Registration Dossier

Administrative data

Description of key information

Acute oral toxicity:
LD50= 708 mg cobalt diacetate tetrahydrate/kg bw (confidence interval: 569-880 mg/kg bw)
Acute dermal toxicity:
Conduct of an acute dermal toxicity study for cobalt di(acetate) 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
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
Methodology well-documented Minor deviations from the guideline: - The stability of the test item was not stated. - According to the guideline, necropsy of all animals should be carried out. There was no information,if necropsy of the animals was carried out. - According to the guideline, the observation period should be at least 14 days. In this study only an observation period of 10 days was used. - According to the guideline, the number of animals that died or were killed during the test and the time of death after dosing should be stated. This information was missing in this publication. -According to the guideline, the LD50 values for the sex dosed determined at 14 days should be stated. The LD50 for combined sexes determined at 10 days was stated. - According to the guideline, the animals should be fasted before test item administration. There is no statement in the study, if this was done. - According to the guideline the individual weights of animals should be determined shortly before the test substance is administered, weekly thereafter and at death; changes in weight should be calculated and recorded when survival exceeds one day. At the end of the test surviving animals are weighed and then sacrificed. This information is missing in the report.
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Version / remarks:
adopted 1987-02-24
Deviations:
yes
Remarks:
, see "rational for reliability"
GLP compliance:
not specified
Test type:
standard acute method
Limit test:
no
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: The colony of the Animal Breeding Unit, National institute of Public Health, Bilthoven
- Weight at study initiation: approx. 100 g
- Housing: Caged singly or in pairs of the same sex and dose group, in wire cages.
- Diet (ad libitum): Semi-purified diet (Murneon-SSP Tox (Trouw Ltd. Putten)
- Water (ad libitum): Drinking water

ENVIRONMENTAL CONDITIONS
- Temperature: 22- 25 °C
- Relative humidity: 35 - 55 %
No further information on the test animals was stated.
Route of administration:
oral: gavage
Vehicle:
water
Details on oral exposure:
VEHICLE
The compound was dissolved in in distilled water.
No further information about the oral exposure was stated.

Doses:
250 mg/kg bw, 375 mg/kg bw, 560 mg/kg bw, 840 mg/kg bw, 1260 mg/kg bw
No. of animals per sex per dose:
5 males / 5 females
Control animals:
not specified
Details on study design:
- Duration of observation period following administration: 10 days
- Frequency of observations and weighing: Signs of reaction and deaths were recorded for 10 days, and the rectal temperature was mesured in all survivng rats 1.5, 24 and 48 hr after administration of the cobalt compound.
- Necropsy of survivors performed: No data
No further information on the study design was stated.
Statistics:
The oral LD50 values for male and female combined, were calculated according to the method of maximum likelihood of Finney (1971).
Sex:
male/female
Dose descriptor:
LD50
Effect level:
708 mg/kg bw
95% CL:
569 - 880
Remarks on result:
other: This is the LD50 for the cobalt compound tested.
Sex:
male/female
Dose descriptor:
LD50
Effect level:
503 mg/kg bw
Remarks on result:
other: This is the LD50 for the anhydrous form of the test item. The LD50 of the anhydrous form of the cobalt compound was derived from the LD50 data of the cobalt compound tested.
Sex:
male/female
Dose descriptor:
LD50
Effect level:
168 mg/kg bw
Remarks on result:
other: This is the LD50 for the cobalt (II) ion. The LD50 of the cobalt (II) ion was derived from the LD50 data of the cobalt compound tested.
Mortality:
No data
Clinical signs:
The highest dose caused sedation and diarrhoea. Respiratory disturbances were apparent in rats given the test item. A decrease in body temperature was recorded. The temperature reductions were time- and dose-related.
Body weight:
No data
Gross pathology:
No data
Interpretation of results:
Toxicity Category IV
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
The following LD50 value was determined for cobalt (II) acetate tetrahydrate:
LD50 (combined male and female rats): 708 mg/kg bw (95 % confidence interval: 569-880 mg/kg bw)
According to the criteria specified by Directive 67/548/EEC and subsequent regulations, the test item is classified as harmful.
According to the EC Regulation No. 1272/2008 and subsequent regulations, the test item is classified as Category 4.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LD50
Value:
708 mg/kg bw

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 references Speijers (1982) and Llobet, Domingo (1983) are considered as the key studies for acute oral toxicity and will be used for classification. Female/male rats were dosed cobalt diacetate tetrahydrate at 250, 375, 560, 840, 1260 mg/kg orally via gavage and at 600, 645, 693, 745, 801, 861, 926 and 995 mg/kg orally via gavage respectively. During the conduct of the study mortalities occurred, thus the following LD50 values were derived:

  • Speijers (1982): LD50 (combined male and female rats): 708 mgcobalt diacetate tetrahydrate/kg bw /kg bw (95 % confidence interval: 569-880 mg/kg bw)
  • Llobet, Domingo (1983): LD50: 819 mgcobalt diacetate tetrahydrate/kg bw (Confidence interval: 751 - 891)

The classification criteria according to regulation (EC) 1272/2008 as acutely toxic category 4 are met since the ATE is above 300 mg/kg body-weight and below 2,000 mg/kg body-weight.Cobalt diacetate will be classified as acutely toxic category 4 (H302).

 

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 the toxic effects observed in the acute oral toxicity test already leads to an acute oral toxicity classification. No additional effects in animals or humans are known that would justify a specific target organ toxicant (STOT) – single exposure: oral classification.

 

Acute dermal toxicity

Conduct of an acute dermal toxicity study for cobalt di(acetate) 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 di (acetate) 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 extrathoracic 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 di(acetate) of 708 mg/kg observed in an acute oral toxicity test, it is therefore proposed to adopt the classification as acutely inhalation toxic category 4 also for cobalt di(acetate), 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.