Naphthenic acids, cobalt salts

Endpoint summary

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LOAEL

Study duration:

subacute

Species:

rat

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEC

Study duration:

chronic

Species:

other: human data

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Introductory remark – read-across

 

Read-across entails the use of relevant information from analogous substances (the ‘source’ information) to predict properties for the ‘target’ substance(s) under consideration. Substances whose physicochemical or toxicological properties are likely to be similar or follow a regular pattern as a result of structural similarity may be considered as a category of substances. Structural similarity is a pre-requisite for any read-across approach under REACH (ECHA Read-Across Assessment Framework, 2015).

 

In accordance with Annex XI, 1.5 of the REACH regulation and the ECHA Guidance Read-Across Assessment Framework (ECHA, 2017), the similarities may be based on:

 

1) A common functional group (i.e. chemical similarity within the group);

2) Common precursors and/or likelihood of same breakdown products through physical and/or biological processes which result in structurally-similar degradation products (i.e. similarity through (bio) transformation); or

3) A constant pattern in the changing of the potency of the properties across the group (i.e. of physical-chemical and/or biological properties).

 

Due to the absence of substance specific information for the majority of substances within the cobalt category, the approach will read-across data from representative source substances to all other members of the read-across group.

 

Due to the route-specific toxicological properties of the cobalt category substances, several read-across groups are formed as shown in the table below:

 

	Route	Read-across group
Cobalt category	oral-systemic	bioavailable cobalt substances group
		inorganic poorly soluble
		poorly soluble in aqueous solutions with organic ligand
	inhalation-local	reactive
		non-reactive

 

 

Further details on the read-across approach are given in Appendix 1.1 of the CSR for the oral systemic effects and Appendix 1.2 of the CSR for the inhalation local effects.

 

Naphthenic acids, cobalt salts is assigned to the read-across groups (i) oral-systemic: Poorly soluble in aqueous solutions with organic ligand and (ii) inhalation-local: reactive

As discussed in the chapter on inhalation read-across (see attachement in Section 13 of the IUCLID), the substance

Naphthenic acids, cobalt salts has not yet been assigned to either inhalation-local read-across group due to ongoing testing. The registrant will update the dossier immediately upon availability of the test data.

 

 

Human data - inhalation

 

Repeated dose toxicity - local effects

The comprehensive discussion of the available human data can be found at the beginning of chapter 5 of the CSR and in section 7.10 of the IUCLID.

 

The overall outcome was that, based on the findings of the epidemiological studies in workers by Swennen et al. (1993) and Verougstraete et al. (2004), Roto (1980) and Sauni et al. (2010) a cobalt concentration of 0.12 mg Co/m³ will be used as NOAEC for setting a DNEL (inhalation, chronic, local effects).

 

Repeated dose toxicity - systemic effects

An investigation on the effects of cobalt exposure in a Finnish cobalt plant in Kokkola on the cardiovascular system of workers was published by Linna et al. (2004). The cross-sectional study population comprised 203 male workers with at least one year of exposure to cobalt at the end of 1999. The average exposure time was 15.0 years with a mean cumulative exposure to cobalt of 0.40 mg-year (median 0.18 mg-year, range 0.02-2.52). The control group consisted of an age-stratified sample of 94 male workers in a zinc plant that had not been exposed to cobalt, arsenic or lead. The zinc exposure level was 0.1-0.2 mg/m³ for four fifths of the workers, and for one fifth it was about 1 mg/m³. No significant differences in the electrocardiography findings and conduction parameters, heart rate, blood pressure and laboratory tests (inter alia serum T4 and TSH levels) were found between the cobalt exposed and control workers. There were no significant differences between the exposed group and the control group in the prevalence of reported cardiovascular diseases, diabetes mellitus, or pulmonary diseases, except asthma, diagnosed by a physician. Echocardiography was performed on a subset of 122 cumulatively most exposed workers, of which 109 was analysed, and 60 controls with same age distribution, of which 57 were analysed. The average exposure time was 21.2 years with a mean exposure to cobalt of 0.58 mg-year (median 0.47 mg-year, range 0.03-2.52). The echocardiographic data were studied using a regression analysis and an analysis of covariance (ANCOVA). In the final analyses high and low exposure was determined on the basis of being above or below the median mg-years of cobalt exposure. Two of the echocardiography parameters measured was associated with cobalt exposure. In the higher exposure group the left ventricular isovolumic relaxation time (mean 53.3, 49.1, and 49.7 ms in the high exposure (>0.47 mg-year), low exposure (<0.47 mg-year), and control groups, respectively) and the deceleration time of the velocity of the early rapid filling wave (mean 194.3, 180.5, and 171.7 ms for those in the high exposure, low exposure, and control groups, respectively) were prolonged, indicating altered left ventricular relaxation and early filling. The clinical significance of these changes, however, remains to be evaluated. Minor increases in the left ventricular wall thickness concurred with these observations. No signs of systolic cardiac dysfunction were found. The ejection fraction, fractional shortening, and the left ventricular end diastolic diameter were similar in the exposed and control groups.

