Registration Dossier

Administrative data

Description of key information

Acute oral toxicity: key studies carried out according to OECD guideline no 401 or 423 indicating for both micro- and nanomaterial zinc oxide LD50 > 2000 mg/kg bw
Acute inhalation toxicity: key study carried out according to OECD guideline no 403 indicating for micro zinc oxide LC50 > 5.7 mg/L/4hrs.    
Acute dermal toxicity: key study carried out according to OECD guideline no 402 indicating for nano zinc oxide LD50 >2000 mg/kg bw.

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records
Reference
Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Used in EU risk assessment for zinc oxide, limited study details provided
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
GLP compliance:
not specified
Test type:
standard acute method
Limit test:
yes
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals and environmental conditions:
5 per sex
Route of administration:
oral: gavage
Vehicle:
water
Details on oral exposure:
single dose by oral gavage in water and observed for 14 days
Doses:
single dose of 5 gZnO/kg bw
No. of animals per sex per dose:
5 per sex
Control animals:
not specified
Details on study design:
no further information
Statistics:
no data
Preliminary study:
no further information
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 5 000 mg/kg bw
Mortality:
no mortality
Clinical signs:
no adverse signs of toxicity
Body weight:
no adverse signs of toxicity
Gross pathology:
no adverse signs of toxicity

none

Interpretation of results:
practically nontoxic
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
LD50 > 5000 mg ZnO/kg bw was determined.
Executive summary:

In an acute toxicity test Wistar rats (5/sex) were given a single dose of 5 g ZnO/kg bw (in water) by gavage and observed for 14 days. No mortality and signs of toxicity were observed. The LD50for rats is therefore >5 g ZnO/kg bw.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Value:
5 000 mg/kg bw

Acute toxicity: via inhalation route

Link to relevant study records
Reference
Endpoint:
acute toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Used in EU risk assessment for zinc oxide, guideline study, reliable with restrictions
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 403 (Acute Inhalation Toxicity)
GLP compliance:
not specified
Test type:
standard acute method
Limit test:
yes
Species:
rat
Strain:
not specified
Sex:
male/female
Details on test animals and environmental conditions:
no information available
Route of administration:
inhalation
Type of inhalation exposure:
nose/head only
Vehicle:
other: no data
Analytical verification of test atmosphere concentrations:
not specified
Duration of exposure:
ca. 4 h
Concentrations:
Aerosol concentration was 5.7 mg/l
No. of animals per sex per dose:
10 per sex
Control animals:
yes
Details on study design:
10 male and 10 female animals per group were exposed to zinc oxide aerosol (head and nose only) for 4 h. Aerosol concentration was 5.7 mg/l and the particle size distribution had a mass median aerodynamic diameter of 4 µm ± 2.9 (GSD). Only one concentration and a control group were tested. All animals survived up to day 14 post exposure.
Statistics:
no information
Preliminary study:
no information
Sex:
not specified
Dose descriptor:
LC50
Effect level:
> 5 700 mg/m³ air
Exp. duration:
4 h
Mortality:
no mortality
Clinical signs:
other: only a dusty fur on the head, no adverse effects noted
Body weight:
no change in body weights observed
Gross pathology:
no adverse effects observed.
Other findings:
none observed

no information

Interpretation of results:
practically nontoxic
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
LC50 4 hours >5.7 mg ZnO/l
Executive summary:

In an acute inhalation toxicity study, 10 male and 10 female animals per group were exposed to zinc oxide aerosol (head and nose only) for 4 h. Aerosol concentration was 5.7 mg/l and the particle size distribution had a mass median aerodynamic diameter of 4mm ± 2.9 (GSD). Only one concentration and a control group were tested. All animals survived up to day 14 post exposure. Apart from a dusty fur on the head the day after the exposure, no effects were seen. Body weights developed normally. At pathological examination all organs were normal. The LC50was >5.7 mg/l.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LC50
Value:
5 700 mg/m³

Acute toxicity: via dermal route

Link to relevant study records
Reference
Endpoint:
acute toxicity: dermal
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: The study is conducted accordign to the OECD Guideline in compliance with GLP.
Qualifier:
according to
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Deviations:
no
GLP compliance:
yes (incl. certificate)
Test type:
standard acute method
Limit test:
yes
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River, Sulzefeld, Germany
- Age at study initiation: 10 - 11 weeks
- Weight at study initiation: males (mean): 308.92 g, females (mean): 193.28 g
- Housing: 2 rats of same sex per cage, wooden absorbing bedding
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 4 weeks

