Pyrithione zinc

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Effect on fertility: via oral route

Dose descriptor:

NOAEL

0.5 mg/kg bw/day

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.

   Effects on fertility

Multi-generation reproduction toxicity studies are compiled in Table 5.14

A GLP two generation reproduction toxicity study to US EPA 83-4, which complies with OECD 416, byRidgeway (1989),investigated the administration of Sodium Pyrithione to the rat over 104 weeks.

The NOAEL in rats with respect to fertility and developmental toxicity was considered to be > 3.5 mg/kg/day, although parental toxicity was considered to be responsible for impaired mating performance. 

The NOEL for other effects such as hindlimb weakness, was 0.5 mg/kg/day.

Table 5.14: Summary of fertility effects

Method	Results	Remarks	Reference
US EPA 83-4, which complies with OECD 416. GLP Oral, Crl: CD (SD) RR, 25 per sex per dose.0, 0.5, 1.5 and 3.5 mg/kg/day, 2-generation Reproduction Rat Toxicity study.	NO(A)EL Parental – 1.5 NO(A)EL F1 – Males: 1.5 Females: 0.5 NO(A)EL F2 – 1.5  In high dose group, parents reduction in bodyweight gain and atrophy of hind-limb muscles with related hind-limb paralysis was detected, as well as adverse effects on F0 generation fertility and mating performance. There was evidence of a slight retardation of development during lactation in the offspring. In the mid dose group, atrophy of the hind-limb muscles was observed in three females in the F1 generation. Parental toxicity was considered to be responsible for impaired mating performance.	Reliability – 1 Purpose flag Study result type Test material: Sodium pyrithione 40% Aqueous solution	Ridgeway P and Wood CM (1989) (unpublished)

Developmental toxicity

Key studies are summarised in Table 5.15.

A GLP developmental toxicity study to US EPA 83-3, which Complies with OECD 414. bySchardein (1993),investigated the administration of Zinc Pyrithione to the New Zealand white rabbit.

The NOAEL for this study is 0.5 mg/kg/day (for maternal toxicity)and 1.5 mg/kg/day for malformations and developmental variations. Although, due to the severity of maternal toxicity observed at the 1.5 mg/kg dose group resorptions and implanation losses were observed.

A GLP developmental toxicity study to US EPA 83-3, which Complies with OECD 414. by Schardein (1993) investigated the administration of zinc pyrithione to the rat GD 6-15.

The NOAEL administered orally to rats during gestation days 6-15 was 0.75 mg/kg/day with regard to maternal and development toxicity.

A GLP developmental toxicity study to U.S. EPA (1998). Health Effects Test Guidelines. OPPTS 870.3700, which Complies with OECD 414. byBarnett (2005),investigated the dermal administration of Zinc Pyrithione to the rat, administered from Gestation Day 0-21. over 104 weeks.

On the basis of these data, thematernal no-observable-adverse effect-level (NOAEL) of zinc pyrithione is 15 mg/kg/daywhen dosed from gestational day 0 - 21. Reductions in body weight, body weight gain and/or body weight losses and absolute and/or relative feed consumption values occurred in the 30 and 60 mg/kg/day dosage groups. Reductions in muscle tone and/or muscle mass occurred in the 60 mg/kg/day dosage group. 

The developmental NOEL is 30 mg/kg/day(gravid uterine weights, foetal body weights and skeletal ossification average were reduced and skeletal variations were increased in the 60 mg/kg/day dosage group). 

Zinc Pyrithione is not a selective developmental toxicant.

