Registration Dossier

Administrative data

Description of key information

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Dose descriptor:
NOAEL
0.5 mg/kg bw/day
Study duration:
subchronic
Species:
rat

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Dose descriptor:
NOAEC
0.46 mg/m³
Study duration:
subchronic
Species:
rat

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion
Dose descriptor:
NOAEL
5 mg/kg bw/day
Study duration:
chronic
Species:
rat

Additional information

The toxicity of sodium pyrithione was investigated in several studies using the oral (gavage) and feeding, dermal and inhalation routes. The studies are summarised in Table 7.5.1 below. 

 

The long term (>90 days) NOAEL in repeated oral dose studies was 0.5 mg/kg bw/day and found in a long term combined chronic toxicity / carcinogenicity study in rats with sodium pyrithione.

 

Repeated exposures to NaPT via oral gavage for 90-days produced clinical signs that were confined to the high doses animals that consisted primarily of a progressive hindlimb weakness observed a majority of the females and several of the male animals.

  

Repeated inhalation of NaPT produced minimal effects following exposure for 90-days. Several female animals in the high dosed group were observed with bilateral hindlimb weakness and a 12% decrease in body weight gain. One female, again in the high dosed group died on the last day of the study during clinical observations just prior to terminal sacrifice. Pathological findings were consistent with the finding of hindlimb weakness showing a regenerative process in the skeletal muscle associated with those animals exhibiting the hindlimb weakness. 

 

Based on the confounding factor of oral ingestion through preening in the 90-day whole-body inhalation toxicity study the study should be viewed with some caution.

           

The consistent toxic endpoint effect observed in rats (not observed in mice, dogs, or primates) is a reversible hind limb weakness.  In dermal and inhalation studies in the rat, decreased food consumption and a decrease in body weight gain was observed. The 90-day whole-body inhalation NOAEL for NaPT is 0.46 mg/m3.

 

7.5.1 Oral administration

 

A 4 week oral toxicity study in cynomolgus monkeys was carried out with sodium pyrithione via oral gavage [reference 7.5.1.003, EZPTF 6041-003] by Johnson et al (1988). 

 

For the first 16 days 1 male and 1 female animal received 0, 1, 5, 15, or 50 mg/kg once daily and from day 17 to day 23 animals received 0, 100, 5, 15, or 200 mg/kg and on days 24 to 28 they received 0, 400, 1200, 15, or 800 mg/kg, respectively. The consistent sign of emesis was observed in the animals beginning at doses above 200 mg/kg i.e. 400, 800, and 1200 mg/kg. One female animal died on the last day of the study at the 1200 mg/kg dose. No other signs of toxicity were observed in any of the animals. The 4 week study was designed as a range-finding study for a one year toxicity study. The authors concluded that a dose above 200 mg/kg would be inappropriate for a one year study.

 

A GLP study carried out under USEPA Guideline 83-1[reference 7.501.004, EZPTF 6041-004] by Johnson (1989) evaluated the toxicity of NaPT in cynomolgus monkeys via oral gavage following one year of exposures. Doses administered were 0, 5, 25, 150 (for the first 6 weeks) which was reduced to 75 mg/kg due to overt toxicity at 150 mg/kg. Three animals were sacrificedin extremisin the high dosed group, one female at 6 weeks (reason for lowering the high dose of 150 to 75 mg/kg), one male at week 13 and another female at week 35. In the pathological examination there was no visible test article related findings in any of the animals. The only other finding was a significant decrease in red cell parameters e.g. erythrocytes, haemoglobin and hematocrit at the intermediate (25 mg/kg) and the high dosed animals. The one-year NOAEL for sodium pyrithione in monkeys is 5.0 mg/kg/day.

 

An oral 1-year NOAEL 5.0 mg/kg/day for sodium pyrithione in non-human primates.

 

A GLP study to Guideline US EPA 40 CFR 798.2650 by Coles et al (1997), [reference 7.5.1.001, EZPTF 6041-001] investigated the oral (gavage) administration of Sodium Pyrithione to rats over 90 days. This study also included a Neurotoxicity Functional Observation Battery assessment.

