Brodifacoum (PIM 077)

<HTML> <HEAD> <META HTTP-EQUIV="Content-Type" CONTENT="text/html; charset=iso-8859-1"> <TITLE>Brodifacoum (PIM 077)</TITLE> </HEAD> <BODY BGCOLOR="#FFFFFF"> <A HREF="http://www.inchem.org"><IMG SRC="../../inchemhead.jpg" WIDTH="630" HEIGHT="65" BORDER="0" ALT="IPCS INCHEM Home"></A><CENTER><H1>Brodifacoum</H1></CENTER> <CENTER><TABLE WIDTH=500> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER><A HREF="#PartTitle:1. NAME">1. NAME</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>   <A HREF="#SectionTitle:1.1 Substance">1.1 Substance</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>   <A HREF="#SectionTitle:1.2 Group">1.2 Group</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>   <A HREF="#SectionTitle:1.3 Synonyms">1.3 Synonyms</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>   <A HREF="#SectionTitle:1.4 Identification numbers">1.4 Identification numbers</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>      <A HREF="#SubSectionTitle:1.4.1 CAS number">1.4.1 CAS number</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>      <A HREF="#SubSectionTitle:1.4.2 Other numbers">1.4.2 Other numbers</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>   <A HREF="#SectionTitle:1.5 Main brand names, main trade names">1.5 Main brand names, main trade names</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>   <A HREF="#SectionTitle:1.6 Main manufacturers, main importers">1.6 Main manufacturers, main importers</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER><A HREF="#PartTitle:2. SUMMARY">2. SUMMARY</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>   <A HREF="#SectionTitle:2.1 Main risks and target organs">2.1 Main risks and target organs</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>   <A HREF="#SectionTitle:2.2 Summary of clinical effects">2.2 Summary of clinical effects</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>   <A HREF="#SectionTitle:2.3 Diagnosis">2.3 Diagnosis</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>   <A HREF="#SectionTitle:2.4 First-aid measures and management principles">2.4 First-aid measures and management principles</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER><A HREF="#PartTitle:3. PHYSICO-CHEMICAL PROPERTIES">3. PHYSICO-CHEMICAL PROPERTIES</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>   <A HREF="#SectionTitle:3.1 Origin of the substance">3.1 Origin of the substance</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>   <A HREF="#SectionTitle:3.2 Chemical structure">3.2 Chemical structure</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>   <A HREF="#SectionTitle:3.3 Physical properties">3.3 Physical properties</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>      <A HREF="#SubSectionTitle:3.3.1 Colour">3.3.1 Colour</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>      <A HREF="#SubSectionTitle:3.3.2 State/form">3.3.2 State/form</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>      <A HREF="#SubSectionTitle:3.3.3 Description">3.3.3 Description</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>   <A HREF="#SectionTitle:3.4 Hazardous characteristics">3.4 Hazardous characteristics</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER><A HREF="#PartTitle:4. USES">4. USES</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>   <A HREF="#SectionTitle:4.1 Uses">4.1 Uses</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>      <A HREF="#SubSectionTitle:4.1.1 Uses">4.1.1 Uses</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>      <A HREF="#SubSectionTitle:4.1.2 Description">4.1.2 Description</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>   <A HREF="#SectionTitle:4.2 High risk circumstance of poisoning">4.2 High risk circumstance of poisoning</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>   <A HREF="#SectionTitle:4.3 Occupationally exposed populations">4.3 Occupationally exposed populations</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER><A HREF="#PartTitle:5. ROUTES OF ENTRY">5. ROUTES OF ENTRY</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>   <A HREF="#SectionTitle:5.1 Oral">5.1 Oral</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>   <A HREF="#SectionTitle:5.2 Inhalation">5.2 Inhalation</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>   <A HREF="#SectionTitle:5.3 Dermal">5.3 Dermal</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>   <A HREF="#SectionTitle:5.4 Eye">5.4 Eye</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>   <A HREF="#SectionTitle:5.5 Parenteral">5.5 Parenteral</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>   <A HREF="#SectionTitle:5.6 Others">5.6 Others</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER><A HREF="#PartTitle:6. KINETICS">6. KINETICS</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>   <A HREF="#SectionTitle:6.1 