 Table 5.15: Summary of developmental effects

Method	Results	Remarks	Reference
US EPA 83-3, which Complies with OECD 414. GLP (self Certification by the laboratory). Oral(gavage) Rabbit, New Zealand White, 20 females per dose.0, 0.5, 1.5 and 3.0   Exposure period: Days 6 through 19 of gestation.	NO(A)EL maternal – 0.5 mg/kg bw/day NO(A)EL teratogenicity embryotoxicity – 0.5 mg/kg bw/day Maternal toxicity:Body weight gain was decreased during the dosing period only, by 40% in mid dose group and the females failed to gain weight in high dose group. Teratogenicity:There was a significant increase in the number of foetuses with developmental variations in the mid dose group compared with controls.	Reliability – 1 Purpose flag Study result type Test material: Zinc pyrithione, 48% Dispersion	Schardein JL (1993) (unpublished)
US EPA 83-3, which Complies with OECD 414. GLP (self Certification by the laboratory). Oral(gavage) Rat, Charles River, Crl: CD VAF/PLUS, 30 females per dose.0, 0.75, 3.0 and 15.   Exposure period: Days 6 through 15 of gestation.	NO(A)EL maternal – 0.75 mg/kg bw/day NO(A)EL teratogenicity embryotoxicity – 0.75 mg/kg bw/day Maternal toxicity:Body weight was decreased in the high dose group by 10% from day 12 until study termination. Body weight gain and food consumption were also decreased by 30% and 15% respectively in the high dose group, throughout the study. Teratogenicity: In the high dose group, a clear increase in post implantation loss, a reduction in the number of viable foetuses (by 14%), a decrease in foetal weight (by 17%), marked increases in the incidence of vertebral malformations with or without associated rib malformations and specific limb malformations were observed. In the mid dose group, a slight increase in the incidence of foetal malformations and a less pronounced increase in mean post implantation loss was observed.	Reliability – 1 Purpose flag Study result type Test material: Zinc pyrithione 48% Dispersion	Schardein JL (1993) (unpublished)
U.S. EPA (1998). Health Effects Test Guidelines. OPPTS 870.3700 Dermal,Rat – Sprague Dawley females; 23-25 animals per dose group. 0, 15, 30, and 60 mg/kg/day Exposure period – Day 0 through 21 of gestation	NO(A)EL maternal – 15mg/kg/day NO(A)EL teratogenicity embryotoxicity – 30 mg/kg/day Maternal: Reductions in body weight, body weight gain and/or body weight losses and absolute and/or relative feed consumption values occurred in the 30 and 60 mg/kg/day dosage groups. Reductions in muscle tone and/or muscle mass occurred in the 60 mg/kg/day dosage group.  Developmental:  Gravid uterine weights, fetal body weights and skeletal ossification average were reduced and skeletal variations were increased in the 60 mg/kg/day dosage group..  Zinc Pyrithione is not a selective developmental toxicant.	Reliability – 1 Purpose flag Study result type Test material: Zinc Pyrithione	Barnett (2005) (unpublished)

Effects on developmental toxicity

Effect on developmental toxicity: via oral route

Dose descriptor:

NOAEL

0.5 mg/kg bw/day

Effect on developmental toxicity: via dermal route

Dose descriptor:

NOAEL

30 mg/kg bw/day

Additional information

Key studies are summarised in 7.8.2

 

A GLP developmental toxicity study to US EPA 83-3, which Complies with OECD 414. by Schardein (1993), [reference 7.8.2.001, EZPTF 6081-001], investigated the administration of Zinc Pyrithione to the New Zealand white rabbit.

 

Groups of twenty inseminated New Zealand White SPF female rabbits were treated with 0.5, 1.5 or 3.0 mg/kg/day on days 6 - 18 of gestation. All fetuses from all litters were examined externally, viscerally and skeletally for malformations and/or variations. There was reduced food consumption at 1.5 and 3 mg/kg/day. There were statistically significant decreases in mean maternal weight gain during dosing in the mid and high groups and an increased incidence of red fluid in the refuse pan was noted for the high dose females relative to that in the control group. There was a higher incidence of decreased defecation observed for animals in the treated groups than for the control animals. One doe in the high-dose group aborted at gestation day 27. Whole litter resorption occurred for one doe in the mid-dose group and five does in the high-dose group.

 

In addition, there was an increase in the mean post-implantation loss and a decrease in the mean number of viable fetuses in both the mid and high-dosed groups. All parameters for the low-dose group were similar to control animal values.  The high-dose group fetuses were observed to have an increase in the incidence of malformations primarily in the cephalic and limb regions. Multiple cephalic and limb malformations were observed in three fetuses from two litters, with another fetus from one of these litters having a vertebral malformation with an associated rib malformation.

                                                           

There were no treatment related or statistically significant differences in the incidence of malformations between the control and the low and mid-dose groups. In addition, there were no dose-related differences in the incidence of developmental variations noted between the control and any treatment group.