ENVIRONMENTAL CONDITIONS
- Temperature: 22 +/- 2°C
- Humidity: 55 +/- 15%
- Air changes (per hr): fully airconditioning
- Photoperiod (hrs dark / hrs light): 12 h / 12 h
Type of coverage:
semiocclusive
Vehicle:
corn oil
Details on dermal exposure:
TEST SITE
- Area of exposure: back

REMOVAL OF TEST SUBSTANCE
- Washing (if done): water
- Time after start of exposure: 24 h

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 2000mg/kg bw
- Concentration (if solution): 0.5mg test item in 400µl corn oil
- Constant volume or concentration used: no
- For solids, paste formed: yes
Duration of exposure:
24 h
Doses:
2000 mg/kg bw
No. of animals per sex per dose:
5/sex
Control animals:
other: untreated skin of same animal
Details on study design:
- Duration of observation period following administration: 14 d
- Frequency of observations and weighing: Twice a day, once on weekends
- Necropsy of survivors performed: Yes
- Other examinations performed: Clinical signs, body weight, gross pathology
Statistics:
Means and standard deviation were calculated using standard statistical tests.
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Remarks on result:
other: No mortality occured
Mortality:
Not observed
Clinical signs:
Slight signs of general discomfort as often seen in dermal toxicity studies, the general health status was good throughout the study
Body weight:
Treatment related effects were not observed
Gross pathology:
No abnormalties detected
Interpretation of results:
not classified
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
Under the test conditions, the LD50 of nanoscaled ZnO is estimated to be > 2000mg/kg bw.
Executive summary:

The study was conducted to determine the acute dermal toxicity of nanoscaled ZnO according to the OECD Guideline 402 in compliance with GLP.

2000 mg/kg bw of the test substance were semiocclusively administered for 24 h as pasty formulation in corn oil to the shaved and defaffed back of 5 female and 5 male rats. After the end of the exposure period, the test substance paste was recovered as effectively as possible using water and the animals were observed for 14 d. During the present study no mortality occurred and there were no indications of systemic toxicity, no effects regarding the body weight and neither clinical signs nor pathological findings observed.

The LD50 of the test substance is therefore estimated to be > 2000 mg/kg bw.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Value:
2 000 mg/kg bw

Additional information

- With LD50values consistently exceeding 2,000 mg/kg bw, zinc oxide (LD50ranges between 5,000 and 15,000mg/kg bw), shows very low level of acute oral toxicity.
- With LC50 value > 5.7 mg/L/4hrs, zinc oxide is shown to be of low acute inhalation toxicity. 
- There are no available data on which to evaluate acute dermal toxicity for ZnO micromaterial. However, acute dermal toxicity can be considered to be low in view of the poor absorption by this route.

Zinc oxide nanomaterial:

 

Tests performed specifically on nano-ZnO demonstrate alsovery low acute oral toxicity (i.e. LD50 values consistently exceeding 2,000 mg/kg bw). The only available inhalation data on nano-ZnO indicates an LC50 value of > 1.79 mg/L. However, only this one single dose of 1.79 mg/L was tested which wasthe maximum attainable exposure concentration for achieving respirable particle size.Data on nano-ZnO confirms low acute dermal toxicity with LD50>2000 mg/kg bw.

 

In conclusion, for nano-ZnO no nano-specific acute toxicity could be identified. Zn2+ion determines the toxicity of ZnO and read across between various forms of ZnO (micro-scale, nano, coated or not) is fully supported. 

Of significance for humans from an acute toxicity standpoint is the occurrence of metal fume fever following exposure to ultrafine particles of special grades of zinc oxide in context of very specific operations such as cutting or welding of galvanised steel. Metal fume fever is exclusively associated with freshly formed ultrafine particulate zinc oxide (<0.1 µm). As these ultrafine particles (nanoparticles) rapidly agglomerate to bigger particles, which are normally encountered at production and processing sites, at these sites there is no indication for metal fume fever. According to the response from 11 zinc companies to a questionnaire, there have been no observations of zinc metal fume fever over the last decade and in recent occupational practice (EU RAR, 2004a-f). However in light of responsible care and since no studies are available that allow the establishment of a NOAEL for metal fume fever with a reasonable degree of certainty, a LOAEL (5 mg ZnO/m3) for 2 hours (showed the typical metal fume fever symptoms beginning 4 to 8 hours after exposure and disappearing within 24 hours) can be used for metal fume fever based on the study by Gordon et al.(1992).

Justification for classification or non-classification

Zinc oxide (micro- and nanomaterial) isof low acute, dermal and inhalation toxicity not requiring a classification for acute toxicity according to the EC criteria.