Registration Dossier

Administrative data

Key value for chemical safety assessment

Effects on fertility

Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Quality of whole database:
Data on toxicity to reproduction of zinc bis[12-hydroxyoctadecanoate] are not available. Data on other zinc compounds have been used, as the basic assumption is made that after intake all zinc compounds (including zinc bis[12-hydroxyoctadecanoate]) 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 the zinc compounds. This approach is in accordance to the European RAs on zinc and zinc compounds. As part of the RAs, available toxicological data was extensively discussed and scrutinised by the experts from Member States and other stakeholders during the meetings of the “Technical committee on new and existing substances” (TCNES), during which the relevant data sets were approved. Data used in the RARs on zinc metal and zinc compounds are the main data source for this chapter. Decisions on data quality and relevancy approved by TCNES are used as in the EU risk assessment process. Consequently, the current analysis will focus on the data considered relevant, adequate and reliable, and hence of high quality, for the assessment within the framework of Regulation (EC) No 1907/2006. The toxic potential of the fatty acid chain, i.e. 12-hydroxystearate, is assumed to be negligible. Fatty acids are generally not considered to represent a risk to humans, which is reflected in their exclusion from REACH registration requirements (c.f. REACH Annex V (Regulation (EC) No 987/2008)). The most relevant dose descriptors have been derived from epidemiological studies that investigated the association between zinc exposure through food supplementation and 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. This approach is in accordance to the European RAs on zinc and zinc compounds.
Additional information

Zinc bis[12-hydroxyoctadecanoate]

Data on the reproductive toxicity of zincbis[12-hydroxyoctadecanoate]are not available. Data on other zinc compounds have been used as it is assumed that during exposure or after intake and absorption zincbis[12-hydroxyoctadecanoate]is changed (at least in part) to ionic zinc and that only ionic zinc is determining biological activities.The reproductive toxicity potential of the fatty acid chain, i.e. 12-hydroxystearate, is assumed to be negligible. Fatty acids are generally not considered to represent a risk to humans, which is reflected in their exclusion from REACH registration requirements (c.f. REACH Annex V (Regulation (EC) No 987/2008)). A full read-across of data based on the solubility and zinc content correction is considered for zincbis[12-hydroxyoctadecanoate]. The effect level for zinc bis[12-hydroxyoctadecanoate] was based on the effect level for zinc (as described below) assuming an average zinc content of zinc bis[12-hydroxyoctadecanoate] of 10%.

 

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 health effects of zinc compounds by the US Agency for Toxic Substances and Disease Registry (2005), the toxicological review of zinc and compounds by the US Environmental Protection Agency (2005) or the review by the 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 zinc bis

[12-hydroxyoctadecanoate].

 

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). Further information on potential effects of zinc compounds on male or female reproductive organs could be retrieved from subchronic toxicity studies. 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 or when other study non-zinc relevant study specificities could have impacted the study outcome.

In a large number of controlled trials, dietary supplementation with a 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).

These data are relevant for zinc bis[12-hydroxyoctadecanoate].

NOAEL (animals): > 20 mg Zn/kg bw/day

NOAEL (humans): > 0.83 mg Zn/kg bw/day

For comprehensive assessment of the fertility effects of “Zinc”, see the Chemical Safety Assessment of "Zinc" within the framework of Regulation (EC) No 1907/2006 in Appendix 1of the CSR and cited in excerpts below.

Read-across approach and conclusion are in accordance to conclusion on toxicity for reproduction in EU RAR Zinc stearate (CAS# 91051-01-3, CAS# 557-05-1) Part II – Human Health. EUR 21168 EN (http://echa.europa.eu/documents/10162/08799aec-42c5-44e0-9969-baa022c66db1):

„No data were provided on the reproductive toxicity of zinc distearate. Data on other zinc compounds have been used, based on the assumption that after intake the biological activities of the zinc compounds are determined by the zinc cation.

For fertility no 1- or 2-generation or other applicable guideline studies are available. When male rats were dosed with approximately about 200 mg Zn2+/kg bw via the food for 30-32 days before mating, a statistically significant reduction in male reproductive performance was observed. This effect was attributed to a reduction in sperm motility. In females receiving 200 mg Zn2+/kg bw, reduced conception was observed when they were dosed after mating, but not when they were dosed before and during pregnancy. It is not known whether the reduced sperm motility in males and the contradictory effects on conception in females are a direct effect of zinc on the sperm cells, embryos or uterine function, or whether they are the result of disturbances in other physiological functions. From a study by Schlicker and Cox (1968), it is known that this dose level (and even levels of 100 mg additional Zn2+/kg bw/day) may result in impaired copper balance in females.

