Reaction mass of zinc oxide and zinc peroxide

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Description of key information

A range of studies have been conducted to assess the effects of zinc on fertility and reproductive performance, most of them with very soluble zinc chloride and zinc sulphate. A complete overview and review of available fertility studies is available in the EU risk assessment of zinc compounds (EU RAR, 2004), the review of the of health effects of zinc compounds by the US Agency for Toxic Substances and Disease Registry (ATSDR, 2005), the toxicological review of zinc and compounds by the US Environmental Protection Agency (US EPA, 2005) or the review by the WHO (WHO, 2001). The results of the key experimental studies addressing potential effects of zinc compounds on fertility are summarised below.

Link to relevant study records

Reference

Endpoint:

one-generation reproductive toxicity

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Justification for type of information:

REPORTING FORMAT FOR THE ANALOGUE APPROACH

1. HYPOTHESIS FOR THE ANALOGUE APPROACH
The target substance Zinc peroxide and the source substances Zinc oxide, Zinc Chloride, Zinc sulfate, Zinc nitrate are ionic and consist of the Zinc2+ cation and the respective anion.
The read-across is based on the assumption that the zinc cation (as measure for dissolved zinc species) is the determining factor for (eco)toxicity.
For further details, see Justification for read-across attached to IUCLID chapter 13

2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
See Justification for read-across attached to IUCLID chapter 13

3. ANALOGUE APPROACH JUSTIFICATION
See Justification for read-across attached to IUCLID chapter 13

4. DATA MATRIX
See Justification for read-across attached to IUCLID chapter 13

Reason / purpose for cross-reference:

read-across: supporting information

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across source

Dose descriptor:

NOAEL

Remarks:

human data

Effect level:

20 mg/kg bw/day (nominal)

Based on:

other: Zn2+

Sex:

female

Basis for effect level:

other: no adverse effects observed

Dose descriptor:

NOAEL

Remarks:

human data

Generation:

F1

Effect level:

>= 20 mg/kg bw/day

Based on:

other: Zn2+

Sex:

male/female

Basis for effect level:

other: no adverse effects observed

Reproductive effects observed:

no

Effect on fertility: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

29.8 mg/kg bw/day

Study duration:

chronic

Species:

rat

Effect on fertility: via inhalation route

Endpoint conclusion:

no study available

Effect on fertility: via dermal route

Endpoint conclusion:

no study available

Additional information

No data on toxicity to reproduction are available for the target substance Zinc peroxide. However, reliable data are available for Zinc compounds as well as on hydrogen peroxide. A justification for read-across is attached to IUCLID section 13.

 

Data on Zinc

Non-human information

The reproductive toxicity of zinc compounds has been investigated in one and two generation reproductive toxicity studies in which rats or mice were dosed by gavage or via the diet with soluble zinc compounds (i. e., zinc chloride, zinc sulphate) at exposure levels up to 14 mg Zn/kg bw/day (gavage) or 200 mg Zn/kg bw/day (diet) (Khan et al.,2001, 2003, 2007; Samanta et al, 1986). Further information on potential effects of zinc compounds on male or female reproductive organs could be retrieved from subchronic toxicity studies as conducted by Maita et al.(1981) and Edwards and Buckley (1995).

Maita et al. (1981) reported that mice and rats fed with zinc sulphate in dietary concentrations up to 30,000 mg/kg feed did not produce adverse effects on either male or female sex organs after 13 weeks of exposure. This dietary level was equal to ca. 1100 mg or 565 mg Zn/kg bw/day for mice and rats, respectively. Edwards and Buckley (1995) showed that rats exposed to 13 or 60 mg Zn/kg bw/day in the diet over a period of 90 days did not show any detrimental effects on sex organs. In the exposure group of 335 mg Zn/kg bw/day, all males showed hypoplasia in testes and seminiferous tubules in males hypoplastic uterus in females, but these findings are not considered reliable as the animals of this high dose group were generally of poor health conditions and killed for humane reasons prior to study termination.

