Assessment of the Equivalence of Technical Materials - European ...

More documents

Recommendations

Info

Irrespective of the above three paragraphs, if a more severe hazard classification is necessaryfor the new source compared to the reference source, equivalence can not be stated.7.1.4 ReportingA report must be prepared in the currently available format (see Appendix VII)7.2 Ecotoxicity7.2.1 Data requirements and evaluation processIn analogy to the toxicity evaluation process, the objective is to identify whether there is anunacceptable increase in the ecotoxicity of the new source caused by new impurities and/orsignificantly increased levels of impurities already present in the reference substance(compare chapter 6.1.2).If new or increased levels of impurities are present, the applicant must provide a case and/ordata to show that the new source is not significantly more ecotoxic than the reference source.If there is evidence that a new or increased level of an impurity will NOT have a significantadverse effect on the ecotoxicity of the new source compared with the reference source, thenew source is equivalent to the reference source. However, if there is evidence that a new orincreased level of an impurity will have a significant adverse effect on the ecotoxicity of thenew source compared with the reference source, the new source is not equivalent to thereference source.The assessment of the ecotoxicity of impurities should, in principle, address all organism taxaand endpoints given in Directive 91/414/EEC, Annex II chapter 8 (i.e., a change in thecomposition of the active substance should not lead to a higher hazard to any species in theenvironment) and thereupon follow similar considerations as described for the toxicologyassessment in chapter 6.1.2 a) and b). However, the existing differences in assessmentstrategies between toxicology and ecotoxicology imply a different weighting of possibleapproaches for performing assessments in situations with few available experimental data onecotoxicity. In particular, the use of SAR or QSAR approaches is limited by the loweravailability of reliable models for the whole spectrum of taxonomic groups occurring in theenvironment.10
a) Prediction of the expected increase in toxicity for assessing the ecotoxicologicalrepresentativenessA generic approach based on the pharmacological reference concept of concentrationadditivity (Loewe & Muischnek, 1926; Finney, 1971; Kortenkamp et al.., 2010) is suggestedas the preferred choice in cases where experimental ecotoxicity data on the new source orspecific impurities are lacking. This concept postulates a strictly similar mode-of-action (onthe molecular scale) of the mixture component, whereas the individual potency (efficacy) canvary. For a multi-component system of n compounds, the concept allows a prediction ofmixture effect concentrations based on single-compound effect concentrations according tothe following equation.ECx( mix)() i()⎛ p= ⎜∑ n⎝ i ECxi⎞⎟⎠−1(1)with:n = number of mixture componentsi = index from 1…n, assigns the mixture componentsmix = mixtureEC x = concentration causing x % effectp(i) = relative fraction of the i-th component in the mixtureApplication for a binary mixture ABThe scenario refers to a binary mixture AB consisting of the impurity to be assessed, A at anamount of p(A) and the active substance, B (in this context: sum of all other mixturecomponents) at an amount of p(B) = 1 – p(A). If it is assumed that the toxicity of the impuritycompound A is higher by a factor of f than the active-substance compound B, the followingequation can be derived.ECx( AB)× ECx( A)( −1) × p( A) + 1= ff(2)If a value is known for the toxicity of the impurity compound A, this can be used forcalculating the factor f based on the also already known value for the overall toxicity of themixture AB as follows.( B)( A)( AB) − p( A) × ECx( AB)( A) − p( A) × EC ( AB)ECxECxf = =(3)EC ECxxxCare must be taken that the effect concentrations of all individual compounds for an endpointof interest are obtained under identical or at least largely similar test conditions (species, testduration, type of exposure, etc.), in order to allow the equation to be used. If suchexperimental values for effect concentrations do not exist, it is possible as an alternativeoption to estimate the order of magnitude of unknown effect concentrations using a validatedQSAR model. The applicability of a certain model for the concrete case must always besubstantiated.11
Page 1 and 2: EUROPEAN COMMISSIONHEALTH AND CONSU
Page 3 and 4: 1 Implementing scheduleThis amended
Page 5 and 6: Significant impuritiesImpurities th
Page 7 and 8: 7.1.2 Evaluation processThe objecti
Page 9: If the answer is yes, it might be a
Page 13 and 14: Bridging across different media (e.
Page 15 and 16: Loewe, S, Muischnek, H. (1926). Üb
Page 17 and 18: 1. Ascertainment of the necessity t
Page 19 and 20: Appendix Ib: Evaluation and decisio
Page 21 and 22: Appendix III, which is based on a l
Page 23 and 24: tests with information provided on
Page 25 and 26: Appendix IV Guideline triggers for
Page 27 and 28: Appendix V How to judge what is an
Page 29 and 30: Appendix VI Example calculations fo
Page 31 and 32: TABLE OF CONTENTS1 STATEMENT OF THE
Page 33 and 34: A.4 MANUFACTURER’S DEVELOPMENT CO
Page 35 and 36: XXXXXXAccuracy:XXXXXXPrecisionXXXXX
Page 37: SUMMARY OF THE TECHNICAL EQUIVALENC

Assessment of the Equivalence of Technical Materials - European ...

You also want an ePaper? Increase the reach of your titles

Delete template?

Save as template?