Guidelines for the Notification and Testing of New Substances: Chemicals and Polymers

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SECTION 8 - Recommended Test Protocols and Alternative Approaches

• 8.1 Test Protocols
  • 8.1.1 Organisation for Economic Co-operation and Development (OECD) Test Guidelines (TG)
• 8.2 Accepted Test Methods
• 8.3 Good Laboratory Practice (GLP)
  • 8.3.1 Accreditation of Laboratories
• 8.4 Alternative Approaches
  • 8.4.1 Alternative Test Protocols
  • 8.4.2 Reduction, Refinement and Replacement
  • 8.4.3 Structure-Activity Relationships
    • 8.4.3.1 Qualitative Structure-Activity Relationships
    • 8.4.3.2 Acceptance of Read-Across Data
    • 8.4.3.3 Examples of Read-Across Data
    • 8.4.3.4 Quantitative Structure-Activity Relationship (QSAR) Estimates
    • 8.4.3.5 Other Calculation Methods
• 8.5 Test Data on UVCBs and Impure Substances
• 8.6 Sources of Test Methods
  • 8.6.1 Organisation for Economic Co-operation and Development (OECD)
  • 8.6.2 Environment Canada Biological Test Methods
  • 8.6.3 U.S. Environmental Protection Agency
• 8.7 Waiver Requests for Information Requirements
  • 8.7.1 Introduction
    • 8.7.1.1 Waivers Requested under Paragraph 81(8)(a) of the Act
    • 8.7.1.2 Waivers Requested under Paragraph 81(8)(b) of the Act
    • 8.7.1.3 Waivers Requested under Paragraph 81(8)(c) of the Act
  • 8.7.2 Class Considerations of Waivers
    • 8.7.2.1 Cationic Class Waivers
• 8.8 Pre-notification Consultations (PNC)

8.1 Test Protocols

8.1.1 Organisation for Economic Co-operation and Development (OECD) Test Guidelines (TG)

Subsection 15(1) of the Regulations states that the conditions to be met and the test procedures to be followed in developing the required test data for a substance must be consistent with the conditions and procedures set out in the OECD TG that are current at the time the test data are developed. The OECD TG are set out in Annex 1 of the OECD Decision of the Council Concerning the Mutual Acceptance of Data in the Assessment of Chemicals, adopted by the OECD on May 12, 1981.

The appropriateness of the OECD TG method for the substance must be determined, and any necessary deviations must be reported and explained. The OECD TG are not intended to serve as rigid test procedures appropriate for all substances; rather, they allow flexibility for expert judgement and adjustments to new developments.

8.2 Accepted Test Methods

Examples of test methods recommended by the NS program for the generation of physical-chemical, toxicity and ecotoxicity data are provided in Tables 8-1 to 8-4 below. The acceptability of these test methods depends on the applicability of the methods to the substance under investigation. Sources of test methods listed in Tables 8-1 to 8-4 are given in section 8.6 of these Guidelines.

8.3 Good Laboratory Practice (GLP)

Subsection 15(2) of the Regulations states that the laboratory practices to be followed in developing data for the following tests must comply with the practices set out in the "Principles of Good Laboratory Practice" that are current at the time the test data are developed. The principles are set out in Annex 2 of the OECD Decision of the Council Concerning the Mutual Acceptance of Data in the Assessment of Chemicals, adopted by the OECD on May 12, 1981 (www.oecd.org):

1. acute mammalian toxicity tests;
2. repeated-dose mammalian toxicity tests;
3. genotoxicity tests;
4. tests to assess skin irritation;
5. skin sensitization tests;
6. acute fish, daphnia or algal toxicity tests; and
7. biodegradation tests.

If any of the tests mentioned above were commenced or completed before the day on which the Regulations came into force, the laboratory practices used must be consistent with the practices set out in the "Principles of Good Laboratory Practice".

The "Principles of Good Laboratory Practice" are intended to promote the quality and validity of test data and to establish a basis for mutual acceptance of data among jurisdictions at the international level. They cover the organizational processes and conditions under which studies are planned, performed, monitored, recorded and reported.

