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Chemicals Management Plan Challenge Advisory Panel Summary Report

July 27, 2009

• Panel members present: Dr. T. Boadway (Chair), Dr. J. Bend, Dr. C. Brunk, Dr. S. Findlay, Mr. G. Granville, Dr. S. Maguire, Dr. P. Orris.
• Regrets: Dr. N. Cherry, Dr. J. Eyles, Ms. L. Lusby, Dr. G. Muckle, Dr. D. Scott

Outline:

The Challenge Advisory Panel meeting agenda was structured around an overview of Batch 7 draft screening assessments. Government staff members were present to make presentations, answer questions and clarify information concerning approaches applied in the Batch 7 assessments. The charge question (see below) presented concerned the use of information on analogue substances in one of the draft screening assessments for a human health priority substance.

Meeting Summary:

The meeting began with a scheduled in camera session for Panel members. Government staff were invited to attend following the in camera session.

Welcome and Introductory Comments

The Chair welcomed all members and government staff. The meeting was opened with introductory remarks from the Chair as well as from senior Government staff in attendance.

Panel Discussion on Batch 7 draft screening assessment reports

Government staff presented an overview of draft screening assessments for the substances in Batch 7 of the Challenge. Batch 7 consists of nine ecological priority substances and five health priority substances.

Topics raised by Panel members during the overview of Batch 7 draft screening assessments included the following:

• The Panel asked about application of significant new activity provisions under the Canadian Environmental Protection Act, 1999 (CEPA 1999) and about the Domestic Substances List (DSL) Inventory Update and the intent of these tools. Government staff provided background.
• The topic of impurities in substances, and particularly in "mixtures" (i.e., substances of variable composition) was raised by the Panel, and highlighted as a topic for discussion at the next meeting.
• There was a discussion around the potential uncertainties associated with screening assessments relying primarily on the use of modelled, rather than empirical, data.

There was discussion of the distinctions between threshold and non-threshold carcinogens in the specific context of certain substances included in Batch 7. The topic of threshold versus non-threshold carcinogens in the overall context of the Challenge was highlighted as another topic for discussion at the next meeting.

One question raised by the Panel was whether it might be possible in the future to indicate a measure of the precision (for example, confidence intervals) for some of the estimates in draft screening assessment reports. Government officials indicated they would look into this possibility and report back at a future meeting.

The Panel considered that weight of evidence and precaution were applied appropriately in the draft screening assessment reports.

Charge Question for the Panel - Health Priority

The charge question posed to the Panel, in relation to the Batch 7 health priority substance n-Butyl glycidyl ether, was as follows:

In its risk assessment of n-Butyl glycidyl ether (n-BGE), Health Canada made use of data on the toxicity of the substance itself as well as for several analogue substances to inform understanding of the potential health effects associated with exposure to n-BGE. Does the panel agree that the use of information on analogue substances constitutes appropriate application of weight of evidence within the context of the n-BGE screening assessment prepared under the Challenge?

Background Information Provided to the Panel

• n-BGE was determined to be a high priority for further work during categorization as it was classified by the European Union (EU) as category 3 for its carcinogenicity (causes concern to man owing to possible carcinogenic effects) and category 3 for its genotoxicity (causes concern to man owing to possible mutagenic effects) and it was found to pose intermediate potential for exposure (IPE) in Canada.
• There are no chronic cancer studies available for n-BGE. The EU based the classification for carcinogenicity of n-BGE on data from the chemical analogue allyl glycidyl ether (AGE) as well as on the evidence for genotoxicity for n-BGE itself.
• For the purpose of the Challenge draft screening assessment, Health Canada examined data on several analogue substances in order to inform understanding of the potential health effects associated with exposure to n-BGE (further information is available in the draft screening assessment report).
• The selection of these analogues was based on structural and physicochemical similarities, as well as the availability of long-term carcinogenicity studies. The glycidyl (ether) group was identified as the most important criterion for assessing carcinogenic potential, due to the presence of the epoxy ring. Epoxides are known to act as DNA alkylating agents, thus they could potentially be involved in a carcinogenic mode of action.
• Genotoxicity results for the analogues are comparable to n-BGE, both in terms of the type of test conducted and the results produced.
• Reproductive toxicity (testicular atrophy in rats) was identified as a non-cancer critical effect for n-BGE. The analogue substances also induce male reproductive effects.
• The use of data on analogue substances data in hazard assessment is a recognized approach by various regulatory authorities (e.g. OECD, US Environmental Protection Agency, the European Chemicals Agency in the EU).
• The underlying principle of an analogue approach is that chemicals with common features (e.g. structure, physicochemical properties), will exert similar toxicological properties due to a common mode of action, and that a hazard assessment should use the totality of the information, thus applying weight of evidence considerations.

Amendment to the Question

The Panel agreed to amend the question to include the application of precaution in addition to that of weight of evidence.

Discussion around the Question

• Discussion around the question focused on the criteria used to select analogue substances to support risk assessments by the Government of Canada and in other jurisdictions. Panel members emphasized that criteria for the determination of the analogue set should be explicitly reported. Government officials acknowledged this comment and indicated that most jurisdictions apply essentially the same basic principles to guide the selection of analogues (such as structural similarities and shared physicochemical properties), but that it is also recognized by other agencies that expert judgement and weight of evidence play important roles in the selection of analogues in a less formalized manner.
• A Panel member commented that the principle of precaution also has applications to the selection of analogue substances.

Panel Response

"The Panel agrees that the use of information on analogue substances constitutes appropriate application of precaution and weight of evidence within the context of the n-BGE screening assessment prepared under the Challenge."

The Panel also asked government officials to bring to the attention of the Panel any future instances in which government officials make use of an analogue approach in screening assessments, so that the approach taken in each circumstance could be discussed.

Topics for Discussion at the Next Panel Meeting

Finally, the Panel recommended that the next Panel meeting should be 1.5 days in length. The intent of the additional half-day pre-meeting session would be to discuss topics in a context outside the scope of a particular Batch of substances under the Challenge. By consensus, the Panel indicated an interest in discussing the two following topics:

1. The topic of impurities in substances, and particularly in "mixtures" (i.e., substances of variable composition): how these are being estimated, and how their chemical characteristics are being ascertained.
2. The topic of threshold versus non-threshold carcinogens, and how these are defined and assessed under the Challenge.