In addition to those key reproductive toxicity studies(Khan et al.,2001, 2003, 2007; Samanta et al, 1986), some additional studies indicating high oral doses of zinc (i.e., exposures greater that 25 mg day/kg bw/day) to impair fertility as indicated by a decreased number of implantations sites and increased number of resorptions are of note:

A study was carried out to determine the effect of zinc supplementation on the number of implantation sites and resorptions in pregnant rats. The control group consisting of 12 pregnant females was maintained on 10 % vegetable protein diet (containing 30 ppm zinc) from Day 1 through Day 18 of pregnancy. The experimental group consisting of 13 animals was also maintained on the same diet, but received additionally 150 ppm zinc as a 2% zinc sulphate solution administered daily orally. All the animals were sacrificed on Day 18 of pregnancy, and their uteri examined for implantation sites and resorptions. Of a total number of 101 implantation sites in the 12 control animals there were two resorptions, one in each of two animals. In marked contrast, in the 13 zinc supplemented animals, there were 11 resorptions out of 116 implantations. Eight of the animals had at least one resorption each. This difference was statistically significant. The result indicates that oral administration of moderately high levels of zinc (150 ppm) may be associated with harmful effects during pregnancy of rat (Kumar et al., 1976). The low protein diet may have affected the physiology of the animals resulting in an increased sensitivity for zinc. As this hypothesis cannot be further assessed and also considering the limited available study information, this study is only of limited validity for the assessment of effects of zinc exposure on fertility (EU RAR, 2004).

Another study aimed at determining the effect of post-coitum, and pre- and post-coitum dietary zinc supplementation on the conception in the Charles-Foster rat. In the post-coitum study (test 1), two groups of 15 pregnant rats were fed 0 and 4,000 ppm zinc as zinc sulphate in diet (i.e., approximately 200 mg Zn/kg bw/day) from day 1 through day 18 of pregnancy. In the pre- and post-coitum study (test 2), two groups of 15 female rats were treated with same doses for 21 days pre-mating period, maximum 5 days of mating period and 18 days of post-coitum period. All the females were sacrificed on Day 18 of gestation and uterus content and fetuses were examined. In test 1, significant decrease in the incidences of conception and number of implantation sites per mated female was observed in the treatment group with respect to the control group. However, the difference in implantation sites when considered per pregnant female was not significant. In test 2, no significant difference in incidences of conception and implantation sites was observed in the control and treatment groups. In both the tests, there was no treatment-related change in the fetal and placental weights, stillbirths and malformed fetuses were absent and the number of resorption sites was negligible. Based on these results, dietary zinc supplementation at 4,000 ppm did not affect the fetal growth in pregnant rats. This dose, however, altered the normal conception when started after coitus but showed no effect when initiated sufficient time before coitus (Pal et al., 1987).

The available information suggests that high oral doses of zinc (i. e., exposure levels greater than 20 mg Zn/kg bw/day) may adversely affect spermatogenesis and result in impaired fertility indicated by decreased number of implantation sites and increased number of resorptions (US EPA, 2005). However, these effects were only observed in the presence of maternal toxicity as seen in the one or two generation studies conducted by Khan et al. (2001, 2003, 2007) or, in case of the study conducted by Kumar et al. (1976), when other study non-zinc relevant study specificities could have impacted the study outcome.

 

Effects on Fertility, Human information

In reviews by the World Health Organisation in the Environmental Health Criteria for Zinc (WHO, 2001) and by the US Agency for Toxic Substances and Disease Registry in the Toxicity Profile for Zinc (ATSDR, 2005), existing human studies which examined the responses of women to zinc supplementation during pregnancy have been summarised. Studies on large controlled trials that were conducted to investigate the effects of dietary zinc supplementation in healthy pregnant women were peer reviewed. The reviewers concluded that zinc at a rate of 20mg/day and 30 mg/day did not result in any adverse reproductive effects during pregnancy (Hunt et al.,1984; Kynast and Saling et al.,1986).Two exemplar studies are summarised in the following:

A double blind trial was conducted in 56 pregnant women at risk of delivering a small for gestational-age baby to determine the effects of dietary zinc supplementation during the last 15-25 weeks of pregnancy following administration of 22.5 mg zinc/day. No adverse reproductive effects were observed (Simmer et al.,1991).

Pregnant women who received 0.3 mg zinc/kg bw/day as zinc sulphate capsules during the last two trimesters did not exhibit any changes in maternal body weight gain, blood pressure, postpartum haemorrhage or infection, inidicating no adverse reproductive effects (Mahomed et al.,1989).

 

Data on hydrogen peroxide

Cited from theSummary Risk Assessment Report on Hydrogen peroxide (2003):

“No appropriate studies were available for a complete evaluation of reproductive and developmental toxicity. Limited studies with mice and rats exposed to H2O2 in drinking water suggested no grave disturbances on the male or female reproductive functions. Moreover, an appropriate 90-day drinking water study with catalase-deficient mice, and carcinogenicity studies with mice and F344 rats did not identify testes or ovaries as target organs. The only available developmental toxicity (feeding) study in rats showed foetotoxic effects, but the study contains major uncertainties regarding the exposure and mode of action; therefore, it could not be used for an evaluation.

