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Administrative data

Description of key information

The oral NOAEL of 0.83 mg Zn/kg bw/day (recalculated from the NOAEL of 50 mg Zn/day for a 60 kg human being), derived from a 10 week oral human volunteer study on zinc gluconate will be used as the starting point for deriving DNELs for worker and general population. NOAELs for zinc exposure via the dermal or inhalatory route can be estimated by taking into account the bioavailability of zinc via the different exposure routes (for details see section 5.1 of Appendix 1 of the CSR). By zinc content correction, these data are read-across to zinc bis[12-hydroxyoctadecanoate].

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
8.3 mg/kg bw/day
Study duration:
subchronic
Species:
other: human data, NOEAL is derived from dietary supplement studies on zinc gluconate and recalculated to zinc bis[12-hydroxyoctadecanoate] based on zinc content
Quality of whole database:
Data are not available on the repeated dose 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 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 descriptor has been derived from oral human volunteer studies and human experience from the use of zinc in food supplementation. This approach is in accordance to the European RAs on zinc and zinc compounds.

Additional information

Zinc bis[12-hydroxyoctadecanoate]

Data on the repeated dose toxicity of zinc bis[12-hydroxyoctadecanoate] are not available. Data on other zinc compounds have been used, as it is assumed that after intake 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)).In accordance with section 1, Annex XI of Regulation (EC) No 1907/2006 (REACH), human data can be used to address an endpoint. Please refer to IUCLID section 7.10.3 "Direct observations: clinical cases, poisoning incidents and other" for data on repeated dose toxicity". The most relevant dose descriptor has been derived from oral human volunteer studies and human experience from the use of zinc in food supplementation. This approach is in accordance to the European RA on zinc and zinc compounds.

A full read-across of data based on the solubility and zinc content correction is considered for zinc bis[12-hydroxyoctadecanoate]. The oral NOAELof 0.83 mg Zn/kg bw/day was recalculated from the NOAEL of 50 mg Zn/day for a 60 kg human beingas derived from a 10-week oral human-volunteer study with zinc gluconate. NOAELs for zinc exposure via the dermal or inhalatory route were estimated by taking into account the bioavailability of zinc via the different exposure routes (for details see section 5.1 of Appendix 1). NOAELs derived for zinc are as follows (see also below):

Oral (human): NOAEL = 0.83 mg Zn/kg bw/day (recalculated from the NOAEL of 50 mg Zn/day for a 60 kg human being).At a LOAEL of 2.5 mg Zn/kg bw/day decreased ESOD (erythrocyte superoxide dismutase) activity and effects as a result of copper imbalance were observed. NOEAL is derived from dietary supplement studies with zinc gluconate.

Oral (animal): Lowest established NOAEL = 13 mg Zn/kg bw/day. At higher exposure levels, haematological and biochemical effects; pathological changes in kidneys, GI tract, thyroid and pancreas. NOAEL is derived from studies with soluble zinc compounds.

Inhalation (human): For DNEL calculation, NOAEL for zinc exposure via inhalatory route are estimated by use of the human oral NOAEL (see above) taking into account the bioavailability of zinc via the different exposure routes.

Inhalation (animal):NOAEL = 2.7 mg ZnO/m³. At highest dose total lung capacity decreased and wet lung weights were increased. NOAEL derived from a non-standard study, 5-day inhalation in guinea pigs not suitable for classification.

Dermal: No data available. For DNEL calculation, NOAEL for zinc exposure via dermal route are estimated by use of the human oral NOAEL (see above) taking into account the bioavailability of zinc via the different exposure routes.

The read-across approach and conclusion are in accordance to conclusions on repeated dose toxicity in the EU RAR of the structural analogue 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 repeated dose 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.

