Registration Dossier

Administrative data

Description of key information

Acute oral toxicity:
LD50(rat)> 5000 mg cobalt hydroxide oxide/kg bw
Acute dermal toxicity:
Conduct of an acute dermal toxicity study for cobalt hydroxide oxide is unjustified since dermal uptake is considered negligible.
Acute inhalation toxicity:
The classification from the acute oral toxicity is read-across to the acute toxicity via inhalation. Further results from the ongoing testing programme will be included upon availability.

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
Study period:
2010-08-23 to 2010-09-16
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP guideline study reliable without restrictions
Qualifier:
according to guideline
Guideline:
OECD Guideline 425 (Acute Oral Toxicity: Up-and-Down Procedure)
Deviations:
no
GLP compliance:
yes
Test type:
up-and-down procedure
Limit test:
no
Species:
rat
Strain:
Sprague-Dawley
Sex:
female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Ace Animals, Inc., Boyertown, PA
- Age at study initiation: 9-11 weeks
- Weight at study initiation: 176-205 g
- Fasting period before study: Naive rats were fasted overnight.
- Housing: The animals were singly housed in suspended stainless steel caging with mesh floors, which conform to the size recommendations in the most recent Guide for the Care and Use of Laboratory Animals (Natl. Res. Council, 1996). Litter paper was placed beneath the cage and was changed at least three times per week.
- Diet: Purina Rodent Chow # 5012; feed was replaced approx. 3-4 hours after dosing.
- Water (ad libitum): Filtered tap water
- Acclimation period: 8-21 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19-22
- Humidity (%): 47-77; humidity was above the targeted upper limit for one day during the study. A portable dehumidifier was used to lower the humidity levels during this time.
- Photoperiod (hrs dark / hrs light): 12-hour light/dark cycle
Route of administration:
oral: gavage
Vehicle:
water
Details on oral exposure:
VEHICLE
- Concentration in vehicle: The test substance was administered as a 60% w/w mixture in distilled water.
- Justification for choice of vehicle: Preliminary solubility test conducted by EPSL indicated that mixtures in excess of 60% (i.e., 70% or 80%) were too viscous to be administered properly.

MAXIMUM DOSE VOLUME APPLIED:
5,000 mg/kg

DOSAGE:
Individual doses were calculated based on the initial body weights, taking into account the specific gravity (determined by EPSL) and concentration of the test mixture.

Based on a limit dose of 5,000 mg/kg, at the request of the sponsor, a Main test was conducted using a default starting dose level of 175 mg/kg administered to one healthy female rat and following the Up and Down procedure, five additional females were dosed.
Doses:
175, 550, 1,750 or 5,000 mg/kg bw
No. of animals per sex per dose:
1 animal per 175 mg/kg dose level
1 animal per 550 mg/kg dose level
1 animals per 1,750 mg/kg dose level
3 animals per 5,000 mg/kg dose level
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: All animals were observed for mortality, signs of gross toxicity and behavioral changes during the first several hours post-dosing and at least once daily thereafter for 14 days after dosing. Individual body weights were recorded prior to administration (initial) and again on Days 7 and 14 (termination) following dosing.
- Necropsy of survivors performed: yes; all rats were euthanized via CO2 inhalation at the end of the 14-day observation period. Gross necropsies were performed on all animals. Tissues and organs of the thoracic and abdominal cavities were examined.
- Other examinations performed: Observations included gross evaluation of skin and fur, eyes and mucous membranes, respiratory, circulatory, autonomic and central nervous systems, somatomotor activity and behavior pattern. Particular attention was directed to observations of tremors, convulsions, salivation, diarrhea and coma.
Statistics:
The Acute Oral Toxicity (Guideline 425) Statistical Program (Westat, version 1.0, May 2001) was used for all data analyses including: dose progression selections, stopping criteria determinations and/or LD50 and confidence limit calculations.
Sex:
female
Dose descriptor:
LD50
Effect level:
> 5 000 mg/kg bw
Based on:
test mat.
Mortality:
All animals of the 175, 550, 1750 and 5000 mg/kg dose levels survived the test substance administration.
Clinical signs:
All animals of the 175, 550, 1750 and 5000 mg/kg dose levels appeared active and healthy during the study; no signs of gross toxicity, adverse pharmacologic effects or abnormal behaviour were noted.
Body weight:
All animals of the 175, 550, 1750 and 5000 mg/kg dose levels gained body weight during the study.
Gross pathology:
No gross abnormalities were noted for any of the animals when necropsied at the conclusion of the 14-days observation period.
Interpretation of results:
not classified
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
Under the conditions of this study, the acute oral LD50 of Cobalt Oxide Hdyroxide is estimated to be greater than 5,000 mg/kg in female rats.
According to the criteria specified by Directive 67/548/EEC and subsequent regulations, the test item is not classified.
According to the EC Regulation No. 1272/2008 and subsequent regulations, the test item is not classified.
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed

