Transfluthrin: Comparative efficacy and toxicity of reference and generic versions
•Analytical procedures focused on purity do not necessarily quantify reactive impurities.•Impurities
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| Veröffentlicht in: | Regulatory toxicology and pharmacology 2015-02, Vol.71 (1), p.78-92 |
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| container_title | Regulatory toxicology and pharmacology |
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| creator | Pauluhn, Juergen Ozaki, Keisuke |
| description | •Analytical procedures focused on purity do not necessarily quantify reactive impurities.•Impurities |
| doi_str_mv | 10.1016/j.yrtph.2014.11.003 |
| format | Article |
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Stringent requirements are in place for the evaluation and registration of new compounds with biocidal or pesticidal activities. However, the registration requirements for established compounds from new suppliers or for established compounds produced by a different manufacturing process have been less clear and ambiguity exists as to how ‘equivalence of health hazards’ can unequivocally be demonstrated analytically and by toxicological assays. The case presented in this analysis focuses on the chiral pyrethroid transfluthrin (TFL) synthesized by esterification of an acid chloride and alcoholic moiety. According to any modifications of the process of synthesis and purification, new potentially highly toxic and yet chemically reactive impurities in low concentrations (<0.1%) may be formed. Amongst these, that with the structural alert ‘organic acid anhydride’ was given heightened concern as the most potent putative toxicologically significant impurity. The course taken in this analysis focused on the comparison of reference TFL with commercialized generic TFL from two alternative manufacturing sources in India and China. Despite their apparent high racemic purity, TFLs from generic sources were biologically less effective, genotoxic in the Ames’ assay, demonstrated sensory lung irritation and lung/skin sensitization in specialized bioassays. While the off-patent reference TFL was unequivocally negative in all assays (anhydride content not detectable, LOQ <0.01%), positive results with high batch-to-batch variability were a frequent outcome in generic TFLs. Tier I analytical assays failed to detect this relevant impurity in the absence of impurity-specific optimized analytical procedures. This finding suggests that a well-balanced combined approach of analytical and toxicological assays provides the best means to assure that all critical impurities are identified and accounted for. Similarly, putative ‘structural alert’-based toxicity tests proved to be more predictive than any indiscriminant battery of standard bioassays commonly applied to demonstrate equivalence, such as acute oral/dermal toxicity and/or eye/skin irritation assays.</description><identifier>ISSN: 0273-2300</identifier><identifier>EISSN: 1096-0295</identifier><identifier>DOI: 10.1016/j.yrtph.2014.11.003</identifier><identifier>PMID: 25448443</identifier><language>eng</language><publisher>Netherlands: Elsevier Inc</publisher><subject>Administration, Inhalation ; Animals ; Bayothrin ; Chemical Industry ; China ; Culicidae - drug effects ; Cyclopropanes - blood ; Cyclopropanes - pharmacokinetics ; Cyclopropanes - toxicity ; Dermatitis, Allergic Contact - etiology ; Fluorobenzenes - blood ; Fluorobenzenes - pharmacokinetics ; Fluorobenzenes - toxicity ; Germany ; Guinea Pigs ; India ; Irritants - blood ; Irritants - pharmacokinetics ; Irritants - toxicity ; Male ; Permethric acid derivatives ; Pesticides - blood ; Pesticides - pharmacokinetics ; Pesticides - toxicity ; Rabbits ; Rats, Wistar ; Relevant impurities ; Respiratory Hypersensitivity - etiology ; Risk characterization ; Sensitization ; Toxicity Tests ; Transfluthrin</subject><ispartof>Regulatory toxicology and pharmacology, 2015-02, Vol.71 (1), p.78-92</ispartof><rights>2014 The Authors</rights><rights>Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c437t-e48aa4180300fb8af54114359dd295a61ecbf9ee63320956943032978aeaa0b53</citedby><cites>FETCH-LOGICAL-c437t-e48aa4180300fb8af54114359dd295a61ecbf9ee63320956943032978aeaa0b53</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.yrtph.2014.11.003$$EHTML$$P50$$Gelsevier$$Hfree_for_read</linktohtml><link.rule.ids>315,781,785,3551,27929,27930,46000</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/25448443$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Pauluhn, Juergen</creatorcontrib><creatorcontrib>Ozaki, Keisuke</creatorcontrib><title>Transfluthrin: Comparative efficacy and toxicity of reference and generic versions</title><title>Regulatory toxicology and pharmacology</title><addtitle>Regul Toxicol Pharmacol</addtitle><description>•Analytical procedures focused on purity do not necessarily quantify reactive impurities.•Impurities <0.1% may be difficult to quantify unless specific assays are developed.•Structural-alert based bioassays and analytical methods are needed side-by-side.•Technical equivalence of substances require integrated Tier I and II approaches.