 

No clinically significant cardiac dysfunction, no evidence of polycythaemia and only equivocal indications of interferences with thyroid metabolism were observed in workers occupationally exposed to inorganic cobalt compounds. Therefore, it can be concluded that systemic effects following inhalation exposure are expected at higher dose levels compared to the dose levels for local effects. Thus, no DNEL(inhalation, systemic) will be derived for workers and the general population.

 

 

Animal data - inhalation

 

Repeated dose toxicity

 

Cobalt sulfate

In 13-week inhalation toxicity studies, groups of 10 F344 rats and 10 B6C3F1 mice of each sex were exposed to aerosols of cobalt sulfate heptahydrate at concentrations of 0, 0.3, 1.0, 3.0, 10 or 30 mg/m³ (0, 0.063, 0.21, 0.63, 2.1 or 6.3 mg Co/m³), 6 hours/day, 5 days/week (Bucher et al., 1990). The MMAD of the aerosol was in the range of 0.83 to 1.10 µm. Mean body weights of mice exposed to 30 mg/m³ were lower than those of the controls throughout the study, and two of 10 males in this group died before the end of the study. At the end of the studies, lung weights were generally increased in rats and mice exposed to 1 mg/m³ and higher. The above described exposure of rats and mice to aerosols of cobalt sulfate heptahydrate resulted primarily in necrotising injury to the respiratory tract. The larynx appeared to be the most sensitive tissue, showing squamous metaplasia lesions after exposure at concentrations as low as 0.3 mg/m³ cobalt sulfate heptahydrate (equivalent to 0.063 mg cobalt/m³). Rats developed chronic inflammation of the larynx at concentrations of 1 mg/m³ and more severe effects in the nose, larynx, and lung at higher concentrations. Mice exhibited acute inflammation of the nose at concentrations of 1 mg/m³ and more severe effects in the nose, larynx, and lung at higher exposures. A NOAEC for local effects in the respiratory was not reached in these studies, as lesions, particularly in the larynx, were observed at the lowest concentration of 0.3 mg/m³ cobalt sulfate thus representing a LOAEC.

 

Thyroid function as indicated by serum T3, T4, and thyrotropin concentrations did not appear to be consistently affected in rats. Polycythemia was seen at 10 and 30 mg/m³ for female rats and at concentrations of 3 mg/m³ for male rats. No consistent significant haematological effects were seen in mice. At 6.3 mg Co/m³, mice showed hyperplasia of the mediastinal lymph nodes.

 

Reproductive system effects were more prominent in mice than in rats.Decreases of testicular and epididymal weights and of sperm counts and increased numbers of abnormal sperm occurred in mice exposed to 30 mg/m³. The NOAEC for testicular weight decrease in mice is 10 mg/m³. Sperm motility was significantly reduced in mice at 0.63 mg Co/m³ (lower concentrations were not evaluated) and at higher concentrations. In female mice, the oestrous cycle was significantly longer in the highest dose group. However, it is unclear to what extent the changes of these reproductive parameters were associated with a decline in fertility because effects on fertility were not studied. No statistically significant effects on sperm motility, sperm counts, or the incidence of abnormal sperm were observed in F344 rats exposed under identical dosing conditions.

 

Shortcomings of the study: The study report presents data on the effect on the respiratory tract in mice and rats in all dose groups comprehensively, and therefore allows the derivation of a NOAEC/LOAEC for local effects. However, since only selected species and/or dose groups were chosen for (i) histopathological examination (and where presented, the severity of such lesions is not indicated), (ii) investigation of reproductive system data, (iii) serum and thyroid function values, neither target organs for systemic toxicity nor any dose-response relationship for systemic effects can be determined. The body weight and clinical data which are available for both species and dose groups allow only the establishment of a NOAEC for general toxicity, but do not address non-lethal organ toxicity of minimal or moderate severity.