The OECD has developed a series of decisions and guidelines relating to GLP. Documents are available via the OECD web site at www.oecd.org.

To be GLP compliant, the final test report must include the CAS registry number (if applicable), name or trade name and the purity of the tested substance. The following information must also be provided:

1. the name, title and dated signature of the Study Director;
2. a GLP Compliance Statement from the Study Director;
3. the name, title and dated signature of the Principal Investigator;
4. the name, title and dated signature of the Quality Assurance Program;
5. Quality Assurance Statements from the Quality Assurance Program; and
6. dates and explanations of Quality Assurance Audits, including in-life audits.

Required studies submitted that are not compliant with GLP or do not contain the above-mentioned items will not be accepted, and the assessment period will not start until the appropriate and/or acceptable information has been provided.

For studies of physical-chemical properties, GLP compliance is not mandatory. However, the notifier is obliged to submit a test report with sufficient information to allow the NS program to assess the quality of these studies and their results. This information should include:

• identification of the test guideline and methodology employed;
• identification of the test substance and its purity;
• reference methods, standards and controls employed;
• name and address of the test facility and the name of the person responsible for the study;
• dates on which the study was initiated and completed;
• raw data;
• deviations from the test protocol;
• analytical details, including sample preparation and instrument settings; and
• a presentation of results, calculations and statistical methods employed.

8.3.1 Accreditation of Laboratories

If the test data submitted are from an accredited facility, then the accreditation should be stated and identified.

8.4 Alternative Approaches

Information in support of an NSN package may also be obtained from alternative test protocols or from calculation or estimation methods. These alternative approaches will be acceptable when, in the opinion of the NS program, they are equally or better suited to measure the endpoint under investigation. Requests for waivers of information are not required when submitting information from an acceptable alternative procedure.

Although it is not required, notifiers are encouraged to contact the NS program by submitting a PNC request (see section 8.8 of these Guidelines) while the NSN package is being prepared, to ensure that the procedure would be acceptable and to obtain answers to any questions regarding the use of alternative test procedures. This includes, but is not limited to:

• determining if the data that were generated prior to establishment of current standards of laboratory practice and method sensitivity are acceptable; and
• determining if alternative protocols or modifications to OECD protocols are acceptable.

Modifications or additions to the test protocol or the use of another protocol may be recommended by the NS program.

If an NSN package contains alternative data and a PNC was not requested, then the alternative data will be assessed, during the assessment period, by the NS program to determine whether it is acceptable. If during the assessment period it is determined that the alternative data is not acceptable, the submission will be considered incomplete, and the assessment period will be restarted on day 1 once a complete NSN package has been submitted.

8.4.1 Alternative Test Protocols

Alternative protocols include other domestic or internationally recognized protocols -e.g., test methods developed by the NS program, International Organization for Standardization (ISO), American Society for Testing and Materials (ASTM), the United States Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA) and the United States TSCA. In addition, protocols developed by individual companies or associations may also be acceptable. The method used by the notifier must be clearly referenced and described in sufficient detail to permit evaluation.

The alternative protocol must provide the desired data to a degree of accuracy acceptable to the NS program and must be described by the notifier in sufficient detail to allow an evaluation of the procedure and results.

The description of the alternative protocol should include, but not be limited to, a detailed description of the test principles and design, the methodology and controls used, validation studies of the accuracy and variability of the test method in comparison with the prescribed method and any references to the protocol in the scientific or technical literature. Descriptions of internationally recognized methods (e.g., ASTM, USEPA, Environment Canada, ISO) may not need to be provided, but must be referenced.

Properly conducted human patch tests (positive or negative response) may be an acceptable alternative to animal testing for skin irritation or skin sensitization. The concentration of notified substance used in the test will be a critical factor in determining the acceptability of this information. Well-documented human use experience may also be an acceptable alternative to the prescribed test protocols for toxicological endpoints, especially skin irritation or skin sensitization tests (positive response only). The human use experience must be well-described and give particular emphasis to quantifying the exposure (concentration, duration, frequency) as accurately as possible. Anecdotal information from persons handling or exposed to the substance is not an acceptable substitute for performing a prescribed test.