Absorption by route of exposure">6.1 Absorption by route of exposure</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>   <A HREF="#SectionTitle:6.2 Distribution by route of exposure">6.2 Distribution by route of exposure</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>   <A HREF="#SectionTitle:6.3 Biological half-life by route of exposure">6.3 Biological half-life by route of exposure</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>   <A HREF="#SectionTitle:6.4 Metabolism">6.4 Metabolism</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>   <A HREF="#SectionTitle:6.5 Elimination by route of exposure">6.5 Elimination by route of exposure</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER><A HREF="#PartTitle:7. TOXICOLOGY">7. TOXICOLOGY</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>   <A HREF="#SectionTitle:7.1 Mode of Action">7.1 Mode of Action</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>   <A HREF="#SectionTitle:7.2 Toxicity">7.2 Toxicity</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>      <A HREF="#SubSectionTitle:7.2.1 Human data">7.2.1 Human data</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>         <A HREF="#DivisionTitle:7.2.1.1 Adults">7.2.1.1 Adults</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>         <A HREF="#DivisionTitle:7.2.1.2 Children">7.2.1.2 Children</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>      <A HREF="#SubSectionTitle:7.2.2 Relevant animal data">7.2.2 Relevant animal data</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>      <A HREF="#SubSectionTitle:7.2.3 Relevant in vitro data">7.2.3 Relevant in vitro data</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>      <A HREF="#SubSectionTitle:7.2.4 Workplace standards">7.2.4 Workplace standards</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>      <A HREF="#SubSectionTitle:7.2.5 Acceptable daily intake (ADI) and other guideline levels">7.2.5 Acceptable daily intake (ADI) and other guideline levels</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>   <A HREF="#SectionTitle:7.3 Carcinogenicity">7.3 Carcinogenicity</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>   <A HREF="#SectionTitle:7.4 Teratogenicity">7.4 Teratogenicity</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>   <A HREF="#SectionTitle:7.5 Mutagenicity">7.5 Mutagenicity</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>   <A HREF="#SectionTitle:7.6 Interactions">7.6 Interactions</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER><A HREF="#PartTitle:8. TOXICOLOGICAL ANALYSES AND BIOMEDICAL INVESTIGATIONS">8. TOXICOLOGICAL ANALYSES AND BIOMEDICAL INVESTIGATIONS</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>   <A HREF="#SectionTitle:8.1 Material sampling plan">8.1 Material sampling plan</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>      <A HREF="#SubSectionTitle:8.1.1 Sampling and specimen collection">8.1.1 Sampling and specimen collection</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>         <A HREF="#DivisionTitle:8.1.1.1 Toxicological analyses">8.1.1.1 Toxicological analyses</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>         <A HREF="#DivisionTitle:8.1.1.2 Biomedical analyses">8.1.1.2 Biomedical analyses</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>         <A HREF="#DivisionTitle:8.1.1.3 Arterial blood gas analysis">8.1.1.3 Arterial blood gas analysis</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>         <A HREF="#DivisionTitle:8.1.1.4 Haematological analyses">8.1.1.4 Haematological analyses</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>         <A HREF="#DivisionTitle:8.1.1.5 Other (unspecified) analyses">8.1.1.5 Other (unspecified) analyses</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>      <A HREF="#SubSectionTitle:8.1.2 Storage of laboratory samples and specimens">8.1.2 Storage of laboratory samples and specimens</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>         <A HREF="#DivisionTitle:8.1.2.1 Toxicological analyses">8.1.2.1 Toxicological analyses</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>         <A HREF="#DivisionTitle:8.1.2.2 Biomedical analyses">8.1.2.2 Biomedical analyses</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>         <A HREF="#DivisionTitle:8.1.2.3 Arterial blood gas analysis">8.1.2.3 Arterial blood gas analysis</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>         <A HREF="#DivisionTitle:8.1.2.4 Haematological analyses">8.1.2.4 Haematological analyses</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>         <A HREF="#DivisionTitle:8.1.2.5 Other (unspecified) analyses">8.1.2.5 Other (unspecified) analyses</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>      <A HREF="#SubSectionTitle:8.1.3 Transport of laboratory samples and specimens">8.1.3 Transport of laboratory