Stringent requirements are in place for the evaluation and registration of new compounds with biocidal or pesticidal activities. However, the registration requirements for established compounds from new suppliers or for established compounds produced by a different manufacturing process have been less clear and ambiguity exists as to how ‘equivalence of health hazards’ can unequivocally be demonstrated analytically and by toxicological assays. The case presented in this analysis focuses on the chiral pyrethroid transfluthrin (TFL) synthesized by esterification of an acid chloride and alcoholic moiety. According to any modifications of the process of synthesis and purification, new potentially highly toxic and yet chemically reactive impurities in low concentrations (<0.1%) may be formed. Amongst these, that with the structural alert ‘organic acid anhydride’ was given heightened concern as the most potent putative toxicologically significant impurity. The course taken in this analysis focused on the comparison of reference TFL with commercialized generic TFL from two alternative manufacturing sources in India and China. Despite their apparent high racemic purity, TFLs from generic sources were biologically less effective, genotoxic in the Ames’ assay, demonstrated sensory lung irritation and lung/skin sensitization in specialized bioassays. While the off-patent reference TFL was unequivocally negative in all assays (anhydride content not detectable, LOQ <0.01%), positive results with high batch-to-batch variability were a frequent outcome in generic TFLs. Tier I analytical assays failed to detect this relevant impurity in the absence of impurity-specific optimized analytical procedures. This finding suggests that a well-balanced combined approach of analytical and toxicological assays provides the best means to assure that all critical impurities are identified and accounted for. Similarly, putative ‘structural alert’-based toxicity tests proved to be more predictive than any indiscriminant battery of standard bioassays commonly applied to demonstrate equivalence, such as acute oral/dermal toxicity and/or eye/skin irritation assays.</description><subject>Administration, Inhalation</subject><subject>Animals</subject><subject>Bayothrin</subject><subject>Chemical Industry</subject><subject>China</subject><subject>Culicidae - drug effects</subject><subject>Cyclopropanes - blood</subject><subject>Cyclopropanes - pharmacokinetics</subject><subject>Cyclopropanes - toxicity</subject><subject>Dermatitis, Allergic Contact - etiology</subject><subject>Fluorobenzenes - blood</subject><subject>Fluorobenzenes - pharmacokinetics</subject><subject>Fluorobenzenes - toxicity</subject><subject>Germany</subject><subject>Guinea Pigs</subject><subject>India</subject><subject>Irritants - blood</subject><subject>Irritants - pharmacokinetics</subject><subject>Irritants - toxicity</subject><subject>Male</subject><subject>Permethric acid derivatives</subject><subject>Pesticides - blood</subject><subject>Pesticides - pharmacokinetics</subject><subject>Pesticides - toxicity</subject><subject>Rabbits</subject><subject>Rats, Wistar</subject><subject>Relevant impurities</subject><subject>Respiratory Hypersensitivity - etiology</subject><subject>Risk characterization</subject><subject>Sensitization</subject><subject>Toxicity Tests</subject><subject>Transfluthrin</subject><issn>0273-2300</issn><issn>1096-0295</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kEtPwzAQhC0EoqXwC5BQjlwS1rGTOEgcUMVLqoSEytlynDV1lRd2WpF_T9oCR0572Jmd2Y-QSwoRBZrerKPB9d0qioHyiNIIgB2RKYU8DSHOk2MyhThjYcwAJuTM-zUAxEJkp2QSJ5wLztmUvC2darypNv3K2eY2mLd1p5zq7RYDNMZqpYdANWXQt19W234IWhM4NOiw0bjffGCDzupgi87btvHn5MSoyuPFz5yR98eH5fw5XLw-vczvF6HmLOtD5EIpTgWM_UwhlEk4pZwleVmO7VVKURcmR0wZiyFP0pwzYHGeCYVKQZGwGbk-3O1c-7lB38vaeo1VpRpsN17SNOGp4JlIRyk7SLVrvR_ry87ZWrlBUpA7mHIt9zDlDqakVI4wR9fVT8CmqLH88_zSGwV3BwGOb24tOum13XEprUPdy7K1_wZ8AwUehvY</recordid><startdate>201502</startdate><enddate>201502</enddate><creator>Pauluhn, Juergen</creator><creator>Ozaki, Keisuke</creator><general>Elsevier Inc</general><scope>6I.</scope><scope>AAFTH</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7ST</scope><scope>7T2</scope><scope>7U1</scope><scope>7U2</scope><scope>7U7</scope><scope>C1K</scope><scope>SOI</scope></search><sort><creationdate>201502</creationdate><title>Transfluthrin: Comparative efficacy and toxicity of reference and generic versions</title><author>Pauluhn, Juergen ; Ozaki, Keisuke</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c437t-e48aa4180300fb8af54114359dd295a61ecbf9ee63320956943032978aeaa0b53</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><topic>Administration, Inhalation</topic><topic>Animals</topic><topic>Bayothrin</topic><topic>Chemical Industry</topic><topic>China</topic><topic>Culicidae - drug effects</topic><topic>Cyclopropanes - blood</topic><topic>Cyclopropanes - pharmacokinetics</topic><topic>Cyclopropanes - toxicity</topic><topic>Dermatitis, Allergic Contact - etiology</topic><topic>Fluorobenzenes - blood</topic><topic>Fluorobenzenes - pharmacokinetics</topic><topic>Fluorobenzenes - toxicity</topic><topic>Germany</topic><topic>Guinea