8.4.2 Reduction, Refinement and Replacement

The NS program supports the principles of the Three R's (Reduction, Refinement and Replacement) approach to the use of alternative test methods for minimizing unnecessary and avoidable animal use and suffering, where the quality of the information generated to conduct a risk assessment is not compromised. The method must have been satisfactorily validated in terms of scientific rigour, reproducibility and predictability.

An alternative that would reflect the reduction approach is one in which the number of animals needed to assess a particular endpoint can be decreased without affecting the scientific value of the test. Examples of reduction alternatives already in acceptance by international regulatory agencies include the updated OECD TG for acute toxicity (OECD TG 420, 423 and 425) and skin sensitization (OECD TG 429).

Refinement alternatives are aimed at reducing the distress or discomfort experienced by laboratory animals, during and following testing, by improving the design and/or efficiency of the test. Some examples of this include eliminating unnecessary handling and restraint of animals, availability of veterinary assistance, provisions for continual monitoring of health status and early termination of animals suffering undue pain or discomfort.

A replacement alternative is one that does not involve the use of a living animal. These include the use of validated computer-based models, physical-chemical information (e.g., information on pH to assess irritation potential), lower (e.g., invertebrate) organisms and in vitro tests on mammalian tissues and cell cultures.

8.4.3 Structure-Activity Relationships (SARs)

Relationships exist between the structure of a substance and its physical properties and toxicity. Knowledge of these relationships, particularly within certain chemical groups, can be used to predict the physical, chemical, toxicological and ecotoxicological properties of a substance.

Data generated using SARs fall into two main categories:

1. estimates based on qualitative SARs; and
2. estimates based on Quantitative Structure-Activity Relationships (QSARs).

Calculation or estimation methods will be acceptable if the validity of the provided data is demonstrated.

8.4.3.1 Qualitative Structure-Activity Relationships

Qualitative SARs, often referred to as "read-across" data or surrogate data, provide a qualitative estimate of a particular property through the submission of experimental data on a similar substance(s) (e.g., substances with a chemical structure closely related to that of the notified substance). Surrogate data submitted in lieu of experimental data on the notified substance must be supported with the following information:

1. a rationale justifying the use of the surrogate data comprising a comparison of the structural features of the notified and surrogate substance(s);
2. a comparison of the notified substance and surrogate substance(s) physical and chemical properties to help validate the estimate for the test under consideration;
3. test report(s) for the surrogate substance(s), containing information sufficient to assess the test under consideration;
4. a description of the test method used to generate the data on the surrogate substance(s) in order to determine the appropriateness of the method, if it is an alternative protocol; and
5. test data on the notified substance from a range-finding test, if applicable (e.g., a limit test).

8.4.3.2 Acceptance of Surrogate Data

The validity of surrogate data will largely depend on the structural similarity between the notified and surrogate substance(s). Surrogate data is applicable when:

1. the notified substance possesses a "trivial" structural difference from the surrogate substance(s); or
2. the structural difference between the notified substance and the surrogate substance(s) is not considered "trivial" but will affect the property in a manner that can be accurately predicted.

A "trivial" structural difference between two substances is any change from the notified substance that is not reasonably expected to markedly alter the physical-chemical, biological or toxicological properties of the substance.

8.4.3.3 Examples of Surrogate Data

Examples of what may constitute a trivial structural change are:

1. a change in a counter ion of a large charged organic chemical (e.g., sodium dodecyl sulphonate to potassium dodecyl sulphonate); or
2. the addition or subtraction of a single methylene group in a long alkyl chain (e.g., C₁₀H₂₂ to C₁₁H₂₄).

