Reaction mass of zinc oxide and zinc peroxide

Endpoint summary

Description of key information

Non-human information
Oral: NOAEL = 0.83 mg/kg bw/d (chronic, human data; read across from zinc gluconate; decreased ESOD activity and effects are seen as a result of copper imbalance)
Inhalation: NOEC = 2 mg/m³ (chronic, human data)

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Reference

Endpoint:

sub-chronic toxicity: oral

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Justification for type of information:

REPORTING FORMAT FOR THE ANALOGUE APPROACH

1. HYPOTHESIS FOR THE ANALOGUE APPROACH
The target substance Zinc peroxide and the source substances Zinc oxide, Zinc Chloride, Zinc sulfate, Zinc nitrate are ionic and consist of the Zinc2+ cation and the respective anion.
The read-across is based on the assumption that the zinc cation (as measure for dissolved zinc species) is the determining factor for (eco)toxicity.
For further details, see Justification for read-across attached to IUCLID chapter 13

2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
See Justification for read-across attached to IUCLID chapter 13

3. ANALOGUE APPROACH JUSTIFICATION
See Justification for read-across attached to IUCLID chapter 13

4. DATA MATRIX
See Justification for read-across attached to IUCLID chapter 13

Reason / purpose for cross-reference:

read-across: supporting information

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across source

Dose descriptor:

NOAEL

Effect level:

13.26 mg/kg bw/day (nominal)

Based on:

other: Zn2+

Sex:

male/female

Basis for effect level:

other: pancreatic cell necrosis, reduction in pigmented macrophages in the spleen

Key result

Dose descriptor:

NOAEL

Remarks:

human data

Effect level:

0.83 mg/kg bw/day (nominal)

Based on:

other: Zn2+

Sex:

male/female

Basis for effect level:

other: ESOD activity

Critical effects observed:

no

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEL

0.83 mg/kg bw/day

Study duration:

chronic

Species:

other: human data

Quality of whole database:

In studies in which humans were supplemented with zinc (as zinc gluconate), at a LOAEL of 2.5 mg Zn/kg bw/day (150mg/day) decreased ESOD activity and effects are seen as a result of copper imbalance. The NOAEL= 0.83 mg/kg bw/day (50 mg/day)

System:

haematopoietic

Organ:

blood

other: ESOD activity

Repeated dose toxicity: inhalation - systemic effects

Link to relevant study records

Reference

Endpoint:

short-term repeated dose toxicity: inhalation

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Justification for type of information:

REPORTING FORMAT FOR THE ANALOGUE APPROACH

1. HYPOTHESIS FOR THE ANALOGUE APPROACH
The target substance Zinc peroxide and the source substances Zinc oxide, Zinc Chloride, Zinc sulfate, Zinc nitrate are ionic and consist of the Zinc2+ cation and the respective anion.
The read-across is based on the assumption that the zinc cation (as measure for dissolved zinc species) is the determining factor for (eco)toxicity.
For further details, see Justification for read-across attached to IUCLID chapter 13

2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
See Justification for read-across attached to IUCLID chapter 13

3. ANALOGUE APPROACH JUSTIFICATION
See Justification for read-across attached to IUCLID chapter 13

4. DATA MATRIX
See Justification for read-across attached to IUCLID chapter 13

Reason / purpose for cross-reference:

read-across: supporting information

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across source

Species:

rat

Strain:

Wistar

Sex:

male/female

Route of administration:

inhalation: aerosol

Type of inhalation exposure:

nose only

Vehicle:

clean air

Duration of treatment / exposure:

28 days, 5 consecutive days per week, 6 h per day

Frequency of treatment:

5 consecutive days per week

Dose descriptor:

NOAEC

Effect level:

ca. 0.5 mg/m³ air

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: see 'Remark'

Critical effects observed:

not specified

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEC

2 mg/m³

Study duration:

chronic

Species:

other: human data

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 data on repeated dose toxicity are available for the target substance Zinc peroxide. However, reliable data are available for Zinc compounds as well as on hydrogen peroxide. A justification for read-across is attached to IUCLID section 13.

 

Data on Zinc

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.

 

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.

 

“A study with exposed workers is used for the derivation of a MAK value for the inhalable fraction. Neither lung function disorders nor asthmatic symptoms were found in 234 zinc ore smelting workers with an average 5.5 years of zinc oxide exposure (total dust 2.5 to 4.5 mg/m³, zinc content 90%).“ From this, a MAK value for the inhalable fraction of the aerosols of zinc compounds of 2 mg/m³ zinc was derived (List of MAK and BAT Values 2015. DFG, Deutsche Forschungsgemeinschaft).

 

Data on peroxide

Cited from the Summary Risk Assessment Report on Hydrogen peroxide (2003):

“Decreased body weight gain was a typical finding in gavage studies in rats employing a dose range of 50-500 mg/kg bw/day; regarding other effects, decreased values of blood parameters were not uncommon observations. When administered in drinking water H2O2 consistently decreased the body weight gain at 1,500 ppm (0,15%) in rats and at 3,000 ppm in mice.

Reduction of water intake was also characteristic. This indicates that the NOAEL of H2O2 in drinking water was 100 ppm implying a daily dose of 26-37 mg/kg bw. The LOAEL was 300 ppm (76-103 mg/kg bw) based on reductions in food and water consumption and on duodenal mucosal hyperplasia.

Concerning repeated inhalation toxicity of H2O2, there are indications of local effects in the skin, airways, and the lungs at about 10 mg/m3 in rats and dogs. A recent 28-day range finding inhalation toxicity study in the rat showed a respiratory tract irritation and concentration-related necrosis and inflammation of the epithelium in anterior regions of the nasal cavity from 14.6 mg/m3, but not at 2.9 mg/m3. Industrial experience from health surveillance of H2O2 production workers suggested no exposure-related effects on simple respiratory functions at airborne levels up to 0.8 mg/m3 or less than 1.4 mg/m3 with short-term peaks up to about 5 mg/m3. A health monitoring study of a small group of aseptic packaging workers linked sustained respiratory tract irritation and inflammation, susceptibility to respiratory infections, and asthma symptoms to airborne peroxide exposure at 2-3 mg/m3 (apparent LOAEL) as a time-weighted average over the whole shift with peaks up to 11 mg/m3. Since there is no evidence that exposure to airborne hydrogen peroxide at levels well below the OEL causes adverse effects in the respiratory system, it is provisionally considered that peroxide concentrations in excess of the OEL (1.4 mg/m3 for 8-hour TWA) cause risk. Acknowledging the uncertainties especially involving pulmonary effects, a careful follow up of relevant future studies in workers exposed to peroxide vapours, as well as all possible information on repeated inhalation toxicity on sodium perborate would be desirable. Also a single human case of an interstitial lung disease has been reported, which occurred during occupational exposure to about 12-41 mg/m3 of H2O2.”

 

In the transformation/dissolution test conducted with the target source Zinc peroxide, it was demonstrated, that only low levels of hydrogen peroxide are released. Thus, bolus or high concentration (local) effects of hydrogen peroxide are not relevant for the target substance.In the view of the high degradation capacity for hydrogen peroxide in blood, it is unlikely that hydrogen peroxide released from ZnO2 is systemically distributed, and therefore the endogenous steady state levels of hydrogen peroxide in tissues are unlikely to be affected.

 

Overall, the human NOAEL of 0.83 mg/kg bw/d will be used as key value in chemical safety assessment. The MAK value of 2 mg/m³ will be used as worker DNEL for exposure via the inhalation route.

Justification for classification or non-classification

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.