Naphthenic acids, cobalt salts

Endpoint summary

Description of key information

Acute oral toxicity: LD50 (female rats): 3129 mg/kg bw (approx. 95% CL: 1750 - 5000 mg/kg) (OECD 425; GLP compliant) 
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:

2011-09-22 to 2011-10-31

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: GLP guideline study eliable 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 - Sprague-Dawley derived, albino
- Source: Harlan Laboratories
- Age at study initiation: 9 - 10 weeks
- Weight at study initiation: 185 - 222 g
- Fasting period before study: prior to each dosing, fasted overnight by removing the feed from their cages; Feed was replaced approximately 3 -4 hours after dosing.
- 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). Litter paper was placed beneath the cage and was changed at least three times per week.
- Diet (ad libitum, except during fasting): HArlan Teklad Global 16% Protein Rodent Diet® #2016
- Water (ad libitum): filtered tap water
- Acclimation period: 9 - 19 days

During the fasting period, the rats were examined for health adn weighed (initial).

ENVIRONMENTAL CONDITIONS
- Temperature: 19 - 23°C
- Relative humidity: 33 - 91%
- Air changes: 15 hours
- Photoperiod (hrs dark / hrs light): 12/12

Route of administration:

oral: gavage

Vehicle:

corn oil

Details on oral exposure:

VEHICLE
- Justification for choice of vehicle: preliminary solubility testing conducted by the laboratory indicated that the substance was not soluble in distilled water or a 0.5% w/v solution of carboxymethylcellulsoe in distilled water and mixtures in excess of 40% (i.e., 50 - 80%) were too viscous to be administered properly.

MAXIMUM DOSE VOLUME APPLIED: individual doses were calculated based on the initial body weights, taking into account the density (as determiend by the laboratory) and concentration of the test mixture.

DOSAGE PREPARATION: prior to use, the test substance was ground in a coffee mill (Cuisinart, Model DCG-20N). The ground sample was administered as a 40% w/w mixture in corn oil.

Initially, a single animal received a limit dose of 5000 mg/kg. Due to the mortality of this animal, a Main test was conducted.

Doses:

175, 550, 1750 and 5000 mg/kg

No. of animals per sex per dose:

1 animal per 175 mg/kg dose level
1 animal per 550 mg/kg dose level
3 animals per 1750 mg/kg dose level
4 animals per 5000 mg/kg dose level (one animal from the limit test)

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 a t least once daily thereafter for 14 days after dosing 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 necropsies were performed on all decedents and euthanized animals. Tissues and organs of the thoracic and abdominal cavities were examined.

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:

3 129 mg/kg bw

Based on:

test mat.

95% CL:

1 750 - 5 000

Remarks on result:

other: LD50 based on an assumed sigma of 0.5.

Mortality:

175 and 550 mg/kg (1 animal per dose level):
Each animal from the above dose level survived test substance administration.
1750 mg/kg (3 animals):
All animals survived test substance administration.
5000 mg/kg (4 animals):
All animals died within three days of test substance administration.

Clinical signs:

other: 175 and 550 mg/kg (1 animal per dose level): Each animal from the above dose level appeared active and healthy.There were no signs of gross toxicity, adverse pharmacologic effects, or abnormal behaviour in either rat att hese dose levels. 1750 mg/kg (3 a

Gross pathology:

175 and 550 mg/kg (1 animal per dose level).
No gross abnormalities were noted for either of these animals when necropsied at the conclusion of the 14-day observation period.
1750 mg/kg (3 animals):
No gross abnormalities were noted for these animals when necropsied at the conclusion of the 14-day observation period.
5000 mg/kg (4 animals):
Gross necropsy of the decedents revealed dark intestines, mottled liver and distention of the stomach and/or intestines.

Interpretation of results:

not classified

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

LD50 (female rats): 3129 mg/kg bw (approx. 95% CL: 1750 - 5000 mg/kg)
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

Dose descriptor:

LD50

Value:

3 129 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
Waight of evidence data.

Justification for classification or non-classification

Acute oral toxicity

Reference Durando (2012) will be used as key study for acute oral toxicity and will be used for classification.

The LD50 was determined to be 3129 mg/kg bw. Thus, according to regulation (EC) 1272/2008 and subsequent amendments the substance is not classified.

 

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

According to Durando (2012) the classification criteria acc. 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 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 naphthenate of 3129 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.