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Key value for chemical safety assessment

Effects on fertility

Effect on fertility: via oral route
Dose descriptor:
NOAEL
200 mg/kg bw/day
Effect on fertility: via dermal route
Additional information

FATTY ACIDS, C14-18 AND C16 - 18 - UNSATD., ZINC SALTS:

No data are available on the reproductive toxicity of Fatty acids, C14 -18 and C16 -18 -unsatd., zinc salts. Data on other zinc compounds have been used, as the basic assumption is made that after intake all zinc compounds (including metallic zinc) are changed (at least in part) to the ionic species and it is this zinc cation that is the determining factor for the biological activities of zinc compounds. A full read-across of data based on the solubility and a molecular weight correction is considered for Fatty acids, C14 -18 and C16 -18 -unsatd., zinc salts, see the hazard assessment of "Zinc" within the framework of Regulation (EC) No 1907/2006 below.

The effect level for Fatty acids, C14 -18 and C16 -18 -unsatd., zinc salts was based on the effect level for zinc (as described below) assuming an average zinc content of Fatty acids, C14 -18 and C16 -18 -unsatd., zinc salts of 10%.

Zinc:

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) (Khanet al.,2001, 2003, 2007). Further information on potential effects of zinc compounds on male or female reproductive organs could be retrieved from subchronic toxicity studies as conducted by Maitaet al.(1981) and Edwards and Buckley (1995).

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 Khanet al.,(2001, 2003, 2007) or, in case of the study conducted by Kumaret al., (1976), when other study non-zinc relevant study specificities could have impacted the study outcome.

In a large number of controlled trials, dietary supplementation with zinc rate of 20 mg/day and 30 mg/day did not result in any adverse reproductive effects in healthy pregnant women as summarised in WHO (2001) and ATSDR (2005). 

Overview of experimental studies on fertility

Test substance

Method

Results

Remarks

Reference

Zinc chloride

One-generation study in ratsadministered zinc chloride at doses of 0, 3.6, 7.2, 14.4 mg Zn/kg bw/d in water over one generation by gavage. Exposure started 77 days prior to mating

As of 3.5 mg Zn/kg bw/day:

P - Mortalityá; body weight gainâ; fertility indextâ; thymus atrophy

F1 - litter size (non significant)â; number of surviving pubs (non significant)â;

 

As of 7.2 mg Zn/kg bw/day:

P – hemosidosis of spleen; lymphocyte deficiency

F1 - number of surviving pubsâ; BW gain (PND 21)â

2 (reliable with restrictions)

supporting study

Khanet al., 2001

Zinc chloride

One-generation study in miceadministered zinc chloride at doses of 0, 0.75, 1.5 and 3, mg Zn/kg bw/d respectively, 0. 1.5, 3 and 6, mg Zn/kg bw/d in water with 1.5mL HNO3/l over one generation by gavage. Exposure started 49 days prior to mating

0.75 resp. 1.5 mg Zn/kg bw/day:

P- Mortalityá; body weight gainâ; abs./rel. Liver/thymus/ spleen weightâ; fertility indextâ; number pregnanciesâ

F1- litter size (non significant)â; number of surviving pubs (non significant)â;

 

1.5 resp. 3 mg Zn/kg bw/day:

P- body weight gainâ;

F1– 14day survival indexâ;

 

3 resp. 6 mg Zn/kg bw/day:

F1– only 1 birth; 9 still births.

2 (reliable with restrictions)

supporting study

Khanet al., 2001

Zinc chloride

Two-generation study in ratsadministered zinc chloride at doses of 7.5, 15and 30 mg/kg bw/d in water over two successive generations via the oral route. Application procedure not specified but likely oral gavage. Exposure started 77 days prior to mating.

As of 3.5 mg Zn/kg bw/day:

P - Mortalityá; body weight gainâ; abs/rel liver/kidney weightâ; lesions in GI tract, inflammation in prostate

F1 - Mortalityá; body weight gainâ; abs/rel brain/prostate/spleen weightâ;

F2 – no effects

 

7.2 mg Zn/kg bw/day:

P – abs./rel. brain/seminal vesicle weightâ;

F1 - abs/rel liver/adrenal/seminal vesicle weightâ

F2 – no effects

 

14.1 mg Zn/kg bw/day:

P – abs./rel. Spleen/uterus weightâ;

F1 - body weight gain (PND21)â; abs/rel kidney weightâ; litter size and #surviving pubs until PND4â;

F2 – body weight gain (PND21)â; abs/rel kidney weightâ; litter size and number surviving pubs until PND4â;

 

Maternal toxicity at any dose level. The NOAEL for fertility and development toxicity is about 15 mg ZnCl2/kg bw/d, this corresponds to 7.2 mg Zinc/kg bw/day. No NOAEL for systemic toxicity could be derived.

2 (reliable with restrictions)

supporting study

Khanet al., 2007

Zinc sulphate

Charles foster rats fed with a diet containing 4000ppm Zn (in form of zinc sulphate); exposure equals 200 mg Zn/kg bw exposure started 30-32 days prior to mating.

200 mg Zn/kg bw/day

P – Zn-concentration in testis and spermá; sperm mobilityâ; number of pregnanciesâ

F1 – number of live birthsâ

2 (reliable with restrictions)

supporting study

Samantaet al., 1986



Short 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, 2008), 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 in the CSR. These data are relevant for Fatty acid, C14 -18 and C16 -18 -unsatd., zinc salts.