samples and specimens</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>         <A HREF="#DivisionTitle:8.1.3.1 Toxicological analyses">8.1.3.1 Toxicological analyses</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>         <A HREF="#DivisionTitle:8.1.3.2 Biomedical analyses">8.1.3.2 Biomedical analyses</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>         <A HREF="#DivisionTitle:8.1.3.3 Arterial blood gas analysis">8.1.3.3 Arterial blood gas analysis</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>         <A HREF="#DivisionTitle:8.1.3.4 Haematological analyses">8.1.3.4 Haematological analyses</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>         <A HREF="#DivisionTitle:8.1.3.5 Other (unspecified) analyses">8.1.3.5 Other (unspecified) analyses</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>   <A HREF="#SectionTitle:8.2 Toxicological analyses and their interpretation">8.2 Toxicological analyses and their interpretation</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>      <A HREF="#SubSectionTitle:8.2.1 Tests on toxic ingredient(s) of material">8.2.1 Tests on toxic ingredient(s) of material</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>         <A HREF="#DivisionTitle:8.2.1.1 Simple qualitative test(s)">8.2.1.1 Simple qualitative test(s)</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>         <A HREF="#DivisionTitle:8.2.1.2 Advanced qualitative confirmation test(s)">8.2.1.2 Advanced qualitative confirmation test(s)</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>         <A HREF="#DivisionTitle:8.2.1.3 Simple quantitative method(s)">8.2.1.3 Simple quantitative method(s)</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>         <A HREF="#DivisionTitle:8.2.1.4 Advanced quantitative method(s)">8.2.1.4 Advanced quantitative method(s)</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>      <A HREF="#SubSectionTitle:8.2.2 Tests for biological specimens">8.2.2 Tests for biological specimens</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>         <A HREF="#DivisionTitle:8.2.2.1 Simple qualitative test(s)">8.2.2.1 Simple qualitative test(s)</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>         <A HREF="#DivisionTitle:8.2.2.2 Advanced qualitative confirmation test(s)">8.2.2.2 Advanced qualitative confirmation test(s)</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>         <A HREF="#DivisionTitle:8.2.2.3 Simple quantitative method(s)">8.2.2.3 Simple quantitative method(s)</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>         <A HREF="#DivisionTitle:8.2.2.4 Advanced quantitative method(s)">8.2.2.4 Advanced quantitative method(s)</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>         <A HREF="#DivisionTitle:8.2.2.5 Other dedicated method(s)">8.2.2.5 Other dedicated method(s)</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>      <A HREF="#SubSectionTitle:8.2.3 Interpretation of toxicological analyses">8.2.3 Interpretation of toxicological analyses</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>   <A HREF="#SectionTitle:8.3 Biomedical investigations and their interpretation">8.3 Biomedical investigations and their interpretation</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>      <A HREF="#SubSectionTitle:8.3.1 Biochemical analysis">8.3.1 Biochemical analysis</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>         <A HREF="#DivisionTitle:8.3.1.1 Blood, plasma or serum">8.3.1.1 Blood, plasma or serum</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>         <A HREF="#DivisionTitle:8.3.1.2 Urine">8.3.1.2 Urine</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>         <A HREF="#DivisionTitle:8.3.1.3 Other fluids">8.3.1.3 Other fluids</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>      <A HREF="#SubSectionTitle:8.3.2 Arterial blood gas analyses">8.3.2 Arterial blood gas analyses</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>      <A HREF="#SubSectionTitle:8.3.3 Haematological analyses">8.3.3 Haematological analyses</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>      <A HREF="#SubSectionTitle:8.3.4 Interpretation of biomedical investigations">8.3.4 Interpretation of biomedical investigations</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>   <A HREF="#SectionTitle:8.4 Other biomedical (diagnostic) investigations and their interpretation">8.4 Other biomedical (diagnostic) investigations and their interpretation</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>   <A HREF="#SectionTitle:8.5 Overall interpretation of all toxicological analyses and toxicological investigations">8.5 Overall interpretation of all toxicological analyses and toxicological investigations</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER><A HREF="#PartTitle:9. CLINICAL EFFECTS">9. CLINICAL