Substance-Specific Issues

Classification of Titanium Dioxide-Containing Products with respect to Carcinogenicity

Substance(s):

Titanium Dioxide; CAS No. 13463-67-7

Issue:

Does titanium dioxide, as a pure substance, or tested or untested mixtures containing titanium dioxide at a concentration of 0.1% w/w or more fall within the Controlled Products Regulations (CPR) criteria for carcinogenicity?

Background:

As opposed to referencing tests, the criteria for carcinogenicity specified in section 54 of the CPR for pure substances and tested mixtures refer to classifications established by ACGIH and IARC. The criteria for untested mixtures in section 58 of the CPR cross-reference section 54.

Substances included by reference to Group 1 or 2 in the IARC Monographs are considered to be carcinogens under the CPR [1].

Titanium dioxide, previously denoted by IARC as not classifiable as to its carcinogenicity to humans, was reclassified by IARC in February 2006 as an IARC Group 2B carcinogen "possibly carcinogenic to humans" [2].

Studies showed that high concentrations of pigment-grade and ultrafine titanium dioxide caused lung tumours in rats when administered by inhalation and intratracheal instillation. These results provided sufficient evidence in experimental animals for the carcinogenicity of titanium dioxide [2, 3].

While the IARC assessment of titanium dioxide has yet to be published in the IARC Monographs Volume 93 (in press), the classification decision has been published on the IARC website and in a summary article published in The Lancet [3].

Titanium dioxide accounts for 70% of the total production volume of pigments worldwide. It is widely used to provide whiteness and opacity to products such as paints, plastics, papers, inks, foods and toothpastes. It is also used in cosmetic and skin care products, and it is present in almost every sunblock, where it helps protect the skin from ultraviolet light [4].

With such widespread use of titanium dioxide, it is important to understand that the IARC conclusions are based on very specific evidence. The series of biological events or steps that produced the rat lung cancers (e.g. particle deposition, impaired lung clearance, cell injury, fibrosis, mutations and ultimately cancer) have also been observed in people working in dusty environments. Therefore, the observations of cancer in animals were considered by IARC as relevant to people doing jobs with exposures to titanium dioxide dust [4].

Products in which titanium dioxide might be considered "inextricably bound": Since the posting of IARC's revised classification, National WHMIS Office has received a number of enquiries from suppliers, including paint manufacturers, about the implications of the revised IARC classification for their products containing titanium dioxide, particularly in relation to the statement on the IARC Web site (in subsection 5.1 of the "Summary of the Data Reported") that "No significant exposure to titanium dioxide is thought to occur during the use of products in which titanium dioxide is bound to other materials, such as in paints".

At a meeting in March 2007, federal, provincial, and territorial WHMIS regulatory authorities expressed concerns about potential exposures to respirable titanium dioxide during the application of paint products, including ultrafine spray and powder coatings. Regarding mixtures containing titanium dioxide, the regulators' position was that the IARC statement regarding paints did not address all potential exposures to titanium from products that may be considered paints.

Untested mixtures containing titanium dioxide at a concentration of 0.1% w/w or more should be considered as falling within the criteria set out in section 58 of the CPR, unless there is evidence that the carcinogenic effects associated with titanium dioxide are not applicable to the products being sold or imported. If scientific testing demonstrates that, for a particular product which contains titanium dioxide, the titanium dioxide is inextricably bound and, under normal conditions of use or during foreseeable emergencies, cannot become airborne and result in worker exposure, then the product would not fall within the criteria described in section 58 of the CPR with respect to the cross reference to section 54 as it pertains to titanium dioxide.

Could the toxicity observed from exposure to titanium dioxide not be chemical specific? The US National Institute for Occupational Safety and Health (NIOSH) has reviewed the relevant animal and human data for assessing the carcinogenicity of titanium dioxide [5]. In a draft document for public review and comment, NIOSH concluded that the tumorigenic effects of titanium dioxide exposure in rats appear not to be chemical specific nor a direct action of the chemical substance itself. NIOSH reported that the effects appear to be a function of particle size and surface area acting through a secondary genotoxic mechanism associated with persistent inflammation. However, in the same report NIOSH noted that the evidence of tumorigenicity in rats at high exposure concentrations warrants the use of prudent health-protective measures.

A conclusion different to that of NIOSH was reported by Warheit et al. in 2006 [6]. They conducted pulmonary instillation studies with nanoscale titanium dioxide particles in rats. They found evidence to indicate that toxicity associated with titanium dioxide is not dependent upon particle size and surface area. Also, they concluded that their results did not support the postulation that surface area is a major factor associated with the pulmonary toxicity of nanoscale particle types. However, other studies with nanoscale and fine-quartz particles in rats demonstrated that the pulmonary toxicities of alpha-quartz particles appear to correlate better with surface activity than particle size and surface area [7].