Examples of possible surrogate data applications include:

1. if an ester was shown to hydrolyze rapidly, toxicity data (except dermal toxicity, irritation and sensitization) for the alcohol and the acid might be acceptable;
2. if a high-molecular-weight substance had repeating units, an estimate of the physical-chemical properties or toxicity of surrogate substances that possess fewer or more units might be acceptable;
3. the water solubility of an ionizable substance might be estimated to be greater than that of an appropriate similar substance that possessed fewer ionizable functional groups and exhibited very high water solubility; and
4. if complex mixtures had similar carbon ranges, boiling ranges, percentage aromatics, olefinics and heteroatom content, an estimate of the physical-chemical properties or toxicity of surrogate substances might be acceptable.

Confidence in surrogate data will be strengthened if the notified substance lies within a series of substances that have similar structural features and for which reliable data are provided. It is important to note that one surrogate may not be appropriate for all data endpoints. Although it is not required, notifiers are encouraged to submit a PNC request (see section 8.8 of these Guidelines), while the NSN package is being prepared, to determine the acceptability of information resulting from alternative methods.

8.4.3.4 Quantitative Structure-Activity Relationship (QSAR) Estimates

QSARs provide quantitative estimates of particular properties and are often generated by computer programs that use regression analysis or molecular descriptors that mathematically represent the structural components of a molecule. Linear or multiple regression of a particular property against another property (e.g., octanol- water partition coefficient versus water solubility, or vapour pressure versus boiling point) can be used to derive an empirical relationship for one or several classes of chemicals. An estimate calculated using molecular descriptors can be based either on experimental values for each molecular descriptor or on experimental values for several molecules containing a common molecular descriptor.

The validity of the QSAR estimate must be explained in the NSN package, in terms of whether the estimate is reasonable in comparison with measured data, taking into account the structural features of the notified substance in comparison with the substances used to develop the estimate. The appropriateness of the QSAR must be discussed in terms of the ability of the model to correctly predict the behaviour of the notified substance.

Information to support the acceptance of data based on QSARs should include:

1. a validation of the estimate (this may include the reporting of chemicals and/or structures used to generate the estimate and the experimental data for these chemicals); and
2. the level of confidence associated with the estimate.

The NS program assesses a wide variety of substances, many of which are considered "model difficult" due to the substance falling outside the applicability domain of a model, with features of the molecule not represented in the training set. Consequently, the NS program advocates the judicious use of modelled data, predicting properties of well-understood classes of chemicals using robust models with strong training sets.

8.4.3.5 Other Calculation Methods

Other methods used to calculate data for an NSN package (e.g., extrapolation of data generated at different temperatures to provide a value at ambient temperature) will be assessed on a case-by-case basis. The NS program provides the opportunity for notifiers to submit a PNC request (see section 8.8 of these Guidelines) to determine if the other methods will be acceptable for the NSN package.

8.5 Test Data on UVCBs and Impure Substances

UVCB substances are defined as substances that are of unknown or variable composition, complex reaction products or of biological origin. These materials are derived from natural sources or complex reactions and cannot be characterized in terms of constituent chemical compounds because their composition is too complex or variable. These substances are considered a single substance under the New Substances provisions of the Act; therefore, all tests should be performed on the entire UVCB substance. Where a prescribed test is not appropriate (e.g., melting point), the use of alternative methods should be considered (e.g., softening point). Also, the provision of information on any of the known components of the UVCB substance will assist in the interpretation of data generated on the UVCB substance.

Difficulties may also occur when substances are tested that contain high levels of impurities (e.g., residual starting materials, solvent and by-products), because impurities can confound the interpretation of test data. Consequently, tests should be performed on a high-purity sample of the substance. However, if further purification of the substance is neither technically feasible nor practical, tests on the crude product may be acceptable. In all cases, the purity of the tested material must be stated and information documenting efforts to isolate the substance must be provided. Information on the physical-chemical or toxicological properties of any of the impurities will assist in the interpretation of the data generated on the impure substance. In cases where information generated on the mixture would not be meaningful for the assessment of the notified substance (e.g., the notified substance comprises only a very small proportion of the mixture and further purification is not feasible), a request for a waiver on the grounds of technical infeasibility will be considered.