 

Salivation after test substance administration and increased water consumptions were observed. Clinical observations in one high dosed female may have been caused by the characteristic pyrithione neuropathy. Increases of liver weights and histological changes in the liver were detected. Treatment related changes, i.e. hypertrophy of hepatocytes, were observed in each of the dosed groups. These effects in the liver are considered as adaptive liver changes and were not indicative of an adverse effect on health.

 
An NOAEL of 0.5 mg/kg body weight per day was established in this study.

 

A GLP study to Guideline US EPA 40 CFR 798.2650 by Husband et al (1988), [reference 7.5.1.002, EZPTF 6041-002] investigated the oral (gavage) administration of Sodium Pyrithione to rats over 90 days. This study also included a Neurotoxicity Functional Observation Battery assessment.

 

Treatment related clinical signs were mostly confined to high dose animals and mainly comprised a general, progressive hindlimb paralysis seen in 16/20 females and 4/20 males. The severity of this effect also associated with emaciation, piloerection, and hunched posture, was greater in females which also induced a general deterioration in the condition of 10/20 of these animals to the point that they were withdrawn from the study. High dosed animals also were observed to have significant decrease in body weight gain that resulted in a terminal body weight that was 20% lower than controlanimals. Bodyweights were unaffected at the other doses. Food consumption in the high dose animals was decreased by approximately 10%. Again in the high dosed animals an observed treatment related increase in liver and kidney weights were observed; however the pathology for both organs was unremarkable. The principal macroscopic finding was the observation of skeletal muscle wasting and a lack of subcutaneous fat seen in the majority of high dose animals.

 

Microscopic findings observed mainly in the high dosed female animals and a few high dosed males was skeletal muscle atrophy of the upper hindlimbs and subcutaneous panniculus muscle. Similar, but less severe affects were observed in the intermediate dosed male and female animals. 

 

An NOEL of 0.5 mg/kg body weight per day was established in this study.

 

A GLP study to Guideline US EPA 83-2, which complies with OECD 453. by Husband (1991), [reference 7.5.1.005, Doc IV EZPTF 6051-001]investigated the oral (gavage) administration of Sodium Pyrithione to rats over 104 weeks. This study constituted a combined carcinogenicity / chronic toxicity study.

 

Sodium Pyrithione did not affect tumour formation adversely. Decreases in body weight gain, hind limb muscle atrophy and histopathological changes in skeletal muscle, spinal cord, and in the eyes were observed in the high dose group. Some, but not all of these effects were observed to a lesser degree in the mid dose group.

 

An NOEL of 0.5 mg/kg bw/day was established in the study.

 

A GLP study to Guideline US EPA OPPTS 870.4300 which complies with OCED 453 by Cicalese et al (2004), [reference 7.5.1.006, EZPTF 6051-002] investigated the oral (gavage) administration of Sodium Pyrithione to rats over 104 weeks. This study constituted a combined carcinogenicity / chronic toxicity study.

 

Signs of toxicity, such as, leaning to one side and/or impaired limbs, and/or motility impairment and/or hunched posture and/or ataxia were recorded for animals of the mid- and high-dose groups. In addition, a lower body weight was noted in high-dose males and in mid- and high-dose females when compared to controls.

 

At microscopic examination, treatment-related changes were seen in the skeletal muscle of male and female animals in the mid- and high-dose groups at term. In addition, the changes observed in the sciatic nerve were seen to be clearly related to the treatment only in the mid- and high-dose animals, where the severity degree was seen to be increased. Minor changes, possibly treatment related, were seen in the liver of treated animals when compared to controls.

 

An NOAEL for both sexes can be considered to be 0.5 mg/kg/day.


7.5.2 Dermal administration

 

A GLP study to Guideline US EPA 83-2, which complies with OECD 453. by Husband (1991),[reference 7.5.2.001, EZPTF 6071-001], investigated the DERMAL administration of Sodium Pyrithione to the mouse over 80 weeks. This was a life-time carcinogenicity study.