EFFECTS</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>   <A HREF="#SectionTitle:9.1 Acute poisoning">9.1 Acute poisoning</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>      <A HREF="#SubSectionTitle:9.1.1 Ingestion">9.1.1 Ingestion</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>      <A HREF="#SubSectionTitle:9.1.2 Inhalation">9.1.2 Inhalation</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>      <A HREF="#SubSectionTitle:9.1.3 Skin exposure">9.1.3 Skin exposure</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>      <A HREF="#SubSectionTitle:9.1.4 Eye contact">9.1.4 Eye contact</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>      <A HREF="#SubSectionTitle:9.1.5 Parenteral exposure">9.1.5 Parenteral exposure</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>      <A HREF="#SubSectionTitle:9.1.6 Other">9.1.6 Other</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>   <A HREF="#SectionTitle:9.2 Chronic poisoning">9.2 Chronic poisoning</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>      <A HREF="#SubSectionTitle:9.2.1 Ingestion">9.2.1 Ingestion</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>      <A HREF="#SubSectionTitle:9.2.2 Inhalation">9.2.2 Inhalation</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>      <A HREF="#SubSectionTitle:9.2.3 Skin exposure">9.2.3 Skin exposure</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>      <A HREF="#SubSectionTitle:9.2.4 Eye contact">9.2.4 Eye contact</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>      <A HREF="#SubSectionTitle:9.2.5 Parenteral exposure">9.2.5 Parenteral exposure</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>      <A HREF="#SubSectionTitle:9.2.6 Other">9.2.6 Other</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>   <A HREF="#SectionTitle:9.3 Course, prognosis, cause of death">9.3 Course, prognosis, cause of death</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>   <A HREF="#SectionTitle:9.4 Systematic description of clinical effects">9.4 Systematic description of clinical effects</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>      <A HREF="#SubSectionTitle:9.4.1 Cardiovascular">9.4.1 Cardiovascular</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>      <A HREF="#SubSectionTitle:9.4.2 Respiratory">9.4.2 Respiratory</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>      <A HREF="#SubSectionTitle:9.4.3 Neurological">9.4.3 Neurological</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>         <A HREF="#DivisionTitle:9.4.3.1 Central Nervous System (CNS)">9.4.3.1 Central Nervous System (CNS)</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>         <A HREF="#DivisionTitle:9.4.3.2 Peripheral nervous system">9.4.3.2 Peripheral nervous system</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>         <A HREF="#DivisionTitle:9.4.3.3 Autonomic nervous system">9.4.3.3 Autonomic nervous system</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>         <A HREF="#DivisionTitle:9.4.3.4 Skeletal and smooth muscle">9.4.3.4 Skeletal and smooth muscle</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>      <A HREF="#SubSectionTitle:9.4.4 Gastrointestinal">9.4.4 Gastrointestinal</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>      <A HREF="#SubSectionTitle:9.4.5 Hepatic">9.4.5 Hepatic</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>      <A HREF="#SubSectionTitle:9.4.6 Urinary">9.4.6 Urinary</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>         <A HREF="#DivisionTitle:9.4.6.1 Renal">9.4.6.1 Renal</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>         <A HREF="#DivisionTitle:9.4.6.2 Others">9.4.6.2 Others</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>      <A HREF="#SubSectionTitle:9.4.7 Endocrine and reproductive systems">9.4.7 Endocrine and reproductive systems</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>      <A HREF="#SubSectionTitle:9.4.8 Dermatological">9.4.8 Dermatological</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>      <A HREF="#SubSectionTitle:9.4.9 Eye, ears, nose, throat: local effects">9.4.9 Eye, ears, nose, throat: local effects</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>      <A HREF="#SubSectionTitle:9.4.10 Haematological">9.4.10 Haematological</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>      <A HREF="#SubSectionTitle:9.4.11 Immunological">9.4.11 Immunological</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>      <A HREF="#SubSectionTitle:9.4.12 Metabolic">9.4.12 Metabolic</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>         <A HREF="#DivisionTitle:9.4.12.1 Acid-base disturbances">9.4.12.1 Acid-base disturbances</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>         <A HREF="#DivisionTitle:9.4.12.2 Fluid and electrolyte disturbances">9.4.12.2 Fluid and electrolyte