8.6 Sources of Test Methods

8.6.1 Organisation for Economic Co-operation and Development (OECD)

www.oecd.org/publications/0,2743,en_2649_201185_1_1_1_1_1,00.html

1. "Guidelines for Testing of Chemicals" (November 2004)
2. "Principles of Good Laboratory Practice" (July 2001)

Available in Canada from:

Renouf Publishing Company
1294 Algoma Road
Ottawa, Ontario
K1B 3W8

Les Éditions La Liberté
3020, chemin Sainte-Foy
Sainte-Foy (Québec)
G1X 3V6

Federal Publications Ltd.
165 University Avenue
Toronto, Ontario
M5H 3B8

Available internationally from:

OECD Bookshop
2, rue André Pascal
F-75775 Paris Cedex 16
France
www.oecd.org/publications/0,2743,en_2649_201185_1_1_1_1_1,00.html

8.6.2 Environment Canada Biological Test Methods

1. Environment Canada. "Biological Test Methods: Acute Lethality Test - Rainbow Trout" (July 1990, amended May 1996). Report EPS1/RM/9.
2. Environment Canada. "Biological Test Methods: Acute Lethality Testing - Daphnia magna" (July 1990, amended May 1996). Report EPS1/RM/11.
3. Environment Canada. "Biological Test Methods: Growth Inhibition Test Using the Freshwater Algae - Selenastrum capricornutum" (September 1992, amended November 1997). Report EPS1/RM/25.
4. Environment Canada. "Biological Test Method: Reference Method for Determining Acute Lethality of Effluents to Rainbow Trout" (December 2000). Report EPS1/RM/13.

Available from:

www.etc-cte.ec.gc.ca/organization/bmd/bmd_publist_e.html

Communications Services – Publications
Environment Canada
Ottawa, Ontario
K1A 0H3

Order by:

Telephone:
1-800-734-3232 (toll free within North America)
819-953-5750 (outside North America)

Facsimile: 819-994-5629

E-mail: epspubs@ec.gc.ca

8.6.3 U.S. Environmental Protection Agency

1. "Algal Acute Toxicity Test U.S. Environmental Protection Agency Environmental Effects Testing Guidelines" (August 1982). EPA 560/6-82-002, PB 82-232992.

Available from:

National Technical Information Service
United States Department of Commerce
5285 Port Royal Road
Springfield, VA 87007
U.S.A.

8.7 Waiver Requests for Information Requirements

8.7.1 Introduction

Under subsection 81(8) of the Act, a request to waive the requirement for any of the prescribed information may be made to the NS program. The decision to grant a waiver will be made, on a case-by-case basis based on whether at least one of three criteria has been met. The statutory criteria for a waiver of information that are identified in subsection 81(8) of the Act are:

1. in the opinion of the Ministers, the information is not needed in order to determine whether the substance is toxic or capable of becoming toxic;
2. a substance is to be used for a prescribed purpose or manufactured at a location where, in the opinion of the Ministers, the notifier requesting the waiver is able to contain the substance so as to satisfactorily protect the environment and human life; or
3. it is not, in the opinion of the Ministers, practicable or feasible to obtain the test data necessary to generate the information.

Waiver requests must be submitted in writing as part of the NSN package and should include a well- documented rationale to support the request. Rejection of a waiver request may result in a delay in the assessment (see section 9.3.4 of these Guidelines). To determine if waivers are acceptable and to avoid unnecessary delays in the assessment, the NS program provides the opportunity for and encourages notifiers to submit a PNC request (see section 8.8 of these Guidelines), while the NSN package is being prepared, to determine if the waivers are acceptable.

Appendix 8 of these Guidelines provides examples of conditions under which waivers may be granted. This list is not intended to be exhaustive, but describes some independent conditions that, in most cases, would be considered to be sufficient justification to grant a waiver. Waiver requests may also be based on a combination of factors (e.g., physical properties, inherent toxicity and potential for exposure to the substance).

