Zinc di(acetate)

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Effect on fertility: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

372 mg/kg bw/day

Effect on fertility: via inhalation route

Endpoint conclusion:

no study available

Effect on fertility: via dermal route

Endpoint conclusion:

no study available

Additional information

Weight of evidence: Experimental data on rats and mice with Zinc Acetate and read-across approach from experimental results on rats and mice treated with Citric Acid, Sodium Citrate, and Zinc Sulfate.

Experimental data on Zinc Acetate:

In the study reported by Piao et al. (2003), the toxic effect of Zinc acetate on the functions of various tissues and organs in male rats was studied. The rats were randomly divided into groups (14 in each group). One normal control group received saline and two groups received zinc acetate (4 mg/kg bw/day and 8 mg/kg bw/day) and the other group cyclophosphamide (50 mg/kg bw, as a positive control of micronucleated polychromatic erythrocytes). The saline and zinc acetate were administrated intraperitoneally to rats once every two days, seven times in total. Cyclophosphamide was given intraperitoneally to rats once. It was observed that zinc acetate at the same dose did not cause and elevated abnormal sperm percentage in rats indicating that zinc does not have a harmful effect on the male reproductive system.

The NOAEL was equal or higher than 8 mg/kg bw/day (reproduction effects in male rats).

In the study reported by Lastra et al. (1997), a model of BALB/c mice received Zinc acetate in drinking water concentrations of 500 and 1000 mg/L during the periods of gestation, lactation and postweaning. The sequence employed in this study was: (I) 0/0, (II) 500/500, (III) 1000/1000, (IV) 0/0/0, (V) 500/500/500, and (VI) 1000/1000/1000 with their respective controls.

No changes were observed in the general appearance, growth curves, hematocrit or signs of achromotrichia between treated and control animals. The exposure of up to 372 mg zinc/kg bw/day in mice prior to and throughout pregnancy did not result in changes in reproductive index (for parents and developmental toxicity).

Read-across approach from experimental results obtained with analogues Citric Acid and Sodium Citrate:

In the study reported by Wright et al., 1976, a fertility and a one-generation study are described. This study examines the effect of a 5% dietary supplement of Citric acid (ca. 2.5 g/kg bw/day) on the reproductive capacity of rats and mice. Animals were treated before, during, and after mating. No effects were seen on number of pregnancies, number of young born, or survival of young in treated rats and mice with ca. 2.5 g/kg bw/day Citric Acid, compared to controls.

The read-across approach is applied and the NOAEL with Zinc Acetate is calculated to be 3582.06 mg/kg bw/day on rats and mice (basis for effects: number of pregnancies, number of young born, or survival of young).

In the paper reported by Bonting et al., 1956, a fertility test was carried out on rats with Citric Acid. Exposure began 29 weeks prior to mating and continued for a few months after mating. Animals were fed diets containing 1.2% citric acid (about 600 mg/kg bw/day). No effects were detected. The NOAEL for reproductive effects was 600 mg/kg bw/day. The LOAEL was greater than 600 mg/kg bw/day for the same effects.

Applying the read-across approach, the NOAEL with the substance Zinc acetate is calculated to be 859.69 mg/kg bw/day, and LOAEL higher than 859.69 mg/kg bw/day.

Bonting et al. also describes another fertility test on rats with Citric Acid, sodium salt. The method was exactly the same, the only difference is the given dose. In this case, treated animals received fed diets containing 0.1% citric acid, sodium salt (ca. 50 mg/kg bw/day). No effects were detected. The NOAEL for reproductive effects was 50 mg/kg bw/day. The LOAEL was higher than 50 mg/kg bw/day.

Applying the read-across approach, the NOAEL with the substance Zinc acetate is calculated to be 64.28 mg/kg bw/day, and LOAEL higher than 64.28 mg/kg bw/day for reproductive effects.

Read-across approach from experimental results obtained with analogue Zinc Sulfate:

To see whether zinc supplementation during pregnancy affects maternal and fetal outcome, Mahomed et al. (1989) performed a prospective study which started at booking and continued till discharge of mother and baby from the maternity hospital. Mothers were randomly assigned to receive zinc supplementation (as capsule, 0.3 mg Zinc/kg bw/day as Zinc sulfate) or placebo in a double blind trial. 494 Mothers were followed up till the end of pregnancy. Pregnant women receiving capsules containing zinc did not exhibit any reproductive effects (no changes in maternal body weight gain, blood pressure, postpartum hemorrhage, or infection). No complications occurred in the pregnancies of these women. The NOAEL was equal or greater than 0.3 mg Zinc elemental/kg bw/day (for maternal and neonatal toxicity).