Thus there is a clear data gap regarding developmental toxicity for H2O2. However, during the risk assessment process no further testing on this endpoint was required, since conventional study protocols were judged unlikely to show specific embryonal or foetal effects: firstly, because it is doubtful whether H2O2 would reach the foetus (as opposed to degradation products oxygen and water) and secondly, because local effects and hence potential general toxicity are expected in the mother.”

 

In the transformation/dissolution test conducted with the target source Zinc peroxide, it was demonstrated, that only low levels of hydrogen peroxide are released. Thus, bolus or high concentration effects of hydrogen peroxide are not relevant for the target substance.In the view of the high degradation capacity for hydrogen peroxide in blood, it is unlikely that hydrogen peroxide released from ZnO2 is systemically distributed, and therefore the endogenous steady state levels of hydrogen peroxide in tissues are unlikely to be affected.

 

Overall, Zinc peroxide is not considered to be a reproductive toxicant.

Effects on developmental toxicity

Description of key information

Several prenatal toxicity studies are available that examined the developmental toxicity of various zinc compounds in rats, mice, rabbit or hamsters up to dietary exposure levels of 200 mg Zn/kg bw/day or 50 mg Zn/kg bw/day by gavage (for details see Table developmental toxicity studies). No developmental toxicity has been observed in these studies and there NOAEL’s have been established at the highest doses tested.
Although some developmental effects such as decreases in body weights or decrease in individual organ weights were observed in F1 and/or F2 generations in the one or two generation reproductive toxicity studies conducted by Khan et al. (2007) at high exposure levels, these observations are, however, not suitable for risk assessment or hazard classifications as they were always accompanied with maternal toxicity. Moreover, no developmental toxicity was observed at non-maternally toxic doses in a teratogenicity study in which CF-1 albino mice were administered intraperitoneally 0, 12.5, 20.5 and 25 mg/kg on Day 11 of gestation (test 1) and at 20.5 mg/kg on Days 8 -11 of gestation (test 2) (Chang et al., 1979).

Link to relevant study records

Reference

Endpoint:

developmental toxicity

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Justification for type of information:

REPORTING FORMAT FOR THE ANALOGUE APPROACH

1. HYPOTHESIS FOR THE ANALOGUE APPROACH
The target substance Zinc peroxide and the source substances Zinc oxide, Zinc Chloride, Zinc sulfate, Zinc nitrate are ionic and consist of the Zinc2+ cation and the respective anion.
The read-across is based on the assumption that the zinc cation (as measure for dissolved zinc species) is the determining factor for (eco)toxicity.
For further details, see Justification for read-across attached to IUCLID chapter 13

2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
See Justification for read-across attached to IUCLID chapter 13

3. ANALOGUE APPROACH JUSTIFICATION
See Justification for read-across attached to IUCLID chapter 13

4. DATA MATRIX
See Justification for read-across attached to IUCLID chapter 13

Reason / purpose for cross-reference:

read-across: supporting information

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across source

Dose descriptor:

NOAEL

Effect level:

50 mg/kg bw/day (nominal)

Based on:

other: Zn2+

Basis for effect level:

other: no adverse effect observed

Abnormalities:

no effects observed

Dose descriptor:

NOAEL

Effect level:

50 mg/kg bw/day (nominal)

Based on:

other: Zn2+

Sex:

male/female

Basis for effect level:

other: no adverse effect observed

Abnormalities:

no effects observed

Developmental effects observed:

no

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

50 mg/kg bw/day

Species:

rat

Effect on developmental toxicity: via inhalation route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEC

7.5 mg/m³

Study duration:

subacute

Species:

rat

Additional information

No data on developmental toxicity are available for the target substance Zinc peroxide. However, reliable data are available for Zinc compounds as well as on hydrogen peroxide. A justification for read-across is attached to IUCLID section 13.

 

Data on Zinc

Non-human information

The developmental toxicity of zinc compounds can be assessed on the basis of prenatal toxicity studies that have been conducted with soluble zinc sulphate and zinc chloride and slightly soluble zinc carbonate in rats, mice, hamsters or rabbits. Moreover, a total of three (one or two generation) reproductive toxicity studies conducted by Khan et al.(2001, 2003, 2007) provide further information on potential teratogenic effects of zinc compounds.

No prenatal toxicity was observed with either zinc sulphate, zinc chloride or zinc carbonate at exposure levels up to 50 mg Zn/kg bw/day by oral gavage or 200 mg Zn/kg bw/day if the zinc was dosed via the diet. Established NOAELs in these studies were typically at highest dose tested and systemically tolerated by the dams. Developmental effects such as decrease in body or organ weights were, however, observed in F1 and/or F2 generations in the one or two generation reproductive toxicity studies conducted by Khan et al. (2001, 2003, 2007). These studies are not considered suitable for the assessment of teratogenic effects for hazard classification or risk assessment purposes since they were always observed in the presence of maternal toxicity.