 

Sodium Omadine did not affect tumour formation adversely. The only observed lesion, which appeared to be related to the treatment, was epidermal hyperplasia (dermal irritation) at the application sites of high and mid dose animals.

 

An NOEL of 5.0 mg/kg bw/day was established in the study for any signs of toxicity with 15.0 mg/kg/day resulting in a tendency for dermal irritiaton. The overall NOEL for tumor formation is 40 mg/kg/day for the dermal route.

 

7.5.3 Administration by inhalation

A GLP study to guideline to US EPA guideline 82-4, subdivision F, which is equivalent to EC guideline B.29 (reference 7.5.3.001, ESPTF 6043-001) by Ulrich CE (1989) evaluated the thirteen week subchronic inhalation toxicity of sodium pyrithione in rats.

 

The most significant observation from the study was the observation of depressed body weights of females in the high level group (depressed by approximately 12%). In addition, four females in the high level dose group were observed with a slight bilateral impaired hindlimb function. However, this is most likely due to oral ingestion from preening. Those females exhibiting affects in the hindlimbs also were observed with microscopic findings of a regenerative process occurring in the skeletal muscle.

 

An NOEL of 0.46 mg/m3 was established in the study. 

Based on the confounding factor of oral ingestion through preening in the 90-day whole-body inhalation toxicity study this study should not be considered reliable in assessing long term toxicity by inhalation.

Table 7.5.1             Summary of repeated dose toxicity

Route

Duration

Species
Strain
Sex
no/group

Dose levels[mg/kg bw/day]
frequency of application

Results

LO(A)EL

NO(A)EL

Reference

[mg/kg bw/day]

Oral

1 month

Monkey

Rangefinding Study

0; 1/100/400; 5/1200; 15; and 50/200/800

 

Test Material – Sodium Pyrithione 40% aqueous solution

One female died in the 5/1200 dose at day 28 at the end of the 1200 mg/kg dosing regiment.  Emesis was observed in animals receiving dosages of 400, 1200, 15, or 800 mg/kg but not any other dose. 

15 mg/kg emesis was observed

Animals receiving dosages of 1, 5, 50, 100 or 200 mg/kg were without any signs of toxicity.

7.5.1.003

 

EZPTF 6041-003

 

Johnson, D.E. (1988)

 

(unpublished)

Oral

 

90 days

 

Rat

Charles River Sprague-Dawley Crl:CD®BR 10 per sex per dose

 

US EPA Guideline 40 CFR 798.2650.

 

(GLP self certification by the laboratory).

 

0.1; 0.5; and 2.5 mg/kg body weight per day.

 

Test material: Sodium Pyrithion 40% solution.

Salivation after test substance administration and increased water consumptions were observed. Clinical observations in one high dosed female may have been caused by the characteristic pyrithione neuropathy. Increases of liver weights and histological changes in the liver were detected. Treatment related changes, i.e. hypertrophy of hepatocytes, were observed in each of the dosed groups. These effects in the liver are considered as adaptive liver changes and were not indicative of an adverse effect on health.

LOAEL is 2.5 mg/kg body weight per day

NOAEL is 0.5 mg/kg body weight per day.

Key Study

7.5.1.001

 

ESPTF 6041-001

 

Coles et al (1997)

(unpublished)

 

Oral

3 months

Rat

0, 0.5, 2.0, and 8.0 mg/kg./day

 

Test Material – NaPT 40% aqueous solution.

At the 8.0 mg/kg dosa a progressive hindlimb weakness was observed in a majority of the females and several of the male animals.

2.0 mg/kg.day

0.5 mg/kg/day

7.5.1.002

 

EZPTF 6041-002

 

Husband et al. (1988)

Oral

1 year

Monkey

0, 5, 25, 75 mg/kg (note high dose was reduced to 75 from 150 mg/kg)

 

Test Material – Sodium Pyrithione 40% aqueous solution

One female was sacrificedin extremisat week 6 at 150 mg/kg, one male died during week 13 at 75 mg/kg and one female died at week 35. Emesis was observed for a majority of the low dose animals and for all of the animals in the intermediate and high dosed animals.