In repeated dose toxicity studies with zinc sulphate heptahydrate, no effects on the reproductive organs were seen at dose levels up to ca. 1,100 mg and 565 mg Zn2+/kg bw/day for mice and rats, respectively. In a repeated dose toxicity study with zinc monoglycerolate hypoplasia of several sex organs was observed at doses of ca. 300 mg Zn2+/kg bw/day, but not at 13 or 60 mg Zn2+/kg bw/day. As these effects were only seen at dose levels which produced very severe general toxicity, it is impossible to conclude that these adverse effects are directly related to zinc. It should be noted that these studies are not designed to detect effects on sperm cell motility.

Developmental toxicity studies, according to a study design similar to OECD 414, with mice,rats, hamsters and rabbits were described with unspecified zinc sulphate. These studies do not permit the derivation of a proper NOAEL because neither reproductive nor developmental or maternal effects were observed, not even at the highest dose tested. When it is assumed (worst case) that the heptahydrate was administered from the study with hamsters it can be calculated that the NOAEL for both maternal effects and effects on the offspring is at least 19.9 mg Zn2+/kg bw/day. In other (non-guideline) studies, higher dose levels (up to 200 Zn2+/kg bw/day) have been reported to result in resorptions and retarded foetal growth, but not in external malformations. No resorptions and growth retardation were seen at 100 mg Zn2+/kg bw/day but as the study was too limited, this dose level cannot be taken as an NOAEL for developmental toxicity, either. Besides, at both 100 and 200 mg Zn2+/kg bw/day changes in maternal and fetal copper status were observed. In absence of better information a NOAEL of > 19.9 mg Zn2+/kgbw/day for developmental toxicity in animals is adopted.

In studies with pregnant women receiving additional 0.3 mg Zn2+/kg bw/day (as zinc sulphate or citrate) during the last 6 months of pregnancy, no reproductive or developmental effects were observed. Clear evidence of zinc toxicity in 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 deficiency during pregnancy can cause a variety of adverse effects on the foetus or may result in reduced fertility or delayed sexual maturation in animals as well as in humans (Walsh et al., 1994; ATSDR, 1994; WHO, 1996).”

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

References:

WHO (2001): Environmental Health Criteria 221 Zinc. http://www.inchem.org/documents/ehc/ehc/ehc221.htm#1.0

ATSDR (Agency for Toxic Substances and Disease Registry) (2005). Toxicological profile for zinc. U.S. Department of Health and Human Services, Public Health Service, Agency for Toxic Substances and Disease Registry, Atlanta, GA, USA.

http://www.atsdr.cdc.gov/toxprofiles/tp60.pdf]

US EPA, 2005- US-EPA (US Environmental Protection Agency) (2005) Toxicological review of zinc and compounds. Washington, DC, USA

http://www.epa.gov/iris/toxreviews/0426tr.pdf]

EU RAR Zinc stearate (CAS# 91051-01-3, CAS# 557-05-1) Part II – Human Health. EUR 21168 EN (http://echa.europa.eu/documents/10162/08799aec-42c5-44e0-9969-baa022c66db1

Khan AT, Atkinson A, Graham TC, Green M, Ali S, Thompson SJ and Shireen KF (2001) Effects of low levels of zinc on reproductive performance of rats. Environ Sci 8: 367—381.

Khan AT, Atkinson A, Graham TC, Thompson SJ, Ali S and Shireen KF (2003) Effects of low levels of zinc on reproductive performance of mice. Environ Sci 10: 279—290

Khan AT, Graham TC, Ogden L, Salwa AS, Thompson SJ, Shireen KF, and Mahboob M (2007). A two-generational reproductive toxicity study of zinc in rats. J. Environ. Sci. Health Part B 42: 403–415.

Maita K, Hirano M, Mitsumori K, Takashi K and Shirasu Y (1981). Subacute toxicity studies with zinc sulfate in mice and rats. J. Pesticide Sci. 6:327-336.

Edwards K and Buckley P (1995). Study report zinc monoglycerolate: 13 week feeding study in rats. EU risk assessment report for zinc metal. Testing laboratory: Environmental Safety Laboratory, Unilever Research, Bedford, England. Report no.: FT930588.

Kumar S (1976). Effect of zinc supplementation on rats during pregnancy. Nutrition Reports International. 13(1): 33-36. Testing laboratory: National Institute of Nutrition, Indian Council of Medical Research, Hyderabad, India.