Applying the read-across approach, the NOAEL with the substance Zinc acetate is calculated to be equal or higher than 0.84 mg/kg bw/day (for maternal and neonatal toxicity).

A thirteen weeks study equivalent to a OECD 422, screening repeat dose toxicity sand reproduction was study was performed. No effects on reproduction organs were observed at male and female rats during the feeding with 234 mg/kg bw/day of ZnSO4·7H2O therefore the NOAEL is higher than 234 mg/kg bw/day.

Applying the read-across approach the NOAEL with the substance Zinc acetate is calculated to be equal or higher than 149.6 mg/kg bw/day.

Short description of key information:
Effects on fertility: Weight of evidence: Experimental data on rats and mice with Zinc Acetate and read-across approach from experimental results on rats and mice treated with Citric Acid, Sodium Citrate, and Zinc Sulfate. No toxicity to reproduction was observed in any case.

Justification for selection of Effect on fertility via oral route:
Section 7.8.1 information

Effects on developmental toxicity

Description of key information

Developmental toxicity/Teratogenicity: Weight of evidence: Experimental data on Zinc Acetate on mice and read-across approach from experimental results on rats, mice, and rabbits treated with Sodium Acetate, Citric Acid, Calcium Formate, Acetic Acid, Zinc Sulfate and Zinc Aspartate. No maternal or developmental toxicity effects were seen in treated animals exposed to high doses of these substances.

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

48.44 mg/kg bw/day

Species:

rat

Effect on developmental toxicity: via inhalation route

Endpoint conclusion:

no study available

Effect on developmental toxicity: via dermal route

Endpoint conclusion:

no study available

Additional information

Weight of evidence: Experimental data on Zinc Acetate on mice and read-across approach from experimental results on rats, mice, and rabbits treated with Sodium Acetate, Citric Acid, Calcium Formate, Acetic Acid, Zinc Sulfate and Zinc Aspartate.

Experimental data on Zinc Acetate:

Zinc acetate (10 mg/kg bw, i.p.) was administered to pregnant CD-1 mice at 48, 24 or 0 hr prior to GD 9 administration of LPS (0, 0.025, 0.05 mg/kg bw). Animals were killed on GD 10. Maternal liver and plasma were taken for trace element and/or MT (metallothionein) analysis. Embryos were examined for viability and dysmorphogenesis.

At 24 hr post LPS, maternal liver Zinc and MT levels increased with dose. Zinc treatment also induced MT. Zinc co-administration exacerbated the effects of LPS (60% and 100% fully resorbed at 0.025 and 0.05 mg/kg bw of LPS) while 24 or 48 hr Zinc pretreatment had a protective effect (5% and 4% fully resorbed at 0.025 and 0.05 mg/kg bw of LPS).

Read-across approach from experimental results obtained with analogue Sodium Acetate:

In the first paper, reported by Kavlock et al., 1987, pregnant CD-1 mice were treated with Sodium Acetate by oral gavage on days 8-12 of gestation at a dose level predicted from a preliminary range finding study to induce a slight degree of maternal toxicity. Day 20 of gestation was considered postnatal day 1 (PD1). On PD1 and 3, the litters were counted and weighed as a unit.

No maternal toxicity and no neonatal effects (mortality and body weight) were observed at a dose level of 1000 mg/kg bw/day.

By read-across approach, for Zinc Acetate the NOAEL is calculated to be equal or higher than 1118.47 mg/kg bw/day (based on maternal toxicity: mortality, pregnancy and resorption; and on neonatal effects: mortality and body weight).

Read-across approach from experimental results obtained with analogue Citric Acid:

In the study reported by Wright et al., 1976, a one-generation study is described. This study examines the effect of a 5% dietary supplement of Citric acid (ca. 2.5 g/kg bw/day) on the reproductive capacity of rats and mice. Animals were treated before, during, and after mating. No effects were seen on number of pregnancies, number of young born, or survival of young in treated rats and mice with ca. 2.5 g/kg bw/day Citric Acid, compared to controls.

The read-across approach is applied and the NOAEL with Zinc Acetate is calculated to be 3582.06 mg/kg bw/day on rats and mice (basis for effects: number of pregnancies, number of young born, or survival of young).

