Summary of public comments received on the science approach document for substances with low human health hazard potential

Offical Title: Summary of Public Comments Received on the Science Approach Document for Substances with Low Human Health Hazard Potential

Comments on the Science Approach Document (SciAD) for Substances with Low Human Health Hazard Potential to be addressed as part of the Chemicals Management Plan (CMP) were provided by KAND EHS Services, American Chemistry Council, Canadian Network for Human Health and the Environment, the Saskatchewan Environmental Society, Prevent Cancer Now, Chemical Sensitivities Manitoba, and Chlorine Institute.

A summary of comments and responses is provided below, organized by topic:

1. New information & data updates

Summarized Comment Summarized Response
Other groups within Health Canada dealing with radiation safety and the regulation of nuclear facilities may have information available on deuterium exposure and toxicity. Other departments were consulted. The toxicity information is presented in Appendix A-12 of the SciAD.
Data on organ weight changes should be considered, when evaluating toxicity. The SciAD was updated to improve clarity regarding the use of data on organ weight changes to evaluate toxicity.
The basis for the determination of low concern for human health for each chemical substance requires more details, including additional information for the exposure descriptions. This SciAD is not an exhaustive or critical review of all available data; rather, it presents a concise description of the methodology and its application to the 14 substances, which includes a list of the studies deemed most critical to this approach. The 14 substances were used to demonstrate how the approach is applied.
In the scientific approach described in the SciAD clarify how candidate substances are to be identified. Health Canada does not provide a description of how each of the 14 substances were selected for evaluation in this approach. After initiation of assessment activities candidate substances will be identified based on available datasets. This is similar to the approach taken for screening assessments conducted under the Canadian Environmental Protection Act, 1999 (CEPA).
When there is a lack of scientific information for a substance, the Government of Canada should use all tools available (including provisions in section 71(3) of CEPA) so that the manufacturers/suppliers of these substances supply the relevant scientific data. The SciAD only applies to substances with adequate data regarding health effects.
Consider adaptive effects, particularly with respect to chronic chemical exposure as adverse unless there is justification to the contrary. Define and scope the soft endpoints. The health effects of concern were harmonized with other internationally accepted methodologies, such as the GHS. The SciAD was updated to improve clarity.

2. Improving transparency

Summarized Comment Summarized Response
The SciAD should describe how the data used in the evaluation were selected. This is necessary for transparency and proper review this draft proposal. The data presented in Tables A-3 to A-13 demonstrate the approach.
The primary route of exposure for each substance was determined by information from Health Canada databases, such as cosmetics, natural health products, and consumer products. The document states that the details of the determinations are not included in the SciAD; however, this selection criteria should be made transparent. Details of exposure were not presented because the focus is on a hazard based approach.
A clear set of criteria should be made transparent for carcinogenicity, mutagenicity/genotoxicity, reproductive/developmental toxicity (CMR) classification. CMR classification is made before nominating a chemical for assessment using this approach. These considerations are therefore beyond the scope of the SciAD.
Health Canada should clarify that agents having no adverse effects or such effects below the Limit Dose could still be deemed non-hazardous to humans after further evaluation. While it is recognized that this proposal is related to screening, substances not excluded under this process should not automatically be assumed to be potential human health hazards. Noted.
Clarify the method for addressing inhalation exposures. There are other considerations for inhalation exposures beyond physicochemical properties.   Inhalation exposures will be assessed on a case by case basis as there were inadequate examples of chemicals with inhalation as the primary route of exposure available for analysis during development of the approach.
The SciAD does not adequately address the risk from the 14 substances considered. It is important that the exposure part of risk assessment be done eventually, and that adverse effects beyond those included in CMR be assessed. The SciAD was updated to improve clarity.
The proposed approach for substances of low human health hazard potential is incomplete and was not demonstrated to apply to organic chemicals. Additionally, there are flaws within several of the example assessments. The SciAD was updated to improve clarity.
In Figure 2.1 a recommendation of a minimum of a 90-day repeat dose study or special studies such as reproductive, developmental, or neurotoxicity is in a footnote but is not discussed. In addition, some of the chemicals in the document were evaluated using studies that are shorter in duration. Clarify these inconsistencies. The SciAD was updated to improve clarity.
With the future use of the approach for chemical evaluations, the stakeholder requests increased data transparency, increased data consistency and more relevant data in the approach. Noted.

