdose and once daily for 14 days for toxicity and pharmacological effects. The animals were observed twice daily for mortality. Body weights were recorded immediately pretest, weekly, at death and at termination in the survivors.

Post Mortem - All animals were examined for gross pathology.
Statistics:
The LD50 and 95% Confidence Limits were calculated by the method of Litchfield J.T. Jr., & F. Wilcoxon JPET 96:99. The LD50 (with Confidence Limits) for males was also calculated using Thompson's Moving Average Method (Thompson's, W.R. "Use of Moving Averages and Interpolation to Estimate Median - Effective Dose" Bacteriological Reviews, Vol. II, No. 2, June, 1947, pp. 115-145).

The LD50 in males was also calculated using the Moving Averages Method (Thompson's, W.R. "Use of Moving Averages and Interpolation to Estimate Median - Effective Dose" Bacteriological Reviews, Vol. II, No. 2, June, 1947, pp. 115-145).

Results and discussion

Effect levelsopen allclose all
Sex:
female
Dose descriptor:
LD50
Effect level:
120 mg/kg bw
Based on:
act. ingr.
95% CL:
79 - 182
Sex:
male
Dose descriptor:
LD50
Effect level:
232 - 249 mg/kg bw
Based on:
act. ingr.
Mortality:
Mortality response to the four oral dose levels is in Table 1. The deaths occurred by day 6.
Clinical signs:
Physical signs in animals that died included lethargy, few feces, soiling of the anogenital area, sagging eyelids, emaciation, ataxia, diarrhea, piloerection, flaccid muscle tone and prostration were observed.

Physical signs noted in survivors included lethargy, diarrhea, soiling of the anogenital area, piloerection, wetness of the anogenital area and ataxia. Surviving animals returned to normal by day 7.
Body weight:
Body weight changes of survivors were normal.
Gross pathology:
Necropsy of the animal which died revealed abnormalities of the lungs, liver, thymus, kidneys, adrenals, pancreas and gastrointestinal tract. Additionally, emaciation, chromorhinorrhea, chromodacryorrhea, brown staining, soiling and wetness of the anogenital area, as well as red staining, brown staining and wetness of the nosefmouth area were also noted.

Mottled appearance of the kidneys were noted at necropsy in a number of survivors.
Other findings:
The LD50 in males was 249 mg a.i./kg (95% Confidence Limits of 4-14,970). Because the Confidence Limits were so wide, we confirmed the male oral LD50 using Thompson's Moving Average Method. Using this method, the LD50 in males was 232 mg a.i./kg with 95% Confidence Limits of 176-306 mg a.i.1kg. This is in good agreement with the oral LD50 determined using the Litchfield Wilcoxon method and in this study the oral LD50 in males is considered to be 232 to 249 mg a.i./kg. The LD50 and 95% Confidence Limits in females are: 120 (79 - 182) mg/kg.

Any other information on results incl. tables

Table 1 Mortality

 Dose mg a.i./kg  # Treated M/F  # Dead M/F
 150  0/6  NA/4
 180  6/6  4/5
 225  6/6  1/5
 300  6/0  6/NA

Applicant's summary and conclusion

Interpretation of results:
Category 3 based on GHS criteria
Remarks:
Migrated information
Conclusions:
The oral LD50 of 2-methyl-4-isothiazolin-3-one is 232-249 mg a.i./kg in males and 120 mg a.i./kg in females.
Executive summary:

Objective:

To determine the potential for toxicity of the test article when administered orally. This study was designed to comply with the standards set forth in EPA Health Effects Test Guidelines, OPPTS 870.1100, final guideline, August 1998.

Method Synopsis:

Eighteen healthy male and eighteen healthy female CD®(BR) rats were assigned to four groups of 6 animals/group and dosed orally with 2-methyl-4-isothiazolin-3-one (supplied as a 50% solution of the active ingredient in water known as Kordek™ 573F Industrial Microbiocide, Lot #8001 J123 TD01-119) as indicated below. All doses were administered as mg of active ingredient per kg of body weight to fasted animals. The rats were observed 1, 2 and 4 hours postdose and once daily for 14 days for toxicity and pharmacological effects. The animals were observed twice daily for mortality. Body weights were recorded immediately pretest, weekly, at death and at termination in the survivors. All animals were examined for gross pathology. The LD50 and 95% Confidence Limits were calculated by the method of Litchfield & Wilcoxon. The LD50 (with Confidence Limits) for males was also calculated using Thompson's Moving Average Method.

Summary:

Mortality response to the four oral dose levels was:

 Dose mg a.i./kg  # Treated M/F  # Dead M/F
 150  0/6  NA/4
 180  6/6  4/5
 225  6/6  1/5
 300  6/0  6/NA

Conclusion:

The LD50 in males was 249 mg a.i./kg (95% Confidence Limits of 4-14,970). Because the Confidence Limits were so wide, we confirmed the male oral LD50 using Thompson's Moving Average Method. Using this method, the LD50 in males was 232 mg a.i./kg with 95% Confidence Limits of 176-306 mg a.i./kg. This is in good agreement with the oral LD50 determined using the Litchfield Wilcoxon method and in this study the oral LD50 in males is considered to be 232 to 249 mg a.i./kg. The LD50 and 95% Confidence Limits in females are: 120 (79 - 182) mg a.i./kg.