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

Skin irritation / corrosion

Administrative data

Endpoint:

skin irritation: in vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

4 June - 16 July 1996

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: GLP/Guideline

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1997

Report date:

1997

Materials and methods

Test guideline

Test guideline 1

Qualifier:

according to guideline

Guideline:

OECD Guideline 404 (Acute Dermal Irritation / Corrosion)

Deviations:

not specified

Test guideline 2

Qualifier:

according to guideline

Guideline:

other: US EPA 40 CFR Part 158; Guideline 81-3

Deviations:

not specified

Test guideline 3

Qualifier:

according to guideline

Guideline:

EU Method B.4 (Acute Toxicity: Dermal Irritation / Corrosion)

Deviations:

not specified

Test guideline 4

Qualifier:

according to guideline

Guideline:

other: U.S. D.O.T. Section 173.137

Deviations:

not specified

GLP compliance:

yes

Test material

Test material information

Constituent 1

Test material form:

other: brown solid

Details on test material:

The test substance, identified as RH-573 Technical (Lot No. SW 1029), was assigned Rohm and Haas Toxicology Department Sample No. 95-100. RH-573 Technical was a brown solid containing 97.8% 2-methyl-4-isothiazolin-3-one as the active ingredient.

Test animals

Species:

rabbit

Strain:

New Zealand White

Details on test animals or test system and environmental conditions:

Adult male New Zealand White rabbits were obtained from Hazleton Research Animals, Denver, PA. Upon arrival, all animals were examined for physical abnormalities, identified by uniquely numbered ear tags, and quarantined for approximately two weeks. The animals were individually housed in stainless steel cages (18 x24x14 in., i.e. 46x61x 37 cm) suspended above absorbent-paper pan liners which were changed 3 times per week. Throughout the test period, all rabbits had free access to filtered tap water (via automatic watering) and were fed approximately 125 g/day of PMI Certified High Fiber Rabbit Diet 5325 (Purina Mills Inc., Richmond, IN). All animal rooms were environmentally controlled with controls set to maintain a temperature of approximately 65°F (18°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 65 to 66°F (18 to 19°C) and average daily humidity ranged from 55 to 66%. Excursions beyond these ranges were minimal and did not affect the integrity of the study. Temperature and humidity remained in compliance with acceptable ranges defined in the "Guide for the Care and Use of Laboratory Animals" NIH Publication No. 86-23, Revised 1996. The light cycle was automatically controlled, 12 hrs on and 12 hrs off.

One day prior to dosing, rabbits were selected from a healthy stock population. At the time they were dosed, the animals were approximately 20 to 25 weeks old and their body weights ranged from 2868 to 3136 g.

Test system

Type of coverage:

other: Semiocclusive for 1 and 4 hour exposure and open for 3 minute exposure.

Preparation of test site:

shaved

Vehicle:

unchanged (no vehicle)

Controls:

not specified

Amount / concentration applied:

The solid test substance was heated to approximately 60°C (the test substance was allowed to cool at room temperature prior to dosing) and applied
(0.5 ml) onto a 1.0-in. square gauze-lined adhesive bandage which was applied to the shaved intact skin of one rabbit.

Duration of treatment / exposure:

4 hrs

Observation period:

1, 24, 48, 72 hrs and at 7 and/or 14 days after patch removal.

Number of animals:

1 animal each for 1 and 4 hour exposures and 6 rabbits for 3 minute exposure

Details on study design:

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 to approximately 60°C (the test substance was allowed to cool at room temperature prior to dosing) and applied (0.5 ml) onto a 1.0-in. square gauze-lined adhesive bandage which was applied to the shaved intact skin of one rabbit for 4 hrs. A semi-occluded dressing (i.e., fabric cuff secured with adhesive tape) was used to wrap the entire trunk of the animal. The rabbit was returned to its cage for a 4 hr exposure period. An additional rabbit was tested on two separate sites for a 1 hr (right side) and 3 minute (left side) exposure. The 1 hr site was treated in the same manner as the 4 hr. The animal remained uncuffed during the 3 minute exposure. Five additional rabbits were tested for 3 minute exposures to complete DOT testing requirements. The cuff and patch were removed after the appropriate exposure and the application site wiped with paper towels saturated with tap water. The application site was blotted dry with paper towels.

Observations and Determinations
Skin irritation was evaluated at approximately 1, 24, 48, 72 hrs and at 7 andlor 14 days after patch removal. The degree of irritation was evaluated
according to the criteria of Draize et al. (J. Pharmacol. Exp. Therap. 82, 377-390, 1944). In addition, all other skin reactions or signs of systemic toxicity were recorded. Animals were observed daily for mortality and reaction to treatment.

