2-methyl-2H-isothiazol-3-one

Endpoint summary

Description of key information

Acute toxicity: oral - An acute oral toxicity study was condcuted in accordance with Good Laboratory Practice (GLP) and as per US EPA OPPTS 870.1100 guideline. Groups of CD (BR) rats were administered orally via gavage 2 -methylisothiazol-3(2H)-one at 150, 180, 225 and 300 mg a.i./kg. Under the conditions of the study, the oral LD50 of 2-methyl-4-isothiazolin-3-one was 232-249 mg a.i./kg in males and 120 mg a.i./kg in females.

Acute toxicity: inhalation - An acute inhalation toxicity study was condcuted in accordance with Good Laboratory Practice (GLP) and as per OECD 403 guideline. Groups of CD (BR) rats were exposed to an aerosol of 2 -methylisothiazol-3(2H)-one via nose only at concentrations of 0.046, 0.012, 0.150, 1.07 and 2.09 mg/liter air. Under the conditions of the study, the four hour combined inhalative LC50 of 2-methyl-4-isothiazolin-3-one was calculated to be 0.11 mg RH-573 Technical per liter of air with 95% confidence limits of 0.07 to 0.25 mg/L. The LC50 for male rats was 0.13 mg/L (95% confidence limits = 0.06-0.53 mg/L) and for female rats the LC50 was 0.10 mg/L (confidence limits could not be calculated). There was no significant difference in the mortality response between male and female rats exposed to RH-573 Technical by nose-only inhalation.

Acute toxicity: dermal - An acute dermal toxicity study was condcuted in accordance with Good Laboratory Practice (GLP) and as per US EPA OPPTS 870.1200 and OECD 402 guidelines. Groups of CD (BR) rats were exposed dermally to 2 -methylisothiazol-3(2H)-one at 100, 200, 300 and 400 mg a.i./kg under occlusive conditions. Under the conditions of the study, the combined dermal LD50 of 2-methyl-4-isothiazolin-3-one was 242 mg/kg with 95% confidence limits of 192 to 294 mg/kg.

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:

20 November - 4 December 2001

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: GLP/Guideline study

Qualifier:

according to guideline

Guideline:

EPA OPPTS 870.1100 (Acute Oral Toxicity)

Deviations:

not specified

GLP compliance:

yes

Test type:

standard acute method

Limit test:

no

Species:

rat

Strain:

other: CD (BR)

Sex:

male/female

Details on test animals or test system 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.

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).

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:

other: 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 l

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.

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

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.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LD50

Value:

120 mg/kg bw

Quality of whole database:

Klimisch 1

Acute toxicity: via inhalation route

Link to relevant study records

Reference

Endpoint:

acute toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

key study

Study period:

26 June - 3 August 1995

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: GLP/Guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 403 (Acute Inhalation Toxicity)

Deviations:

not specified

GLP compliance:

yes

Test type:

standard acute method

Limit test:

yes

Species:

rat

Strain:

other: Crl: CD®BR

Sex:

male/female

Details on test animals or test system and environmental conditions:

- Source: Crl: CD®BR, Charles River, Kingston (Stone Ridge, NY, USA)
- Age: Males: 7-8 weeks; females: 9-10 weeks
- Weight at study initiation: males: 201-329 g; females: 200-257 g
- Number of animals: 60 (24/sex)
- Controls: Not described.

Route of administration:

inhalation: aerosol

Type of inhalation exposure:

nose only

Vehicle:

other: water

Details on inhalation exposure:

- Type of exposure: 4 hour nose-only inhalation
- Concentrations: 0.046, 0.012, 0.150, 1.07 and 2.09 mg/L air
- Particle size: 3.5, 3.1, 3.8, 5.2 and 5.3 um
- Type or preparation of particles: aerosol and vapor

Analytical verification of test atmosphere concentrations:

yes

Remarks:

HPLC analysis of captured airborne concentration in impingers

Duration of exposure:

4 h

Concentrations:

Analytical concentrations were 0.046, 0.012, 0.150, 1.07 and 2.09 mg RH-573 Technical/L air

No. of animals per sex per dose:

6 males and 6 females

Control animals:

not specified

Details on study design:

Observations and Evaluations
All animals were weighed just prior to exposure (day 0), and again on days 7 and 14 post-exposure. The animals were observed for signs of toxicity during the exposure, upon removal from the chamber, and 3 to 4 hours after termination of the exposure. For the remainder of the study, the animals were observed at least once daily for morbidity, mortality and clinical signs. At the end of the fourteen-day observation period, all surviving animals were anesthetized with sodium pentobarbital (50 mg/kg, ip), exsanguinated from the abdominal aorta, and necropsied. Visual examinations were made of external structures and body orifices. Thoracic and abdominal organs were also examined. In addition, although not specified in the protocol, the cervical lymph nodes, salivary glands and thyroids were examined.