Pigs</topic><topic>India</topic><topic>Irritants - blood</topic><topic>Irritants - pharmacokinetics</topic><topic>Irritants - toxicity</topic><topic>Male</topic><topic>Permethric acid derivatives</topic><topic>Pesticides - blood</topic><topic>Pesticides - pharmacokinetics</topic><topic>Pesticides - toxicity</topic><topic>Rabbits</topic><topic>Rats, Wistar</topic><topic>Relevant impurities</topic><topic>Respiratory Hypersensitivity - etiology</topic><topic>Risk characterization</topic><topic>Sensitization</topic><topic>Toxicity Tests</topic><topic>Transfluthrin</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Pauluhn, Juergen</creatorcontrib><creatorcontrib>Ozaki, Keisuke</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect:Open Access</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Environment Abstracts</collection><collection>Health and Safety Science Abstracts (Full archive)</collection><collection>Risk Abstracts</collection><collection>Safety Science and Risk</collection><collection>Toxicology Abstracts</collection><collection>Environmental Sciences and Pollution Management</collection><collection>Environment Abstracts</collection><jtitle>Regulatory toxicology and pharmacology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Pauluhn, Juergen</au><au>Ozaki, Keisuke</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Transfluthrin: Comparative efficacy and toxicity of reference and generic versions</atitle><jtitle>Regulatory toxicology and pharmacology</jtitle><addtitle>Regul Toxicol Pharmacol</addtitle><date>2015-02</date><risdate>2015</risdate><volume>71</volume><issue>1</issue><spage>78</spage><epage>92</epage><pages>78-92</pages><issn>0273-2300</issn><eissn>1096-0295</eissn><abstract>•Analytical procedures focused on purity do not necessarily quantify reactive impurities.•Impurities <0.1% may be difficult to quantify unless specific assays are developed.•Structural-alert based bioassays and analytical methods are needed side-by-side.•Technical equivalence of substances require integrated Tier I and II approaches.
Stringent requirements are in place for the evaluation and registration of new compounds with biocidal or pesticidal activities. However, the registration requirements for established compounds from new suppliers or for established compounds produced by a different manufacturing process have been less clear and ambiguity exists as to how ‘equivalence of health hazards’ can unequivocally be demonstrated analytically and by toxicological assays. The case presented in this analysis focuses on the chiral pyrethroid transfluthrin (TFL) synthesized by esterification of an acid chloride and alcoholic moiety. According to any modifications of the process of synthesis and purification, new potentially highly toxic and yet chemically reactive impurities in low concentrations (<0.1%) may be formed. Amongst these, that with the structural alert ‘organic acid anhydride’ was given heightened concern as the most potent putative toxicologically significant impurity. The course taken in this analysis focused on the comparison of reference TFL with commercialized generic TFL from two alternative manufacturing sources in India and China. Despite their apparent high racemic purity, TFLs from generic sources were biologically less effective, genotoxic in the Ames’ assay, demonstrated sensory lung irritation and lung/skin sensitization in specialized bioassays. While the off-patent reference TFL was unequivocally negative in all assays (anhydride content not detectable, LOQ <0.01%), positive results with high batch-to-batch variability were a frequent outcome in generic TFLs. Tier I analytical assays failed to detect this relevant impurity in the absence of impurity-specific optimized analytical procedures. This finding suggests that a well-balanced combined approach of analytical and toxicological assays provides the best means to assure that all critical impurities are identified and accounted for. Similarly, putative ‘structural alert’-based toxicity tests proved to be more predictive than any indiscriminant battery of standard bioassays commonly applied to demonstrate equivalence, such as acute oral/dermal toxicity and/or eye/skin irritation assays.</abstract><cop>Netherlands</cop><pub>Elsevier Inc</pub><pmid>25448443</pmid><doi>10.1016/j.yrtph.2014.11.003</doi><tpages>15</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Administration, Inhalation Animals Bayothrin Chemical Industry China Culicidae - drug effects Cyclopropanes - blood Cyclopropanes - pharmacokinetics Cyclopropanes - toxicity Dermatitis, Allergic Contact - etiology Fluorobenzenes - blood Fluorobenzenes - pharmacokinetics Fluorobenzenes - toxicity Germany Guinea Pigs India Irritants - blood Irritants - pharmacokinetics Irritants - toxicity Male Permethric acid derivatives Pesticides - blood Pesticides - pharmacokinetics Pesticides - toxicity Rabbits Rats, Wistar Relevant impurities Respiratory Hypersensitivity - etiology Risk characterization Sensitization Toxicity Tests Transfluthrin |
| title | Transfluthrin: Comparative efficacy and toxicity of reference and generic versions |
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