Once an assessment is complete and the waiver has been recommended for acceptance by the NS program, the substance name, company name, use of the substance and specific waiver request are sent to the Assistant Deputy Minister for approval. Once the waiver of information is granted, then the particulars of the waiver will be published in the Canada Gazette, Part I, in accordance with subsection 81(5) of the Act. The published waiver notice will contain only a) the name of the notifier (or company) to whom the waiver is granted; and b) the type of information to which it relates (e.g., Company X, biodegradability information). The notice will not specify the substance to which the waiver applies or the NSN reference number.

Substances for which waivers have been granted under paragraphs 81(8)(a) or 81(8)(c) of the Act will generally be eligible for entry onto the DSL if the criteria under subsection 87(1) of the Act have been satisfied. An exception to this would be for polymers with insignificant amounts of low-molecular-weight species (e.g., <0.1% species <1000 daltons) and that are not expected to break down, for which waivers for health data have been granted on that basis. These substances will only be eligible for listing on the DSL if there is a SNAc Notice issued. This will ensure that health hazard toxicity data are provided for polymers that do not meet the cut-off criteria for low-molecular-weight species and therefore would not satisfy the RRR polymer criteria.

When waivers have been granted, the notifier must provide any corrections to the information used to justify and assess the waivers as per subsection 81(11) of the Act (see section 10.1.1 of these Guidelines). The Minister may then, if necessary, request the notifier to provide the information item that was waived or take appropriate control measures.

A waiver should not be requested when information to address the data element is provided on a surrogate substance or using alternative methods. Waivers should also not be requested on the basis that another data element was waived (e.g. a waiver on a waiver). Furthermore, predictions should not be used based on another data element being predicted (e.g. a prediction on a prediction). If the NSN package contains any of these, noted above, it will be deemed incomplete and the assessment period will be terminated.

8.7.1.1 Waivers Requested under Paragraph 81(8)(a) of the Act

Waiver requests may be granted if it can be established that the test is unnecessary to determine whether the substance is toxic. In cases where the requirement for one part of a prescribed test depends on the result of a previous part (e.g., mutagenicity test data), it is suggested that the tests be completed based on a self-evaluation of test results or a consultation with the NS program through a PNC request (see section 8.8 of these Guidelines). After receipt of the PNC request or the NSN package, the NS program will assess the submitted information to determine if the information provided is acceptable.

Examples of situations in which information may be waived under paragraph 81(8)(a) of the Act are as follows:

1. the hydrolysis test may be waived if the substance contains only functional groups that are known to not hydrolyze; therefore, it can be assumed that the rate of hydrolysis of the substance will be very slow, and any data generated would not provide additional insight into the environmental effects of the substance; or
2. if an in vivo mammalian genotoxicity test gave a positive result, the in vitro mutagenicity tests may be waived because the substance would be classified as an in vivo mutagen and the results of in vitro tests would not change this assessment.

8.7.1.2 Waivers Requested under Paragraph 81(8)(b) of the Act

Regulations must be developed before these waivers can be granted which would delay the assessment and approval of these substances. No regulations have been made for the purposes of paragraph 81(8)(b) of the Act.

8.7.1.3 Waivers Requested under Paragraph 81(8)(c) of the Act

Many of the potential waivers that can be requested under paragraph 81(8)(c) relate to instances where it is technically arduous or impossible to perform the required tests using conventional technology because of the physical or chemical properties of the substance. Examples of such waivers include:

1. water solubility determinations for substances that react dangerously with water; and
2. skin irritation tests using substances for which topical administration is not technically feasible.

The use of alternative protocols or surrogate data to fulfil the information requirement should be considered before it is judged to be infeasible or impractical to provide certain information. In these cases, a waiver should not be requested. The cost of obtaining data cannot alone be used as a reason for the infeasibility or impracticability of providing the prescribed information.