 

In a subsequent combined chronic inhalation toxicity/carcinogenicity studies, groups of male and female F344/N rats and B6C3F1 mice were exposed to aerosols of cobalt sulfate hexahydrate at concentrations of 0, 0.3, 1.0, or 3.0 mg/m³ for 6 hours/day, 5 days/week for 105 weeks (Bucher et al.). The MMAD (µm) ± GSD of the aerosol was in the range from 1.4 ± 2.1 to 1.6 ± 2.2. The study represents a highly reliable study without restrictions (RL 1). The respiratory tract was the primary site of non-neoplastic lesions and neoplasms.

 

In rats, proteinosis, alveolar epithelial metaplasia, granulatomous alveolar inflammation, and interstitial fibrosis were observed in the lung of all exposed groups. The incidence of hyperplasia of the respiratory epithelium of the lateral wall of the nose and atrophy of the olfactory epithelium in all exposed groups was significantly greater than those in controls, and the severity of these lesions increased with increasing exposure concentration. Nasal lesions in mice were less severe than in rats, but olfactory epithelial atrophy was observed at 1.0 mg/m³. The incidence of squamous metaplasia of the epiglottis in all exposed groups of rats and mice was significantly increased, and the severity of this lesion increased in rats with higher concentrations as well.

 

Taken together, 2-year exposure of rats and mice to cobalt sulfate resulted in non-neoplastic lesions of the nose, larynx and lung at all concentrations studied. Taking into account the lack of a NOAEC in the concentration-response assessment of cobalt sulfate a benchmark dose (BMD) was calculated using the US EPA BMD software (Version 2.0) with the Gamma Model (Version 2.13). The numbers of alveolar/bronchiolar adenoma or carcinoma in the lung of rats and mice were selected as benchmark response. The 95% lower confidence limit of the BMD for a treatment-related increase in response of 10% was calculated (BMDL10). The lowest BMDL10 value was that for female rat tumours with 0.414 mg/m³ cobalt sulfate which is equivalent to a cobalt concentration of 0.093 mg/m³.

 

 

Cobalt metal

Groups of five male and five female core study rats were exposed to cobalt metal particulate aerosol by inhalation at concentrations of 0, 2.5, 5, 10, 20, or 40 mg/m³, 6 hours per day, 5 days per week for 16 days. Additional groups of five female rats were exposed to the same concentrations for 16 days for tissue burden studies. All rats exposed to 40 mg/m³ and all male and three female rats exposed to 20 mg/m³ died before the end of the study. Mean body weights of males exposed to 10 mg/m³ and of females exposed to 10 or 20 mg/m³ were significantly decreased. Females exposed to 20 mg/m³ lost weight during the study.

Exposure-related clinical findings included abnormal breathing, lethargy, and thinness in male rats exposed to 20 or 40 mg/m³, and in females exposed to 40 mg/m³. Dark lungs were observed at necropsy in all rats exposed to 40 mg/m³ and most rats exposed to 20 mg/m³ that died early.

Increased incidences of nonneoplastic lesions of the lung occurred in exposed male and female rats and included haemorrhage, acute inflammation, alveolar epithelium hyperplasia, histiocytic cellular infiltration of the alveolus, cytoplasmic vacuolization of bronchiolar epithelium, necrosis of the bronchiolar epithelium, and interstitial fibrosis of the alveolar epithelium. Increased incidences of nonneoplastic lesions of the nose occurred in exposed male and female rats and included olfactory epithelium necrosis, olfactory epithelium atrophy, respiratory epithelium necrosis, and respiratory epithelium squamous metaplasia. Tissue concentrations of cobalt increased with increasing exposure concentration in all tissues examined.

