Pyrithione zinc

Repeated dose toxicity: oral

Administrative data

Endpoint:

chronic toxicity: oral

Remarks:

combined repeated dose and carcinogenicity

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:

2004

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

OECD Guideline 453 (Combined Chronic Toxicity / Carcinogenicity Studies)

GLP compliance:

yes

Test material

Test material information

Constituent 1

Reference substance name:

Pyridine-2-thiol 1-oxide, sodium salt

EC Number:

223-296-5

EC Name:

Pyridine-2-thiol 1-oxide, sodium salt

Cas Number:

3811-73-2

Details on test material:

- Analytical purity: 40.8%
- Lot/batch No.: 99072150

Test animals

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Harlan Nossan Srl
- Age at study initiation: 27-29 days

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

water

Duration of treatment / exposure:

104 weeks (except low dose males, which were sacrificed during week 98)

Frequency of treatment:

Daily

Doses / concentrations

Remarks:

Doses / Concentrations:
0, 0.5, 1.4, 4.0/2.8/2.1 mg a.s. / kg bw. High dose was reduced from 4.0 mg a.s. / kg bw to 2.8 mg a.s. / kg bw from week 7 onwards due to severe toxicity. High dose was further reduced to 2.1 mg a.s. / kg bw for females after 9 months of treatment
Basis:

No. of animals per sex per dose:

-Main group: 56
-Control, low dose, medium dose: 12
-High dose: 20
-Veterinary control: 16

Examinations

Observations and examinations performed and frequency:

-Bodyweight
-Food consumption
-Water consumption
-Clinical signs
-Behaviour
-Palpation
-Ophthalmic examination
-Haematology:
Number of animals: 20 animals/sex/group
Time points: After 3, 6, 12, 18, 24 months of treatment
Parameters: Haematocrit, haemoglobin concentration, erythrocyte count, reticulocyte count, MCV, MCH, MCHC, total and differential leukocyte count, platelet count, prothrombin time
-Clinical chemistry:
Number of animals: 10 animals/sex/group
Time points: After 6, 12, 18, 23 months of treatment
Parameters: alkaline phosphatase, alanine aminotransferase, aspartate amino¬transferase, urea, creatinine, glucose, albumin, total bilirubin, total cholesterol, total protein, sodium, potassium, calcium, chloride.
Other Determination of acetylcholinesterase of surviving animals of the high dosed and the control satellite groups.
-Urinalysis:
Number of animals: 10 animals/sex/group
Time points: After 3, 6, 12, 18, 24 months of treatment
Parameters: Appearance, volume, specific gravity, pH, protein, glucose, blood, ketones, bilirubin.
Other Microscopic examination of the sediment.

Sacrifice and pathology:

-Organ weights: adrenals, brain, epididymides, heart, liver, kidneys, ovaries, spleen, testes, uterus
-Histopathology: adrenals, aorta, bone marrow, brain, caecum, colon, duodenum, epididymides, eyes, Harderian gland, heart, ileum, jejunum, kidneys, larynx, liver, lungs, lymph nodes – cervical and mesenteric, mammary area, nasal cavity, nasopharynx, oesophagus, optic nerves, ovaries, pancreas, paranasal sinuses, parathyroid, pharynx, pituitary, prostate, rectum, salivary glands, sciatic nerve, seminal vesicle, skeletal muscle, skin, spinal cord, spleen, sternum, stomach, testes, thyroid, trachea, urinary bladder, uterus.

Statistics:

Continuous variables: analysis of variance followed by Dunnett's test.
Tumour incidence: Fishers exact test.
Histopathology findings: non-parametric Kolmogorov-Smirnov test

Results and discussion

Results of examinations

Clinical signs:

effects observed, treatment-related

Mortality:

mortality observed, treatment-related

Body weight and weight changes:

effects observed, treatment-related

Food consumption and compound intake (if feeding study):

no effects observed

Food efficiency:

not examined

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

no effects observed

Ophthalmological findings:

no effects observed

Haematological findings:

effects observed, treatment-related

Clinical biochemistry findings:

effects observed, treatment-related

Urinalysis findings:

effects observed, treatment-related

Behaviour (functional findings):

effects observed, treatment-related

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Gross pathological findings:

effects observed, treatment-related

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Histopathological findings: neoplastic:

effects observed, treatment-related

Details on results:

-Mortality: Control: 1 female in week 29.
Low dose: 2 females (week 21 and 45).
Mid dose: 1 male (week 52) and 1 female (week 43)
High dose: 1 male (week 49) and 3 females (weeks 6, 26, 37)
-Body weight: A significant lower body weight was observed in the high dosed males and females, compared to the control. The body weight gain was also significantly lower in the mid dosed females.
-Clinical signs: Some toxic signs as ataxia, motility impairment, emaciation, etc. were noted in few animals of the mid dosed group and in the high dosed group in few males and most females.
-Motor activity: An increase in locomotor activity was noted in high dosed animals, compared to the control
-Reactivity to stimuli: A significant decrease in landing foot splay was noted in mid- and high-dosed animals
-Macroscopic post mortem: Decedents:Possibly treatment-related findings were: reduced size of skeletal muscle and thickness of the sciatic nerve.
Terminals:Thickness of the sciatic nerve and reduced size of skeletal muscle were mainly noted in high dosed females.
-Organ weights: No effects in males. Females: significant decrease of the heart weight in high dosed animals, compared to the control.
-Histopathology: Decedents: Skeletal muscle: mild to moderate myofiber degeneration, necrosis and atrophy, in one case also adipose tissue replacement and focal inflammation, in high dosed animals. Lower degree of findings in the mid dosed female.
Terminals: Skeletal muscle and sciatic nerve were the main targets:
Skeletal muscle: slight to marked myofiber degeneration, necrosis and atrophy, and slight to moderate adipose tissue replacement of myofibers were reported in males and females of the mid- and high-dosed groups, with a dose-related trend. Inflammatory cell infiltrations were observed in high dosed animals of both sexes.
Sciatic nerve: slight to moderate fibre degeneration in 5/17 high dosed females. Mild degree of this change was reported in single males from the mid- and high-dose groups and in a mid-dose female.
Other organs: Findings such as bile duct proliferation in livers or neoplastic lesions were considered of no or minor relevance.

Effect levels

Dose descriptor:

NOAEL

Effect level:

0.5 mg/kg bw/day (nominal)

Sex:

male/female

Target system / organ toxicity

Critical effects observed:

not specified

Applicant's summary and conclusion

Conclusions:

Peripheral nervous tissue (the sciatic nerve was investigated histopathologically) and skeletal muscle are the main targets of toxic action and related clinical signs such as ataxia, necropsy findings and histological changes were found in the 3 dosed groups in both sexes in a dose-related expression. The NOAEL is 0.5 mg/kg body weight per day for the 12 months toxicity study. 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.