In order to determine the airborne concentration of RH-573 Technical in the exposure chamber atmosphere, a two (Groups 1 and 2) or one (Groups 3,4 and 5) impinger train located outside the chamber was used for sampling. During the method development phase, it was determined for Groups 3, 4 and 5 that the concentrations were at a level where no break-through of the primary impinger would occur. Therefore, a single impinger was used for sampling for these groups. Each impinger (SKC, Inc., Eighty Four, PA) contained 12 ml of milli-Q water and was placed in an ice bath. The chamber atmosphere was drawn through the impingers at a flow rate of 0.7 L/min for 1 minute for Groups 1 and 2, 3 minutes for Groups 3 and 5, and 6 minutes for Group 4. Four samples were collected during each exposure.

After obtaining an impinger sample, the solution was transferred to a pre-weighed 20 ml scintillation vial and weighed again to determine the total material present. The solution was then sent to the Biocides Research Analytical Group for analysis by High Performance Liquid Chromatography (HPLC). The results of these analyses were reported in ug/ml of RH-573 Technical. Using the following equations, these results were converted to airborne concentrations in milligrams per liter (mg/L) of chamber atmosphere:

(1) mg of RH-573 a.i. = ug/ml a.i./1.0 g/ml* x (g of solution/1000)
(2) mg/L RH-573 in air = mg RH-573 (a.i.)/(sample duration x flow rate)
* density of Milli-Q water

In addition, gravimetric determinations of the aerosol concentration were made periodically during each exposure. A known volume of exposure chamber atmosphere was drawn through a pre-weighed glass fiber filter. The change in weight of the filter divided by the sample volume yielded the aerosol concentration. The gravimetric filters were used solely as a means of monitoring the total aerosol concentration during exposure, and not to determine an analytical concentration of RH-573 Technical in the chamber atmosphere. Therefore, these values were not reported.

Particle Size Determination
Particle size determination was determined at least once during each exposure by drawing samples of the chamber atmosphere through an 8-stage Anderson cascade impactor fitted with glass fiber collection disc (Anderson, 1966).

Statistics:

The calculation of mass median aerodynamic diameter (MMAD) and geometric standard deviation (GSD) was performed by computer using a log-probit regression analysis program (Hagan, 1980). The respirable fraction was calculated from the MMAD and the GSD in the RFB program (Moss and Baldwin, 1983) on a programmable calculator. This program defines "respirable fraction" as that fraction of an aerosol that would pass a size-selector described by the American Conference of Governmental Industrial Hygienists (ACGIH), with the following characteristics: 90% of /=10 um particles will pass through the selector (Lippman, 1978).

References:
Hagan, J.V. (1980). SAS program. Copy retained in Rohm and Haas Co., Toxicology Department S.O.P. Section 19.8.2.a.

Lippman, M. (1978). Respirable Dust Sampling. Section G Sampling Dust Instruments. American Conference of Governmental Industrial Hygienists, Cincinnati, OH.

Moss, O. and Baldwin, R.C. (1983). Program written for an HP-97 calculator by O. Moss and modified for use on an HP-41C calculator by R.C. Baldwin. Program documented in Rohm and Haas Co., Toxicology Department S.O.P. Secion 19.8.2.b.

Key result

Sex:

male/female

Dose descriptor:

LC50

Effect level:

0.11 mg/L air

Based on:

test mat.

95% CL:

0.07 - 0.25

Exp. duration:

4 h

Key result

Sex:

male

Dose descriptor:

LC50

Effect level:

0.13 mg/L air

Based on:

test mat.

95% CL:

0.06 - 0.53

Exp. duration:

4 h

Key result

Sex:

female

Dose descriptor:

LC50

Effect level:

0.1 mg/L air

Based on:

test mat.