 

Groups of 10 male and 10 female core study rats were exposed to particulate aerosols of cobalt metal by inhalation at concentrations of 0, 0.625, 1.25, 2.5, or 5 mg/m³, 6 hours per day, 5 days per week for 14 weeks. Additional groups of 10 male rats (clinical pathology study) were exposed to the same concentrations for 14 weeks. All male and female rats survived to the end of the study. Final mean body weights of males and females exposed to 5 mg/m³ were significantly less than those of the chamber controls, and the mean body weight gain of 5 mg/m³ males was significantly less than that of the chamber controls. At necropsy, pale foci were noted in the lungs of most exposed male and female rats. In male rats, exposure concentration-related increases in the haemoglobin concentration, erythrocyte count, haematocrit value, and manual packed cell volume occurred in the 2.5 and 5 mg/m³ groups on days 3 and 23 and in all exposed groups by week 14; at week 14, female rats also had increases in these parameters. Exposure concentration-related decreases in cholesterol concentrations were observed at all three time points in male and female rats. While this change was not always observed in the lower exposure groups, decreases were consistently observed in the 2.5 and 5 mg/m³ groups of both sexes on day 23 and at week 14. In addition, glucose concentration was decreased in males exposed to 1.25 mg/m³ or greater at week 14.

In the lung, chronic active inflammation and alveolar proteinosis occurred in all exposed males and females, and bronchiole epithelium hyperplasia occurred in all males and females exposed to 1.25 mg/m³ or greater. In the nose, incidences of olfactory epithelium degeneration and respiratory epithelium hyperplasia were significantly increased in males and females exposed to 2.5 or 5 mg/m³. The incidences of olfactory epithelium hyperplasia were significantly increased in 2.5 and 5 mg/m³ males and in 5 mg/m³ females. Significantly increased incidences of turbinate atrophy occurred in 2.5 mg/m³ females and 5 mg/m³ males and females. Tissue concentrations of cobalt increased with increasing exposure concentration in all tissues examined.,

 

Groups of five male and five female mice were exposed to cobalt metal particulate aerosol by inhalation at concentrations of 0, 2.5, 5, 10, 20, or 40 mg/m³, 6 hours per day, 5 days per week for 17 days. Three male and three female mice exposed to 40 mg/m³ died before the end of the study. Final mean body weights were significantly decreased in male and female mice exposed to 20 or 40 mg/m³, and mean body weight gains of 20 and 40 mg/m³ males and all exposed groups of females were significantly less than those of the chamber controls. Females exposed to 20 mg/m³ and males and females exposed to 40 mg/m³ lost weight during the study. Exposure-related clinical findings included abnormal breathing, lethargy, and thinness in male mice exposed to 20 or 40 mg/m³ and females exposed to 10 mg/m³ or greater. At necropsy, tan lungs were observed in most males and females exposed to 20 or 40 mg/m³. Lung weights of both sexes exposed to 10 mg/m³ or greater were significantly greater than those of the chamber controls. Liver weights of exposed male and female mice were significantly less than those of the chamber controls (except relative weight at 40 mg/m³). Increased incidences of nonneoplastic lesions of the lung occurred in exposed male and female mice and included alveolar histiocytic cellular infiltration, cytoplasmic vacuolization of the bronchiolar epithelium, alveolar/bronchiolar epithelium karyomegaly, interstitial fibrosis, and acute inflammation. Increased incidences of nonneoplastic lesions of the nose occurred in exposed groups of male and female mice and included acute inflammation, olfactory epithelium atrophy, olfactory epithelium necrosis, cytoplasmic vacuolization of the respiratory epithelium, and squamous metaplasia of the respiratory epithelium. Tissue concentrations of cobalt increased with increasing exposure concentration in all tissues examined.

 

Groups of 10 male and 10 female core study mice were exposed to particulate aerosols of cobalt metal by inhalation at concentrations of 0, 0.625, 1.25, 2.5, 5, or 10 mg/m³, 6 hours per day, 5 days per week for 14 weeks. One 2.5 mg/m³ female mouse was accidentally killed during the first week of the study; all other mice survived to the end of the study. The mean body weights of males and females exposed to 10 mg/m³ were significantly less than those of the chamber controls. Abnormal breathing was noted in approximately 50% of males and females exposed to 10 mg/m³. At necropsy, tan lungs were noted in mice exposed to 5 or 10 mg/m³. Lung weights of males exposed to 2.5 mg/m³ or greater and females exposed to 5 or 10 mg/m³ were significantly greater than those of the chamber controls. Liver weights of males exposed to 10 mg/m³ and females exposed to 2.5 mg/m³ or greater were significantly less than those of the chamber controls. Kidney weights of males and females exposed to 5 or 10 mg/m³ were significantly less than those of the chamber controls. Testes weights of males exposed to 5 or 10 mg/m³ were significantly less than those of the chamber controls.