8.7.2 Class Considerations of Waivers

As a result of the NS program's experience in assessing new substances, a body of knowledge now exists on classes of substances that can be applied to newly notified substances in those classes. A systematic review of the properties of a class, corresponding to regulatory requirements, can reveal established trends in its properties. In such cases, information for specified endpoints for notified members of the class will likely not be needed to determine whether the substance is toxic or capable of becoming toxic.

Notifiers who are preparing NSN packages for substances that meet the definition of such a class are encouraged to request waivers for the specified endpoints using paragraph 81(8)(a) of the Act. Waivers will be recommended when the NS program concurs that the substance meets the eligibility criteria and no reason has been identified to decline the request.

Notifiers are encouraged to nominate new classes of substances for consideration of class waivers. They are asked to contact the NS program through the NSN Information Line to discuss the information needed to prepare a nomination.

The NS program web site will be updated as definitions of classes are developed. The NS program web site at www.ec.gc.ca/substances/ should be checked for any new information on available classes.

8.7.2.1 Cationic Class Waivers

Available information is considered sufficient to indicate that a class comprising certain cationic polymers is expected to have low toxicity in the toxicological tests prescribed in the Regulations. Thus, notifiers are encouraged to request waivers for all the toxicological test requirements for polymers that meet this class definition.

At this time, this class is defined as polymers that do not meet the criteria for an RRR polymer solely due to the presence of the following cationic or potentially cationic groups:

• primary, secondary or tertiary amine groups;
• carbodiimides; or
• sulphoniums.

Polymers containing other cationic polymers (such as quaternary amines, hindered amines, azides, isocyanates [free and blocked] and phosphoniums) are not included in the above class definition, either because there is currently insufficient information available regarding their toxicity to warrant their inclusion or because available information indicates that there are adverse affects associated with them. For cationic polymers that do not meet the above definition and therefore are not eligible for a class waiver, notifiers may still request waivers with sufficient rationale for specific tests or submit surrogate information for consideration by the NS program on a case-by-case basis. As well, polymers with a number average molecular weight greater than 10 000 daltons will generally not be eligible for waivers for acute and repeated-dose toxicity tests if inhalation is expected to be the most significant route of exposure for the general population based on expected use.

8.8 Pre-notification Consultation (PNC)

A PNC is an option for notifiers who wish to consult with the NS program during the planning or preparation of their NSN package to discuss any questions or concerns they have about the required prescribed information. The notifier may submit his or her request for a PNC through the NSN Information Line (see contact information in these Guidelines). Although not required, a PNC request is recommended when clarification is needed on the notification procedures or information requirements and assistance is needed in determining the acceptability of:

1. waiver requests;
2. test protocols; or
3. data based on calculation or estimation methods (e.g., Structural-Activity Relationships).

PNC requests can be addressed in writing (by mail, facsimile or electronic mail) or through a meeting or conference call.

For meeting and conference call PNC requests, the NS program will make every effort to respond to the proposed queries during the meeting. The NS program requests a minimum of two weeks between receiving the preliminary PNC request, that contains sufficient information, and conducting the meeting. This allows time for the NS program to make an informed response to the question(s) at hand during the meeting. A written response to the queries will be communicated within a period equivalent to the appropriate assessment period for that substance (see below).

For all PNC requests the NS program will make every effort to respond to the queries within a period equivalent to the appropriate assessment period for that substance. This period will start after sufficient information has been provided for the PNC request to proceed.

The information required to begin a PNC includes: information on the substance (e.g., the name, CAS registry number, the structure, reactants etc.); what information needs to be addressed or questions to be answered; and for meetings, a brief agenda.

For example, a PNC request is submitted with sufficient information for a substance that will be subject to Schedule 10 requirements of the Regulations, a response to the PNC request should be issued within 60 days.

The NS program will give opinions based on the information received within the PNC request. The professional opinions of the NS program, expressed during the PNC are not an official commitment, since technical conclusions may differ after a more in-depth assessment has been conducted on the complete NSN package.

In addition to PNC requests, the NS program encourages discussions to clarify any other issues related to the NS program.