 

The NOAEL for this study is 0.5 mg/kg/day (for maternal toxicity)and 1.5 mg/kg/day for malformations and developmental variations. Although, due to the severity of maternal toxicity observed at the 1.5 mg/kg dose group resorptions and implanation losses were observed.

 

 

A GLP developmental toxicity study to US EPA 83-3, which Complies with OECD 414. by Schardein (1993) [reference 7.8.2.002, EZPTF 6081-002], investigated the administration of Zinc Pyrithione to the rat GD 6-15.

 

Thirty mated female Charles River Crl: CD VAD/Plus rats were randomly assigned into treatment groups receiving 0, 0.75, 3.0, or 15.0 mg/kg/day. Twenty-seven litters from the control group, 30 litters from the low-dose group, 25 litters from the intermediate group, and 24 litters from the high dose group were evaluated for fetal malformations. Females in the high-dose (15.0 mg/kg/day) group lost weight or showed reduced weight (Table 6.8.1-1.1). Other indications of toxicity in the high dosed females was a persistent dilation of the pupils through gestation day 15 and the observation of increased salivation immediately after administration of the test article. There was a statistically significant increase post-implantation loss and a reduction in the mean number of viable fetuses, in the high-dose group. Whole litter resorption occurred for three dams in the high-dose group with a reduction in mean fetal body weight and in mean gravid uterine weight. 

 

There was significant maternal toxicity at the mid- and high dose levels and at the high dose level, skeletal malformations and developmental variations were observed in the litters. The most common skeletal malformation was a vertebral malformation with or without an associated rib malformation. Soft tissue malformations observed in one or two fetuses in the high dose group included dimorphism, a malformed brain, and renal hypoplasia. Developmental variations observed in the high dose litters were related to the vertebrae, ribs, and sternebrae; and soft tissue variations were observed in the ureter and renal papillae which were present at an increased incidence relative to control litters. 

                                                           

Fetal survival (increased post-implantation loss) and mean fetal weight were also adversely affected in this treatment group. At the mid dose level, a slight increase in the incidence of fetal malformations and a less pronounced increase in mean post-implantation loss were observed in comparison with the control group. With the exception of fused ribs, the specific malformations seen in the high-dose litters were not evident in the mid dose litter. Skeletal malformations observed in the mid-dose group fetuses included absent lumbar and caudal vertebrae, a pelvic malformation and fused skull bones. Soft tissue malformation observed in the mid-dose litters included a diaphragmatic hernia and, for the fetes with the tail malformation, anal atresia. There were no treatment related or statistically significant differences in the incidence of malformations between the control and low-dose groups. Resorptions and skeletal effects were observed only at maternally toxic doses. Additionally in relationship to the increase in resorptions, an increase was noted in the control animals as well as in the intermediate and the high dose animals. The body weight gains and food consumption were dramatically reduced during the early phase of gestation i.e. gestation days 9-12 demonstrating that the maternal toxicity was clearly associated with the observation of an increase in resorptions. 

 

The NOAEL administered orally to rats during gestation days 6-15 was 0.75 mg/kg/day with regard to maternal and development toxicity.

 

In brief the rat study noted a decrease in body weight gain that was 22% to 27% at the intermediate dose observed throughout the sensitive time of gestation (days 6-15; during the treatment with test article) and at the high dose decreases in body weight were noted (excessive decrease in body weight gain) and in fact a decrease in body weight was noted in the first part of the treatment period. The second half of the treatment period resulted in 27% to 67% decrease in body weight gain. This clearly demonstrates maternal toxicity and represents "severe" maternal toxicity. The severe maternal toxicity clearly impacts the development of the embryo that includes anything from resorptions, minor to major developmental effects to malformations.

 

It should be noted that the body weight gain data for rats showed that at the high dose there was a 37% decrease in body weight gain. Furthermore, the adjusted weights were taken over the entire test period that evaluated days 0-29, treatment occurred from days 6-15 (sensitve time for development) and does not take into account any rebounding effect that may occur when removing the animal from the stress of treatment (apparent in the mid treated animals).