In the lung, alveolar histiocytic cellular infiltration and bronchiole epithelium cytoplasmic vacuolization occurred in the lung of all exposed male and female mice. Bronchiole epithelium hyperplasia occurred in all mice exposed to 2.5 mg/m³ or greater. Alveolar proteinosis and alveolar/bronchiolar epithelium karyomegaly occurred in all males and females exposed to 5 or 10 mg/m³. The incidences of haemorrhage were significantly increased in 5 mg/m³ females and in 5 and 10 mg/m³ males. In the nose, the incidences of olfactory epithelium degeneration were significantly increased in males and females exposed to 1.25 mg/m³ or greater. Incidences of respiratory epithelium degeneration were significantly increased in males exposed to 1.25 mg/m³ or greater and females exposed to 2.5 mg/m³ or greater. Incidences of respiratory epithelium squamous metaplasia were significantly increased in males and females exposed to 2.5 mg/m³ or greater, and incidences of turbinate atrophy and chronic active inflammation were significantly increased in the 5 and 10 mg/m³ groups of males and females. The incidences of squamous metaplasia were significantly increased in the larynx of all exposed groups of males and females. Tissue concentrations of cobalt increased with increasing exposure concentration in all tissues examined.

 

Several studies were identified which do not fulfil the relevance, reliability and adequacy criteria as foreseen by the ECHA Guidance on information requirements. The most prominent deficiencies are: single dose studies, targeted studies examining isolated organ systems, incomplete or unclear description of the experimental procedures, several shortcomings in execution and reporting (e.g. test item insufficiently described, animal strain, age, weight or source not reported, dosing unclear, exposure period unclear or too short). The studies are discussed below in brief for information purposes only (further information is provided in the SIDS (IUCLID)).

·        Miniature swine were exposed to an inhalation of pure cobalt metal powder concentrations of 0.1 and 1.0 mg/m³ (Kerfoot, 1973 and 1975). Early detection of pulmonary disease is apparent from the pulmonary function tests showing a mark decrease in lung compliance, and from electron microscopy showing an increase in the amount of septal collagen.

·        A group of sensitised and non-sensitised guinea pigs were exposed by inhalation to 2.4 mg/m³ cobalt dichloride for six hours a day for two weeks. For the sensitised group, much more lavage liquid was retained in the lungs than in the other groups, and the percentage of neutrophils and eosinophils tended to be higher than in the non-sensitised exposed group.

·        In a publication series by one working group (Johansson, 1980, 1983, 1984, 1986, 1987, 1991, 1992, Berghem, 1987, Johansson and Camner, 1986, Camner and Johansson, 1992), male rabbits were exposed for 4-16 weeks to cobalt dichloride and concentrations of 0.5-2.0 mg/m³. Exposed animals had hyperplasia of type II cells in the lung with small nodules formed, interstitial inflammation, and increased number and activity of alveolar macrophages.

Animal data - oral

 

Based on the read-across approach presented in Section 13 of the IUCLID the substances of the poorly soluble cobalt in aqueous solution with organic ligand cobalt substances are grouped and assessed for their hazardous properties using weight of evidence information from all available repeated dose toxicity studies of that group as summarised below.

 

In addition to the findings for the systemic toxicity following oral administration, additional findings for the cobalt carboxylates need to be taken into account for hazard and risk assessment. Four repeated dose toxicity studies in rats via oral application are available for different members of the poorly soluble cobalt in aqueous solution with organic ligand cobalt substances. The lowest dose descriptor derived from the existing oral repeated dose toxicity studies will be used as point of departure for the DNEL derivation of all members of the poorly soluble cobalt in aqueous solution with organic ligand cobalt substances. The predominant findings in the studies were as follows:

 

Cobalt stearate: The dose level of 5 mg/kg bw/d represents the NOAEL for toxicity in female rats based on decreased body weight and food consumption, clinical signs of toxicity, mortality, and microscopic pathology effects (degeneration/necrosis of mucosal epithelium (villous and crypt epithelium); atrophy of villi and crypts; regeneration of mucosal epithelium, and mucosal inflammation. Lesions were observed in all segments of the small intestine and in the cecum and colon. Lesions were graded as minimal to severe (grades 1 to 4) and were most severe in the jejunum, ileum, and cecum.) at 15 and/or 100 mg/kg bw/d. The no-observed-adverse-effect level (NOAEL) for systemic toxicity in males was 40 mg/kg bw/d, the highest dose level tested.