Results and discussion

In vivo

Results

Results 1

Irritation parameter:

erythema score

Basis:

mean

Time point:

24/48/72 h

Score:

1

Max. score:

2

Reversibility:

not fully reversible within:

Remarks:

7 days

Remarks on result:

positive indication of irritation

Results 2

Irritation parameter:

edema score

Basis:

mean

Time point:

24/48/72 h

Score:

0.4

Max. score:

3

Reversibility:

fully reversible within:

Remarks:

7 days

Remarks on result:

positive indication of irritation

Irritant / corrosive response data:

On the 4 and 1 hr sites, skin irritation indicative of corrositivity (i.e., concave eschar) was observed on day 14 and day 7, respectively. On the 4 hr exposure site, severe erythema was evident at all observation periods. Severe edema was noted up to and including day 7, but was no longer evident on day 14. On the 1 hr site, severe erythema was observed at all observation periods and severe edema was noted up to and including 72 hrs. Edema was no longer evident on day 7.

On the 3 minute site, very slight to well defined erythema was noted up to and including 24 hrs (all rabbits), at 48 hrs (4 rabbits), at 72 hrs (2 rabbits) and very
slight erythema (2 rabbits) was still evident on day 7. Very slight to moderate edema was noted at 1 hr (all rabbits) and at 24 hrs (2 rabbits). Very slight to slight
edema was noted in one rabbit at 48 and 72 hrs. Edema was no longer evident on day 7.

Other effects:

No mortality or clinical signs of systemic toxicity (other than skin effects) were observed during the study.

Any other information on results incl. tables

No additional information available.

Applicant's summary and conclusion

Interpretation of results:

corrosive

Remarks:

Migrated information Criteria used for interpretation of results: expert judgment

Conclusions:

According to the Rohm and Haas Company Acute Toxicity and Irritation Hazard Categories (September, 1994), RH-573 Technical is categorized as CORROSIVE to skin following a 4 hr exposure period (i.e., evidence of irreversible destruction of dermal tissue).

According to DOT Packing Group Classification guidelines for Class 8 material (June, 1990), RH-573 Technical is assigned to PACKING GROUP II (i.e., corrosive at the site of contact when tested on the intact skin of rabbits for a period of greater than 3 minutes but not more than 1 hr).

Executive summary:

Skin irritation of RH-573 Technical (Lot No. SW 1029, Toxicology Department Sample No. 95-100, 97.8% active ingredient) was assessed in New Zealand White rabbits. The solid test substance was heated to approximately 60°C (the test substance was allowed to cool at room temperature prior to dosing) and applied topically (0.5 ml) to the shaved intact skin of one male rabbit. The application site was semi-occluded for 4 hrs. After the 4 hr exposure, the application site was wiped with paper towels saturated with tap water and blotted dry with paper towels. Skin irritation was evaluated according to Draize criteria at approximately 1, 24, 48, 72 hrs and 7 days and 14 days after patch removal. No mortality or clinical signs of systemic toxicity were observed during the study. Skin irritation indicative of corrositivity (i.e., concave eschar) was observed. According to the Rohm and Haas Company Acute Toxicity and Irritation Hazard Categories (September, 1994), RH- 573 Technical is categorized as CORROSIVE to skin (i.e., evidence of irreversible destruction of dermal tissue).

Since corrosive findings were evident at 4 hrs, additional rabbits were tested to determine U.S. Department of Transportation (DOT) Packing Group classification. The solid test substance was heated to approximately 60°C (the test substance was allowed to cool at room temperature prior to dosing) and applied topically for 1 hr (0.5 ml, right side) and for 3 minutes (0.5 ml, left side) to the shaved intact skin of one male rabbit. The 1 hr application site was semi-occluded with a fabric cuff and the 3 minute site was uncuffed during the exposure period. After each exposure period, the application sites were wiped with paper towels saturated with tap water and blotted dry with paper towels. Skin irritation was evaluated according to Draize criteria at approximately 1, 24, 48, 72 hrs and 7 days after patch removal. Skin irritation indicative of corrositivity (i.e., concave eschar) was observed on the 1 hr site. On the 3 minute site, very slight to well defined erythema was noted through day 7 and slight edema was noted at 1 hr. An additional 5 rabbits were subjected to a 3 minute exposure (in the same manner as above) to complete DOT testing. Very slight to well defined erythema was noted through 48 hrs in most rabbits. Very slight to moderate edema was noted at 1 and 24 hrs. Very slight to slight edema was noted in one rabbit at 48 and 72 hrs. According to DOT Packing Group Classification guidelines for Class 8 material (June, 1990), RH-573 Technical is assigned to PACKING GROUP II (i.e., corrosive at the site of contact when tested on the intact skin of rabbits for a period of greater than 3 minutes but not more than 1 hr).