Exp. duration:

4 h

Remarks on result:

other:

Remarks:

95% CL could not be calculated

Mortality:

* Time of death:
- 2.09 mg/L : 3 males & 1 female during exposure ; 2 males & 2 females by day 1 ; 1 male by day 2 (total 9 of 12 died)
- 1.07 mg/L : 6 males and 3 females during exposure (total 9 of 12 died)
- 0.15 mg/L : 2 males and 4 females during exposure and one male and one female died one day later (total 8 of 12 died)
- 0.046 mg/L : 1 male during exposure (total 1 of 12 died)
- 0.012 mg/L: (total 0 of 12 died

* Number of deaths at each dose:
9/12 (6 males & 3 females) at 2.09 mg/L
9/12 (6 males & 3 females) at 1.07 mg/L
8/12 (3 males & 5 females) at 0.15 mg/L
1/12 (1 female) at 0.046 mg/L
0/12 at 0.012 mg/L

Clinical signs:

other: Clinical signs seen in some, yet not all groups included gasping, rales, labored breathing, respiratory noise, salivation, red-stained eyes, muzzle and nasal exudate, passiveness and ataxia. Except for one male exposed to 0.15 mg/L that exhibited respi

Body weight:

With the exception of two females, one exposed to 1.07 mg/L (Group 2) and one exposed to 0.012 (Group 4), all surviving animals exceeded their pre-exposure body weight by day 7. Body weight gain was highly variable with no apparent exposure-related effects.

Gross pathology:

Slight to severe redness in lung, scattered incidences of red pinpoint foci on lungs, and gas-filled stomachs. These findings are consistent with the clinical signs of respiratory irritation.
POTENTIAL TARGET ORGANS: Lungs

Other findings:

Particle size distributions for Groups 1, 2, 3, 4 and 5 were characterized by mean mass median aerodynamic diameters (MMAD) of 5.3 +/- 0.3, 5.2 +/- 0.1, 3.8 +/- 0.3, 3.1 +/- 0 and 3.5 +/- 0.7 um, respectively. The mean geometric standard deviation for Groups 1, 2, 3, 4 and 5 were 2.4 +/- 0.1, 2.2 +/- 0.1, 2.0 +/- 0.1, 2.2 +/- 0 and 2.4 +/- 0.1, respectively. The mean respirable fraction for Groups 1, 2, 3, 4 and 5 were 33.5 +/-2.1, 33.5 +/-0.7, 46.5 +/- 3.5, 54.0 +/- 0 and 49.5 +/- 7.8%, respectively.

The four hour combined LC₅₀ was calculated to be 0.11 mg RH-573 Technical per liter of air with 95% confidence limits of 0.07 to 0.25 mg/L. The LC₅₀ for male rats was 0.13 mg/L (95% confidence limits = 0.06-0.53 mg/L) and for female rats the LC₅₀ was 0.10 mg/L (confidence limits could not be calculated). There was no significant difference in the mortality response between male and female rats exposed to RH-573 Technical by nose-only inhalation.

Interpretation of results:

Category 2 based on GHS criteria

Remarks:

Migrated information

Conclusions:

The four hour combined LC50 was calculated to be 0.11 mg RH-573 Technical per liter of air with 95% confidence limits of 0.07 to 0.25 mg/L. The LC50 for male rats was 0.13 mg/L (95% confidence limits = 0.06-0.53 mg/L) and for female rats the LC50 was 0.10 mg/L (confidence limits could not be calculated). There was no significant difference in the mortality response between male and female rats exposed to RH-573 Technical by nose-only inhalation.

Executive summary:

The acute inhalation toxicity of RH-573 Technical to rats was examined. The four hour combined LC₅₀ was calculated to be 0.11 mg RH-573 Technical per liter of air with 95% confidence limits of 0.07 to 0.25 mg/L. The LC₅₀ for male rats was 0.13 mg/L (95% confidence limits = 0.06-0.53 mg/L) and for female rats the LC₅₀ was 0.10 mg/L (confidence limits could not be calculated). There was no significant difference in the mortality response between male and female rats exposed to RH-573 Technical by nose-only inhalation.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LC50

Value:

0.34 mg/m³ air

Quality of whole database:

Klimisch 1

Acute toxicity: via dermal route

Link to relevant study records

Reference

Endpoint:

acute toxicity: dermal

Type of information:

experimental study

Adequacy of study:

key study

Study period:

No data.