Acute toxicity: via inhalation route

Endpoint conclusion
Endpoint conclusion:
no study available

Acute toxicity: via dermal route

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed

Additional information

Justification for selection of acute toxicity – oral endpoint
Key study

Justification for selection of acute toxicity – dermal endpoint
Weight of evidence information

Justification for classification or non-classification

Acute oral toxicity

The reference Durando (2011) is considered as the key study for acute oral toxicity of cobalt hydroxide oxide and will be used for classification. Female Sprague-Dawley rats were dosed a maximum of 5000 mg/kg orally via gavage. During the observation period of 14 days no adverse effects or mortalities were observed, thus the LD50 is > 5000 mg cobalt hydroxide oxide/kg bw.

The classification criteria according to regulation (EC) 1272/2008 as acutely toxic are not met since the ATE is above 2000 mg/kg body-weight, hence no classification required.

Specific target organ toxicant (STOT) – single exposure: oral

The classification criteria according to regulation (EC) 1272/2008 as specific target organ toxicant (STOT) – single exposure, oral are not met since no reversible or irreversible adverse health effects were observed immediately or delayed after exposure and no effects were observed at the guidance value, oral for a Category 1 classification of 300 mg/kg bw and at the guidance value, oral for a Category 2 classification of 2000 mg/kg bw. No classification required.

Acute dermal toxicity

Conduct of an acute dermal toxicity study for cobalt hydroxide oxide is unjustified since dermal uptake is considered negligible.

 

Specific target organ toxicant (STOT) – single exposure: dermal

Conduct of an acute dermal toxicity study for cobalt hydroxide oxide is unjustified since dermal uptake is considered negligible.

Acute inhalation toxicity and Specific target organ toxicant (STOT) – single exposure: inhalation

Cobalt compounds are not generally associated with local effects following acute inhalation exposure; only after long-term exposure, some inflammatory responses are seen. Thus, any acute inhalation toxicity may reasonably be assumed to be predominantly determined by systemic availability.

Based on the outcome of dustiness testing (Heubach rotating drum method; for details, please refer to the IUCLID endpoint study record under IUCLID section 7.1.1 basic toxicokinetics) coupled with particle size analysis of the airborne fraction, all cobalt compounds have moderate to low values for total dustiness, indicating similar propensities to become airborne. Based on the concurrent particle size analysis, inhalation deposition modelling via MPPD clearly indicates that only minor substance amounts can be expected to be deposited in the pulmonary fraction of the respiratory tract of humans; in contrast, the majority of inhaled material will deposit in the extra thoracic and tracheo-bronchiolar regions, and therefore can safely be assumed to undergo translocation to the gastrointestinal tract via mucociliary escalation and subsequent swallowing.

Thus, any systemic effects may be read across from acute oral toxicity. Based on the LD50 for cobalt hydroxide oxide of >5000 mg/kg observed in an acute oral toxicity test, it is therefore proposed to adopt the classification as not acutely oral toxic also for acute inhalation, and to waive the testing requirement for acute inhalation toxicity in accordance with section 1.1, annex XI of regulation (EC) 1907/2006.

 Furthermore a testing programme is currently being executed, investigation the acute toxicity of eleven cobalt compounds via inhalation. The aim was to cover a wide spectrum of substances to allow read-across to non-testes substances, to reduce the number of animals. The test items were selected according to the following criteria:

- high dustiness, as determined in the Heubach rotating drum method

- small MMAD to ensure highest possible exposure of the respiratory tract of the test animals

- coverage of high, medium and low bioaccessible substances, determined in artificial alveolar lining fluid (ALF)

According to the above criteria, the following substances were selected for testing: cobalt metal powder (fine and coarse sample), cobalt carbonate, cobalt resinate, cobalt stearate, cobalt acetyl acetonate, cobalt sulfate, cobalt monoxide, tricobalt tetraoxide, cobalt sulfide.

The registrant ensures that the results will be included in the respective dossiers upon availability.