Samanta K and Pal B (1986). Zinc feeding and fertility of male rats. Internat. J. Vit. Nutr. Res. 56: 105-107. Testing laboratory: Department of Biochemistry, School of Tropical Medicine, Calcutta, India.


Short description of key information:
Adverse reproductive effects were not noted in pregnant women administered zinc at rates of 20-30 mg/day. Zinc may impair fertility at high exposure levels. In animal experiments these effects were always associated with maternal toxicity. NOAELs have been derived from reliable, adequate and relevant animal one- or two-generation studies and human studies on dietary zinc supplementation. A full read-across of data based on the solubility and zinc content correction is considered for zinc bis[12-hydroxyoctadecanoate].

Justification for selection of Effect on fertility via oral route:
Data on toxicity to reproduction of zinc bis[12-hydroxyoctadecanoate] are not available. Data on other zinc compounds have been used, as the basic assumption is made that after intake all zinc compounds (including zinc bis[12-hydroxyoctadecanoate]) 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 the zinc compounds. This approach is in accordance to the European RAs on zinc and zinc compounds. As part of the RAs, available toxicological data was extensively discussed and scrutinised by the experts from Member States and other stakeholders during the meetings of the “Technical committee on new and existing substances” (TCNES), during which the relevant data sets were approved. Data used in the RARs on zinc metal and zinc compounds are the main data source for this chapter. Decisions on data quality and relevancy approved by TCNES are used as in the EU risk assessment process. Consequently, the current analysis will focus on the data considered relevant, adequate and reliable, and hence of high quality, for the assessment within the framework of Regulation (EC) No 1907/2006. The toxic potential of the fatty acid chain, i.e. 12-hydroxystearate, is assumed to be negligible. Fatty acids are generally not considered to represent a risk to humans, which is reflected in their exclusion from REACH registration requirements (c.f. REACH Annex V (Regulation (EC) No 987/2008)). The most relevant dose descriptors have been derived from epidemiological studies that investigated the association between zinc exposure through food supplementation and 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. This approach is in accordance to the European RAs on zinc and zinc compounds.

Effects on developmental toxicity

Description of key information
Developmental effects were not observed in specifically designed developmental toxicity studies; some developmental effects seen in two generation reproductive toxicity study but only at maternally toxic doses. NOAELs have been derived from reliable, adequate and relevant animal developmental toxicity studies and human studies on dietary zinc supplementation. A full read-across of data based on the solubility and zinc content correction is considered for zinc bis[12-hydroxyoctadecanoate].
Although some developmental effects, including 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, developmental toxicity was not 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., 1977). These data are relevant for zinc bis[12-hydroxyoctadecanoate].
Reference:
Khan AT, Graham TC, Ogden L, Salwa AS, Thompson SJ, Shireen KF, and Mahboob M (2007). A two-generational reproductive toxicity study of zinc in rats. J. Environ. Sci. Health Part B 42: 403–415.
Chang C-H, Mann Jr DE and Gautieri RF (1977) Teratogenicity of zinc chloride, 1,10-Phenanthroline, and a zinc-1,10-Phenanthroline complex in mice. J Pharm Sci 66: 1755—1758
Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Quality of whole database:
Data on developmental toxicity are not available for zinc bis[12-hydroxyoctadecanoate]. Data on other zinc compounds have been used as the basic assumption is made that after intake all zinc compounds (including zinc bis[12-hydroxyoctadecanoate]) are changed (at least in part) to ionic zinc and that only ionic zinc is determining biological activities. This approach is in accordance to the European RAs on zinc and zinc compounds. As part of the RAs, available toxicological data was extensively discussed and scrutinised by the experts from Member States and other stakeholders during the meetings of the “Technical committee on new and existing substances” (TCNES), during which the relevant data sets were approved. Data used in the RARs on zinc metal and zinc compounds are the main data source for this chapter. Decisions on data quality and relevancy approved by TCNES are used as in the EU risk assessment process. Consequently, the current analysis will focus on the data considered relevant, adequate and reliable, and hence of high quality, for the assessment within the framework of Regulation (EC) No 1907/2006. The toxic potential of the fatty acid chain, i.e. 12-hydroxystearate, is assumed to be negligible. Fatty acids are generally not considered to represent a risk to humans, which is reflected in their exclusion from REACH registration requirements (c.f. REACH Annex V (Regulation (EC) No 987/2008)). The most relevant dose descriptors have been derived from epidemiological studies that investigated the association between zinc exposure through food supplementation and 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. This approach is in accordance to the European RAs on zinc and zinc compounds.
Additional information

Zinc bis[12-hydroxyoctadecanoate]

