Fatty acids, tallow, zinc salts

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Effect on fertility: via oral route

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEL

200 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

As no toxicity to reproduction data are available for fatty acids, tallow, zinc salts or for the analogue substances fatty acids, zinc salts, a read-across to soluble and slightly soluble zinc substances is made in accordance to Regulation (EC) No 1907/2006 Annex XI, 1.5.

It is assumed that after intake of fatty acids, tallow, zinc salts are changed (at least in part) to ionic zinc and that only ionic zinc is determining biological activities. Further justification is given within the CSR chapter 5 and the read-across justification.

The effect level for fatty acids, tallow, zinc salts was based on the effect level for zinc (see the Chemical Safety Assessment of "Zinc" within the framework of Regulation (EC) No 1907/2006 in the technical dossier (see IUCLID section 13)) assuming an average zinc content of fatty acids, tallow, zinc salts of 10%.

The read-across approach and conclusion are in accordance to conclusion on toxicity for reproduction in EU RAR on the structural analogue Zinc stearate (CAS# 91051-01-3, CAS# 557-05-1) Part II – Human Health. EUR 21168 EN.

„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).”

Inorganic zinc salts

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). 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).

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.

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 20 mg/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/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).

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.

 

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.

 

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.

 

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.

 

Kynast G & 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.

 

Simmer K, Lort-Phillips L, James C, et al. 1991.A double-blind trial of zinc supplementation in pregnancy. Eur J Clin Nutr 45:139-144.

 

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

 

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 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 Chemical Safety Assessment of "Zinc" within the framework of Regulation (EC) No 1907/2006 in the technical dossier (see IUCLID Section 13). These data are relevant for fatty acids, tallow, 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. No developmental toxicity has been observed in these studies and their 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, tallow, zinc salts.

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no adverse effect observed

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

As no toxicity to reproduction data are available for fatty acids, tallow, zinc salts or for the analogue substances fatty acids, zinc salts, a read-across to soluble and slightly soluble zinc substances is made in accordance to Regulation (EC) No 1907/2006 Annex XI, 1.5.

It is assumed that after intake of fatty acids, tallow, zinc salts are changed (at least in part) to ionic zinc and that only ionic zinc is determining biological activities. Further justification is given within the CSR chapter 5 and the read-across justification.

The effect level for Fatty acids, tallow, zinc salts was based on the effect level for zinc (see the Chemical Safety Assessment of "Zinc" within the framework of Regulation (EC) No 1907/2006 in the technical dossier (see IUCLID section 13)) assuming an average zinc content of Fatty acids, tallow, zinc salts of 10%.

Inorganic zinc salts

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 up to dietary exposure levels of 200 mg Zn/kg bw/day or 50 mg Zn/kg bw/day by gavage. No developmental toxicity has been observed in these studies and their NOAEL’s have been established at the highest doses tested (Food and Drug Research Labs., Inc., 1974).

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 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 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.

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) 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 conclusion, 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).

References:

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.

 

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 no experimental evidence that would justify a classification of zinc compounds including Fatty acids, tallow, zinc salts for hazardous effects for reproductive or developmental toxicity according to Regulation (EC) 1272/2008 or Directive 67/548/EEC.

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.