Pyrithione zinc

Repeated dose toxicity: dermal

Administrative data

Endpoint:

sub-chronic toxicity: dermal

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1993

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

EPA OPP 82-3 (Subchronic Dermal Toxicity 90 Days)

GLP compliance:

yes

Test material

Test material information

Constituent 1

Reference substance name:

Pyrithione zinc

EC Number:

236-671-3

EC Name:

Pyrithione zinc

Cas Number:

13463-41-7

Molecular formula:

C10H8N2O2S2Zn

IUPAC Name:

Bis [1-hydroxy-2(1H)-pyridinethionato-O,S](T-4)-zinc

Details on test material:

52.2% zinc pyrithione with sodium naphthal enesulphonic acud polymer (surfactant)

Test animals

Species:

rat

Strain:

other: CrlCD BR

Sex:

male/female

Details on test animals or test system and environmental conditions:

Source: Charles River Laboratories USA
Age at study initiation: 8 weeks
Weight at study initiation: male 244-305g female 174-200g

Administration / exposure

Type of coverage:

semiocclusive

Vehicle:

water

Details on exposure:

Application area: 3x5cm

Details on analytical verification of doses or concentrations:

Dose volume: 2 ml/kg

Duration of treatment / exposure:

13 weeks
6h/day

Frequency of treatment:

5 days/week

Doses / concentrations

Doses / concentrations 1

Remarks:

Doses / Concentrations:
20 mg/kg
Basis:

Doses / concentrations 2

Remarks:

Doses / Concentrations:
100 mg/kg
Basis:

Doses / concentrations 3

Remarks:

Doses / Concentrations:
1000 mg/kg
Basis:

No. of animals per sex per dose:

15

Control animals:

yes

Examinations

Observations and examinations performed and frequency:

clinical observations: twice daily, weekly detailed observations
mortality: twice daily
body weight: weekly
food consumption: weekly
ophthalmoscopic: pre-test and 13 weeks
haematology: end of study
clinical chemistry: end of study
urinalysis: end of study

Sacrifice and pathology:

Organ weights: liver, kidney, testes, brain
gross and histopathology: brain, spinal cord, pituitary, thyroid, parathyroid, thymus, oesophagus, salivary glands, stomach, small and large intestines, liver, pancreas, kidneys, adrenals, spleen, heart, trachea, lungs, aorta, gonads, uterus, female mammary gland, prostate, urinary bladder, lymph nodes, peripheral nerve, bone marrow, skin, eyes, bone, lachrymal gland, sciatic nerve, and skeletal muscle. In addition, the liver, kidneys, and lungs from the 20-mg/Kg and 100 mg/Kg groups were examined microscopically.

Statistics:

Body weights, food consumption, hematological, biochemical and urinalysis values, and absolute and relative organ weights were analyzed using analysis of variance (one-way classification) and Bartlett’s test for homogeneity of variance. Treatment groups were compared to the control group by sex using the appropriate t-statistic (for equal or unequal variance) as described by Steel and Torrie1. Dunnett’s2 multiple comparison tables or pairwise comparisons with a Bonferroni correction were used to determine the significance of differences. Nonparametric analyses were conducted as appropriate by transforming the data into ranks prior to analysis, as described by Conover and Iman3. All statistical analyses were performed with p ≤ 0.05 and p ≤ 0.01 used as levels of significance.
1 Steel, RGD and Torrie, JH (1980). Principles and Procedures of Statistics, McGraw-Hill Book Co., Inc., New York, NY, 2nd ed., 471-472.
2 Dunnett, CW (1964). New tables for multiple comparisons with a control. Biometrics, 20; 482-491.
3 Conover, WJ and Iman, RL (1981). Rank transformations as a bridge between parametric and nonparametric statistics. The American Statistician. 35; 124-133.

Results and discussion

Results of examinations

Clinical signs:

no effects observed

Dermal irritation:

effects observed, treatment-related

Mortality:

no mortality observed

Body weight and weight changes:

effects observed, treatment-related

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Food efficiency:

not examined

Water consumption and compound intake (if drinking water study):

not examined

Ophthalmological findings:

no effects observed

Haematological findings:

effects observed, treatment-related

Clinical biochemistry findings:

effects observed, treatment-related

Urinalysis findings:

no effects observed

Behaviour (functional findings):

not examined

Organ weight findings including organ / body weight ratios:

no effects observed

Gross pathological findings:

no effects observed

Histopathological findings: non-neoplastic:

no effects observed

Histopathological findings: neoplastic:

not examined

Details on results:

Dermal irritation: Slight dermal irritation seen in the 1,000-mg/Kg dose group in one male (red foci and desquamation on day 29 and 30) and one female (red foci on days 29, 30, and 33).
Body weight gain: Depression in body weight gain in females in the 1,000-mg/Kg dose group. Body weight gain was depressed for the first four weeks of dosing; thereafter, weight gain was similar to controls, but absolute weights remained depressed. No effects were seen in the males.
Food consumption: Depressed in females in the 1,000-mg/Kg dose group. Food consumption was depressed for the first four weeks of dosing; thereafter, food consumption was similar to controls. No effects were seen in the males.
Haematology: Statistically significant differences between the dose groups and the controls were elevated leukocyte counts in the 1,000-mg/Kg males (14.2 vs. 11.0), depressed erythrocyte count in the 1,000-mg/Kg females (6.39 vs. 6.78), and depressed hematocrit level in the 1,000-mg/Kg females (39.2 vs. 41.2). These results were not considered test material related since all values were within the laboratories normal control range, and microscopic evaluations did not indicate any abnormalities that might produce such changes
Clinical chemistry: The only statistically significant difference between the dose groups and the controls was elevation in cholesterol in the 1,000-mg/Kg females (88 vs. 69).

Effect levels

1

Dose descriptor:

NOAEL

Effect level:

100 mg/kg bw/day (nominal)

2

Dose descriptor:

LOAEL

Effect level:

1 000 mg/kg bw/day (nominal)

Target system / organ toxicity

Critical effects observed:

not specified

Applicant's summary and conclusion

Conclusions:

NOAEL=100mg/kg bw/day. The information contained within this robust summary document comes from studies which are in the ownership of Arch Chemicals Inc. and which are protected in several regions globally. This information may not be used for any purpose other than in support of the Chemical safety Report submitted by Arch Chemicals Inc. under Regulation EC 1907/2006.