reaction mass of 5-chloro-2-methyl-4-isothiazolin-3-one and 2-methyl-2H -isothiazol-3-one

Dermal absorption

Administrative data

Endpoint:

dermal absorption in vivo

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

guideline study with acceptable restrictions

Cross-reference

Reason / purpose for cross-reference:

reference to same study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1997

Report date:

1997

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

other: OECD 417

Deviations:

no

GLP compliance:

no

Test material

Test material information

Constituent 1

Test material form:

other: Amber Liquid

Details on test material:

- Name of test material (as cited in study report): Kathon™ 886
- Physical state: Amber liquid
- Stability under test conditions: stable at room temperature

Specific details on test material used for the study:

SOURCE OF TEST MATERIAL
- Source and lot/batch No.of test material: Rohm and Haas, Batch No. 395.0201B, 395.0207, 555.0101 and 555.0201

RADIOLABELLING INFORMATION (if applicable)
- Radiochemical purity: 96.7-98.4 %
- Specific activity: 10.47 mCi/mg (395.0201B and 395.0207), 38.40 µCi/mg (555.0101) and 49.55 µCi/mg (555.0201)
- Locations of the label: 4, 5

STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: Not described
- Stability under test conditions: Stable
- Solubility and stability of the test substance in the solvent/vehicle: Soluble and stable
- Reactivity of the test substance with the solvent/vehicle of the cell culture medium: No

TREATMENT OF TEST MATERIAL PRIOR TO TESTING
- Treatment of test material prior to testing: Dissolution in water
- Preliminary purification step (if any): No
- Final dilution of a dissolved solid, stock liquid or gel: 2.5 to 4000 ppm a.i.

FORM AS APPLIED IN THE TEST (if different from that of starting material)
Liquid

OTHER SPECIFICS: Purity of test material was as follows:
Batch No. 395.0201B, 14 % active substance (3 parts of 14C-CMIT and 1 part of MIT)
Batch No. 395.0201B, 14 % active substance (3 parts of 14C-CMIT and 1 part of MIT)
Batch No. 395.0207, 1.5 % active substance (1.2 % of 14C-CMIT and 0.3 % of MIT)
Batch No. 555.0101, 14.6 % active substance (11 % of 14C-CMIT and 3.6 % of MIT)
Batch No. 555.0201, 14.5 % active substance (11 % of CMIT and 3.5 % of 14C-MIT)

Radiolabelling:

yes

Test animals

Species:

rat

Strain:

other: Albino, Sprague-Dawley and Crl:CD

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Kingston, Stone Ridge, New York, USA
- Age at study initiation: 1-3 months old
- Weight at study initiation: Not reported

Administration / exposure

Type of coverage:

not specified

Vehicle:

not specified

Duration of exposure:

6h, 24h or 4 days with one daily application

Doses:

- Nominal doses: 2.5 to 4000 ppm a.i.
- Dose volume: 0.2 mL

No. of animals per group:

3-5

Control animals:

no

Details on study design:

APPLICATION OF DOSE: Single or repeated dose

REMOVAL OF TEST SUBSTANCE
- Washing procedures and type of cleansing agent: Not described
- Time after start of exposure: After 6 or 24 hours

ANALYSIS
- Method type(s) for identification: HPLC, Liquid scintillation counting

Results and discussion

Signs and symptoms of toxicity:

yes

Remarks:

Mortality

Dermal irritation:

not specified

Absorption in different matrices:

- Skin wash: 6-11% (single 24h dermal application), 0.3-3% (single 6h dermal application), 1-11% (repeated dermal applications during 4 days)
- Skin test site: 39-62% (single 24h dermal application), 54-73% (single 6h dermal application), 26-41% (repeated dermal applications during 4 days)
- Blood
Single 24h dermal application: 14C-Concentration in whole blood 24 hours after dermal application was non-linear with respect to dose level (i.e., a 2-fold increase in dose from 1000 to 2000 ppm a.i. resulted in a 30-fold increase in 14C-concentration)
Single 6h dermal application: Whole blood 14C-concentrations were greater than the corresponding plasma 14C-concentrations. 14C derived from 14C-CMIT peaked within 1 hour, decreased over the initial 24 hours after dosing, and then remained relatively constant at low levels for the remainder of the 7 days. 14C derived from 14C-MIT peaked within 48 hours and then decreased gradually for the remainder of the 7 days.
Repeated dermal applications during 4 days:
- Urine: 5-10% (single 24h dermal application), <23% (single 6h dermal application), 11-19% (repeated dermal applications during 4 days)
- Faeces: Negligible (single 24h dermal application), <35% (single 6h dermal application), <2% (repeated dermal applications during 4 days)

Total recovery:

- Total recovery: >=60%
- Recovery of applied dose acceptable: Yes
- Quantification of values below LOD or LOQ: No

Percutaneous absorption

Percutaneous absorption 1

Key result

Time point:

24 h

Dose:

4000 to 500 ppm a.i.

Parameter:

percentage

Absorption:

>= 27 %

Percutaneous absorption 2

Key result

Time point:

6 h

Dose:

2.5 ppm a.i.

Parameter:

percentage

Absorption:

38 %

Remarks on result:

other: 14C-CMIT; Determined after 7 days

Percutaneous absorption 3

Key result

Time point:

6 h

Dose:

25 ppm a.i.

Parameter:

percentage

Absorption:

27 %

Remarks on result:

other: 14C-CMIT; Determined after 7 days

Percutaneous absorption 4

Key result

Time point:

6 h

Dose:

2.5 ppm a.i.

Parameter:

percentage

Absorption:

43 %

Remarks on result:

other: 14C-MIT; Determined after 7 days

Percutaneous absorption 5

Key result

Time point:

6 h

Dose:

25 ppm a.i.

Parameter:

percentage

Absorption:

26 %

Remarks on result:

other: 14C-MIT; Determined after 7 days

Percutaneous absorption 6

Key result

Time point:

4 d

Dose:

500 or 1000 ppm a.i.

Parameter:

percentage

Absorption:

>= 48 %

Remarks on result:

other: One daily application

Applicant's summary and conclusion

Conclusions:

A significant fraction of dermally administered 14C-Kathon™ biocide-derived 14C-label was recovered in the application site skin, and was thus not readily systemically bioavailable. Peak whole blood 14C -concentrations were disproportionately higher after high dermal dose applications than after lower dermal dose applications indicating nonlinear kinetics. Whole blood 14C -concentrations were greater than the corresponding plasma 14C -concentrations following dermal administration.

Executive summary:

Five toxicokinetic and metabolism studies have been conducted in rats with Kathon™ biocide for regulatory and risk assessment purposes. Kathon™ biocide labelled alternatively on the CMIT and on the MIT part was used. The collective results of these five studies fulfills the requirements for an OECD 417 Toxicokinetic study and have been enclosed in 1997 in the overall report presented here.

A significant fraction of dermally administered¹⁴C-Kathon™biocide-derived¹⁴C-label was recovered in the application site skin, and was thus not readily systemically bioavailable. Peak whole blood¹⁴C -concentrations were disproportionately higher after high dermal dose applications than after lower dermal dose applications indicating nonlinear kinetics. Whole blood¹⁴C -concentrations were greater than the corresponding plasma¹⁴C -concentrations following dermal administration.