Registration Dossier

Administrative data

Description of key information

Acute oral toxicity:
LD50(rat) = 537 mg cobalt dichloride hexahydrate/kg bw (Confidence interval: 479 – 601 mg/kg bw)
Acute dermal toxicity:
Conduct of an acute dermal toxicity study for cobalt chloride 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:
Comparable to guideline study with acceptable restrictions Spanish article translated into english. - The stability of the test item was missing. - According to the guideline, at least 5 rodents of the same sex should be used at each dose level and later at least one group of the other sex should be tested to establish that animals of this sex are not markedly more sensitive to the test substance. In the publication it was not clear how many animals were used at each dose level and it was also not clear how many males and females were used at the different dose levels. - Observation period was only 7 days instead of the recommended 14 days by the guideline. In the publication it was stated that animals rarely died after 48 hours, but it was not clear at which time point for certain animals did not die anymore. According to the guideline, the time of death should be recorded as precisely as possible. In addition, it was not mentioned how many animals showed signs of toxicity. - According to the guideline, the animals should be weighed, but nothing was stated about weighing the animals. - According to the guideline, clinical examination should be made at certain time intervals. In the publication was nothing stated about the time points at which observations were made. - According to the guideline, animals which die during the test are necropsied, and at the conclusion of the test the surviving animals are sacrificed and necropsied. In the publication it was only stated that surviving animals were sacrificed after 7 days. - According to the guideline, the volume administered to rodents should not exceed 1 ml/100g body weight, except in the cases of aqueous solutions where 2 ml/ 100 g may be used. Variability in the test volume should be minimised by adjusting the concentration to ensure a constant volume at all dose levels. There was no indication on what volume was administered to the rats and if it was at a constant volume.
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Deviations:
yes
Remarks:
, see "rational for reliability"
GLP compliance:
not specified
Test type:
standard acute method
Limit test:
no
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Weight at study initiation: Mean weight 192.5 +/- 22.3 g
- Diet: ad libitum
- Water:ad libitum
- Fasting period before study: Fasted for 24 hours before administration
No further information on the test animals was stated.




Route of administration:
oral: gavage
Vehicle:
water
Details on oral exposure:
Rationale for the selection of the dose levels: They chose the dose levels based on pre-tests with a small number of rats. It was tested at which dose no deaths occurred and at which dose all test animals died.
No further information on the oral exposure was stated.
Doses:
350 mg/kg, 392 mg/mg/kg, 450 mg/kg, 518 mg/kg, 595 mg/kg, 684 mg/kg, 787 mg/kg
No. of animals per sex per dose:
8 or 10 animals (It was not clearly stated in the publication how many males and females were used per dose and if the genders were equally distributed.)
Control animals:
yes
Details on study design:
- Duration of observation period following administration: 7 days
- Frequency of observations and weighing: No data
- Necropsy of survivors performed: Yes
No further information on the study design was stated.
Statistics:
Method for determination of LD50, and confidence limit according to Litchfield and Wilcoxon (1949).
Sex:
male/female
Dose descriptor:
LD50
Effect level:
537 mg/kg bw
95% CL:
479 - 601
Mortality:
Death occurred in 95 % of animals within the first 24 hours after administration. Most animals even died within the first 6 hours. Rats rarely died after 48 hours.
The following percentage of animals died at the different dose levels:
350 mg/kg: 0 %
392 mg/kg: 10 %
450 mg/kg: 37.5 %
518 mg/kg: 50 %
595 mg/kg: 75 %
684 mg/kg: 75 %
787 mg/kg: 100 %
Clinical signs:
Intoxication symptoms: (occurred shortly after intoxication) decrease of general activity and especially exploiting behaviour, frequency of "getting up"; increase of water consumption; deficit in motivity of hind legs, less pain sensitivity
Clinical signs: general redness, bleeding around the eye, increase of the rhythm of the heart, and irregularly increase of the respiratory, intensive diarrhoea, all animals showed pilo erection.
Most effects disappeared after 72 hours.
Body weight:
No data
Gross pathology:
No marcoscopic alterations were observed at the most significant organs.
Interpretation of results:
Toxicity Category IV
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
Cobalt dichloride hexahydrate is moderately toxic if administered orally.
LD50: 537 mg/kg (Confidence interval: 479 - 601 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
537 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 at 500, 600, 720, 864, 1137 mg/kg bw orally via gavage and at 350, 392, 450, 518, 595, 684, 787mg/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): 766 mg/kg bw (95 % confidence interval: 677 - 867 mg/kg bw)
  •  Llobet, Domingo (1983): LD50: 537 mg/kg (Confidence interval: 479 – 601 mg/kg bw)

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 chloride hexahydrate 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 chloride 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 chloride 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 chloride of 537 mg/kg observed in an acute oral toxicity test, it is therefore proposed to adopt the classification as acutely oral toxic category 4 also for cobalt chloride, 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.