No data are available on the reproductive toxicity of zinc bis[12-hydroxyoctadecanoate]. Data on other zinc compounds have been used as the basic assumption is made that after intake all zinc compounds (including zinc bis[12-hydroxyoctadecanoate]) are changed (at least in part) to ionic zinc and that only ionic zinc is determining biological activities. The toxic potential of the fatty acid chain, i. e. 12-hydroxystearate, is assumed to be negligible. Fatty acids are generally not considered to represent a risk to humans, which is reflected in their exclusion from REACH registration requirements (c. f. REACH Annex V (Regulation (EC) No 987/2008)). A full read across of data based on the solubility and zinc content correction is considered for zinc bis[12-hydroxyoctadecanoate], see zinc assessment in Appendix 1 of the CSR and cited in excerpts below.

The effect level for zincbis[12-hydroxyoctadecanoate] was based on the effect level for zinc (as described below) assuming an average zinc content of zinc bis[12-hydroxyoctadecanoate] of 10%.

Several prenatal toxicity studies are available that examined the developmental toxicity of various zinc compounds in rats, mice, rabbit or hamsters. Prenatal toxicity was not 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 zinc was dosed via diet. Established NOAELs in these studies were typically at the highest dose tested and systemically tolerated by the dams. 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, developmental toxicity was not 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., 1977).

 

In studies with women receiving zinc supplementation during pregnancies at levels of approximately ≤ 0.3 mg Zn/kg bw/day, reproductive or developmental effects were not 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).

 

These data are relevant for zinc bis[12-hydroxyoctadecanoate.

NOAEL: >50 mg Zn/kg bw/day

NOAEL (humans): > 0.83 mg Zn/kg bw/day

 

For a comprehensive assessment of the developmental toxicity of “Zinc”, see the Chemical Safety Assessment of "Zinc" within the framework of Regulation (EC) No 1907/2006 in Appendix 1 of the CSR and cited in excerpts below.

 

Read-across approach and conclusion are in accordance to conclusion on toxicity for reproduction in EU RAR Zinc stearate (CAS# 91051-01-3, CAS# 557-05-1) Part II – Human Health. EUR 21168 EN (http://echa.europa.eu/documents/10162/08799aec-42c5-44e0-9969-baa022c66db1)

(see above).

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

References:

[Chang C-H, Mann Jr DE and Gautieri RF (1977) Teratogenicity of zinc chloride, 1,10-Phenanthroline, and a zinc-1,10-Phenanthroline complex in mice. J Pharm Sci 66: 1755—1758.]

[EU RAR Zinc stearate (CAS# 91051-01-3, CAS# 557-05-1) Part II – Human Health. EUR 21168 EN (http://echa.europa.eu/documents/10162/08799aec-42c5-44e0-9969-baa022c66db1.]

[EU (2004 a) Zinc metal. Risk assessment report, 2nd priority list, Volume 42, European Commission, Joint Research Center, Institute for Health and Consumer Protection, European Chemicals Bureau, Ispra, Italy.]

[Food and Drug Research Labs., Inc (1973). Teratologic evaluation of FDA 71-49 (zinc sulfate). Report no.: PB-221 805.]

[Food and Drug Research Labs., Inc (1974b). Teratologic evaluation of compound FDA 71-49. Zinc sulfate in rabbits. Not reported. Testing laboratory: Food and Drug Research Labs., Inc. Report no.: PB-267 191.]

[Khan AT, Atkinson A, Graham TC, Green M, Ali S, Thompson SJ and Shireen KF (2001) Effects of low levels of zinc on reproductive performance of rats. Environ Sci 8: 367—381.]

[Khan AT, Atkinson A, Graham TC, Thompson SJ, Ali S and Shireen KF (2003) Effects of low levels of zinc on reproductive performance of mice. Environ Sci 10: 279—290.]

[Khan AT, Graham TC, Ogden L, Salwa AS, Thompson SJ, Shireen KF, and Mahboob M (2007). A two-generational reproductive toxicity study of zinc in rats. J. Environ. Sci. Health Part B 42: 403–415.]

[SCF 2003 - SCF (2003) Opinion of the Scientific Committee on Food on the tolerable upper intake level of zinc. Scientific Committee on Food SCF/CS/NUT/UPPLEV/62. Final, 19 March 2003 (expressed on 5 March 2003), Brüssel, Belgien.]

[Uriu-Hare JY, Stern JS, Keen CL (1989) Influence of maternal dietary Zn intake on expression of diabetes-induced teratogenicity in rats Diabetes38(10):1282-90.]

