Pyrithione zinc

Endpoint summary

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:

chronic

Species:

rat

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion

Dose descriptor:

NOAEL

100 mg/kg bw/day

Study duration:

chronic

Species:

rat

Additional information

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.

The toxicity of zinc pyrithione was investigated in several studies using the oral (gavage) and feeding, dermal and inhalation routes. The studies are summarised inTable22toTable24below. In some cases, studies have been carried out on the toxicologically equivalent substance sodium pyrithione.

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.

Inhalation of ZPT is harmful to toxic from an acute basis and the 90-day inhalation study, which was a whole body exposure, produced findings of pulmonary irritation and death without any other significant clinical findings. The incidence of deaths in the intermediate and high dosed animals was believed to be partially contributed to the fact that the inhalation exposures was a whole body exposure and significant preening occurred leading to oral exposures as well as via inhalation. Again, the pathology was unremarkable and mostly contained to the lungs, consistent with irritation.  A more recent 21-day inhalation toxicity study in rats via nose-only exposures supported the fact that oral administration through preening must have occurred in the original 90-day inhalation study as doses producing death in the original 90-day study failed to produce signs of toxicity other than irritation which was again contained to the lungs. The 21-day inhalation study was carried out with ZPT powder and the powder is corrosive to the eyes and thus is presumed to be highly irritating to mucosal membranes. A majority of the findings following inhalation of ZPT are due to irritation and not to systemic effects as no hind limb weakness was reported in either the 90-day or 21-day inhalation studies.

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.

A GLP study to MITI (Japan) Guidelines (equivalent to EC Guideline B.7) by Funato (1992),[investigated the oral (gavage) administration of ZPT to Cynomolgus monkeys for 28 days followed by a 2 week recovery period.

An NOEL of 11.0 mg/kg bw/day was established in the study.

A non-GLP non-guideline study byDrobeck et al (1973),investigated the oral (dietary) administration of ZPT to albino rats for 3 months.

An NOEL of 25 ppm (equivalent to 1.75/2.13 mg/kg bw/day) was established in the study.

A non-GLP non-guideline study byDrobeck et al (1973),investigated the oral (dietary) administration of ZPT to Rhesus monkeys for 3 months.

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

A GLP study to Guideline 40 CFR 798.2650 byColes et al (1997),investigated the oral (gavage) administration of ZPT to rats over 90 days.

An NOAEL of 1.0 mg/kg bw/day is therefore supported by the results of the study.

A GLP study to Guideline US EPA 83-2, which complies with OECD 453. byHusband (1991),investigated the oral (gavage) administration of Sodium Pyrithione to rats over 104 weeks. This study constituted a combined carcinogenicity / chronic toxicity study.

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 byCicalese et al (2004),investigated the oral (gavage) administration of Sodium Pyrithione to rats over 104 weeks. This study constituted a combined carcinogenicity / chronic toxicity study.

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

Table22: Summary of repeat dose oral toxicity

Method	Results	Remarks	Reference
MITI guidelines GLP (self certification by the laboratory) Oral, Monkey Cynomolgus, 4 per sex per dose. 0, 5.5, 11 and 22 mg/kg bw/day Duration: 28 days	LO(A)EL – 22 mg/kg bw/day NO(A)EL – 11 mg/kg bw/day One female in the high dose group died on day 10. The surviving animals in this group had decreased spontaneous activity and vomiting and/or diarrhoea. There was also an increase in liver weights and decreases in erythrocyte counts, hematocrit values and haemoglobin concentrations in high dose animals. Clinical symptoms and haematological changes were reversible during the post-dosing recovery period.	Reliability – 1 Purpose flag Study result type Test material: Zinc pyrithione, 96.3%	Funato M (1992) (unpublished)
No specific guidelines Oral, Rat Charles River CD Albino, 20 per sex per dose. 0, 5, 25 and 125 ppm in diet (estimated intakes for males were 0, 0.35, 1.75 and 10.04 mg/kg bw/day and 0, 0.39, 2.13 and 10.26 mg/kg bw/day for females) Duration: 3 months	LO(A)EL – 125 ppm (10.04/10.26 mgkg bw/day) NO(A)EL – 25 ppm (1.75/2.13 mg/kg bw/day)	Reliability – 1 Purpose flag Study result type Test material: Zinc pyrithione powder, purity not stated.	Drobeck HP, Willand J, Hunt CE and Donilian MR (1973) (unpublished)
No specific guideline Oral, Monkey Rhesus, 6 per sex per dose. 0, 0.5, 2.0 and 8.0 mg/kg bw/day Duration: 3 months	LO(A)EL – 2.0 mg/kg bw/day NO(A)EL – 0.5 mg/kg/day There was a decrease in the weight of the uterus in females and relative weight of kidneys of all animals in the intermediate and high dose groups.	Reliability – 1 Purpose flag Study result type Test material: Zinc pyrithione powder, purity not stated.	Drobeck HP, Gumaer KI, Owen SD and Donikian MR (1973) (unpublished)
40 CFR 798.2650 Oral, Rat Sprague-Dawley Crl:CD BR, 10 per sex per dose. 0.2, 1, and 5 mg/kg body weight per day (The high dose was reduced to 2.5 mg/kg from day 17 and 18 onwards, due to marked deterioration of health of the animals) Duration: 90 days	LO(A)EL – 1.0 mg/kg/day NO(A)EL – 0.2 mg/kg/day (this has been corrected to 1.0 mg/kg/day due to irritation to the forestomach being of questionable relevance to humans)	Reliability – 1 Purpose flag Study result type Test material: Zinc Pyrithione, purity not stated in report but determined to be % from certificate of analysis.	Coles LJ, Thomas ON, Bartlett AJ, Woods E, Brooks PN (1997) (unpublished)
US EPA 83-2, which complies with OECD453. GLP Oral, (gavage) Rat Crl: CD (SD) (VAF Plus), 50 per sex per dose. 0, 0.5, 1.5 and 3.5 mg/kg/day Duration:2 years	LO(A)EL – 1.5 mg/kg bw/day NO(A)EL – 0.5 mg/kg bw/day Sodium Omadine did not affect tumour formation adversely. Decreases in body weight gain, hind limb muscle atrophy and histopathological changes in skeletal muscle, spinal chord and in the eyes were observed in the high dose group.	Reliability – 1 Purpose flag Study result type Test material: Sodium pyrithione, 41.2% aqueous dispersion.	Husband RFA, Newman AJ and Lee PN (1991) (unpublished)
OECD 453. EPA OPPTS 870.4300. GLP study Oral, Rat Sprague-Dawley, 56 per sex per dose. Doses: 0, 0.5, 1.4 and 2.1 mg/kg/day Duration: 2 years	LO(A)EL – 1.4 mg/kg/day NO(A)EL – 0.5 mg/kg bw/day 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.	Reliability: 1 Purpose flag Study result type Test material: Sodium Pyrithione, 40% aqueous dispersion.	Key study Cicalese R, Argentino-Storino A (2004) (unpublished)