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 20). 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). These data are relevant for Fatty acids, C14 -18 and C16 -18 -unsatd., zinc salts.
Effect on developmental toxicity: via oral route
Dose descriptor:
LOAEL
500 mg/kg bw/day
Additional information

FATTY ACIDS, C14 -18 and C16-18, unsatd., ZINC SALTS:

No data are available on the reproductive toxicity of Fatty acids, C14 -18 and C16 -18 -unsatd., zinc salts. Data on other zinccompounds have been used, as the basic assumption is made that after intake all zinc compounds (including metallic zinc) are changed (at least in part) to the ionic species and that it is this zinc cation that is the determining factor for the biological activities of zinc compounds. A full read across of data based on the solubility and a molecular weight correction is considered for Fatty acids, C14 -18 and C16 -18 -unsatd., zinc salts, see zinc assessment below.

The effect level for Fatty acids, C14 -18 and C16 -18 -unsatd., zinc salts was based on the effect level for zinc (as described below) assuming an average zinc content of Fatty acids, C14 -18 and C16 -18 -unsatd., zinc salts of 10%.

Zinc:

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 Khanet 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 dose 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 Khanet 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.

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, 2008; WHO, 2001).

Overview of experimental studies on developmental toxicity

Test substance*

Species

Route

Method

Result

Remark

Reference

Zinc sulphate

Mouse

CD-1

Oral

Females received daily doses of 0, 0.3, 1.4, 6.5 and 30 mg ZnSO4(unspecified)/kg bw by oral gavage during days 6-15 of gestation.

No discernible effects were seen on or maternal or foetal survival. No difference in number of abnormalities found in foetuses.

NOAEL:

30 mg/kg bw/day equalling

12mg Zn/kg bw/d (anhydrate);

6.8mg Zn/kg bw/d (heptahydrate);

2 (reliable with restrictions)

Key study

Food and Drugs Research Labs., Inc, 1973*

Zinc sulphate

Rat

Wistar

Oral

Females received daily doses of 0, 0.4, 2.0, 9.1 and 42.5 mg ZnSO4(unspecified)/kg bw by oral gavage during days 6-15 of gestation.

No discernible effects were seen on or maternal or foetal survival. No difference in number of abnormalities found in foetuses.

NOAEL:

30 mg/kg bw/day equalling

17mg Zn/kg bw/d (anhydrate);

9.6 mg Zn/kg bw/d (heptahydrate);

2 (reliable with restrictions)

Key study

Food and Drugs Research Labs., Inc, 1973*

Zinc sulphate

Rat

Charles Foster

Oral

Females received daily doses of 0, and 200 mg Zn/kg bw (in form of ZnSO4) in diet during days 1-18 of gestation

No discernible effects were seen on or maternal or foetal survival. A reduced number of implantations observed. No difference in number of abnormalities found in foetuses.

NOAEL:

200 mg/kg bw/day

2 (reliable with restrictions)

Key study

EU RAR, 2008

Zinc sulphate

Hamster

Oral

Females received daily doses of 0, 0.9, 4.1, 19, and 88 mg ZnSO4(unspecified)/kg bw by oral gavage during days 6-10 of gestation.

No discernible effects were seen on or maternal or foetal survival. No difference in number of abnormalities found in foetuses.

NOAEL:

20 mg/kg bw/day

 

2 (reliable with restrictions)

Key study

Food and Drugs Research Labs., Inc, 1973*

Zinc sulphate

Rabbit

Dutch

Oral

Females received daily doses of 0, 0.6, 2.8, 13 and 60 mg ZnSO4(unspecified)/kg bw during days 6-18 of gestation.

No discernible effects were seen on or maternal or foetal survival. No difference in number of abnormalities found in foetuses.

NOAEL:

13.6 mg/kg bw/day

 

2 (reliable with restrictions)

Key study

Food and Drugs Research Labs., Inc, 1974*

Zinc carbonate

Rat

Sprague Dawley

Oral

Females received daily doses of 0, 2.5, and 50 mg Zn/kg bw (in form of ZnCO3) in diet during days 1-20 of gestation.

No discernible effects were seen on or maternal or foetal survival. No difference in number of abnormalities found in foetuses.

NOAEL:

50 mg/kg bw/day

 

2 (reliable with restrictions)

Key study

Uriu-Hare, 1989

Toxicity to reproduction: other studies

Additional information

FATTY ACIDS, C14 -18 and C16-18, unsatd., ZINC SALTS:

No data are available on the reproductive toxicity of Fatty acids, C14-18 and C16-18 -unsatd., zinc salts. Data on other zinc compounds have been used, as the basic assumption is made that after intake all zinc compounds (including metallic zinc) are changed (at least in part) to the ionic species and that it is this zinc cation that is the determining factor for the biological activities of zinc compounds. A full readacross of data based on the solubility and a molecular weight correction is considered for zinc stearate, seezincassessment below. The effect level for FATTY ACIDS,

C14-18 and C16-18-unsatd., ZINC SALTS was based on the effect level for zinc (as described below) assuming an average zinc content of FATTY ACIDS, C14 -18 and C16 -18 -unsatd., ZINC SALTS of 10%.

Zinc:

Effects in 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 (Huntet al.,1984; Kynast and Salinget 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 (Simmeret al.,1991).

Pregnant women who received 0.3 mg zinc/kg/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 (Mahomedet al.,1989).

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 (Mukherjeeet 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) 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 (Mahomedet al., 1989).

Justification for classification or non-classification

There is no experimental evidence that would justify a classification of zinc compounds incl. Fatty acids, C14 -18 and C16 -18 -unsatd., zinc salts for hazardous effects for reproductive or developmental toxicity according under the Dangerous Substance Directive 67/548/EEC or Regulation (EC) No 1272-2008 on the classification, labelling and packaging of substances and mixtures. The available reproductive and developmental toxicity information has been exclusively 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.