disturbances</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>         <A HREF="#DivisionTitle:9.4.12.3 Others">9.4.12.3 Others</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>      <A HREF="#SubSectionTitle:9.4.13 Allergic reactions">9.4.13 Allergic reactions</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>      <A HREF="#SubSectionTitle:9.4.14 Other clinical effects">9.4.14 Other clinical effects</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>      <A HREF="#SubSectionTitle:9.4.15 Special risks">9.4.15 Special risks</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>   <A HREF="#SectionTitle:9.5 Others">9.5 Others</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>   <A HREF="#SectionTitle:9.6 Summary">9.6 Summary</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER><A HREF="#PartTitle:10. MANAGEMENT">10. MANAGEMENT</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>   <A HREF="#SectionTitle:10.1 General principles">10.1 General principles</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>   <A HREF="#SectionTitle:10.2 Life supportive procedures and symptomatic treatment">10.2 Life supportive procedures and symptomatic treatment</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>   <A HREF="#SectionTitle:10.3 Decontamination">10.3 Decontamination</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>   <A HREF="#SectionTitle:10.4 Enhanced elimination">10.4 Enhanced elimination</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>   <A HREF="#SectionTitle:10.5 Antidote treatment">10.5 Antidote treatment</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>      <A HREF="#SubSectionTitle:10.5.1 Adults">10.5.1 Adults</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>      <A HREF="#SubSectionTitle:10.5.2 Children">10.5.2 Children</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>   <A HREF="#SectionTitle:10.6 Management discussion">10.6 Management discussion</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER><A HREF="#PartTitle:11. ILLUSTRATIVE CASES">11. ILLUSTRATIVE CASES</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>   <A HREF="#SectionTitle:11.1 Case reports from literature">11.1 Case reports from literature</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER><A HREF="#PartTitle:12. ADDITIONAL INFORMATION">12. ADDITIONAL INFORMATION</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>   <A HREF="#SectionTitle:12.1 Specific preventive measures">12.1 Specific preventive measures</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>   <A HREF="#SectionTitle:12.2 Other">12.2 Other</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER><A HREF="#PartTitle:13. REFERENCES">13. REFERENCES</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER><A HREF="#PartTitle:14. AUTHOR(S), REVIEWER(S), DATE(S) (INCLUDING UPDATES), COMPLETE ADDRESS(ES)">14. AUTHOR(S), REVIEWER(S), DATE(S) (INCLUDING UPDATES), COMPLETE ADDRESS(ES)</A></TD></TR> </TABLE></CENTER> <PRE> BRODIFACOUM International Programme on Chemical Safety Poisons Information Monograph 077 Chemical <A NAME = "PartTitle:1. NAME"></A>1. NAME <A NAME = "SectionTitle:1.1 Substance"></A>1.1 Substance <PIM1.1>Brodifacoum</PIM1.1> <A NAME = "EndSectionTitle:1.1 Substance"></A><A NAME = "SectionTitle:1.2 Group"></A>1.2 Group <PIM1.2>Coumarin derivative</PIM1.2> <A NAME = "EndSectionTitle:1.2 Group"></A><A NAME = "SectionTitle:1.3 Synonyms"></A>1.3 Synonyms <PIM1.3>3-[-(4'-bromobiphenyl-4-yl)-1,2,3,4-tetrahydro-1- naphthyl]-4-3-[3-(4'-bromo[1,1'-biphenyl]-4-yl)-1,2,3,4- tetrahydro-1-bromfenacoum</PIM1.3>; <PIM1.3>super-warfarin</PIM1.3> <A NAME = "EndSectionTitle:1.3 Synonyms"></A><A NAME = "SectionTitle:1.4 Identification numbers"></A>1.4 Identification numbers <A NAME = "SubSectionTitle:1.4.1 CAS number"></A>1.4.1 CAS number <PIM1.4.1><PrimaryCasNo>56073-10-0</PrimaryCasNo></PIM1.4.1> <A NAME = ":1.4.1 CAS number"></A><A NAME = "SubSectionTitle:1.4.2 Other numbers"></A>1.4.2 Other numbers <A NAME = ":1.4.2 Other numbers"></A><A NAME = "EndSectionTitle:1.4 Identification numbers"></A><A NAME = "SectionTitle:1.5 Main brand names, main trade names"></A>1.5 Main brand names, main trade names <PIM1.5>Klerat (Uruguay, UK)<NL> Ratak (USA)<NL> Talon (USA, New Zealand)</PIM1.5> <A NAME = "EndSectionTitle:1.5 Main brand names, main trade names"></A><A NAME = "SectionTitle:1.6 Main manufacturers, main importers"></A>1.6 Main manufacturers, main importers <A NAME = "EndSectionTitle:1.6 Main manufacturers, main importers"></A><A NAME = "EndPartTitle:1. NAME"></A><A NAME = "PartTitle:2. SUMMARY"></A>2. SUMMARY <A NAME = "SectionTitle:2.1 Main risks and target organs"></A>2.1 Main risks and target organs <PIM2.1>The target system is the haematological system, with impairment of clotting. The main risks are associated with potentially fatal gastrointestinal and intracerebral haemorrhage.