Studies in animals

No repeated dose toxicity studies after dermal exposure are available in animals. After inhalation exposure mainly studies of short duration (3-6 days) are available. In a 3-day inhalation study with guinea pigs a concentration of 2.3 mg ultra fine ZnO/m3 (3 hours/day) was a marginal LOAEL, showing changes in neutrophils and activities of lactate dehydrogenase and alkaline phosphatase in the pulmonary fluid. At higher concentrations increased protein concentration, neutrophils, and enzyme activities in lung lavage fluids were seen, together with significant centriacinar inflammation of the pulmonary tissue. A dose of 2.7 mg ultra fine ZnO/m³ (3 hours/day for 5 days) did not alter the lung function parameters in guinea pigs but at 7 mg ultra fine ZnO/m³ (3 hours/day for 5 days) or at 5 mg ultra fine ZnO/ m³ (3 hours/day for 6 days) a gradual decrease in total lung capacity, vital capacity and reduction of the carbon monoxide diffusing capacity were seen in combination with inflammatory changes and edema. The relevance of the findings in studies with ultra-fine zinc oxide fumes is unclear with respect to commercial grade zinc oxide, as the latter is of much larger particle size and can have different toxicological characteristics.

In two oral 13-week studies with zinc sulphate (one with rats and one with mice) and an oral 13-week study with zinc monoglycerolate in rats, the lowest oral NOAEL was found in the study with zinc monoglycerolate. This overall NOAEL is 31.52 mg zinc monoglycerolate/kg bw (≈ 13.26 mg Zn2+/kg bw). At higher doses the most important effects the rats developed were hypocupremia, and significant changes in the pancreas (focal acinar degeneration and necrosis) and the spleen (decreased number of pigmented macrophages). It should be noted that in the studies with zinc sulphate mice and rats could be maintained up to 13 weeks on a diet containing 30,000 mg ZnSO4.7 H2O/kg feed (equivalent to 6,794 mg Zn2+/kg feed), while in the 13-week study with zinc monoglycerolate with rats 1.0% zinc monoglycerolate in the diet (equivalent to 4,420 mg Zn2+/kg feed) was so detrimental that animals had to be killed on humane grounds after 9 weeks.

Studies in humans

Upon supplementing men and women with 150 mg Zn2+/day (as zinc sulphate capsules), women appeared to be more sensitive than men to the effects of high zinc intake: clinical signs such as headache, nausea and gastric discomfort were more frequent among women, and women but not men had decreased activities of serum ceruloplasmin and ESOD. In some earlier oral studies in which humans were supplemented with moderately high amounts of zinc (50 mg Zn2+/day), a reduction in ESOD activity was also observed and again women appeared to be more sensitive to this effect. Hence, a reduction in ESOD was thought to be a sensitive indicator of copper status. However, in more recent and more sophisticated studies using the same dose level, ESOD was only marginally reduced (without a correlation with changes in copper balance), while findings on more specific copper deprivation signs (decreased serum ceruloplasmin and platelet cytochrome c oxidase) indicated that a sub-optimal intake of zinc was more effective than a moderately high intake of zinc in inducing changes associated with a decreased copper status in postmenopausal women. Given this, and degree of the observed ESOD reduction in comparison to the natural variability in its activity, the zinc-induced decrease in ESOD activity is considered to have marginal biological significance, if any, also because it may not have been caused by an interference with copper metabolism.

Overall, it is concluded from studies in which humans were supplemented with zinc (as zinc gluconate), that women are more sensitive to the effects of high zinc intake and that a dose of 50 mg Zn2+/day is a NOAEL. At the LOAEL of 150 mg Zn2+/day, clinical signs and indications for disturbance of copper homeostasis have been observed. The human oral NOAEL of 50 mg Zn2+/day (0.83 mg/kg bw/day) will be taken across to the risk characterisation.”

ZINC:

The biological activities of zinc compounds are determined by their ability to release zinc under the respective exposure conditions. Hence, information on the effects of systemically available zinc allows the repeated dose toxicity assessment across all those zinc compounds covered in this safety report.

Non-human information

The repeated dose toxicity of water soluble zinc sulphate and zinc monoglycerolate has been examined in a total of 3 subchronic oral feeding studies. Due to the different dosing regimens, the lowest NOAEL was determined to be 31.5 mg/kg bw/day of zinc monoglycerolate which equals a total zinc exposure of approximate 13 mg/kg bw/day. The zinc NOAEL derived from the feeding studies with zinc sulphate was determined to be 104 mg Zn/kg bw/day in mice and approximately 53.5 mg/kg bw/day in rats. At higher doses the most important effects in the rats were the development of hypocupremia, and significant changes in the pancreas (i.e., focal acinar degeneration and necrosis) and a decreased number of pigmented macrophages in spleen.

