Cobalt molybdate

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DMEL (Derived Minimum Effect Level)

Value:

0.257 µg/m³

Most sensitive endpoint:

carcinogenicity

Route of original study:

By inhalation

Acute/short term exposure

DNEL related information

Local effects

Acute/short term exposure

DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DMEL (Derived Minimum Effect Level)

Value:

0.005 µg/kg bw/day

Most sensitive endpoint:

carcinogenicity

Route of original study:

By inhalation

Acute/short term exposure

DNEL related information

Local effects

Acute/short term exposure

Hazard assessment conclusion:

no DNEL required: short term exposure controlled by conditions for long-term

Additional information - workers

Cobalt molybdenum oxide (CoMoO₄) is classified as a genotoxic carcinogen. As there are no data available on the carcinogenic potential of cobalt molybdenum oxide, the carcinogenicity data are read-across from a study performed with the surrogate substance cobalt sulfate heptahydrate (NTP, 1998). The carcinogenicity data on the surrogate substance are considered suitable for read-across within an analogue approach. For details refer to analogue justification.

In a 2 year inhalation study, groups of mice and rats of both sexes were exposed to cobalt sulfate heptahydrate aerosols at concentrations of 0.3, 1, and 3 mg/m³ (calculated as anhydrous salt and equivalent to 0.4, 1.4 and 4.2 mg CoMoO₄/m³) for 6 hours/day and 5 days/week (NTP, 1998). Although many of the alveolar/bronchiolar lesions were morphologically similar to those arising spontaneously, the lesions in rats, unlike those in mice, were predominantly fibrotic, squamous or mixtures of alveolar/bronchiolar epithelium and squamous or fibrous components. Squamous metaplasia of alveolar/bronchiolar epithelium, which is a common response to pulmonary injury, was observed in number of rats.

In summary, test substance was found to be carcinogenic in mice and rats when administered by inhalation. There was clear evidence of carcinogenicity in male and female mice as well as female rats, based on increased incidences of lung tumors. Some evidence of carcinogenicity in male rats was observed, based on increased incidences of lung tumors at the highest exposure level.

Under the conditions of the test, the most sensitive species were the female mice. They exhibited a concentration-related increase in the incidence of malignant alveolar/bronchiolar neoplasms. The incidences of malignant alveolar/bronchiolar neoplasms were 1/50, 1/50, 4/50, and 9/50 for 0, 0.4, 1.4 and 4.2 mg CoMoO₄/m³, respectively. No NOAECs were identified neither for rats nor for mice. The LOAECs for mice and rats were determined to be 0.4 mg CoMoO₄/m³.

Based on present knowledge, even the slightest exposure to the test substance entails a cancer risk. In such a case, the REACh Regulation contains only qualitative measures for the protections of human health (appropriate risk management measures and operational conditions). However, it can be useful to include in the qualitative assessment an additional semi-quantitative element in order to assess the likelihood that effects are avoided. Therefore, the European Chemicals Agency (ECHA) has developed the concept of derived minimal effect levels[Guidance on information requirements and chemical safety assessment, Chapter R.8: Characterisation of dose[concentration]-response for human health, ECHA, Version 2, December 2010]. The derived minimal effect level (DMEL) is a reference risk level which is considered to be of very low concern. In accordance with the ECHA guidance document the DMEL derived should be seen as a tolerable level of effects and it should be noted that the DMEL is not a level where no potential effects can be foreseen. Although not strictly required under REACh, it is strongly recommended to develop a DMEL.

The ECHA guidance document set out two methodologies which can be applied for deriving the DMEL: the linearized approach and the large assessment factor approach (EFSA approach). For cobalt molybdenum oxide, the linearized approach was selected as the dose-response curve is expected to be linear. Within a linearized approach, the dose descriptor T25 should be selected as the default dose descriptor. The T25 is defined as the chronic dose rate that will give 25% of the animals´ tumors at a specific tissue site after correction for spontaneous incidence within the standard life time of the species. In addition, taking into account that the carcinogenicity data are read-across from a study performed with the surrogate substance cobalt sulfate heptahydrate (NTP, 1998), the more conservative dose descriptor BMCL10 was used to consider uncertainties in the context of a read-across approach. The BMCL10 (benchmark concentration lower bound) is defined as the lower 95% confidence concentration of a benchmark concentration representing a 10% tumor response upon lifetime exposure, i. e. the lower 95% confidence concentration of a BMD(C)10.