Read-across approach from experimental results obtained with analogue Calcium Formate:

In the third paper, reported by Malorny (1969), a three-generation study was performed with Calcium formate in Wistar rats. Animals were treated by drinking water at doses of 0 or 200 mg/kg bw/day of test substance. No effects on fertility were observed. Number, weight and length of offspring did not differ in treated animals from controls. A portion of the offspring was also sacrificed shortly after birth for evaluation of developmental toxicity. No statistical differences in organ or bone abnormalities were found. The growth of treated offspring was similar to controls. The NOAEL for maternal and developmental toxicity was equal or higher than 200 mg/kg bw/day.

The read-across approach is applied and the NOAEL for maternal and developmental toxicity with Zinc Acetate is calculated to be equal or higher than 282.06 mg/kg bw/day (overall effects).

Read-across approach from experimental results obtained with analogue Acetic Acid:

In the paper reported by FDA (1974), a one-generation study is presented on female mice, rats and rabbits with Acetic acid. Pregnant animals were dosed daily by oral intubation, beginning on day 6 of gestation. Tested doses were 0, 16, 74, 345, and 1600 mg/kg bw/day. No effects on nidation or on maternal or fetal survival were observed at doses up to 1600 mg/kg bw/day. The number of abnormalities seen in either soft or skeletal tissues of the test groups did not differ from the number occurring in the controls.

Based on the experimental results and the molecular weights, the read-across approach was applied and the NOAEL with the substance Zinc acetate is calculated to be equal or higher than 2446.63 mg/kg bw/day for maternal and developmental toxicity in mice, rats, and rabbits.

Read-across approach from experimental results obtained with analogue Zinc Sulfate:

To see whether zinc supplementation during pregnancy affects maternal and fetal outcome, Mahomed et al. (1989) performed a prospective study which started at booking and continued till discharge of mother and baby from the maternity hospital. Mothers were randomly assigned to receive zinc supplementation (as capsule, 0.3 mg Zinc/kg bw/day as Zinc sulfate) or placebo in a double blind trial. 494 Mothers were followed up till the end of pregnancy. Pregnant women receiving capsules containing zinc did not exhibit any reproductive effects (no changes in maternal body weight gain, blood pressure, postpartum hemorrhage, or infection). No complications occurred in the pregnancies of these women. The NOAEL was equal or higher than 0.3 mg Zinc elemental/kg bw/day (for maternal and neonatal toxicity).

The read-across approach was applied and the NOAEL with the substance Zinc acetate is calculated to be equal or higher than 0.84 mg/kg bw/day (for maternal and neonatal toxicity).

Zinc sulfate NOEL was determined to be 42.5 mg/kg bw for maternal and neonatal toxicity in a NTP study performed similar to OECD 414.

Based on the experimental results obtained with the analogue Zinc sulfate on Wistr rats, and the molecular weights, the read-across approach was applied and the NOEL with the substance Zinc acetate is calculated to be equal or higher than 48.44 mg/kg bw/day (for maternal and neonatal toxicity).

A thirteen weeks study equivalent to a OECD 422 reported at 07.08.01_14, screening repeat dose toxicity sand reproduction was study was performed. No effects on reproduction organs were observed at male and female rats during the feeding with 535 mg/kg bw/day of ZnSO4·7H2O therefore the NOAEL is higher than 234 mg/kg bw/day.

Applying the read-across approach the NOAEL with the substance Zinc acetate is calculated to be equal or higher than 149.6 mg/kg bw/day.

Read-across approach from experimental results obtained with analogue Zinc Aspartate:

In the study reported by Kynast et al. (1986), the effects of the oral application of Zinc aspartate in pregnancy women is investigated in a randomly selected study group of 179 patients and a control group of 345 patients. This study confirms the prophylactic effectiveness of zinc replacement in reducing the overall complication rate for both mother and fetus and in particular for large-for-date and small-for-date infants. The therapy is well tolerated and accepted by the patients and causes no side effects. The results are in line with those of other working groups reporting on zinc as an important element with protective effects on fetal growth and development in pregnancy. The NOAEL was equal or higher than 0.3 mg/kg bw/day of zinc aspartate (for maternal and developmental toxicity).

The read-across approach was applied and the NOAEL with the substance Zinc acetate is calculated to be equal or higher than 0.16 mg/kg bw/day (for maternal and developmental toxicity).

No adverse effects were observed for the substance and analogues during studies according or equivalent to OECD 422 and 414 for zinc therefore is no need for further investigation.

Justification for selection of Effect on developmental toxicity: via oral route:
Section 7.8.2 information. Studies on animals and humans

Justification for classification or non-classification

Based on the available data on effects on fertility and developmental toxicity of the substance and its analogues the substance is not classified.