 

Both the rat and rabbit developmental studies with ZPT demonstrated significant to severe maternal toxicity that was well above what most regulators and researchers consider significant, at much greater than 10% decrease in body weight gain and at the high doses decreases in overall body weight (no body weight gains) was observed.

 

Furthermore, in a study in rats administered ZPT via the most typical human route of exposure, dermal, (see below) clearly demonstrated that when maternal toxicity is mild (~10% decrease in body weight gain) no developmental effects nor malformations are observed. However, when maternal toxicity is increased (>>10%) minor developmental toxicity can be observed.

 

A GLP developmental toxicity study to U.S. EPA (1998). Health Effects Test Guidelines. OPPTS 870.3700, which Complies with OECD 414. by Barnett (2005), [reference 7.8.2.003, EZPTF 6081-003], investigated the dermal administration of Zinc Pyrithione to the rat, administered from Gestation Day 0-21. over 104 weeks.

 

No deaths related to the test substance occurred. One rat in the 15 mg/kg/day dosage group and one rat in the 60 mg/kg/day dosage group were found dead on DG 5. These deaths were not considered related to the test substance based on the early day of gestation and a lack of adverse clinical signs in these dams.  

 

There was an increased number of rats with limited use of hind limbs in the 30 mg/kg/day dosage group and an increased number or significantly increased number of rats in the 60 mg/kg/day dosage group with: erythema (grade 1), flaking (grade 1), limited use of the hind limbs, shuffling gait, dehydration, ungroomed coat, urine-stained abdominal fur, low carriage, chromodacryorrhea, emaciation, chromorhinorrhea, hunched posture and no use of hind limbs. 

 

Body weights were significantly reduced in the 30 mg/kg/day dosage group on DGs 13 to 21 and DGs 7 to 21 in the 60 mg/kg/day dosage groups. 

 

Dosage-dependent, significant reductions in body weight gains occurred in the 30 and 60 mg/kg/day dosage groups for the entire dosage period, as compared with the vehicle control group values. Body weight gains in the 10, 15, 30 and 60 mg/kg/day dosage groups were 96.7%, 93.4%, 77.4% and 30.0%, respectively, of vehicle control group values during the dosage period. Uterine weights in the 60 mg/kg/day dosage group were significantly reduced, as compared to the control group value. Corrected body weights were significantly reduced in the 30 and 60 mg/kg/day dosage groups. Corrected body weight gains were significantly reduced in the 30 and 60 mg/kg/day dosage groups on DGs 9 to 21 (30 mg/kg/day) and in the 60 mg/kg/day dosage group on DGs 7 to 21.

 

Dosage-dependent, significant reductions in absolute feed consumption values occurred in the 30 and 60 mg/kg/day dosage groups for the entire dosage period, as compared with the vehicle control group values and significant reductions in relative feed consumption values occurred in the 60 mg/kg/day dosage groups for the entire dosage period (calculated as DGs 0 to 21). 

 

In the 60 mg/kg/day dosage group, low muscle tone was observed in 1/24 rats on DG 8. There was a significant increase in the number of rats in the 60 mg/kg/day observed with low muscle tone on DGs 12, 16 and 20 and a corresponding significant reduction in the number of rats observed with moderate muscle tone on DGs 12, 16 and 20 in this same dosage group.

 

Muscle mass was slightly reduced on DG 12 in 1/23 rats in the 60 mg/kg/day dosage group. There was a significant increase in the number of rats in the 60 mg/kg/day observed with slightly reduced muscle mass on DGs 16 and 20 and a corresponding reduction or significant reduction in the number of rats observed with normal muscle mass on DGs 16 and 20 in this same dosage group. 

 

Pregnancy occurred in 23 to 24 female rats per dosage group. Fetal body weights were significantly reduced in the 60 mg/kg/day dosage group. The maternally toxic 60 mg/kg/day dosage group had significantly increased numbers of fetuses with any alteration principally composed of significant increases in the number of litters and fetuses with incomplete ossification of the sternal centra and the number of fetuses with wavy ribs.  Significant reductions in the ossification site averages for the caudal vertebrae, forelimb phalanges and metacarpals and hindlimb phalanges and metatarsals per fetus per litter in the 60 mg/kg/day dosage groups. 