The dose descriptor T25 was calculated from the standard curve using linear regression (Microsoft Excel). Based on linear regression analysis, a T25 of 6.42 mg/m³ was determined. For deriving the BMDC10, the freely available EPA (environmental protection agency) software Version 2.3.1 (http://www.epa.gov/ncea/bmds/) was used. Based on the EPA software, a BMCL10 of 2.39 mg/m³ was calculated.

According to the “Guidance on information requirements and chemical safety assessment, Chapter R.8: Characterisation of dose[concentration]-response for human health, Version 2, December 2010”, for workers the exposure time is 8 hours/day (animal study: 6 hours/day), 5 d/week (animal study: 5 days/week), 48 weeks per year for 40 years. This implies that for workers, a correction factor should be applied to the dose descriptor based on animal life-time exposure data. As a default, a value of 1.5 (6/8 x 5/5 x 52/48 x 75/40) is proposed for inhalation studies. Additionally, it should be taken into account that during 8 hours light activity at work the respiratory rate becomes higher (10 m³/person) than standard (6.7 m³/person). Considering these differences, the dose descriptors do not change.

According to the ECHA guidance document, there is currently no EU legislation setting a tolerable risk level for carcinogens in the society. However, cancer risk levels have been set and used in different contexts. Based on these experiences, a cancer risk level of 10^-5 (i. e. a risk for cancer in 1 per 100000 exposed individuals) could be seen as indicative tolerable risk level when setting the DMEL for workers (ECHA guidance document). Depending on whether the dose descriptor represents a 10% or 25% cancer risk, there are two sets of High-to-Low-dose risk extrapolation Factors (HtLF) within the linearized approach. Derivation of the DMEL based on a T25 is arrived at by using a HtLF of 25000. A DMEL for the cancer risk level (10^-5) from a BMCL10 is derived with a HtLF of 10000. As the starting point for the inhalation DMEL is a carcinogenic inhalation study, no additional assessment factors are required.

Based on the dose descriptor T25, the inhalation DMEL representing a 10^-5 risk for cancer is T25/25000 = 6.42/25000 = 0.0002568 mg/m³ = 0.2568 µg/m³

Based on the dose descriptor BMCL10, the inhalation DMEL representing a 10^-5 risk for cancer is BMCL10/10000 = 2.39 mg/m³ / 10000 = 0.000239 mg/m³ = 0.239 µg/m³

Both derived DMELs for the inhalation exposure route are in some concentration range.

 

The carcinogenic inhalation study was also chosen as the starting point for deriving the dermal DMEL as there is no repeated dose toxicity study via the dermal route. According to the “Guidance on information requirements and chemical safety assessment. Chapter R.8: Characterisation of dose [concentration]-response for human health” (ECHA, Version 2, December 2010), the inhalation T25 (0.2568 µg/m³) and BMCL10 (2.39 mg/m³) should be converted into corrected dose descriptors. Therefore, the inhalation concentration is converted to the corresponding air concentration using a standard breathing volume for mice (0.36 m³/kg bw for 6 h exposure).

Corrected T25:Route to route extrapolation (inhalation to dermal): 6.42 mg/m³ * 0.36 m³/kg bw = 2.3112 mg/kg bw

Corrected BMDL10: Route to route extrapolation (inhalation to dermal): 2.39 mg/m³ * 0.36 m³/kg bw = 0.8604 mg/kg bw

Based on the dose descriptor used for DMEL derivation, a HtLF of 10000 or 25000 has to be considered to calculate the dermal DMEL.As the starting point for the dermal DMEL is a carcinogenic inhalation study, interspecies differences need to be taken into account when deriving the dermal DMEL (allometric scaling factor for mice: 7; remaining differences: 2.5). Based on the dose descriptor T25, the dermal DMEL representing a 10^-5 risk for cancer is T25 / (25000*7* 2.5) = 2.3112 mg/kg bw / 437500 = 0.0000053 mg/kg bw = 0.0053 µg/kg bw.

Based on the dose descriptor BMDL10, the dermal DMEL representing a 10^-5 risk for cancer is BMDL10 / (10000*7* 2.5) = 0.8604 mg/kg bw / 175000 = 0.0000049 mg/kg bw = 0.0049 µg/kg bw.

Both derived DMELs for the dermal exposure route are in the same dose range.

 

General Population - Hazard via inhalation route

Systemic effects

Acute/short term exposure

DNEL related information

Local effects

Acute/short term exposure

DNEL related information

General Population - Hazard via dermal route

Systemic effects

Acute/short term exposure

DNEL related information

General Population - Hazard via oral route

Systemic effects

Acute/short term exposure

DNEL related information

Additional information - General Population

The general population is not exposed to cobalt molybdenum oxide based on its identified uses.