1,3,5-triazine-2,4,6(1H,3H,5H)-trione, zinc salt

Endpoint summary

Description of key information

No repeated dose toxicity study with zinc cyanurate is available, thus the repeated dose toxicity will be addressed with existing data on the dissociation products zinc and cyanuric acid. The approach for the assessment entity approach and read-across is described in detail in the document attached in IUCLID section 13.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEL

Study duration:

subacute

Species:

rat

Quality of whole database:

key studies available for all assessment entities

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

No repeated dose toxicity study with zinc cyanurate is available, thus the repeated dose toxicity will be addressed with existing data on the dissociation products zinc and cyanuric acid. The approach for the assessment entity approach and read-across is described in detail in the document attached in IUCLID section 13.

 

Cyanuric acid

The Ministry of Health, Labour and Welfare (MHW) in Japan evaluated isocyanuric acid in a combined repeated oral dose toxicity and reproductive and developmental toxicity screening according to OECD 422 (1996). Groups of 10 females and 10 males were given isocyanuric acid suspended in sesame oil at dose levels of 0, 10, 40, 150 and 600 mg/kg bw/day via oral administration for 44 days (males) and 41-48 days (females). All animals were sacrificed and investigated for general toxicity including body weight changes, haematology, clinical biochemistry, urine analysis as well as histopathological examination. Based on effects observed in gross pathology and histopathology in the kidney and bladder as well as changes in body weight in the high dose groups, the No Observed Effect Level (NOAEL) for systemic toxicity was considered to be 150 mg/kg bw/day for male and female rats.

Biava (1980) evaluated the toxic effects of cyanuric acid in a short-term toxicity study, extended to 59-days. Groups of 5 females and 5 males were given cyanuric acid solved in tap water at dose levels of 0, 400, 1200, 2000 and 4000 ppm via drinking water for 59 days. All animals were subjected to a detailed clinical observation and body weights were recorded throughout the study period. At the end of the study all animals were sacrificed, blood and urine were collected and all animals subjected to a gross pathology and histopathological examination. There were no adverse test substance-related effects observed in any of the treatment groups. Therefore, the No Observed Effect Level (NOAEL) for systemic toxicity was considered to be 4000 ppm, which was equivalent to 520.7 mg/kg bw./day in males and 717.0 mg/kg bw./day in females.

 

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.

In a subacute inhalation study the toxicity profile of ZnO after inhalation exposure, was performed in Wistar rats nose-only exposed to dynamic atmosphere of ZnO for 6 hours per day on 5 consecutive days per week for 4 weeks (28-day study). The target concentrations were 0.5, 1.5, 3.0 and 4.5 mg/m³.Inhalation exposure of 4.5 mg/m3 ZnO caused alopecia in ear region of female animals and impaired the body weight development in males. In bronchoalveolar lavage fluid, neutrophils and other cytological and biochemical parameters were changes significantly in animals exposed to 1.5 mg/m³ and higher. At 3.0 and 4.5 significantly increased absolute and relative lung weight was found. Histological examination

revealed degeneration/regeneration of the olfactory tract in nasal cavity. In accordance to findings in lavage fluid and the increased lung weight, histology of the lung reveals multifocal alveolar histiocytosis which were associated with single or few inflammatory cells. Based on the above mentioned findings, the No Observed Adverse Effect Concentration (NOAEC) was 0.5 mg/m3 under the current study condition.

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 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.

 Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint: 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 Repeated dose toxicity: via oral route - systemic effects (target organ) cardiovascular / hematological: other; digestive: pancreas Repeated dose toxicity: dermal - systemic effects (target organ) other: skin

 

Zinc cyanurate

Since no repeated dose toxicity study is available specifically for zinc cyanurate, information on the individual constituents zinc and cyanuric acid will be used for the hazard assessment of cyanurate. For the purpose of hazard assessment of zinc cyanurate, the point of departure for the most sensitive endpoint of each constituent will be used for the DNEL derivation. In case of cyanuric acid in zinc cyanurate, the NOAEL of 150 mg/kg bw/day in repeated dose toxicity will be used.

Justification for classification or non-classification

Based on the absence of severe adverse effects at low doses in a subacute toxicity study in rats, classification for repeated dose toxicity is not warranted according to Regulation (EC) No. 1272/2008.