</PIM2.1> <A NAME = "EndSectionTitle:2.1 Main risks and target organs"></A><A NAME = "SectionTitle:2.2 Summary of clinical effects"></A>2.2 Summary of clinical effects <PIM2.2>If toxic amounts have been ingested, coagulation will be impaired, with gum bleeding, epistaxis, ecchymosis, haematomata, haematemesis, melenae, haematuria.</PIM2.2> <A NAME = "EndSectionTitle:2.2 Summary of clinical effects"></A><A NAME = "SectionTitle:2.3 Diagnosis"></A>2.3 Diagnosis <PIM2.3>The diagnosis is based on history of exposure (generally by ingestion of a rodenticide); clinical evidence of bleeding, which may appear even several days after exposure; and abnormal prothrombin time.<NL> <NL> A sample of the rodenticide should be kept for toxicological analysis (if feasible). The most relevant biomedical analysis is coagulation studies including:<NL> <NL> * Determination of clotting factors<NL> * Prothrombin time (PT)<NL> * Activated partial thromboplastin time (PTT)</PIM2.3> <A NAME = "EndSectionTitle:2.3 Diagnosis"></A><A NAME = "SectionTitle:2.4 First-aid measures and management principles"></A>2.4 First-aid measures and management principles <PIM2.4>All cases of brodifacoum ingestion should be taken to a hospital for initial clinical and laboratory evalauation. In ingestion was recent (within 3 to 6 hours) the following may be recommended:<NL> <NL> * Decontamination of the patient through gastric lavage/emesis.<NL> * Administration of activated charcoal followed by cathartics.<NL> <NL> Not all patients need to stay in the hospital but prolonged clinical and analytical follow-up is mandatory.<NL> <NL> If more than 24 hours have elapsed since ingestion, decontamination measures are not effective and the patient should be monitored closely using prothrombin time (PT) and plasma thromboplastin time (PTT). <NL> <NL> Treatment is based in the administration of vitamin K1 (phytomenadione) as indicated by the prothrombin time.<NL> <NL> Fresh frozen plasma or whole blood are indicated in cases of acute bleeding.<NL> <NL> Close clinical observation is essential to detect occult bleeding or life-threatening haemorrhage.<NL> <NL> In cases of suspected serious ingestion, vitamin K1 is indicated before signs and symptoms of haemorrhage appear.</PIM2.4> <A NAME = "EndSectionTitle:2.4 First-aid measures and management principles"></A><A NAME = "EndPartTitle:2. SUMMARY"></A><A NAME = "PartTitle:3. PHYSICO-CHEMICAL PROPERTIES"></A>3. PHYSICO-CHEMICAL PROPERTIES <A NAME = "SectionTitle:3.1 Origin of the substance"></A>3.1 Origin of the substance <PIM3.1>This synthetic anticoagulant is obtained by the condensation of 4-hydroxycoumarin with 3-(4'-bromodiphenyl-4-yl)-1,2,3,4-tetrahydronaphtol (CCINFOdisc, 1989).<NL> <NL> It was first introduced in 1975 to deal with the public health problem of warfarin-resistant rodents (Lipton & Klaas, 1984).</PIM3.1> <A NAME = "EndSectionTitle:3.1 Origin of the substance"></A><A NAME = "SectionTitle:3.2 Chemical structure"></A>3.2 Chemical structure <PIM3.2>3-[3-(4'-bromobiphenyl-4-yl)-1,2,3,4-tetrahydro-1-naphtyl] -4-hydroxcoumarin<NL> <NL> 3-[3-(4'-bromo[1,1'-biphenyl]-4-yl)-1,2,3,4-tetrahydro -1-naphthalenyl]-4-hydroxy-2H-1-benzopyran-2-one<NL> <NL> Molecular weight = 523.44<NL> <NL> C31H23-BrO3 C 71.14%, H 4.43%, Br 15.27%, O 9.17% <NL> <NL> Structural formula: <NL> <NL> <IMG SRC="pim077_1.gif" ALT="STRUCTURAL FORMULA 1"> <NL> (Budivari, 1996)<NL> <NL> Brodifacoum exists as cis and trans isomers that may be separated by chromatography and identified by nuclear magnetic resonance spectroscopy. The commercially available preparation contains variable proportions of cis/trans isomers as 50:50 and 70:30. There is no significant difference in activity between the two isomers (ICI).<NL> <NL> The lateral 4-bromo-biphenyl group provides greater stability to the compound and overcomes the development of resistance to the poison in the rat.<NL> <NL> Note: Difenacoum is very similar to brodifacoum in its chemical structure and anticoagulant effect (they are both 4-hydroxycoumarin derivatives).</PIM3.2> <A NAME = "EndSectionTitle:3.2 Chemical structure"></A><A NAME = "SectionTitle:3.3 Physical properties"></A>3.3 Physical properties <A NAME = "SubSectionTitle:3.3.1 Colour"></A>3.3.1 Colour <PIM3.3.1>Off-white to fawn powder</PIM3.3.1> <A NAME = ":3.3.1 Colour"></A><A NAME = "SubSectionTitle:3.3.2 State/form"></A>3.3.2 State/form <A NAME = ":3.3.2 State/form"></A><A NAME = "SubSectionTitle:3.3.3 Description"></A>3.3.3 Description <PIM3.3.3>Melting point: 228癈 to 230癈<NL> &lt 0.13 mPa (25癈).<NL> <NL> Vapour pressure is less than 10 mg/l at 20癈. Insoluble in water and ether, soluble in chloroform and acetone, slightly soluble in: benzene, ethanol, ethylglycerol acetate and polyethyleneglycol.<NL> <NL> Brodifacoum is a weak acid which does not readily form water-soluble salts. It does not lose activity after 30 days in direct sunlight.