Registration Dossier

Administrative data

Description of key information

Acute oral toxicity:
LD50 (female rats)= 355 mg cobalt propionate/kg (Confidence interval: 61.2 - 1890 mg/kg)

Acute dermal toxicity:
Conduct of an acute dermal toxicity study for cobalt propionate is unjustified since dermal uptake is considered negligible.

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:
2006-07-20 to 2007-03-07
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
Guideline study reliable without restrictions Minor deviations with no effect on the results of the study: - The stability of the test material was missing, but it was stated in the report that the test substance appeared to be stable under the conditions of the study. No evidence of instability, such as a change in colour or physical state, was observed. - According to the guideline, the volume for administration of the test substance should not exceed 1 ml /100g of body weight; however in the case of aquoues solution, 2 ml/100 g body weight can be considered. Also, the test substances should be administered in a constant volume. The test substance was not administered in a constant volume and the volume for nonaqueous solutions was exceeded. This was not considered to influence the results.
Qualifier:
according to guideline
Guideline:
OECD Guideline 425 (Acute Oral Toxicity: Up-and-Down Procedure)
Version / remarks:
, adopted 2006-03-23
Deviations:
yes
Remarks:
, see "rational for reliability"
GLP compliance:
yes
Test type:
up-and-down procedure
Species:
rat
Strain:
Crj: CD(SD)
Sex:
female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories, Inc., Raleigh, North Carolina
- Age at study initiation: approx. 10 or 11 weeks old
- Weight at study initiation: 205.1 - 228.3 g (fasted body weight)
- Fasting period before study: approx. 16 - 18 hours prior to dosing, with food being returned to the rats approx. 3-4 hours after dosing
- Housing: All animals were housed singly in stainless steel, wire-mesh cages suspended above cage boards.
- Diet (ad libitum): PMI® Nutrition International, LLC Certified Rodent Lab Diet® 5002
- Water: ad libitum
- Quarantine period: at least six days

ENVIRONMENTAL CONDITIONS
- Temperature: 18 - 26 °C
- Relative humidity: 30 - 70 %
- Photoperiod (hrs dark / hrs light): 12/12
No further information on the test animals was stated.
Route of administration:
oral: gavage
Vehicle:
other: 0.5 % aqueous methylcellulose
Details on oral exposure:
VEHICLE & DOSAGE PREPARATION
Cobalt propionate was suspended in 0.5 % aqueous methylcellulose. The suspension was milled at high speed with glass beads for 15 - 19 hours on a shaker table. A new dose suspension was prepare for each day of dosing. The dosing suspensions were stirred at least 30 minutes prior to and throughout the dosing procedure.

MAXIMUM DOSE VOLUME APPLIED: Individual dose volumes were calculated using the fasted body weights obtained prior to dosing. The rats dosed at 55, 175, or 550 mg/kg were dosed at a volume of 10 mL per keg of body weight. The rat dosed at 306 mg/kg was dosed at a volume of 17.5 ml/kg. the rat dosed at 2000 mg/kg was dosed at a volume of 20 mL per kg of body weight.

- Rationale for the selection of the starting dose:
The starting dose level of 175 mg/kg was chosen based on the absence of toxicity data for this test substance.
No further information on oral exposure was stated.





Doses:
55 mg/kg, 175 mg/kg, 306 mg/kg, 550 mg/kg, 2000 mg/kg
No. of animals per sex per dose:
55 mg/kg: one female
175 mg/kg: two females
306 mg/kg: one female
550 mg/kg: three females
2000 mg/kg: one female
Control animals:
not specified
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: observations for mortality and signs of illness, injury, or abnormal behaviour were made daily throughout the study.Rats were observed for clinical signs at the beginning of fasting, just before dosing (test day =), once during the first 30 minutes after dosing and 2 more times on the day of dosing, and once each day thereafter. Rats were weighed on test days-1, 0, 7, and 14. Test day -1 is prior to fasting and test day 0 is after fasting.
- Necropsy of survivors performed: Yes
On the test day 14, the surviving rats were euthanized and necropsied to detect grossly observable evidence of organ or tissue damage or dysfunction. the rats were anesthetized by carbon dioxide and euthanized by exsanguination. The rats that died were also necropsied.
No further information on the study design was stated.
Statistics:
A software package (A0T425StatPgm) was used to determine the dose progression and to calculate the LD50.
Sex:
female
Dose descriptor:
approximate LD50
Effect level:
354.7 mg/kg bw
95% CL:
61.19 - 1 890
Remarks on result:
other: Approx. LD50 based on maximum likelihood; The 95% CL is a profile likelihood confidence interval
Mortality:
Two rats at 500 mg/kg and the rats dosed at 306 or 2000 mg/kg were found dead on the day of dosing.
Clinical signs:
No clinical signs of toxicity were observed in the rat dosed at 55 mg/kg and in one of the rats dosed at 175 mg/kg. Clinical signs observed in the remaining rats included lethargy, ataxia, low or high carriage, fast or labored breathing, prostrate posutre, decreased muscle tone (rigid spine or rigid whole body), hair loss, paralysis of forelimb/hindlimb, mydriasis, spasm, cold to touch, and/or dry mucous membrane.

Body weight:
No biologically important body weight loss occurred in surviving rats after dosing.
Gross pathology:
There were no test substance-related gross lesions found in the study. The only gross lesion observed, red discolouration (glandular) of the stomach in one rat, was non-specific and not indicative of target organ toxicity.
Interpretation of results:
Toxicity Category IV
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
Under the conditions of this study, the oral LD50 for cobalt propionate was 354.7 mg/kg for female rats.
According to 67/548/EC and subsequent regulations, cobalt propionate is classified as harmful.
According to the EC Regulation No. 1272/2008 and subsequent regulations, cobalt propionate is classified as Category 4.
Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LD50
Value:
355 mg/kg bw

Acute toxicity: via inhalation route

Endpoint conclusion
Endpoint conclusion:
adverse effect observed

Acute toxicity: via dermal route

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed

Additional information

Justification for classification or non-classification

Acute oral toxicity

The reference Finlay (2007) is considered as the key study for acute oral toxicity and will be used for classification. Female CD rats were dosed up to 2000 mg/kg orally via gavage. The LD50 was calculated 355 mg/kg bw with a 95 % confidence interval of 61.2 - 1890 mg/kg.

The classification criteria according to regulation (EC) 1272/2008 as acutely toxic category 4 are met since the ATE is between 300 and 2000 mg/kg body-weight, hence cobalt propionate is classified as acute oral 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 propionate 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 propionate 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 propionate of 355 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 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.