 

A significant reduction in red blood cell parameters e.g. erythrocytes, hemaglobin, and hematocrit for the intermediate and high dosage groups.

25 mg/kg/day

5.0 mg/kg/day

7.5.1.004

 

EZPTF 6041-004

Johnson, D.E. (1989)

 

(unpublished)

Oral (gavage)

2 years

Rat

Crl: CD (SD) (VAF Plus) 50 per sex per dose

US EPA 83-2, which complies with OECD 453. GLP

0, 0.5, 1.5 and 3.5 mg/kg bw/day

 

Test material:

Sodium Omadine®, 41.2% aqueous dispersion.

Sodium Omadine did not affect tumour formation adversely. Decreases in body weight gain, hind limb muscle atrophy and histopathological changes in skeletal muscle, spinal cord, and in the eyes were observed in the high dose group. Some, but not all of these effects were observed to a lesser degree in the mid dose group.

1.5 mg/kg bw/day

0.5 mg/kg bw/day

7.5.1.005

 

EZPTF 6051-001

 

Husband RFA, Newman AJ and Lee PN (1991).

(unpublished)

Oral (gavage)

2 years

Rat Sprague Dawley 56 per sex per dose

OECD 453.
EPA OPPTS 870.4300. GLP Study

Doses: 0, 0.5, 1.4, and 2.1 mg/kg/day

 

Test Material: Sodium Pyrithione, 40% aqueous dispersion

Signs of toxicity, such as, leaning to one side and/or impaired limbs, and/or motility impairment and/or hunched posture and/or ataxia were recorded for animals of the mid- and high-dose groups. In addition, a lower body weight was noted in high-dose males and in mid- and high-dose females when compared to controls.

 

At microscopic examination, treatment-related changes were seen in the skeletal muscle of male and female animals in the mid- and high-dose groups at term. In addition, the changes observed in the sciatic nerve were seen to be clearly related to the treatment only in the mid- and high-dose animals, where the severity degree was seen to be increased. Minor changes, possibly treatment related, were seen in the liver of treated animals when compared to controls.

 

An NOAEL for both sexes can be considered to be 0.5 mg/kg/day.

 

 

1.4 mg/kg/day

0.5 mg /kg bw/day

Key study

7.5.1.006

 

EZPTF 6051-002

 

Cicalese R, Argentino-Storino A, (2004)

(unpublished)

Dermal

80 weeks

Mouse

Crl: CD-1 (ICR) BR (VAF Plus)

50 per sex per dose

US EPA 83-2, which complies with OECD 453. GLP

0, 5, 15 and 40 mg/kg bw/day

 

 

Test material: Sodium Omadine®, 41.2% aqueous dispersion.

Sodium Omadine did not affect tumour formation adversely. The only observed lesion, which appeared to be related to the treatment, was epidermal hyperplasia at the application sites of high and mid dose animals.

15 mg/kg bw/day

Trend for an increase in the frequency of the animals with skin irritaiton

5 mg/kg bw/day is a clear NOEL with 15 mg/kg/day a NOAEL and 40 mg/kg/day a NOEL for tumor formation

7.5.2.001

 

EZPTF 6071-001

 

Husband RFA, Newman AJ and Lee PN (1991)

 

(unpublished)

 

Inhalation

(Whole body)

3 months

Rat

US EPA 82-4 which complies with OECD 413. GLP (self certification by the laboratory).

0, 0.46, 1.1, 3.8 increased to 8.1 mg/m3after 6 weeks (due to a lack of toxicity)

 

Test Material – Sodium pyrithione 40% aqueous solution

Four females in the high dosed group exhibited bilateral hindlimb weakness. In addition, females in the high dosed group were observed with a 12% decrease in bodyweight for weeks 5-13 of the study.

0.46 mg/m3

1.1 mg/m3

7.5.3.001

EZPTF 6043 -001

 

 

Ulrich, CE (1989)

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 RegulationEC 1907/2006.

Justification for classification or non-classification