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Carcinogenicity

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Description of key information

Review hexavalent Chromium compounds: carcinogen (lung and intestine)

Key value for chemical safety assessment

Carcinogenicity: via oral route

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
0.2 µg/kg bw/day

Carcinogenicity: via inhalation route

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
0.01 µg/m³

Carcinogenicity: via dermal route

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed

Additional information

Several review reports or articles are available with respect to the carcinogenicity of hexavalent chromium compounds. In the key study, Seidler et al. (2012) systematically reviewed the scientific literature and quantified the respiratory cancer risk for occupational exposure to hexavalent chromium. Seidler et al. (2012) included 5 studies in their paper, each providing more than one level of occupational Cr (VI) exposure, considering the confounder smoking and using adequate methods. Linear regressions models were used to calculate relative risks and to estimate excess absolute risks. The absolute excess lung cancer risk was found to be 4 excess lung cancer cases per 100,000 workers for life time (40 years, 5 days/week, 8 hours/day) exposure to hexavalent chromium at a Cr(VI) concentration of 0.01 ug/m3.

The OEL derived by Seidler et al (2012) for hexavalent chromium compounds will be used as the starting point for the derivation of the DMEL. The OEL for hexavalant chromium of 0.01 µg/m3 corresponds to a concentration of 0.0667 µg/m3 for both C.I. Pigment Yellow 34 and C.I. Pigment Red 104, taking into account a maximum hexavalent chromium content of 15% in both pigments.

It should be noted that data for poorly soluble hexavalent chromium compounds indicate that these compounds have lower carcinogenic potency than soluble compounds, which may be explained by the relative low bioavailability.

The review by the Scientific Committee on Occupational Exposure Limits (SCOEL, 2004), which is included as a supporting study, defined highly soluble compounds such as sodium and potassium chromates and dichromate (water solubility >100 g/L), sparingly soluble compounds such as strontium, calcium and zinc chromate (water solubility 1-100 g/L), and poorly soluble compounds such as lead and barium chromate (<1 g/L). From the bio-elution studies (see section 4.8), summarized in the toxicokinetics section (7.7.1), the biosolubility of C.I. Pigment Yellow 34 and C.I. Pigment Red 104 could be deduced. At a loading of 2 g/L and after 6 days of incubation in simulated interstitial lung fluid, the chromium concentrations from C.I. Pigment Red 104 and C.I.Pigment Yellow 34 were 0.0035 g/L and 0.0225 g/L, respectively. This concentration is at least 44.4 times lower than the limit of 1 g/L for poorly soluble compounds as defined by SCOEL.

The excess lung cancer risk can only be attributed to the respirable fraction of the hexavalent chromium compound. The non-respirable fraction will be cleared from the respiratory tract and swallowed in the gastrointestinal tract. From the particle size distribution and dustiness tests for C.I. Pigment Yellow 34 and C.I. Pigment Red 104 (see section 4.5) it can be estimated that the respirable fraction is < 2% for both pigments. This implies that the inhalable, non-respirable fraction must be evaluated for excess cancer risk by the oral route of exposure. In the report on the carcinogenicity dose-response analysis of Cr(VI)-containing substances (RAC/27/2013/06 Rev.1), it was concluded that the Occupational Exposure Limit associated with 4 excess intestinal cancer cases per 100,000 workers for life-time (40 years, 5 days/week, 8 hours/day) exposure to hexavalent chromium is 0.2 µg Cr(VI)/ kg body weight/day. The assessment is based on linear extrapolation from intestinal tumour data in mice.

