Fatty acids, C16-18, zinc salts

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Description of key information

No toxicity data on adverse effects on reproduction with Fatty acids, C16-18, zinc salts are available, thus the reproductive toxicity will be addressed with existing data on the moieties liberated upon dissolution, zinc and fatty acids, C16-18. All available information on the two moieties zinc and fatty acids, C16-18 do not indicate any effects on the impairment of male or female fertility.

Effect on fertility: via oral route

Endpoint conclusion:

no adverse effect observed

Effect on fertility: via inhalation route

Endpoint conclusion:

no study available

Effect on fertility: via dermal route

Endpoint conclusion:

no study available

Additional information

Fatty acids, C16-18, zinc salts -Fertility

Information on the moieties zinc and fatty acids, C16-18 will be used for the hazard assessment and, when applicable, for the risk characterisation of Fatty acids, C16-18, zinc salts. For the purpose of hazard assessment of Fatty acids, C16-18, zinc salts, the point of departure for the most sensitive endpoint of each moiety will be used for the DNEL derivation. For Fatty acids, C16 -18, zinc salts, the NOAEL of 0.83 mg/kg bw/day obtained from human data (repeated dose) for the moiety zinc will be used.

Thus, Fatty acids, C16 -18 zinc salts is not expected to be toxic to reproduction, since the two moieties zinc and fatty acids, C16 -18 are considered non-toxic to reproduction.

Read-across approach and conclusion are in line with the EU risk assessment carried out on Fatty acids, C16-18, zinc salts (i.e. zinc stearate) within the framework of EU Existing Chemicals Regulation 793/93 (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).”

Further testing is not required.

Please refer to the respective assessment entity section for data on the moieties zinc and fatty acids C16 -18. In brief:

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 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).

Fatty acids, C16-18

Fatty acids C16 -18 is a mixture of palmitic (C16) and stearic (C18) acid. Palmitic and stearic acid are naturally produced by a wide range of plants and organisms. They are naturally present in butter, cheese, milk and meat. Thus, the following endpoint is covered by publicly available data on fatty acids with the same or similar structure.

The long history of safe use of these acids and their related glycerides and food oils, as well as the GRAS status (Generally Recognised as Safe (GRAS) by the U.S. Food and Drug Administration (US FDA)) for several of the fatty acids and their salts, indicate the low potential for reproductive toxicity of these chemicals.

According to the HERA document on fatty acid salts a “three-generation reproductive study on a C10 fatty did not produce any reproductive effects. Hendrich et al. (1993) conducted a study in which three generations of CBA/2 and C57Bl/6 mice were reared on semipurified diets containing 8.6% crude Cuphea oil. The Cuphea oil contained 76% capric acid (C10 fatty acid). Males of each generation were housed individually and fed for 13-weeks. Food intakes and body weights were measured weekly. The diet containing Cuphea oil did not impair reproductive parameters or cause any pathology in the mouse tissues examined. Cuphea oil moderately suppressed body weights and food intakes of mice in some groups between 4 and 13-weeks of age, but had no long-term effects on body weight, food intake or cholesterol status” (HERA, 2002 and references therein).

“In a 90 day study, groups of ten rats/sex/group were administered 9-Octadecenoic acid in the diet at 0, 3300, 6100, 14,000 mg/kg bw/day. There were no effects on gonads weights, and no gross or histopathological findings for testes, seminal vesicle, ovary, uterus, or prostate. The NOAEL for reproductive effects was 14,000 mg/kg bw, the highest dose tested” (OECD SIDS, 2014).

“Also, it is worth bearing in mind when considering the reproductive toxicity of fatty acids and their salts, that due to their innocuous nature, fats and oils are commonly used as controls and as vehicles in animal toxicity studies. For example, OECD Guideline 408 (repeated dose 90-day oral toxicity study in rodents) recommends the use of “a solution/emulsion in oil (e.g. corn oil)” as a vehicle where an aqueous vehicle is not suitable (OECD, 1993)” (HERA, 2002 and references therein).

This along with the long history of safe use of the fatty acids indicate the low potential for reproductive toxicity of these chemicals.

Effects on developmental toxicity

Description of key information

No toxicity data on adverse effects on development of the offspring with Fatty acids, C16-18, zinc salts are available, thus the reproductive toxicity will be addressed with existing data on the moieties liberated upon dissolution, zinc and fatty acids, C16-18. Fatty acids, C16-18, zinc salts is not expected to impair development, since the moieties zinc and fatty acids, C16-18 have not shown adverse effects on the development of the offspring.