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: GLP/Guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

Deviations:

not specified

Qualifier:

according to guideline

Guideline:

EPA OPPTS 870.1200 (Acute Dermal Toxicity)

Deviations:

not specified

Qualifier:

according to guideline

Guideline:

other: Japan 59 NohSan Notification No. 4200, Acute Dermal Toxicity Study

Deviations:

not specified

Qualifier:

according to guideline

Guideline:

EU Method B.3 (Acute Toxicity (Dermal))

Deviations:

not specified

GLP compliance:

yes

Test type:

standard acute method

Limit test:

no

Species:

rat

Strain:

other: Crl:CD®BR

Sex:

male/female

Details on test animals or test system and environmental conditions:

Adult male and female Crl:CD®BR rats were obtained from Charles River Laboratories, Raleigh, NC. Upon arrival, all animals were examined for physical abnormalities and quarantined/acclimated for approximately one week. The animals were individually housed in suspended stainless steel cages (18x34x20 cm) with wire mesh fronts and bottoms. Cages were suspended above absorbent-paper pan liners which were changed 3 times a week. Throughout the test period, all rats had free access to water (via automatic watering) purified by reverse osmosis and PMI Certified Rodent Diet 5002(C) (Purina Mills Inc., Richmond, IN). The animal room was environmentally controlled with controls set to maintain a temperature of approximately 23°C and a relative humidity range of 30-70%. The temperature and relative humidity were monitored 24 hrs a day. During the study, the average daily temperature ranged from 22 to 23°C and average daily relative humidity ranged from 43 to 52%. Any excursions beyond these ranges were minimal and did not affect the integrity of the study. Temperature and relative humidity remained in compliance with acceptable ranges defined in the "Guide for the Care and Use of Laboratory Animals" ISBN No. 0-309-05377-3, Revised 1996. The light cycle was automatically controlled, 12 hrs on and 12 hrs off.

On the day prior to treatment, rats were selected from a healthy stock population, assigned to the study group using a computer-generated sequence of random numbers and identified by uniquely numbered ear tags. At the time they were dosed, the males were approximately 8 weeks old and the females were approximately 9 weeks old. The body weights ranged from 252 to 309 g for males and from 191 to 235 g for females.

Type of coverage:

occlusive

Vehicle:

unchanged (no vehicle)

Details on dermal exposure:

Approximately 24 hrs prior to the application of the test substance, the hair around the entire trunk between the flank and shoulders was shaved closely with electric clippers. The solid test substance was heated in an oven at approximately 45°C and applied topically to the shaved intact skin of male and female rats at 100, 200, 400 and/or 300 mg/kg body weight. Dose was calculated on an "as is" basis; no adjustment was made for percent active ingredient. The entire trunk of each animal was wrapped in a polyethylene sheet covered with Elastoplast® (Beiersdorf, Inc., Norwalk, CT) and PEG®(Becton-Dickinson Co., Franklin Lakes, NJ) elastic bandages and secured in place with adhesive tape.

The test substance remained in contact with the skin of each animal for 24 hrs. Each cuff was removed after the 24-hr exposure period, and the application site was wiped with paper towels saturated with tap water. The application site was blotted dry with paper towels, and the approximate dimensions of the contact area of the test substance were determined.

Each animal was fitted with a cardboard collar to prevent preening of the application site. The collar was worn throughout the 14 day observation period.

Duration of exposure:

24 hours

Doses:

100, 200, 300 and 400 mg/kg

No. of animals per sex per dose:

6 males and 6 females at 100, 200 and 400 mg/kg and 6 males at 300 mg/kg.

Control animals:

not specified

Details on study design:

The test substance was heated in an oven, dosed and occluded for 24 hrs on the back of rabbits. Test material was removed with a damp towel and a collar remained to keep the animal from licking the test material.

All animals were observed for signs of ill health, or reaction to treatment at approximately 1, 2 and 4 hrs after dosing and once daily thereafter for 14 days. Body weights were recorded on days 0 (prior to dosing), 7 and 14.

Decedents were necropsied as they were found. Surviving rats were killed on day 14 and necropsied. Necropsy consisted of a gross examination of organs in situ.

Statistics:

The mortality incidences of males and females were compared across doses with a categorical data modeling procedure using SAS CATMOD (SAS Institute Inc. SAS User's Guide: Statistics, Version 6 Edition, p 405-517. Cary, NC: SAS Institute Inc., 1990). The criterion of statistical significance was 0.05. Since the results did not indicate a significant difference between the mortality responses across dose groups for males and females, the LD50 was calculated on the pooled mortality incidences at each dose.

The LD50, 95% confidence limits, and slope were calculated from the logarithm of the doses and the incidences of mortality using a SAS PROBIT procedure (SAS Institute Inc. SAS User's Guide: Statistics, Version 6 Edition, p 1324-1350. Cary, NC: SAS Institute Inc., 1990) based on the method of D.J. Finney (Probit Analysis, Third Edition, London: Cambridge University Press, 1971).

Sex:

male/female

Dose descriptor:

LD50

Effect level:

242 mg/kg bw

Based on:

test mat.

