Pyrithione zinc

Developmental toxicity / teratogenicity

Administrative data

Endpoint:

developmental toxicity

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 83-3 (Prenatal Developmental Toxicity Study)

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:

Specification: 48% aq

Test animals

Species:

rabbit

Strain:

New Zealand White

Details on test animals or test system and environmental conditions:

Source: Hazelton Research Products, USA
Age at study initiation: 4-4.5 months
Weight at study initiation: 3101-4213g

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

water

Details on exposure:

Dose volume: 1 ml/kg

Details on mating procedure:

artificial insemination

Duration of treatment / exposure:

exposure: day 6-18 post mating
post-exposure: 11 days

Doses / concentrations

Doses / concentrations 1

Remarks:

Doses / Concentrations:
0.5 mg/kg bw
Basis:

Doses / concentrations 2

Remarks:

Doses / Concentrations:
1.5 mg/kg bw
Basis:

Doses / concentrations 3

Remarks:

Doses / Concentrations:
3.0 mg/kg bw
Basis:

No. of animals per sex per dose:

20

Control animals:

yes, concurrent vehicle

Examinations

Maternal examinations:

Body weight: gestation days 0, 6, 12, 19, 24, 29
Clinical signs: dilay dusring gestation days 6-29

Ovaries and uterine content:

Gravid uterine weight
Number of corpora lutea
Number of implantations

Fetal examinations:

Litter size
Number of dead foetuses
Foetal weight
Sex ratio
Skeletal anad soft tissue

Statistics:

All statistical analyses compared the treatment groups with the control with levels of significance at p≤0.05 and p≤0.01. All means values included the standard deviation. Statistical tests were performed using a VAX computer and SAS or in-house statistical software.
Mean maternal body weights, body weight changes, food consumption, mean numbers of corpora lute, total implantations, live foetuses, mean fatal body weights, and mean gravid uterine weights were compared by analysis of variance (one-way), Bartlett’s test for homogeneity of variance and the appropriate t-test (for equal and unequal variance) using Dennett’s multiple comparison tables or pair wise comparisons with a Bonfarroni correction to determine the significance of differences.
Fetal sex ratios and the proportion of litters with malformations and developmental variations were compared using the Chi-square test for homogeneity of R x C contingency tables to determine the significance of differences.
The proportions of resorbed and dead fetuses and post-implantation losses were compared using the Kruskal-Wallis test. If the test was statistically significant (p≤0.05), then the Mann-Whitney U-test with a Bonfarroni correction was used to determine the significance.

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:

Maternal toxic effects:yes

Details on maternal toxic effects:
Deceased weight gain in the 1.5-mg/Kg and 3.0-mg/Kg dose groups during gestation days 6-12, and decreased weight gain in the 1.5-mg/Kg dose group and weight loss in the 3.0-mg/Kg dose group during gestation days 12-19. Reduced food consumption in the 1.5-mg/Kg and 3.0-mg/Kg dose groups during the treatment period.
Aside from one death in the 1.5-mg/Kg dose group, the only significant clinical observations were an increased incidence of red fluid in the refuse pan in the 3.0-mg/Kg dose group, and decreased defecation relative to the controls in all of the treatment groups. Based on the necropsy results, a gavage error during dosing was considered as a possible cause for the single death. There were no fatalities in the control, 0.5-mg/Kg, and 3.0-mg/Kg groups.

Effect levels (maternal animals)

1

Dose descriptor:

LOAEL

Effect level:

1.5 mg/kg bw/day (nominal)

Basis for effect level:

other: maternal toxicity

2

Dose descriptor:

NOAEL

Effect level:

0.5 mg/kg bw/day (nominal)

Basis for effect level:

other: maternal toxicity

Results (fetuses)

Details on embryotoxic / teratogenic effects:

Embryotoxic / teratogenic effects:yes

Details on embryotoxic / teratogenic effects:
1.1 Teratogenic / embryo¬toxic effects Uterine effects were seen in the 1.5 mg/Kg (mid dose) and 3.0-mg/Kg (high dose) groups. These included: one animal in the 3.0-mg/Kg group aborted on gestation day 27; whole litter resorption in one mid dose animal and 5 high dose animals; and an increase in the mean post-implantation loss and a decrease in the mean number of viable fetuses. The reduced number of viable fetuses also resulted in reduced mean uterine weights in these groups, although the mean fetal weights were comparable those in the control group. In addition there was a slight reduction in the number of implantations compared with the control group, which was mainly due to the increased post-implantation losses. There were no significant differences in the mean number of corpora lutea and the fetal sex ratio compared to the controls.
All parameters in the 0.5-mg/Kg (low dose) group were similar to those in the control group.
Developmental effects to the fetus were observed only at the high dose and included an increase in the incidence of malformations, primarily in the cephalic and limb regions. Three fetuses from two litters showed multiple cephalic and limb malformations. A forth fetus from one of these litters showed a vertebral malformation with associated rib malformation. There were no treatment-related or statistically significant differences in the incidence of malformations between the control and the low-dose or mid-dose groups. There were no dose -related differences in the incidence of developmental variations between the control and any treatment group.

Effect levels (fetuses)

1

Dose descriptor:

LOAEL

Effect level:

1.5 mg/kg bw/day (nominal)

Basis for effect level:

other: embryotoxicity

2

Dose descriptor:

NOAEL

Effect level:

0.5 mg/kg bw/day (nominal)

Basis for effect level:

other: embryotoxicity

Fetal abnormalities

Abnormalities:

not specified

Overall developmental toxicity

Developmental effects observed:

not specified

Applicant's summary and conclusion

Conclusions:

NOAEL = 0.5 mg/kg. 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.