 

On the basis of these data, the maternal no-observable-adverse effect-level (NOAEL) of Zinc Pyrithione is 15 mg/kg/day when dosed from gestational day 0 - 21. Reductions in body weight, body weight gain and/or body weight losses and absolute and/or relative feed consumption values occurred in the 30 and 60 mg/kg/day dosage groups. Reductions in muscle tone and/or muscle mass occurred in the 60 mg/kg/day dosage group. 

 

The developmental NOEL is 30 mg/kg/day(gravid uterine weights, foetal body weights and skeletal ossification average were reduced and skeletal variations were increased in the 60 mg/kg/day dosage group). Zinc Pyridinethione is not a selective developmental toxicant. 

Table 7.8.2

Route	Testtype Method Guideline	Species Strain Sex no/group	Exposure Period	Doses[mg/kg bw/day]	Critical effects dams foetuses	NO(A)EL maternal	NO(A)EL Teratogenicity Embryotoxicity	Reference
						[mg/kg bw/day]
Oral (gavage).	US EPA 83-3, which Complies with OECD 414. GLP (self Certification by the laboratory).	Rabbit, New Zealand White, 20 females per dose, Test material: Zinc Omadine®, 48% Dispersion	Days 6 Through 19 of Gestation	0, 0.5, 1.5 and 3.0	Maternal toxicity:Body weight gain was decreased during the dosing period only, by 40% in mid dose group and the females failed to gain weight in high dose group. Food consumption was decreased during the dosing period only, by 15% and 23% in mid- and high dose groups respectively. Clinical signs included an increased incidence of excretion of red fluid (high dose only) and decreased defecation for all treated groups.   Teratogenicity:Post implantation losses of 65% were observed in high dose group, 29% in mid dose group and 12% in low dose and control group. The number of dams with viable foetuses was decreased in high dose to only 7/20, compared with 15-18/20 in other groups. The incidence of foetuses with abnormalities was increased in high dose group 7/26 compared with 7/105 in the controls (multiple cephalic and limb malformations occurred in 3 of the 7 litters examined in the high dose group). There was a significant increase in the number of foetuses with developmental variations in the mid dose group compared with controls.	0.5	0.5	7.8.2.001   EZPTF 6081-001   Schardein JL (1993) (unpublished)
Oral (gavage)	US EPA 83-3, which Complies with OECD 414. GLP (self Certification by the laboratory).	Rat, Charles river, Crl:CD VAF/PLUS, 30 females per dose, Test material: Zinc Omadine®, 48% Dispersion	Days 6 Through 15 of gestation.	0, 0.75, 3.0 and 15	Maternal toxicity:Body weight was decreased in the high dose group by 10% from day 12 until study termination. Body weight gain and food consumption were also decreased by 30% and 15% respectively in the high dose group, throughout the study. Clinical signs reported were dilated pupils in high dose animals and a dose-related increase in the incidence of excessive salivation in mid- and high dose groups.   Teratogenicity: In the high dose group, a clear increase in post implantation loss, a reduction in the number of viable foetuses (by 14%), a decrease in foetal weight (by 17%), marked increases in the incidence of vertebral malformations with or without associated rib malformations and specific limb malformations were observed. In the mid dose group, a slight increase in the incidence of foetal malformations and a less pronounced increase in mean post implantation loss was observed.	0.75	0.75	7.8.2.002   EZPTF 6081-002   Schardein JL (1993) (unpublished)

Dermal

U.S. EPA (1998). Health Effects Test Guidelines. OPPTS 870.3700

Rat – Sprague Dawley females; 23-25 animals per dose group

Day 0 through 21 of Gestation

0, 15, 30, and 60 mg/kg/day

Maternal: Reductions in body weight, body weight gain and/or body weight losses and absolute and/or relative feed consumption values occurred in the 30 and 60 mg/kg/day dosage groups. Reductions in muscle tone and/or muscle mass occurred in the 60 mg/kg/day dosage group.    Developmental:  Gravid uterine weights, fetal body weights and skeletal ossification average were reduced and skeletal variations were increased in the 60 mg/kg/day dosage group..    Zinc Pyrithione is not a selective developmental toxicant.

15 mg/kg/day

30 mg/kg/day

7.8.2.003   EZPTF 6081-003   Barnett (2005)  (unpublished)