No longer term inhalation studies allowing to derive a robust NOEL for the inhalatory exposure of the respective zinc compounds has been identified. In a short term 3-day inhalation study with guinea pigs, a concentration of 2.3 mg ultrafine ZnO/m3(3 hours/day) resulted in changes in neutrophils and activities of lactate dehydrogenase and alkaline phosphatase in the pulmonary fluid. At higher concentrations increased protein concentration, neutrophils, and enzyme activities in lung lavage fluids were seen, together with significant centriacinar inflammation of the pulmonary tissue. Inhalatory doses of 2.7 mg ultrafine ZnO/m3for 5 days 3hours/day did not alter the lung function parameters in guinea pigs, but at 5 and 7 mg ultrafine ZnO/m3exposure according to a similar pattern, a gradual decrease in total lung capacity, vital capacity and reduction of the carbon monoxide diffusing capacity was seen in combination with inflammatory changes and edema. The relevance of the findings in studies with ultra-fine zinc oxide fumes is unclear with respect to commercial grade zinc oxide, as the latter is of much larger particle size and can have different toxicological characteristics.

Human information

Upon supplementing men and women with 150 mg Zn/day (as zinc sulphate capsules), women appeared to be more sensitive than men to the effects of high zinc intake: clinical signs such as headache, nausea and gastric discomfort were more frequent among women and women but not men had decreased activities of serum ceruloplasmin and ESOD. In some earlier oral studies in which humans were supplemented with moderately high amounts of zinc (50 mg Zn/day), a reduction in ESOD activity was also observed and again women appeared to be more sensitive to this effect. Hence, a reduction in ESOD was thought to be a sensitive indicator of copper status. However, in more recent and more sophisticated studies using the same dose level, ESOD was only marginally reduced (without a correlation with changes in copper balance), while findings on more specific copper deprivation signs (decreased serum ceruloplasmin and platelet cytochrome c oxidase) indicated that a sub-optimal intake of zinc was more effective than a moderately high intake of zinc in inducing changes associated with a decreased copper status in postmenopausal women. Given this, and the degree of the observed ESOD reduction in comparison to the natural variability in its activity, the zinc-induced decrease in ESOD activity is considered to have marginal biological significance, if any and also because it may not have been caused by an interference with copper metabolism as deep tissue SOD increases as a function of zinc exposure was observed.

Overall, it can be concluded that from studies in which humans were supplemented with zinc (as zinc gluconate), that women are more sensitive to the effects of high zinc intake and that a dose of 50 mg Zn/day is the human NOAEL. This equals a daily exposure of 0.83 mg/kg bw. At the LOAEL of 150 mg Zn/day, clinical signs and indications for disturbance of copper homeostasis have been observed.

Reference:

[EU RAR Zinc distearate (CAS-No.: 557-05-1 & 91051-01-3 EINECS-No.: 209-151-9 & 293-049-4) Part II - Human Health (Final report, May 2008;http://echa.europa.eu/documents/10162/08799aec-42c5-44e0-9969-baa022c66db1)]


Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
Data are not available on the repeated dose 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 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 descriptor has been derived from oral human volunteer studies and human experience from the use of zinc in food supplementation. This approach is in accordance to the European RAs on zinc and zinc compounds.

Justification for classification or non-classification

There is not any evidence for intrinsic toxic properties relevant to humans. Data on other zinc compounds have been used, as it is assumed that after intake zinc bis[12-hydroxyoctadecanoate] is changed (at least in part) to ionic zinc and that only ionic zinc is determining biological activities. Zinc is essential for human growth and development, neurological functions and immunocompetence. The main clinical manifestations of zinc deficiency are growth retardation, delay in sexual maturation or increased susceptibility to infections. Health specialists recommend supplementing the diet with zinc in case human diet is zinc deficient. The maximum allowable daily intake has been established to be 50 mg zinc per day. Therefore, classification is not required for repeated dose toxicity according to CLP Regulation (EC) No 1272/2008 and Directive 67/548 EEC with respect to systemic toxicity.