 

Cobalt Borate Neodecanoate: There were no test substance-related effects on mortality, body and organ weights, food consumption, haematology, clinical chemistry, neurobehavioral parameters, pathology and histopathology at any dose level. The no-observed-adverse-effect level (NOAEL) for systemic toxicity in males and females was 5 mg/kg bw/d, the highest dose level tested.

 

Cobalt neodecanoate: Under the conditions of this study, a no-observed-adverse-effect level (NOAEL) for systemic toxicity was not achieved due to effects on mortality, clinical signs of toxicity, body weight parameters, and food consumption parameters at all dosages in males and females. A LOAEL of 5 mg/kg bw/day (equivalent to 0.7 mg cobalt/kg bw) was determined for male and female rats. Adverse effects were observed in males and female animals already at the lowest dose, manifested as decreased weight gain, lethargy, gastro-enteropathy and subsequent secondary effects.

 

Resin acids and Rosin acids, cobalt salts: The lowest dose of 15 mg/kg bw/d Resin acids and Rosin acids, cobalt salts was derived as no-observed-adverse-effect level (NOAEL), based on reduced body weight gain, mean body weights, changes in some haematology factors and histopathology finding in the spleen in male rats at 50 mg/kg bw/d. Moderate epithelial degeneration/necrosis was noted in the cecum and colon at high dose.

 

Table. Overview on repeated dose toxicity studies via oral application

 

	Study type	Most relevant quantitative dose descriptor
Cobalt stearate Co content: 9.5 % Doses: M 0, 5, 15, 40 mg/kg/day; F 0, 5, 15, 100 mg/kg/day 12/sex/dose level Exposure duration: M d 46-47, F d 41-46	OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)	NOAEL(male)= 40 mg/kg bw/day 3.8 mg Co/kg bw/day NOAEL(female, pregnant)= 5 mg/kg bw/day 0.5 mg Co/kg bw/day
Cobalt borate neodecanoate Co content: 22.15% Doses 0, 0.5, 1.5, and 5 mg/kg/day 12/sex/dose level Exposure duration: M d 47-48, F d 39-50	OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)	NOAEL(male)= 5 mg/kg bw/day 1.1 mg Co/kg bw/day NOAEL(female, pregnant)= 5 mg/kg bw/day 1.1 mg Co/kg bw/day
Cobalt neodecanoate Co content: 14.32% Doses 0, 5, 15, or 45 mg/kg/day 12/sex/dose level Exposure duration: M d 48-49, F d 42-49	OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)	LOAEL(male)= 5 mg/kg bw/day 0.7 mg Co/kg bw/day LOAEL(female, pregnant)= 5 mg/kg bw/day 0.7 mg Co/kg bw/day
Resin acids and Rosin acids, cobalt salts Co content: 7.77% Purity: 83.7% Doses 15, 50, 150 mg/kg/day 5/sex/dose level Exposure duration: 29 d	OECD 407 (Repeated Dose (28 Days) Toxicity (Oral))	NOAEL(male)= 15 mg/kg bw/day 1.17 mg Co/kg bw/day NOAEL(female)= 15 mg/kg bw/day 1.17 mg Co/kg bw/day

 

 

Repeated dose toxicity: dermal

The submission of a repeated dose toxicity study via dermal route is considered unjustified, since:

 

(a) Lung function impairment is the predominant finding in human epidemiological data by Swennen et al. (1993) and Verougstraete et al. (2004), Roto (1980) and Sauni et al. (2010), whereas no significant systemic toxicity due to prolonged inhalation exposure towards cobalt substances was found. It can be concluded that systemic effects following inhalation exposure are expected at higher dose levels compared to the dose levels for local effects. In order to be protective against local effects after repeated dose toxicity via inhalation, the human NOAEC derived from the above mentioned human epidemiological data will be used to derive a DNEL for all cobalt substances. Consequently, the inhalation route is considered as the route of exposure showing the highest concern for which safety levels for workers and consumers are to be implemented

 

(b) In total 22 out of 26 cobalt substances prepared by the Cobalt REACH Consortium (CoRC) are legally and/or self-classified for dermal sensitisation properties. The risk management measures for such substances foresee to minimise dermal exposure to as low as reasonably achievable. Protective gloves according to EN 374 have to be worn at all workplaces unless any exposure to the substance can be excluded when taking into account the nature of the conducted process, applied exposure prevention measures and physical appearance of the substance of concern in the specific type of application (e. g. protecting from splashes by containment of emission source).