[WHO (2001) Environmental Health Criteria 221 Zinc. http://www.inchem.org/documents/ehc/ehc/ehc221.htm#1.0]


Justification for selection of Effect on developmental toxicity: via oral route:
Data on developmental toxicity are not available for zinc bis[12-hydroxyoctadecanoate]. Data on other zinc compounds have been used as the basic assumption is made that after intake all zinc compounds (including zinc bis[12-hydroxyoctadecanoate]) are changed (at least in part) to ionic zinc and that only ionic zinc is determining biological activities. This approach is in accordance to the European RAs on zinc and zinc compounds. As part of the RAs, available toxicological data was extensively discussed and scrutinised by the experts from Member States and other stakeholders during the meetings of the “Technical committee on new and existing substances” (TCNES), during which the relevant data sets were approved. Data used in the RARs on zinc metal and zinc compounds are the main data source for this chapter. Decisions on data quality and relevancy approved by TCNES are used as in the EU risk assessment process. Consequently, the current analysis will focus on the data considered relevant, adequate and reliable, and hence of high quality, for the assessment within the framework of Regulation (EC) No 1907/2006. The toxic potential of the fatty acid chain, i.e. 12-hydroxystearate, is assumed to be negligible. Fatty acids are generally not considered to represent a risk to humans, which is reflected in their exclusion from REACH registration requirements (c.f. REACH Annex V (Regulation (EC) No 987/2008)). The most relevant dose descriptors have been derived from epidemiological studies that investigated the association between zinc exposure through food supplementation and 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. This approach is in accordance to the European RAs on zinc and zinc compounds.

Toxicity to reproduction: other studies

Additional information

Zinc bis[12-hydroxyoctadecanoate]

Data are not available on the reproductive toxicity of zinc bis[12-hydroxyoctadecanoate]. Data on other zinc compounds have been used, as the basic assumption is made that after intake all zinc compounds (including zinc bis[12-hydroxyoctadecanoate]) are changed (at least in part) to ionic zinc and that only ionic zinc is determining biological activities. The toxic potential of the fatty acid chain, i. e. 12-hydroxystearate, is assumed to be negligible. Fatty acids are generally not considered to represent a risk to humans, which is reflected in their exclusion from REACH registration requirements (c. f. REACH Annex V (Regulation (EC) No 987/2008)). A full read across of data based on the solubility and zinc content correction is considered for zinc bis[12-hydroxyoctadecanoate], see zinc assessment in Appendix 1 of the CSR and cited in excerpts below.

 

The effect level for zinc bis[12-hydroxyoctadecanoate] was based on the effect level for zinc (as described below) assuming an average zinc content of zinc bis[12-hydroxyoctadecanoate] 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).

References

[ATSDR (Agency for Toxic Substances and Disease Registry) (2005). Toxicological profile for zinc. U.S. Department of Health and Human Services, Public Health Service, Agency for Toxic Substances and Disease Registry, Atlanta, GA, USA.http://www.atsdr.cdc.gov/toxprofiles/tp60.pdf]

[Hunt IF, Murphy NJ, Cleaver AE, Faraji B, Swendseid ME, Coulson AH, Clark VA, Browdy BL, Cabalum MT, & Smith JCJ (1984). Zinc supplementation during pregnancy: effects on selected blood constituents and on program and outcome of pregnancy in low income women of Mexican descent. Am J Clin Nutr, 40: 508–521.]

[Kynast G and Saling E (1986) Effect of oral zinc application during pregnancy. Gynecol Obstet Invest, 21: 117–123.

[Mahomed K, James DK, Golding J and McCabe R (1989). Zinc supplementation during pregnancy: A double blind randomised controlled trial. Br.Med. J. 299: 826-30.]

[Mukherjee MD, Sandstead HH, Ratnaparkhi MV, Johnson LK, Milne DB and Stelling HP (1984). Maternal zinc, iron, folic acid, and protein nutriture and outcome of human pregnancy. Am. J. Clin. Nutr. 40(3):496-507.]

[Simmer K, Lort-Phillips L, James C, et al. 1991.A double-blind trial of zinc supplementation in pregnancy. Eur J Clin Nutr 45:139-1.]

[WHO (2001): Environmental Health Criteria 221 Zinc. http://www.inchem.org/documents/ehc/ehc/ehc221.htm#1.0]

Justification for classification or non-classification

There is not any evidence that would justify a classification of zinc compounds incl. zinc bis[12-hydroxyoctadecanoate] for reproductive or developmental toxicity accordingto CLP Regulation (EC) No 1272/2008 and Directive 67/548 EEC.