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Description of key information

No repeated dose toxicity study with zinc 5-nitroisophthalate is available, thus the repeated dose toxicity will be addressed with existing data on the dissociation products zinc and 5-nitroisophthalic 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

Mode of Action Analysis / Human Relevance Framework

Additional information

No repeated dose toxicity study with zinc 5-nitroisophthalate is available, thus the repeated dose toxicity will be addressed with existing data on the dissociation products zinc and 5-nitroisophthalic acid. The approach for the assessment entity approach and read-across is described in detail in the document attached in IUCLID section 13.

 

5-nitroisophthalic acid/m-nitrobenzoic acid

In a combined repeated dose repro-developmental screen, Crl:CD (SD) male and female rats were treated with m-Nitrobenzoic acid in the concentration of 0, 20, 100, 500 mg/kg/day orally for 42 days in male rats and 55 days (from 14 days before mating to day 4 of lactation). The animals were fed the diet containing the test chemical daily and were observed for clinical signs, mortality, body weight and food consumption changes, haematological and urine analysis, organ weight changes and histopathology.

Toxic changes were observed as death in females at 500mg/kg/day, Salivation in male and female, decrease in locomotor activity, irregular respiration, prone position and drastic worsening in female, decrease in body weight gain and increase food consumption in male rats, Significant decreases in red blood cell count, haemoglobin concentration, and haematocrit value of male and female rat, increase in A/G ratio, Pi, K and decreased BUN, TP and Cl level were observed in male and increase in ALT level in female rats when treated with 500 mg/kg/day. In addition, changes in absolute and relative weigh of Brain, Liver, Kidney, Testes, Epididymides, Thymus and Spleen were observed. Squamous hyperplasia, Erosion and Focal inflammatory cell infiltration in the forestomach, Small and soft testes, Small epididymides, Degeneration in seminiferous tubular epithelium in the testes, Decrease in sperm and Cell debris in the epididymides duct and increase in trabecular bone in the femur bone were observed in 500 mg/kg/day treated and in recovery period male and female rats. Squamous hyperplasia in the forestomach was observed in male rat when treated with 100 mg/kg/day. Therefore, NOEL for male was considered to be 20 mg/kg/day and NOAEL for female was considered to be 100 mg/kg/day when Crl:CD (SD) male and female rat were treated with m-Nitrobenzoic acid orally for 42 days.

 

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 5-nitroisophthalate

Since no repeated dose toxicity study is available specifically for zinc 5-nitroisophthalate, information on the individual constituents zinc and 5-nitroisophthalic acid will be used for the hazard assessment of 5-nitroisophthalate. For the purpose of hazard assessment of zinc 5-nitroisophthalate, the point of departure for the most sensitive endpoint of each constituent will be used for the DNEL derivation. In case of 5-nitroisophthalic acid in zinc 5-nitroisophthalate, the NOAEL of 20 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.