 

Developmental toxicity, Human information

In establishing the Environmental Health Criteria for Zinc, the World Health Organisation has reviewed and summarised existing human studies examining the responses of women to zinc supplementation during pregnancy. None of the studies indicated any significant effects on the developing foetus (WHO, 2001). Two exemplar studies are summarised in the following:

A study was conducted on pregnant women to determine the effects of nutrients during pregnancy on maternal and fetal outcome. Four hundred fifty women were observed during pregnancy and postpartum. Forty-three variables including 12 laboratory indices of maternal nutrient status were assessed. Maternal plasma zinc levels were inversely correlated with fetal weight. Blood examinations revealed a significant association between the total occurrence of fetomaternal complications or fetal distress, and lowest quartile zinc/albumin and highest quartile folate. Under the study conditions, plasma zinc was determined to be a discriminator for fetomaternal complications only in women in the lowest quartile for plasma zinc (Mukherjee et al., 1984).

A double blind trial was conducted on pregnant women to determine the effects zinc supplementation during pregnancy on maternal and fetal outcome. 494 women booking before 20 week of gestation in a hospital were prescribed either 66 mg zinc sulphate (equivalent to 20 mg elemental zinc, 0.3 mg zinc/kgbw/day) capsules or placebo for once daily use, starting from day of booking till delivery. Various adverse outcomes were tested, including maternal bleeding, hypertension, complications of labour and delivery, gestational age, Apgar scores, and neonatal abnormalities. The main outcome measure was birth weight. There were no differences between the mothers and neonates of the zinc supplemented and placebo group. Under the test conditions, zinc supplementation during pregnancy did not affect maternal or fetal outcome (Mahomed et al.,1989).

 

In summary, in studies with women receiving zinc supplementation during pregnancies at levels of approximately ≤ 0.3 mg Zn/kg bw/day, no reproductive or developmental effects were observed (WHO, 2001; SCF, 2003). Evidence of zinc toxicity during human pregnancy has not been reported, but this may be due to the fact that very high exposures to zinc in human pregnancy are unusual. In contrast, zinc is necessary for normal growth and development (e.g., gene expression, vitamin metabolism) and therefore it is not surprising that zinc deficiency during pregnancy can cause a variety of adverse effects to the foetus or may result in reduced fertility or delayed sexual maturation in animals as well as in humans (EU RAR, 2004; WHO, 2001).

 

Data on hydrogen peroxide

Cited from theSummary Risk Assessment Report oin Hydrogen peroxide (2003):

“No appropriate studies were available for a complete evaluation of reproductive and developmental toxicity. Limited studies with mice and rats exposed to H2O2 in drinking water suggested no grave disturbances on the male or female reproductive functions. Moreover, an appropriate 90-day drinking water study with catalase-deficient mice, and carcinogenicity studies with mice and F344 rats did not identify testes or ovaries as target organs. The only available developmental toxicity (feeding) study in rats showed foetotoxic effects, but the study contains major uncertainties regarding the exposure and mode of action; therefore, it could not be used for an evaluation.

Thus there is a clear data gap regarding developmental toxicity for H2O2. However, during the risk assessment process no further testing on this endpoint was required, since conventional study protocols were judged unlikely to show specific embryonal or foetal effects: firstly, because it is doubtful whether H2O2 would reach the foetus (as opposed to degradation products oxygen and water) and secondly, because local effects and hence potential general toxicity are expected in the mother.”

 

In the transformation/dissolution test conducted with the target source Zinc peroxide, it was demonstrated, that only low levels of hydrogen peroxide are released. Thus, bolus or high concentration effects of hydrogen peroxide are not relevant for the target substance.In the view of the high degradation capacity for hydrogen peroxide in blood, it is unlikely that hydrogen peroxide released from ZnO2 is systemically distributed, and therefore the endogenous steady state levels of hydrogen peroxide in tissues are unlikely to be affected.

 

Overall, Zinc peroxide is not considered to be a developmental toxicant.

Justification for classification or non-classification

There is no experimental evidence that would justify a classification of zinc compounds for hazardous effects for reproductive or developmental toxicity according to Regulation (EC) 1272-2008. The available reproductive and developmental toxicity information has been mainly generated with soluble zinc compounds zinc chloride or zinc sulphate which ensure maximum bioavailable concentration of zinc and hence, allow the use of the information also for the assessment of the slightly soluble zinc compounds and insoluble zinc metal on a read across basis. No experimental fertility data were identified for these compounds.