</PIM3.3.3> <A NAME = ":3.3.3 Description"></A><A NAME = "EndSectionTitle:3.3 Physical properties"></A><A NAME = "SectionTitle:3.4 Hazardous characteristics"></A>3.4 Hazardous characteristics <PIM3.4>Storage: commercial formulations are stable at least for two years if protected from extreme temperatures and sunlight. The container should be kept closed to maintain activity of formulation (as a bait). As a solid, it is stable under normal storage conditions. It does not corrode commonly-used metallic objects. Forms amine salts of limited solubility in water.</PIM3.4> <A NAME = "EndSectionTitle:3.4 Hazardous characteristics"></A><A NAME = "EndPartTitle:3. PHYSICO-CHEMICAL PROPERTIES"></A><A NAME = "PartTitle:4. USES"></A>4. USES <A NAME = "SectionTitle:4.1 Uses"></A>4.1 Uses <A NAME = "SubSectionTitle:4.1.1 Uses"></A>4.1.1 Uses <A NAME = ":4.1.1 Uses"></A><A NAME = "SubSectionTitle:4.1.2 Description"></A>4.1.2 Description <PIM4.1.2>Rodenticide effective against warfarin-resistant rats. It is usually sold as ready to use bait in pellets, mini-pellets and waterproof bait containing 0.005% brodifacoum (loose or in bait packs).<NL> <NL> Indicated for control of Norwegian rats, roof rats and house mice in public, industrial and commercial buildings, in residences and outdoor urban areas. The application may be carried out by professional pest control personnel orby the public in general.<NL> <NL> Theoretically, the substance may be considered for development as a therapeutic agent in anticoagulant therapy, but the difficulty in reversal of effects constitutes a major disadvantage (Jones et al., 1984).</PIM4.1.2> <A NAME = ":4.1.2 Description"></A><A NAME = "EndSectionTitle:4.1 Uses"></A><A NAME = "SectionTitle:4.2 High risk circumstance of poisoning"></A>4.2 High risk circumstance of poisoning <PIM4.2>This rodenticide is usually applied as a bait, and possibilities of food or environmental contamination are relatively low.<NL> <NL> Poisoning occurs usually after accidental ingestion by small children or suicide attempts by adults</PIM4.2> <A NAME = "EndSectionTitle:4.2 High risk circumstance of poisoning"></A><A NAME = "SectionTitle:4.3 Occupationally exposed populations"></A>4.3 Occupationally exposed populations <PIM4.3>No specific data were found on risks of occupational exposure in the manufacturing industry when handling the pure substance.</PIM4.3> <A NAME = "EndSectionTitle:4.3 Occupationally exposed populations"></A><A NAME = "EndPartTitle:4. USES"></A><A NAME = "PartTitle:5. ROUTES OF ENTRY"></A>5. ROUTES OF ENTRY <A NAME = "SectionTitle:5.1 Oral"></A>5.1 Oral <PIM5.1>This is the commonest route of entry and the only one described in the published literature.</PIM5.1> <A NAME = "EndSectionTitle:5.1 Oral"></A><A NAME = "SectionTitle:5.2 Inhalation"></A>5.2 Inhalation <PIM5.2>No data available.</PIM5.2> <A NAME = "EndSectionTitle:5.2 Inhalation"></A><A NAME = "SectionTitle:5.3 Dermal"></A>5.3 Dermal <PIM5.3>Only animal data are available: acute dermal toxicity for the male rabbit is 0.25 to 0.625 mg/kg, but if skin is abraded the dermal toxic dose is 1.25 mg/kg (ICI Ltd).</PIM5.3> <A NAME = "EndSectionTitle:5.3 Dermal"></A><A NAME = "SectionTitle:5.4 Eye"></A>5.4 Eye <PIM5.4>No data available.</PIM5.4> <A NAME = "EndSectionTitle:5.4 Eye"></A><A NAME = "SectionTitle:5.5 Parenteral"></A>5.5 Parenteral <PIM5.5>No data available.</PIM5.5> <A NAME = "EndSectionTitle:5.5 Parenteral"></A><A NAME = "SectionTitle:5.6 Others"></A>5.6 Others <PIM5.6>No data available.</PIM5.6> <A NAME = "EndSectionTitle:5.6 Others"></A><A NAME = "EndPartTitle:5. ROUTES OF ENTRY"></A><A NAME = "PartTitle:6. KINETICS"></A>6. KINETICS <A NAME = "SectionTitle:6.1 Absorption by route of exposure"></A>6.1 Absorption by route of exposure <PIM6.1>Brodifacoum is readily absorbed in the gastrointestinal tract.</PIM6.1> <A NAME = "EndSectionTitle:6.1 Absorption by route of exposure"></A><A NAME = "SectionTitle:6.2 Distribution by route of exposure"></A>6.2 Distribution by route of exposure <PIM6.2>Brodifacoum and related compounds bind more strongly to a lipophilic site in the liver than does warfarin. In the poisoned rat, hepatic concentrations of the substance are 20 times higher than the serum concentrations (Bachman & Sullivan, 1983).</PIM6.2> <A NAME = "EndSectionTitle:6.2 Distribution by route of exposure"></A><A NAME = "SectionTitle:6.3 Biological half-life by route of exposure"></A>6.3 Biological half-life by route of exposure <PIM6.3>As with all super-warfarins, brodifacoum has a very long plasma half-life. Metabolic studies in animals have shown a half-life of approximately 24 days (Fitzgerald & Bronstein, 1987), 120 days in the dog (Lipton & Klaas, 1984), and 156 hours in the rat (Bachman & Sullivan, 1983).