Cobalt, borate 2-ethylhexanoate complexes

Endpoint summary

Description of key information

Acute oral toxicity:
LD50=2210 mg/kg
Acute toxicity, dermal:
Conduct of an acute dermal toxicity study is unjustified since dermal uptake is considered negligible (cf. Annex VIII section 8.5 Column 2 of regulation (EC) 1907/2006).
Acute toxicity, inhalation:
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:

2012-12-10 to 2013-03-20

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 425 (Acute Oral Toxicity: Up-and-Down Procedure)

Version / remarks:

2008-10-03

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: Harlan Laboratories, Inc.
- Age at study initiation: 8 - 11 weeks
- Weight at study initiation: 176 - 217 grams
- Fasting period before study: prior to each dosing, experimentally naive rats were fasted overnight by removing the feed from their cages.
- 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, 2011). Enrichment (e.g. toy) was placed in each cage. Litter paper was placed beneneath the cage and was changed at least three times per week. Feed was replaced approximately 3 - 4 hours after dosing.
- Diet ( ad libitum, except during fasting): Harlan Teklad Global 16% Protein Rodent Diet® #2016
- Water (ad libitum): filtered tap water
- Acclimation period: 6 - 26 days

ENVIRONMENTAL CONDITIONS
- Temperature: 19 - 23°C
- Relative humidity: 16 - 52%
- Air changes: 13 and 14 air changes/hour
- Photoperiod (hrs dark / hrs light): 12/12

Route of administration:

oral: gavage

Vehicle:

water

Details on oral exposure:

DOSAGE PREPARATION:
The test substance was administered as a 45% w/w mixture in distilled water. Preliminary solubility testing conducted by the laboratory indicated mixtures in excess of 45% (i.e. 50%-80%) were too viscous to be administered properly.

Individual doses were calculated based on the initial body weights, taking into account the density (determined by the laboratory) and concentration of the test mixture.

initially, a single animal received a limit dose of 5000 mg/kg. Due to mortality of this animal a Main Test was conducted. For the Main Test, the test substance was administered in sequence to the animals as can be seen in table 1 in the field "Any other information on materials and methods incl. tables" below. The decision to proceed with the next animal was based on survival of the previous animal following dosing. Dose progressions and stopping criteria were determined using a statistical program

Doses:

175, 550, 1750 and 5000 mg/kg

No. of animals per sex per dose:

175 mg/kg: 1 animal
550 mg/kg: 4 animals
1750 mg/kg: 6 animals
5000 mg/kg: 4 animals

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: individual body weights of the animals were recorded prior to test substance administration (initial) and again on Days 7 and 14 (termination) following dosing or after death. The animals were observed for mortality, signs of gross toxicity, and behavioural changes during the first several hours post-dosing and at least once daily thereafter for 14 days after doing or until death occurred.
- Necropsy of survivors performed: yes
Surviving rats were euthanized via CO2 inhalation at the end of the 14-day observation period. Gross necropsy were performed on all decendents and euthanized animals. Tissues and organs of the thoracic and abdominal cavities were examined.

Statistics:

The Acute Oral Toxicity (Guideline 425) Statistical Program (Weststat, 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:

2 210 mg/kg bw

Based on:

test mat.

Remarks on result:

other: (based on maximum likelihood); approx. 95% profile-likelihood based confidence interval of 960.4 mg/kg lower to 9430 mg/kg (upper)

Mortality:

- 175 mg/kg dose level (1 animal):
This animal survivied during the study.
- 550 mg/kg dose level (4 animals):
All animals survived during the study.
- 1750 mg/kg dose level (6 animals):
Three females died within three days of test substance administration.
- 5000 mg/kg dose level (5 animals):
Four animals died within seven days of test substance administration, including one animal euthanised for humane reasons on Day 7.

Clinical signs:

other: 175 mg/kg dose level (1 animal): Apart from the animal exhibiting reduced fecal volume on Day 1, there were no other signs of gross toxicity, adverse pharmacologic effects, or abnormal behaviour. - 550 mg/kg dose level (4 animals): All animals appeared ac

Gross pathology:

175 mg/kg dose level (1 animal):
No gross abnormalities were noted for this animal when necorpsied at the conclusion of the 14-day observation period.
- 550 mg/kg dose level (4 animals):
No gross abnormalities were noted for any of the animals when necropsied at the conclusion of the 14-day observation period.
- 1750 mg/kg dose level (6 animals):
Gross necropsy of the decedents revealed discolouration of the intestines and distention of the stomach and/or intestines. No gross abnormalities were noted for the euthanised animals when necropsied at the conclusion of the 14-day observation period.
- 5000 mg/kg dose level (5 animals):
Gross necropsy of the decedents revealed discolouration and/or distention of the intestines and/or stomach. no gross abnormalities were noted for the euthanised animal when necorpsied at conclusion of the 14-day observation period.

Interpretation of results:

GHS criteria not met

Conclusions:

LD50: 2210 mg/kg (based on maximum likelihood) (approx. 95% profile-likelihood based confidence interval of 960.4 mg/kg lower to 9430 mg/kg (upper).
According to the EC-Regulation 1272/2008 and subsequent regulations, the test item is not classified.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

2 210 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 reference McKenzie (2013) is considered as the key study for acute oral toxicity and will be used for classification. The test was conducted according to OECD 425. The LD50 for female rats was calculated to be 2210 mg/kg bw.

According to regulation (EC) 1272/2008 and subsequent amendments the substance will not be classified as acute oral toxic.

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 is unjustified since dermal uptake is considered negligible.

 

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

Conduct of an acute dermal toxicity study 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 LD₅₀for cobalt borate 2 -ethylhexanoate of 355 and 1098 mg/kg observed in two acute oral toxicity test with read-across substances, it is therefore proposed to adopt the classification as acutely oral toxic category 4 also for acute inhalation toxicity, 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.