3. Methodology

Summarized Comment Summarized Response
The approach should consider dermal contact and site irritation/corrosion exposure. The SciAD does not consider dermal contact and site irritation/corrosion exposure because this is addressed by other regulatory programs.
A grouping approach might be appropriate for compounds that are likely sources of phosphate and for those that contain potassium. Substances are assessed as a group on a case-by-case basis.
The proposed approach requires adequate repeat dose studies; this may be of limited value for data poor substances. The Government of Canada should revise the provisions to reduce unnecessary testing. The approach is one of several mechanisms available for human health risk assessment. The SciAD considered other methods for substances with limited datasets.
Hazard identification for endocrine disruption should be investigated and considered to be an inherently toxic effect.   Broadly apply hazard-based approaches to assess Nano-materials and substances that affect biological signaling (such as CMR substances and endocrine disrupting chemicals), for all routes of exposure (including inhalation) and all types of substances (including organic chemicals). Consider effects of low, relevant doses at all ages and stages of life to account for effects such as cellular signaling early in life. The approach considers endocrine activity. Neurotoxicity is considered as serious for the purposes of this approach. The SciAD was updated to improve clarity.
No observed adverse effect levels (NOAEL) should be included in the hazard summary table carcinogenicity evaluations. NOAEL are included where available.
The assessment for sulfuric acid incorporates data from an occupational setting. Worker exposure data are not representative of general population exposures of consumer products. Workers are typically at higher risk of exposure to higher concentrations of a substance. For the purposes of this assessment, these data are not appropriate for evaluating carcinogenicity of substances. Clearly state the criteria for data selection and any exceptions. SciADs are based on the best available data. However, when available and relevant, the science approach considers hazard information from occupational settings.  
Provide a clear description of the types of studies (including species and duration) that should and should not be considered in the SciAD. The purpose of this SciAD is to describe a scientific approach for evaluating human health hazards associated with substances in the environment rather than provide a risk assessment of the 14 substances. The Government of Canada intends to conduct and publish a draft screening assessment based on the SciAD findings and other available information, for public review and comment.
In Decision Point 2, there are no criteria defined to determine whether an assay is adequate or inadequate. Approach documents are based on the best available data from a variety of sources. The Government of Canada determines the adequacy of test results and studies by reviewing factors such as the study protocol, reliability of results, credibility of the source, and level of detail from well-conducted studies of appropriate duration.
If no CMR effects are noted, the document states that the assessment of all health effects of a substance should be based on a weight of evidence approach and account for the totality of the findings and limitations of the data. Further, that adequate repeat dose studies to the primary route of exposure are recommended. This information should be defined and stated more clearly. The SciAD was updated to improve clarity.
In the hazard summary table for sulfuric acid, no carcinogenicity data are available but the recommendations state that there was no health concern for CMR up to 1,000 mg/kg-bw/day. Also, no repeat dose studies for 90 days were available, as recommended earlier in the document. In addition, the evaluation uses inhalation data for oral exposure evaluation. Clarify these inconsistencies. The SciAD provides a brief description of a rather complex and detailed assessment strategy. A variety of case studies, using variable datasets, were included as examples of how the approach could be applied.
Support the conclusion regarding sodium hydroxide with data. If there is no data, add a section to clearly state that no data were available. In addition, clarify how a statement was made about no health concern if no data exists. Perhaps read-across data would have been appropriate to use in this case. In the case study for sodium hydroxide, it is stated “sodium hydroxide is not expected to be systemically available in the body under normal handling and use conditions and hence will not be able to cause any health effects.” (OECD 2002a)
The hydrochloric acid discussion presents weight of evidence information for mutagenicity but without the description of the data. Summarize the data used to reach the conclusion. A reference to where the mutagenicity data was summarized is included in the summary table.
Provide better details on potassium hydroxide and potassium oxide data in sections that state no clear link between potassium oxide and cancer. Potassium chloride and other potassium-containing compounds are used as read-across due to lack of data on potassium hydroxide and potassium oxide.
The scope of applicability of the SciAD must be clearly delineated, and systematic scientific reviews, including topic expert input, are essential for accurate, realistic assessments of human health hazards. Noted.
The approach is fair and reasonable. Overall, the proposed approach for identifying substances with low human health hazard potential is well documented and generally science-based. The approach is primarily a hazard-based screening assessment for substances with low human health hazard potential. However, the approach could also be considered as a screening margin of exposure (MOE) analysis as the identified approach is targeting MOE’s of 10-100 mg/kg-bw/day for mild non-adverse effects. Noted.  
The decision to not include health effects with species-specific mechanisms of toxicity not relevant to human health is supported in this hazard-based approach. Noted.

4. Exposure

Summarized Comment Summarized Conclusion
This approach focuses on hazard but since risk includes both hazard and exposure, Health Canada should consider a similar approach for exposure. The Government of Canada has considered a similar approach for exposure. The Rapid Screening Approach uses conservative estimates of exposure to evaluate the likelihood that a substance may cause harm.

5. Conclusion

Summarized Comment Summarized Response
There is disagreement with the SciAD conclusion that all 14 substances are of low concern with respect to human health. Noted.
The conclusions presented in this publication will serve as the starting basis for the upcoming assessments under the third phase of the CMP. Noted.
Not applying provisions for quantitative risk characterization when there are no serious health effects strengthens the proposed conclusion that the substance is a low concern for human health. Noted.
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