 

(c) Based on the physico-chemical properties of all inorganic cobalt substances being registered by the Cobalt Consortia and the results of a dermal absorption study with a cobalt salt of high in vitro bioaccessibility in artificial sweat, it is reasonable to conclude that the inorganic cobalt substances have a negligible rate of absorption through the skin. A dermal absorption rate of 0.38% for the low exposure scenarios (ca 31.9μg Co/cm² loading) and 1.08% for the high exposure scenarios (ca 319μg Co/cm² loading) was determined. These values also account for part of the material associated with the stratum corneum and the test was conducted with a highly water soluble form of Cobalt in an aqueous solution. Thus, these values are considered to represent a conservative estimate.

 

In conclusion, the dermal absorption of cobalt has been shown to be low in a guideline-conform in-vitro percutaneous absorption study conducted under GLP with the highly soluble substance cobalt dichloride (Roper, 2010). This renders percutaneous uptake a negligible route of entry into the body, which is why this route is not further considered in risk characterisation

 

Conclusions - inhalation

 

In human epidemiological studies following prolonged inhalation exposure, no clinically significant cardiac dysfunction due to cobalt exposure was found. Also no further adverse systemic effects were reported in humans. Therefore, it can be concluded that systemic effects following inhalation exposure are expected at higher dose levels compared to the dose levels for local effects. Thus, a DNEL for systemic effects will not be derived based on these data.

 

Human epidemiological data will be used for the hazard assessment of repeated dose toxicity via inhalation, non-neoplastic lesions. Changes in lung function were the predominant findings in the studies by Swennen et al. (1993) and Verougstraete et al. (2004), Roto (1980) and Sauni et al. (2010). A cobalt concentration of 0.12 mg Co/m³ will be used as NOAEC for the setting of a DNEL (inhalation, local, chronic).

 

Although two carcinogenicity studies with cobalt metal and cobalt sulfate are available, the cobalt metal study will not be considered for risk assessment purposes. The dose descriptor derived from this study (NOAEC: 1.25mg Co/m³) is above the BMDL10 derived from the carcinogenicity study with cobalt sulfate. Following the chronic inhalation exposure of cobalt sulfate in rats and mice, the 95% lower confidence limit of the BMD for a treatment-related increase in response of 10% was calculated (BMDL10), in which the numbers of alveolar/bronchiolar adenoma or carcinoma in the lung of rats and mice were selected as benchmark response (BMDL10: 92.7µg Co/m³). Since the carcinogenic mode of action is identical for both substances, both studies could be used for risk assessment purposes interchangeably. However, the point of departure derived from the cobalt sulfate study is ensuring a higher level of protection for humans, as it provides a significantly lower point of departure and a subsequent lower DNEL value for workers and consumers.

Conclusions - oral

 

The substances of the cobalt category allocated to the soluble inorganic cobalt substances group for which cobalt dichloride was used as source substance. In addition to the findings for the systemic toxicity following oral administration of cobalt dichloride, additional findings of local gastrointestinal toxicity for the poorly soluble in aqueous solution with organic ligand cobalt substances group need to be taken into account for hazard and risk assessment.

 

In a number of oral repeated dose toxicity studies, the cobalt carboxylates show adverse effects as follows:

·        Decreased body weight and food consumption, clinical signs of toxicity

·        Intestinal effects including the following diagnoses: degeneration/necrosis of mucosal epithelium (villous and crypt epithelium); atrophy of villi and crypts; regeneration of mucosal epithelium, and mucosal inflammation

·        Effects on the haematopoietic system were apparent in high doses, already showing significant adverse effects in the digestive tract.

 

It is assumed that these local effects are caused by the surface active/amphiphilic organic anions, exerting an enhancing/promoting effect of the irritating properties of the cobalt cation in the gastro-intestinal tract.

