Concerning the assessment of bioaccumulation of new chemical substances by analog approach, etc. (Announcement)

Transcription

1 Concerning the assessment of bioaccumulation of new chemical substances by analog approach, etc. (Announcement) September 27, 2013 Office of Chemical Safety Evaluation and Licensing Division Pharmaceutical and Food Safety Bureau Ministry of Health, Labour and Welfare Chemical Safety Office Chemical Management Policy Division Manufacturing Industries Bureau Ministry of Economy, Trade and Industry Chemicals Evaluation Office Policy Planning Division Environmental Health Department Environmental Policy Bureau Ministry of the Environment The judgment relating to the notification of new chemical substances, pursuant to paragraph (1) of Article 4 of the Act on the Evaluation of Chemical Substances and Regulation of Their Manufacture, etc., shall be made based on the results of the tests stipulated in the Ministerial Ordinance Specifying Items Concerning the Testing of New Chemical Substances and the Study of the Hazardous Properties of Priority Assessment Chemical Substances (PACs) and Monitoring Chemical Substances as well as based on all available information on New Chemical Substances. With regard to the bioaccumulation of a new chemical substance, some chemical substances have been already assessed by the analog approach, etc. based on another chemical substance which has a similar structure and, whose bioaccumulation is known. However, in light of the importance of streamlining of costs/durations for tests as well as the international demand to reduce animal tests, we believe it is important to further promote such an evaluation/judgment based on analog approach, etc. 1

2 For these reasons, we organized the theories on how to assess the bioaccumulation based on the analog approach, etc. and provide our provisional criteria as per the attached sheet. We will be using these criteria, for the time being, as a guide for bioaccumulation assessments in preliminary consultations of the Advisory Council and, with accumulated experiences, we will continue to review these provisional criteria and streamline/clarify such assessment of bioaccumulation by analog approach, etc. 2

3 (Attached Sheet) Concerning the assessment of bioaccumulation of new chemical substances by analog approach, etc. (Provisional Criteria) 1. Assessment by analog approach based on structural similarity If the substance of concern (hereafter Chemical Substance A or Substance A ) has a similar structure to a chemical substance B whose bioaccumulation is known to be sufficiently low (hereafter Chemical Substance B or Substance B ) and further, if the bioaccumulation of Chemical Substance A is estimated in a rational way to be almost equal to or lower than Chemical Substance B based on their chemical structure, Chemical Substance A may be judged to be not highly bioaccumulative based on analog approach. The specific operation of this judgment shall be based on the following requirements for the time being; once case studies are accumulated, it is time to review those requirements in a timely manner to ensure that the operation becomes more effective. [1] Chemical Substance B whose bioaccumulation is known to be sufficiently low In principle, measured BCF is less than 500 (*1) (The assessment by analog approach based on Chemical Substance B, when only log Pow of the substance has been measured but the BCF has not been done, shall not be adopted for the time being. The rationality of such analog approach will continue to be examined.) [2] Chemical Substances A and B are similar in structure to each other Where Substance A is an isomer (geometric isomers, etc.) of Substance B whose bioaccumulation is known Where Substance A has the same basic skeleton Substance B whose bioaccumulation is known but the structure of Substance A is partially changed from that of Substance B(including a case where the number of carbon atoms of alkyl group was changed) (However, excluding a case where the polarity of Substance A is considered to become decreased from that of Substance B and further, BCF of Substance A is likely to be higher than 500.) 3

