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Description of key information

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/m3 for 5 days 3hours/day did not alter the lung function parameters in guinea pigs, but at 5 and 7 mg ultrafine ZnO/m3 exposure 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. These data are relevant for CAS # 67701-12-6.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Dose descriptor:
NOAEL
133 mg/kg bw/day
Study duration:
subchronic
Species:
rat

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Dose descriptor:
NOAEC
27 mg/m³
Study duration:
subacute
Species:
guinea pig

Additional information

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

No data are available on the repeated dose toxicity of Fatty acids, C14-18 and C16-18-unsatd., zinc salts. Data on other zinc compounds have been used, as it is assumed that after intake Fatty acids, C14-18 and C16-18-unsatd., zinc salts are changed (at least in part) to ionic zinc and that only ionic zinc is determining biological activities. A full read-across of data based on the solubility and zinc content correction is considered for Fatty acids, C14-18 and C16-18-unsatd., zinc salts, see the Chemical Safety Assessment of "Zinc" within the framework of Regulation (EC) No 1907/2006 in Appendix 1. The DNEL derivation for Fatty acids, C14-18 and C16-18-unsatd., zinc salts and any related conversion were based on DNEL values for slightly soluble/ insoluble zinc compounds (see the Chemical Safety Assessment of "Zinc" within the framework of Regulation (EC) No 1907/2006) assuming an average zinc content of 10%.

The oral NOAELof 0.83 mg Zn/kg bw/day (recalculated from the NOAEL of 50 mg Zn/day for a 60 kg human being)as derived from a 10-week oral human-volunteer study with zinc gluconate was used as the starting point for deriving DNELs for worker and general population. 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). By molecular weight correction, these dataare read across to Fatty acids, C14-18 and C16-18-unsatd., zinc salts.

NOAELs derived for zinc &fatty acids, C14-18 and C16-18-unsatd., zinc salts, respectively, 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 LOAEL of 2.5 mg Zn/kg bw/day decreased ESOD (erythrocyte superoxide dismutase) activity and effects as a result of copper imbalance. 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. The NOAEL of 13.3mg Zn/kg bw/day was converted into a NOAEL of 133 mg /kg bw/day for fatty acids, C14-18 and C16-18-unsatd., zinc salts.

Inhalation (human): For DNEL calculation, NOAEL for zinc exposure via inhalatory route will be 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. The NOAEC of 2.7 mg ultrafine ZnO/m3 was converted into a NOAEC of 27 mg/m3for fatty acids, C14-18 and C16-18-unsatd., zinc salts.

Dermal: No data available. For DNEL calculation, NOAEL for zinc exposure via dermal route will be 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 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 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.


Repeated dose toxicity: via oral route - systemic effects (target organ) cardiovascular / hematological: other; digestive: pancreas

Repeated dose toxicity: inhalation - systemic effects (target organ) respiratory: lung

Justification for classification or non-classification

There is no evidence for intrinsic toxic properties relevant to humans. Data on other zinc compounds have been used, as it is assumed that after intake Fatty acids, C14-18 and C16-18-unsatd., zinc salts, are 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 (SCF, 2003). 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. Hence no classification is required.