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Administrative data

Description of key information

No repeated dose toxicity study with zinc m-toluate is available, thus the repeated dose toxicity will be addressed with existing data on the individual moieties zinc and m-toluate.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

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.

 

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 a nd 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.

The lowest established NOAEL = 13.3 mg Zn/kg bw/day selected out of 3 subchronic oral feeding studies with soluble zinc sulphate and zinc monoglycerolate

 

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. There is no experimental sufficient evidence for specific target organ toxicity based on the reversibility of the ‘adverse’ effects demonstrated. Hence no classification is required.

 

m-toluate

In the combined repeated dose/ reproductive and developmental toxicity test, 10 male and 10 female SD rats were exposed orally via gavage to 0, 30, 100, 300 and 1000 mg/kg bw/day m-toluic acid for 41 to 45 days.

No deaths were observed in male and female animals in each group.

In males of the 1000 mg/kg bw/day dose group, the following effects were observed: slightly decreased locomotor activity, increased prothrombin time and increased aspartate aminotransferase values. The statistical significantly increased prothrombin time (14.3 sec) is, although being statistical significant, still within the historical control range for that rat strain (13.3 - 16.5 sec, Lee et al. 2012), thus should be regarded as incidental finding with no biological relevance. The slightly decreased locomotor activity is regarded as transient finding, in the absence of further interrelated clinical or pathological findings should be regarded as not biological relevant. The increased aspartate aminotransferase (AST, 77 ±13 IU/L) might indicate a correlation with the histopathological findings in the liver in the female animals, however the value is still well within the historical control range of that rat strain (48.9-122.7 IU/L). Thus, an NOAEL of 1000 mg/kg bw/day was identified for male animals.

In females of the 1000 mg/kg bw/day dose group, the following effects were observed: significant increase of absolute and relative liver weights and periportal hepatocellular vacuolar degeneration. In females of the 300 mg/kg bw/day dose group, periportal hepatocellular vacuolar degeneration was observed with a grading of minimal to moderate severity. Vacuolar degeneration, also termed cell swelling, characterises a reversible cell injury, occurs in most types of acute injury (Ed.: Haschek, WM et al. 2007 Fundamentals in toxicologic pathology, AP; p. 13). In combination with increased liver weight, this is a common finding in animals being exposed to high doses of xenobiotics and commonly reverses if the injurious stimulus is removed (Ed.: Haschek, WM et al. 2007 Fundamentals in toxicologic pathology, AP; p. 201f). In the absence of degenerative cell lesions, such as necrosis or apoptosis, and based on the minimal to mild manifestation of that injury, this finding is considered a very mild adverse effect. Based on the increased relative and absolute liver weight and the periportal hepatocyte vacuolar swelling, the NOAEL for females was considered at 100 mg/kg bw/day.

 


Justification for non-classification

In a repeated dose toxicity study with reproductive toxicity screening, female rats showed effects, primarily manifested in increased relative and absolute liver weight and the periportal hepatocyte swelling. Such mild and reversible findings do not meet the criteria for the classification as specific target organ toxicant (STOT-RE) in accordance with Regulation (EC) No. 1272/2008 section 3.9. No evidence of organ dysfunction or significant adverse changes in biochemistry parameters were observed (cf. section 3.9.2.8.1 in Annex I of regulation (EC) 1272/2008).

Zinc m-toluate

Since no repeated dose toxicity study is available for zinc m-toluate, information on the individual moieties zinc and m-toluate will be used for the hazard assessment of zinc m-toluate. For the purpose of hazard assessment of zinc m-toluate, the point of departure for the most sensitive endpoint of each moiety will be used for the DNEL derivation.The most sensitive endpoint for the moiety zinc was observed for human data on lifetime oral ingestion (NOAEL(zinc) of 0.83 mg/kg bw/day). The most sensitive endpoint for the moiety m-toluate was observed in a Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening (NOAEL(m-toluate) of 100 mg/kg bw/day).

Justification for classification or non-classification

There is no experimental sufficient evidence for specific target organ toxicity based on the assessment entities zinc and m-toluate. Hence no classification is required.