95% CL:

192 - 294

Mortality:

Dose-related mortality occurred in this study at 200 mg/kg and above (Table 1).

Clinical signs:

other: Clinical signs of toxicity were noted at all dose levels in both sexes. These clinical signs were noted beginning on day 1 and included: scant and/or no feces, passiveness and ataxia. Surviving rats recovered from these signs by day 5. Labored breathing

Gross pathology:

Necropsy of the decedents revealed gastrointestinal changes which included: reddened and/or blackened intestines; red/black and/or yellow material in the intestines; reddened glandular portion of the stomach; and black material in the stomach. Necropsy of the survivors revealed no gross changes

Other findings:

After dermal application, the test substance covered an area approximately 3-4 cm x 4-5 cm.

The LD₅₀ value was calculated from the combined male and female mortality incidence data. The acute dermal LD₅₀ for Kordek 573T in male and female rats was 242 mg/kg with 95% confidence limits of 192 to 294 mg/kg. The log probit slope of the dose- mortality data (probit incidence versus log dose) was 6.79 in this study.

Table 1 Mortality data

Dose (mg/kg)	100	200	300	400
Males	0/6	0/6	5/6	5/6
Females	0/6	3/6	--	6/6
Combined Sexes	0/12	3/12	5/6	11/12

Interpretation of results:

Category 3 based on GHS criteria

Remarks:

Migrated information

Conclusions:

The LD50 value was calculated from the combined male and female mortality incidence data. The acute dermal LD50 for Kordek 573T in male and female rats was 242 mg/kg with 95% confidence limits of 192 to 294 mg/kg. The log probit slope of the dose-mortality data (probit incidence versus log dose) was 6.79 in this study.

Executive summary:

The acute dermal toxicity of Kordek 573T (Lot No. B-1103, Toxicology Department Sample No. 99-019, 97.5% active ingredient) was assessed in Crl:CD^®BR rats. The test substance was heated in an oven and applied to the shaved intact skin to three groups of six male and six female rats at 100, 200 and 400 mg/kg body weight. An additional group of six males were dosed at 300 mg/kg in order to determine the LD₅₀ for male rats. The application sites were occluded for 24 hrs. After the 24-hr exposure, the application sites were wiped with paper towels saturated with tap water and blotted dry with paper towels.

Dose-related mortality occurred in this study at 200 mg/kg and above. The total mortality incidences (no. deaths/no. treated) for males and females in this study were:

Dose (mg/kg)	100	200	300	400
Males	0/6	0/6	5/6	5/6
Females	0/6	3/6	--	6/6
Combined Sexes	0/12	3/12	5/6	11/12

Clinical signs of toxicity were noted at all dose levels in both sexes. These clinical signs were noted beginning on day 1 and included: scant and/or no feces, passiveness and ataxia. Surviving rats recovered from these signs by day 5.

Body weight gain in surviving rats was decreased (29-48%) among both sexes at 200 mg/kg and above when compared to historical control values. Skin effects were observed in both sexes at all levels beginning on day 1 and continuing through day 14. These effects included: blanching, edema, darkened areas, eschar, sloughing, scabbed areas and desiccation.

Necropsy of the decedents revealed gastrointestinal changes. Necropsy of the survivors revealed no gross changes. The LD₅₀ value was calculated from the combined male and female mortality incidence data. The acute dermal LD₅₀ for Kordek 573T in male and female rats was 242 mg/kg with 95% confidence limits of 192 to 294 mg/kg.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LD50

Value:

242 mg/kg bw

Quality of whole database:

Klimisch 1

Additional information

Acute toxicity: inhalation - The LC50 value of 0.07 mg/l air (ppm) was converted to a value 0.34 mg/m3 using a molecular weight of 115.15 for 2-methylisothiazol-3(2H)-one

Justification for classification or non-classification

Acute toxicity: oral - 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 and classified as Category 3 based on GHS criteria.

Acute toxicity: inhalation - The four hour combined LC50 was calculated to be 0.11 mg RH-573 Technical per liter of air with 95% confidence limits of 0.07 to 0.25 mg/L. The LC50 for male rats was 0.13 mg/L (95% confidence limits = 0.06-0.53 mg/L) and for female rats the LC50 was 0.10 mg/L (confidence limits could not be calculated) and classified as Category 2 based on GHS criteria.

Acute toxicity: dermal - The LD50 value was calculated from the combined male and female mortality incidence data. The acute dermal LD50 for Kordek 573T in male and female rats was 242 mg/kg with 95% confidence limits of 192 to 294 mg/kg and classified as Category 3 based on GHS criteria.