 

SCOEL (2004) also reviewed the available information on the possible health effects of Lead Chromate. In addition to the information on Lead Chromate, SCOEL Summary Documents on both Lead and Lead Compounds (SCOEL/SUM 83) and hexavalent Chromium compounds (SCOEL/SUM 86) were taken into account. Compared to other chromates, Lead Chromate has low carcinogenic potential, based on its poor solubility, although mutagenicity and clastogenicity have been reported after solubilisation. However, SCOEL concludes that the risk for lung tumours induced by Lead Chromate must be distinctly lower than the risk calculated for hexavalent Chromium compounds in general. Therefore, SCOEL based the OEL for Lead Chromate on the information available for Lead and Lead compounds, resulting in an OEL of 100μg Pb/m3 (ambient air) and BLV of 30μg Pb/dl blood. The OEL of 100μg Pb/m3 would be equivalent to a concentration of 25μg Cr/m3. Currently, however, the limit value from the dose-response relationship for carcinogenicity of Cr(VI)-containing substances is used (RAC/27/2013/06 Rev.1).

 

Supporting studies available for C.I. Pigment Yellow 34 are summarized below.

 

In a study by Maltoni (1976; only one dose group, only one treatment), the test substance was injected in subcutaneous tissue of the middle right flank (30 mg test substance in 1 ml water, (corresponding to appr. 120 mg/kg bw assuming a mean body weight of 250 g for adult animals). All the animals were kept under observation until spontaneous death. The spontaneous incidence of subcutaneous sarcomas and of the different sarcoma histotypes, in the historical controls of the authors' breed of Sprague-Dawley rat were used as a comparison. Gross pathology was made at spontaneous death and all macroscopic lesions observed at the control were recorded. A complete autopsy was made on each animal and all major organs examined histopathologically. 26/40 rats developed sarcoma (rhabdomyosarcoma and fibrosarcoma) at the site of injection.

Local carcinogenicity effects were also observed when a group of Cr6+-containing substances where intra-tracheally administered to (a metal wire pellet containing the test material is surgically implanted into the left bronchus of an anaesthetised rat; Levy et al., 1986). Of the 20 test materials, three groups gave statistically significant numbers of bronchial carcinomas. Two of these were groups receiving different samples of strontium chromate which gave 43/99 and 62/99 tumours. The third group, zinc chromate (low solubility), gave 5/100 bronchial carcinomas. A further zinc chromate group (Norge composition) produced 3/100 bronchial carcinomas which was not statistically significant. TSS 711 Calcium chromate (used as Positive control) particularly induced 25% bronchial carcinoma in all animals tested with 181000 ppm of Cr6+ content and can be considered as T25 of local tumor formation.

Justification for selection of carcinogenicity via oral route endpoint:
Conclusion on carcinogenicity was based on the carcinogenic properties of hexavalent Chromium compounds.

Justification for selection of carcinogenicity via inhalation route endpoint:
Conclusion on carcinogenicity was based on the carcinogenic properties of hexavalent Chromium compounds.

Carcinogenicity: via oral route (target organ): digestive: other

Carcinogenicity: via inhalation route (target organ): respiratory: lung

Justification for classification or non-classification

In accordance with the current EU classification for C.I. Pigment Yellow 34 and C.I. Pigment Red 104, which was based on read across from other more soluble hexavalent chromium compounds, C.I. Pigment Yellow 34 and C.I. Pigment Red 104 are classified for carcinogenicity (R45 or CLP Cat 1B), although the likelihood of carcinogenicity risk is considered very low due to very poor bioavailability of these two substances. Three epidemiological studies in lead chromate pigment manufacturing plants "did not produce evidence supporting any association between lead chromate [pigments] and lung cancer". However limitations in cohort size, due to the limited number of workers in this industry, limits the use of such studies. Nonetheless as the worst case, the carcinogenicity risk of these two pigments will be used in this hazard assessment, using the carcinogenic properties of hexavalent chromium compounds as described by Seidler et al. (2012) for Cr(VI) compounds and as recommended by RAC (RAC/27/2013/06 Rev.1). However, due to the very poor solubility and bioavailability of C.I. Pigment Yellow 34 and C.I. Pigment Red 104 the currently derived DMEL will vastly overestimate the carcinogenic potential of the pigments.