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

Fatty acids, C16-18, zinc salts -Development

Information on the moieties zinc and fatty acids, C16-18 will be used for the hazard assessment and, when applicable, for the risk characterisation of Fatty acids, C16-18, zinc salts. For the purpose of hazard assessment of Fatty acids, C16-18, zinc salts, the point of departure for the most sensitive endpoint of each moiety will be used for the DNEL derivation. For Fatty acids, C16 -18, zinc salts, the NOAEL of 0.83 mg/kg bw/day obtained from human data (repeated dose) for the moiety zinc will be used.

Thus, Fatty acids, C16 -18, zinc salts is not expected to be toxic to reproduction, since the two moieties zinc and fatty acids, C16 -18 are considered non-toxic to reproduction.

Read-across approach and conclusion are in line with the EU risk assessment carried out on Fatty acids, C16-18, zinc salts (i.e. zinc stearate) within the framework of EU Existing Chemicals Regulation 793/93 (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).

Further testing is not required.

Please refer to the respective assessment entity section for data on the moieties zinc and fatty acids C16 -18. In brief:

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 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 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.

 

Fatty acids, C16-18

Fatty acids C16 -18 is a mixture of palmitic (C16) and stearic (C18) acid. Palmitic and stearic acid are naturally produced by a wide range of plants and organisms. They are naturally present in butter, cheese, milk and meat. Thus, the following endpoint is covered by publicly available data on fatty acids with the same or similar structure.

According to a very recent ECHA report, non-branched aliphatic fatty acids (C5-C24) “are expected to be of low toxicity by their nature (similar to high purity fatty acids of natural origin which do not need to be registered as included in Annex V to REACH). […] From a human health perspective, substances in this group are considered to have a low systemic toxicity profile with no specific target organ toxicity or CMR properties. Some have irritant and/or corrosive properties that are reflected in the classification and labelling. Risk from these properties can be avoided by implementing risk management measures in supply chains based on the correct classification and labelling products. Therefore, there is no need for further action on the substances belonging to the group of aliphatic fatty acids non-branched (C5-C24)” (ECHA, 2020: Integrated Regulatory Strategy Annual Report May 2020).

Further, available data do not provide evidence of significant developmental toxicity of fatty acid salts. The long history of safe use of the fatty acids and their related glycerides and food oils, as well as the GRAS status (Generally Recognised as Safe (GRAS) by the U.S. Food and Drug Administration (US FDA))

for several members of the fatty acids and their salts, indicate the low potential for developmental toxicity of these chemicals.

“In a study following the Chernoff/Kavlock Developmental Toxicity Screen, groups of female mice (26-30/dose) were treated via oral gavage on gestation days 8-12 with 10,000 mg/kg bw/day of 9,12-octadecadienoic acid. There were no effects on number of litters, number of resorptions, number of pups/litter, number of live and dead births, postnatal survival rates, pup weights at days 1 and 3 or external abnormalities among dead pups. The NOEL for developmental toxicity is >= 10,000 mg/kg bw/day for mice with exposure on gestation days 8-12” (OECD SIDS, 2014).

“Ishii et al. (1990) studied the effects of natural soap on the development of mouse embryos cultured in vitro. They found that there was no effect on embryo development at concentrations up to 0.05%. More than 0.05% natural soap gave rise to precipitates in the culture medium” (HERA, 2002 and references therein).

It is also important to bear in mind when considering the toxicity of fatty acids and their salts that due to their innocuous nature, fats and oils are commonly used as controls and as vehicles in animal toxicity studies. For example OECD Guideline 408 recommends the use of “a solution/emulsion in oil (e.g. corn oil)” where an aqueous vehicle is not suitable (OECD, 1993).

Beside of animal data also human breast feeding indicate that fatty acids are essential for human development. A breast-fed of 3 months age has an average weight of 6.5 kg (WHO 2013) and the infant ingests approx. 180mL/kg bw of milk per day (Riordan 2001), being 1170 mL for a baby at an age of 3 months. The fat content of mother milk is approx. 4.2% (United Nations 1996), with a content of stearic acid of approx. 7.5% (total content of C18 fatty acids: C18:0, C18:1, C18:2 and C18:3 = 58.2%) (Finley et al. 1985). This results in a total “exposure” for a 3 month old baby of 3.7 g stearic acid per day, being 570 mg/kg bw/day.

Stearic and palmitic acid are essential human and animal nutrients. Based on evaluation of a wealth of human medical and nutritional data, it is concluded that stearic and palmitic acid, do not pose any hazard for reproduction and/or developmental toxicity. Classification for toxicity to reproduction is not warranted.

Justification for classification or non-classification

Fatty acids, C16-18, zinc salts is not expected to impair fertility or development, since the two moieties zinc and fatty acids, C16-18 have not shown adverse effects in reproduction or prenatal developmental toxicity studies. Fatty acids, C16 -18, zinc salts does not require classification for reproductive/developmental toxicity according to the classification, labelling and packaging (CLP) regulation (EC) No 1272/2008 and its subsequent amendments.