 

Statement on the preferential use of human data in risk assessments for human health

 

(I) In almost 20 years of practical conduct of risk assessments under the “Existing Substances Regulation (793/93), human data has been given preference over animal studies. This is documented in the Technical Guidance Document in chapter 3.1 as follows: „Generally human data will only be available for existing substances. If both animal data and human data are available, as a general rule, well reported relevant human data for any given endpoint is to be given preference for the risk assessment.“ (ECB, 2003).

 

(II) Similarly, the US Environmental Protection Agency (EPA) in their guidance have stated that they look to human data whenever possible in completing human risk assessments: "If adequate human studies (confirmed for validity and applicability) exist, these studies are given first priority in the dose-response assessment, and animal toxicity studies are used as supportive evidence" (EPA, 1989). Often, such data can be obtained from epidemiological studies, which do not involve the intentional dosing of research participants, but rather evaluate the effects of exposures that have occurred in an occupational setting or because of the peculiarities of a specific geographical setting. Regardless of the origins of such human data, risk assessments based on human data have the advantage of avoiding the problems inherent in interspecies extrapolation" (EPA, 1993). In the same document, EPA also states: “The default assumptions that are of particular relevance to the issues raised by third-party intentional human dosing studies are those that bridge gaps between animal results and estimates of effects in humans. In the context of FIFRA, for example, EPA has routinely divided the calculated "safe" dose for animals by a factor of 10, to account for the possibility that humans are more sensitive to the substance being tested than are the animal species. Third-party submitters of human dosing studies have been particularly interested in modifying this default assumption by introducing data obtained directly from human studies.”

 

(III) When addressing the relevance and use of human data, ECHA guidance specifies the requirements for such studies as follows in section B.4.3.3 (human data) of their guidance, for the following four types of human data (ECHA, 2008):

 

Analytical epidemiology studies on exposed populations (case-control, cohort and cross-sectional studies) are useful for identifying a relationship between human exposure and effects and may provide the best data for risk assessment.

 

Descriptive or correlation epidemiology studies are useful for identifying areas for further research but are not very useful for risk assessment since they often can only identify patterns or trends but cannot ascertain the causal agent or degree of human exposure.

 

Case reports may demonstrate effects which cannot be observed in experimental animals. Thorough assessment of the reliability and relevance of case reports is needed because they often lack critical information on e.g. substance purity, human exposure, and effects.

 

Controlled studies in human volunteers are acceptable in very rare cases. Testing with human volunteers is strongly discouraged but when good quality data are already available, they should be used as appropriate in well justified cases.

 

In the case of cobalt and cobalt substances, the human studies that were used for the derivation of DNELs were assessed for their reliability and relevance, and were found to be of acceptable quality for the purpose envisaged.

 

(IV) Finally, the use of human data in risk assessment largely avoids a need for the application of assessment or extrapolation factors to account for differences in toxicokinetics, toxicodynamics, metabolic capacity and species sensitivity.

 

 

References

ECB (2003) Technical Guidance Document on Risk Assessment in support of Commission Directive 93/67/EEC on Risk Assessment for new notified substances, Commission Regulation (EC) No 1488/94 on Risk Assessment for existing substances, Directive 98/8/EC of the European Parliament and of the Council concerning the placing of biocidal products on the market, Part I, EUR 20418 EN/1

 

ECHA (2008) Guidance on information requirements and chemical safety assessment, Guidance on information requirements and chemical safety assessment, Part B: Hazard Assessment, European Chemicals Agency, 2008

 

EPA (1989) Risk Assessment Guidance for Superfund, Vol. 1: Human Evaluation Manual, EPA/540-1-89/002, US Environmental Protection Agency. available at:www.epa.gov/cgi-bin/claritgw?op-Display&document=clserv:OSWER:1175;&rank=4&template=epa

 

EPA (1993) Reference Dose (RfD): Description and Use in Health Risk Assessments, § 1.3.2.2.1, US Environmental Protection Agency, background document, available at:www.epa.gov/IRIS/rfd.htm.

 

IGHRC (2006) Guidelines on route-to-route extrapolation of toxicity data when assessing health risks of chemicals. The Interdepartmental Group on Health Risks from Chemicals, http://www.silsoe.cranfield.ac.uk /ieh/ighrc/ighrc.htm