A GLP study to Guideline USEPA OPPTS 870.3465 byCarter (2005),investigated the inhalation toxicity of ZPT to rats via nose-only over 21-days with a 5-day interim sacrifice.

The classification of the histopathological effects in the animals in the low dose animals was judged to be minimally perceivable to very mild which supports the fact that exposure to 2.0 mg/m3 for 6 hours per day 5-days per week for 21-days was effectively the no-observable adverse effect level (NOAEL). Again the findings in the 21-day inhalation study can be attributed to signs of irritation and not systemic effects.

A GLP study to Guideline US EPA 82-3 (equivalent to EC B28) byUlrich (1993),investigated the inhalation toxicity of ZPT to rats over 90 days.

The most significant observations from the study were animal deaths at both 2.5 and 10 mg/m3.

Oral ingestion from preening was probably a contributing factor to this toxicity since the test material is moderately toxic by the oral route. Two previously conducted acute inhalation toxicity studies and, one by whole-body exposure generated from a suspension of the test material and one by nose-only exposure generated from a dust of the test material, found higher levels of toxicity with whole body exposures (140 mg/m3 vs. 610 mg/m3 for the 4-hour LC50).

An NOEL of 0.5 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.

Table23:Summary of repeat dose inhalation toxicity

Method	Results	Remarks	Reference
US EPA OPPTS NO. 870.3465 GLP study Inhalation, Rat Sprague-Dawley 15 per sex per dose. Doses tested 0, 2.0, 6.0 and 13.5 mg/m3 Duration: 21 days	LO(A)EL – 6.0 mg/m3 for 6 hrs/day 21 days NO(A)EL – 2.0 mg/m3 6 hrs/day 21 days Increase in lung weights and signs of pulmonary irritation.	Reliability – 1 Purpose flag                 Study result type Test article: ZPT powder	Carter (2005) (unpublished)
US EPA 82-4 which complies with OECD 413. GLP (self certified by the laboratory) Inhalation, (whole body) Rat Sprague-Dawley albino (Charles River CD) 15 per sex per dose. 0, 0.5, 2.5 and 10 mg/m3 Duration: 3 months	LO(A)EL – 2.5 mg/m3 NO(A)EL – 0.5 mg/m3 One male and one female animal died in the mid dose group and 3 males and 4 females in the high dose group during the study. Daily observations of these animals included laboured breathing, increased salivation and decreased activity.	Reliability – 1 Purpose flag Study result type Test material: Zinc Omadine FPS, 52.2% aqueous suspension.	Key study Ulrich CE (1993) (unpublished)

A GLP study to Guideline US EPA 82-3 (equivalent to EC B28) byUlrich (1993),investigated the dermal administration of zinc pyrithione to rats over 13 weeks.

An NOEL of 100 mg/kg bw/day was established in the study.

A GLP study to Guideline US EPA 83-2, which complies with OECD 453 byHusband (1991),investigated the dermal oral (gavage) 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 irritation. The overall NOEL for tumour formation is 40 mg/kg/day for the dermal route.

Table24:Summary of repeat dose dermal toxicity

Method	Results	Remarks	Reference
US EPA 82-3, which complies with OECD 411. GLP (self classification by the laboratory) Dermal, Rat, Sprague-Dawley, 15 per sex per dose. 0, 20, 100 and 1000 mg/kg bw, 6h/day. Duration: 3 months	LO(A)EL – 1000 mg/kg bw/day NO(A)EL – 100 mg/kg bw/day There was a decrease in body weight and body weight gain in high dose groups and increases in relative brain, kidney and liver weights. Additionally, slight dermal irritation was detected in two animals at the high dose group.	Reliability – 1 Purpose flag Study result type Test material: Zinc Omadine, 48% dispersion.	Ulrich CE (1993) (unpublished)
US EPA 82-3, which complies with OECD 453. GLP Dermal, Mouse Crl: CD-1 (1CR) BR (VAF Plus) 50 per sex per dose. 0, 5, 15 and 40 mg/kg bw/day Duration: 80 weeks	LO(A)EL – 15 mg/kg bw/day Trend for an increase in the frequency of the animals with skin irritation. NO(A)EL – 5 mg/kg bw/day is a clear NOEL with 15 mg/kg/day a NOAEL and 40 mg/kg/day a NOEL for tumour formation. 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.	Reliability – 1 Purpose flag Study report type Test material: Sodium Omadine, 41.2% aqueous dispersion.	Husband RFA, Newman AJ and Lee PN (1991) (unpublished)