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Administrative data

Endpoint:
acute toxicity: dermal
Type of information:
experimental study
Adequacy of study:
key study
Study period:
Nov 2017
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Justification for type of information:
Material tested is a substance related to the reference substance which is considered sufficiently similar to be covered as well by the dossier of the reference substance. This merging is also agreed by the SIEF and is reflected in the substance identity section of the dossier (Section 1.1). Therefore, even though the CAS numbers might differ, the tested material sufficiently represents the reference substance. Therefore, provision of a read across justification is not required.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2018
Report date:
2018

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Version / remarks:
February 24, 1987
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Remarks:
(from the competent authority) Landesanstalt für Umwelt Baden-Württemberg
Test type:
fixed dose procedure
Limit test:
yes

Test material

Constituent 1
Chemical structure
Reference substance name:
Zirconium, bis(nitrato-.kappa.O)oxo-, hydrate
Cas Number:
14985-18-3
Molecular formula:
ZrO(NO3)2 · xH2O
IUPAC Name:
Zirconium, bis(nitrato-.kappa.O)oxo-, hydrate
Details on test material:
- Batch No. of test material: MKCC6997
- Date of production: 10 Mar 2017
- Expiration date of the lot/batch: March 10, 2019
- Purity: 99.4 %
- Physical state / color: solid / white
Specific details on test material used for the study:
STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: room temperature
- Solubility and stability of the test substance in the solvent/vehicle: The homogeneity of the test item preparation during application was ensured by stirring with a magnetic stirrer. The stability of the test item in the vehicle was determined indirectly by concentration control analysis. For this purpose, the samples taken were stored at room temperature over the maximum duration of the administration period, subsequently deep-frozen and sent to the sponsor.

TREATMENT OF TEST MATERIAL PRIOR TO TESTING
- Treatment of test material prior to testing: The test item was ground with a mortar and pestle. The test item preparation was produced shortly before applied by stirring with a high-speed homogeniser (Ultra-Turrax) and a magnetic stirrer.

FORM AS APPLIED IN THE TEST (if different from that of starting material)
Suspension

Test animals

Species:
rat
Strain:
Wistar
Remarks:
Crl:WI (Han) SPF
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Wiga GmbH, Germany
- Females (if applicable) nulliparous and non-pregnant: yes
- Age at study initiation: males approx. 8 weeks, females approx. 12 weeks
- Weight at study initiation: animals of comparable weight (± 20 % of the mean weight)
- Housing: single housing in Makrolon cage type III, fully air-conditioned rooms
- Diet (e.g. ad libitum): VRF1(P); SDS Special Diets Services, 67122 Altrip, Germany, ad libitum
- Water (e.g. ad libitum): tap water ad libitum
- Acclimation period: at least 5 days before the beginning of the experimental phase

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 °C ± 3 °C
- Humidity (%): 30 - 70 %
- Air changes (per hr): approx. 10
- Photoperiod (hrs dark / hrs light): 12 h / 12 h

Administration / exposure

Type of coverage:
semiocclusive
Vehicle:
corn oil
Remarks:
Ph. Eur.
Details on dermal exposure:
TEST SITE
- Area of exposure: dorsal and dorsolateral parts of the trunk, about 40 cm²
- % coverage: at least 10 % of the body surface
- Type of wrap if used: semi-occlusive dressing

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

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 5 mL/kg bw
- Concentration (if solution): 40 g/100 mL
- Constant volume or concentration used: yes
Duration of exposure:
24 h
Doses:
2000 mg/kg bw
No. of animals per sex per dose:
5
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Individual body weights shortly before application (day 0), weekly thereafter and on the last day of observation. Clinical signs for each animal were recorded several times on the day of application and at least once during each workday thereafter.
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight, mortality, pathology
Statistics:
Calculations were performed using Microsoft Excel 2010 and checked with a calculator.

Results and discussion

Effect levels
Key result
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Remarks on result:
other: no mortality occurred
Mortality:
No mortality occurred.
Clinical signs:
No systemic clinical signs were observed during clinical examination. No local skin effects were observed.
Body weight:
The body weight of all male animals and of two female animals increased within the normal range throughout the study period. Two other female animals showed slight loss of body weight during the first week, while another animal showed stagnation of body weight within this week. All three animals gained weight in a normal range during the second week. Due to the fact that stagnation or slight loss of body weight is commonly known for females after dermal application, this stagnation is considered to be unspecific.
Gross pathology:
No macroscopic pathologic abnormalities were noted in any animal examined on the last day of observation (5 males and 5 females).

Any other information on results incl. tables

Table 1: Mortality

Dose [mg/kg bw]

2000

2000

Sex

Male

Female

Application

1

1

No. of animals

5

5

Mortality (animals)

No mortality

No mortality

Table 2: Maximum incidence of systemic clinical signs

Dose [mg/kg bw]

2000

Sex

Male

Female

Application

1

No. of animals

10

Animal No.

R 658

R 659

R 660

R 661

R 662

R 663

R 664

R 665

R 666

R 667

Abnormalities

-

-

-

-

-

-

-

-

-

-

Table 3: Nature and duration of local clinical signs

Dose [mg/kg bw]

2000

Sex

Male

Female

Application

1

No. of animals

10

Animal No.

R 658

R 659

R 660

R 661

R 662

R 663

R 664

R 665

R 666

R 667

Abnormalities

-

-

-

-

-

-

-

-

-

-

Table 4: Individual body weight changes

Dose [mg/kg bw]

2000

Sex

Male

Female

Application

1

Animal No.

R 658

R 659

R 660

R 661

R 662

R 663

R 664

R 665

R 666

R 667

Body weight at study day [g]:

 

 

 

 

 

 

 

 

 

 

0

225

217

222

224

217

210

209

207

205

194

7

261

255

260

252

252

206

203

208

215

199

14

299

288

301

286

285

216

210

216

221

207

Table 5: Gross pathology

Dose [mg/kg bw]

2000

Sex

Male

Female

Application

1

No. of animals

10

Animal No.

R 658

R 659

R 660

R 661

R 662

R 663

R 664

R 665

R 666

R 667

Abnormalities

-

-

-

-

-

-

-

-

-

-

Applicant's summary and conclusion

Interpretation of results:
GHS criteria not met
Conclusions:
Under the conditions of this study the median lethal dose (LD50) of the test substance after dermal application was found to be greater than 2000 mg/kg bw in male and female rats. No mortality was observed.
Executive summary:

In an acute dermal toxicity study (Limit Test), young adult Wistar rats (5 males and 5 females) were dermally exposed to a single dose of 2000 mg/kg bw of the test substance (as suspension in corn oil Ph. Eur.). The clipped application site (dorsal and dorso-lateral parts of the trunk, comprising at least 10 % of the total body surface) was covered by semi-occlusive dressing during the 24-hour exposure period. The animals were observed for 14 days.

- No mortality occurred.

- Neither signs of systemic toxicity nor local skin effects were observed.

- The body weight of all male animals and of two out of five female animals increased within the normal range throughout the study period. Two other female animals showed slight loss of body weight during the first week, while another animal showed stagnation of body weight within this week. All three females gained weight in a normal range during the second week. Due to the fact that stagnation or slight loss of body weight is commonly known for females after dermal applications, this stagnation is considered to be unspecific.

- No macroscopic pathologic abnormalities were noted in any animal examined at the end of the study (5 males and 5 females).

Accordingly, the acute dermal median lethal dose (LD50) was determined to be > 2000 mg/kg bw for male and female rats.

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