4 [3] The bioaccumulation of Chemical Substance A is estimated to be almost equal to or lower than Chemical Substance B based on their chemical structure (specific conditions are (i) or (ii)) (i) Where the estimated BCF value by using QSAR model (*2) for Chemical Substance A is almost equal to or lower than both the measured and estimated BCF value for Chemical Substance B. (This is limited to only a case where the measured and estimated BCF value for Substance B are not significantly different from each other. In addition, if the measured BCF value for Substance B is extremely small, the estimated BCF value for Substance A, even if this estimated value is sufficiently small, may be higher than both the measured and estimated BCF value for Substance B. In such a case, it can be assessed that the bioaccumulation of Chemical Substance A is almost equal to or lower than Chemical Substance B.) (ii) Where there exist two or more structurally similar substances whose measured BCF values are less than 100. (This is limited only in a case where a substance is similar in structure to Substance A and the bioaccumulation of the substance is considered to be almost equal to or lower than Substance A.) (*1) Because the judgment criterion for high bioaccumulation is based on BCF of 5,000 or higher, bearing in mind a safety factor of 10, we shall adopt BCF <500 as a requirement for any candidate substance for analog approach. (*2)Any business operator who intends to make notification for Chemical Substance A, shall examine, as exhaustively as possible, all chemical substances both with structural similarities to Substance A and with known BCF values and shall submit those results. In addition, such business operator shall also submit the QSAR estimated BCF values for all those substances (excluding cases that are applicable to [3] (ii) mentioned in the above). Recommended QSAR models are BCFBAF (EPI SUITE) and BCF base-line model (OASIS Catalogic), both of which have been confirmed in terms of reliability by NITE. Estimated values obtained from other types of QSAR models shall be adopted only after the reliability of those QSAR models has been validated. 2. Assessment based on the comparison of hydrophilicity (polarity) by HPLC If the substance of concern (Substance A) has a similar structure to Substance B whose 4

5 bioaccumulation is known and further, if it is observed that Substance A is more hydrophilic (polar) than Substance B by reverse-phase HPLC, only when Substance B is not highly bioaccumulative and has a certain level (or higher level) of hydrophilicity, Substance A may be assessed to be not highly bioaccumulative. However, in light of streamlining of costs/durations required for the notification of a new chemical substance as well as the international demand to reduce animal tests, we intend to aggressively promote the asssessment of bioaccumulation based on these theories. For the time being, the specific operation of this assessment shall be based on the following: As it is considered that there are actually various cases, we do not set up detailed rules at this time but will make a case-by-case judgment depending on the individual consultations with business operators. Once some sets of information are accumulated, it is time to establish and examine more detailed rules. However, if Substance B has a measured BCF value of less than 500 (BCF<500), on the basis of this theory, it may, in principle, be assessed that Substance A is not highly bioaccumulative (excluding a substance with extremely high lipophilicity (for example, log Pow > 6.0), even if it s BCF is less than 500). With this theory, it is considered that we can also estimate bioaccumulation by from the parent substance to degradant, from degradant A to degradant B or from degradant to parent substance. In these cases, it is considered that such estimation can be made only if the chemical structure (in particular, the basic skeleton) of the substance of concern is observed to be similar to that of the counterpart, for example, by mass spectrum. Besides, the comparison of hydrophilicity (polarity) by HPLC shall not be applied, for the time being, to surfactants, organometallic compounds, low purity substances, and inorganic substances. In addition, the judgment on whether Substances A and B are similar in structure to each other A and B shall be made based on the same criteria as described in the above Provision 1. (Note 1) If Chemical Substance A is suspected of being highly bioaccumulative based on the available information about it, even when it is applicable to either the above-mentioned Provision 1. or 2., the substance may not be assessed to be not highly accumulative and the 5

6 business operator (notifier) may be requested to conduct actual testing, etc. (Note 2) The degradants generated from polymers during biodegradation testing may be difficult to be isolated and identified and, therefore, both their hydrophilicity (polarity) evaluation by using HPLC and bioconcentration testing may be difficult to be conducted. In such a case, the bioaccumulation of the degradant may be assessed, in accordance with the theory shown in Provision 1., by analog approach based on the rationally estimated chemical structure of the degradant and the bioaccumulation data of a parent compound, etc. Since it is considered that there are various cases (including such a case) in which degradants generated from polymers are involved, we will not simply apply these criteria to any case but will make a case-by-case judgment, in light of the theory of the criteria, depending on the individual consultations with business operators. (End of the document) 6