Appendix A, "Clarifications and Interpretations of the Hazard Communication Standard" to U.S. OSHA Directive CPL 2-2.38D, states:

"Any substance which is inextricably bound in a product is not covered under the HCS. For example, a hazard determination for a product containing crystalline silica may reveal that it is bound in a rubber elastomer and under normal conditions of use or during foreseeable emergencies cannot become airborne and, therefore, cannot present an inhalation hazard. In such a situation, the crystalline silica need not be indicated as a hazardous ingredient since it cannot result in employee exposure."

Considerations:

In relation to the carcinogenicity criteria specified in section 54 of the CPR, the following guidelines on the use of professional judgement were developed by a tripartite technical subcommittee and endorsed by WHMIS stakeholders including representatives of chemical suppliers, employers, organized labour and federal, provincial and territorial governments:

"There is no opportunity to use professional judgement in the classification of carcinogens when the substance or tested mixture is included in the referenced lists.... Where a substance or tested mixture does not appear on the referenced lists and the supplier has information to show that the product may be a carcinogen, the supplier should use professional judgement to decide if the product should be classified as carcinogenic."

The status of the publication of an IARC monograph does not preclude the obligation to take this information into account if the information is readily available. In the case of titanium dioxide, IARC has posted their reclassification decision on their Web site [2]:

• http://monographs.iarc.fr/ENG/Meetings/93-titaniumdioxide.pdf

For purposes of classification under the Controlled Products Regulations, posting of an IARC classification on the IARC Web site is considered sufficient for inclusion in the applicable IARC Group irrespective of whether the official monograph has been published.

Conclusions:

Titanium dioxide, as a pure substance, is considered to fall within the criteria set out in section 54 of the Controlled Products Regulations irrespective of whether the IARC monograph is published or its status is "publication pending".

With regard to tested mixtures containing titanium dioxide at a concentration of 0.1% w/w or more, professional judgement should be used to determine whether the product should be classified as a carcinogen. Where test results show evidence of carcinogenicity in humans or in animals, then the mixture would be considered to be a carcinogen under the Controlled Products Regulations.

Unless there is evidence that the carcinogenic effects associated with titanium dioxide are not applicable to the products being sold or imported (for example, if scientific testing demonstrates that the titanium dioxide is inextricably bound and, under normal conditions of use or during foreseeable emergencies, cannot become airborne and result in worker exposure to respirable titanium dioxide), untested mixtures containing titanium dioxide at a concentration of 0.1% w/w or more are considered to fall within the criteria set out in section 58 of the Controlled Products Regulations with respect to the cross reference to section 54.

Suppliers and manufacturers of products containing titanium dioxide are expected to review and update their labels and MSDSs immediately, and to transmit the updated label and MSDS upon subsequent product sales.

References:

1. Health Canada; Reference Manual for the WHMIS Requirements of the Hazardous Products Act (HPA) and Controlled Products Regulations (CPR); (see section 54 of theCPR). http://www.hc-sc.gc.ca/ewh-semt/pubs/occup-travail/ref_man/index_e.html
2. International Agency for Research on Cancer (IARC): Titanium dioxide (IARC Group 2B) , Summary of data reported, February 2006. http://monographs.iarc.fr/ENG/Meetings/93-titaniumdioxide.pdf
3. Baan, R., Straif, K., Grosse, Y., Secretan, B., El Ghissassi, F. and V. Cogliano. 2006. Carcinogenicity of carbon black, titanium dioxide, and talc. The Lancet Oncology, 7: 295-296.
4. Canadian Centre for Occupational Health and Safety (CCOHS): Titanium Dioxide Classified as Possibly Carcinogenic to Humans, August 2006.
5. Evaluation of Health Hazard and Recommendations for Occupational Exposure to Titanium Dioxide - NIOSH Docket #100 http://www.cdc.gov/niosh/review/public/tio2/pdfs/TIO2Draft.pdf
6. Warheit, D.B., Webb, T.R., Sayes, C.M., Colvin, V.L. and K. L. Reed. 2006. Pulmonary instillation studies with nanoscale TiO2 rods and dots in rats: toxicity is not dependent upon particle size and surface area. Toxicological Sciences, 91(1): 227-236. http://toxsci.oxfordjournals.org/cgi/content/abstract/91/1/227
7. Warheit, D.B., Webb, T.R., Colvin, V.L., Reed, K.L. and C.M. Sayes. 2006. Pulmonary bioassay studies with nanoscale and fine-quartz particles in rats: toxicity is not dependent upon particle size but on surface characteristics. Toxicological Sciences, 95(1): 270-280. http://toxsci.oxfordjournals.org/cgi/content/abstract/95/1/270
8. U.S. Department of Labour; Occupational Safety and Health Administration: Standard Interpretations: 11/19/1997 - Carcinogen status of titanium dioxide relative to OSHA Standards. Standard Number: 1910.1200 http://www.osha.gov/pls/oshaweb/owadisp.show_document?p_table=INTERPRETATIONS &p_id=22497