<NL> <NL> Warfarin has a plasma half-life of 42 hours and, assuming a normal liver function and diet, its anticoagulant effect disappears in a few days. By contrast, the anticoagulant effect of brodifacoum may last for more than 7 weeks in the poisoned patient (Jones et al., 1984).</PIM6.3> <A NAME = "EndSectionTitle:6.3 Biological half-life by route of exposure"></A><A NAME = "SectionTitle:6.4 Metabolism"></A>6.4 Metabolism <PIM6.4>The metabolism of brodifacoum has not been fully defined, but considering that it has a substituted 4-hydroxycoumarin ring structure, it is probably metabolized in a similar manner to warfarin. It is hydroxylated to inactive compounds by mixed function oxidase enzymes in hepatic microsomes (Jones et al., 1984). Phenobarbital is known to increase the activity of the hepatocellular microsomal enzyme system, and would increase brodifacoum's metabolism as it does with warfarin. In the animal, it has been demonstrated that pretreatment with phenobarbital decreases the anticoagulant effect of brodifacoum (Bachman & Sullivan, 1983).</PIM6.4> <A NAME = "EndSectionTitle:6.4 Metabolism"></A><A NAME = "SectionTitle:6.5 Elimination by route of exposure"></A>6.5 Elimination by route of exposure <PIM6.5>The elimination of brodifacoum is probably similar to that of warfarin: compounds resulting from the hydroxylation in the hepatocellular mixed function oxidases system are excreted in the urine (Jones et al., 1984).</PIM6.5> <A NAME = "EndSectionTitle:6.5 Elimination by route of exposure"></A><A NAME = "EndPartTitle:6. KINETICS"></A><A NAME = "PartTitle:7. TOXICOLOGY"></A>7. TOXICOLOGY <A NAME = "SectionTitle:7.1 Mode of Action"></A>7.1 Mode of Action <PIM7.1>Brodifacoum acts by inhibiting the vitamin K epoxide reductase in the vitamin K1-epoxide cycle (Park et al., 1979), impeding the cyclic regeneration of vitamin K1, resulting in hypoprothrombinemia. Under physiological conditions, the oxidation of vitamin K in the hepatocyte is coupled to a carboxylation step essential for activation of prothrombin factors from inactive precursors. Brodifacoum produces hypoprothrombinaemia because the coupled carboxylationreaction is inhibited (Lipton & Klaas, 1984). If therapeutic doses of vitamin K1 are given, additional substrate becomes available to resume the cycle and continue the carboxylation process, reversing the hypoprothrombinaemia(Lipton & Klaas, 1984).<NL> <NL> The superwarfarins produce a diminution of the vitamin K-dependent carboxylation of glutamic acid residues in prothrombin factor precursors. This effect is 100 times greater on molar basis than that of warfarin. This, with brodifacoum's very long plasma half-life, results in a potent anticoagulant effect.<NL> <NL> A longitudinal analysis of alterations in specific coagulation factors in a poisoning case reported by Hoffman et al. (1988) demonstrated a profound decrease of factors II, VII, IX and X, lasting at least 43 days post-ingestion.</PIM7.1> <A NAME = "EndSectionTitle:7.1 Mode of Action"></A><A NAME = "SectionTitle:7.2 Toxicity"></A>7.2 Toxicity <A NAME = "SubSectionTitle:7.2.1 Human data"></A>7.2.1 Human data <A NAME = "DivisionTitle:7.2.1.1 Adults"></A>7.2.1.1 Adults <PIM7.2.1.1>The ingestion of thirty 50 g packages of brodifacoum over a two-day period by a 31-year-old psychotic woman produced generalized ecchymosis and abortion. The estimated ingested dose was 75 mg (Lipton & Klaas, 1984).<NL> <NL> A 17-year-old male adolescent ingested approximately 7.5 mg (0.12 mg/kg) of brodifacoum and was admitted to the hospital with flank pain and important haematuria, followed by epistaxis and gum bleeding. Therapy with vitamin K1 had to be maintained for over 50 days (Jones et al., 1984).<NL> <NL> The ingestion of 1 mg of brodifacoum in an adult produced bleeding that persisted for more than 2 months (Chong et al., 1986).<NL> <NL> No clearly defined toxic dose has been established in the human, and few clinical reports are available.</PIM7.2.1.1> <A NAME = "EndDivisionTitle:7.2.1.1 Adults"></A><A NAME = "DivisionTitle:7.2.1.2 Children"></A>7.2.1.2 Children <PIM7.2.1.2>Very few reports are available specifying the toxic dose, although ingestion of long-acting rodenticides have been reported in children.<NL> <NL> Anticoagulation has been detected but without clinical symptomatology in most cases (Smolinske et al., 1987).</PIM7.2.1.2> <A NAME = "EndDivisionTitle:7.2.1.2 Children"></A><A NAME = ":7.2.1 Human data"></A><A NAME = "SubSectionTitle:7.2.2 Relevant animal data"></A>7.2.2 Relevant animal data <PIM7.2.2>LD50 oral (female rat) 0.37 to 0.68 mg/kg<NL> <NL> LD50 oral (beagle dog) 0.25 to 1 mg/kg<NL> <NL> LD50 oral (cat) estimated as 25 mg/kg.<NL> <NL> The acute dermal toxicity (male rabbits) with intact skin was estimated to be 0.25 to 0.625 mg/kg. When the skin is abraded, the dose is 1.25 mg/kg (ICI Ltd).<NL> <NL> Brodifacoum is slightly irritant when applied to the skin of rabbits and to the eye.</PIM7.2.2> <A NAME = ":7.2.2 Relevant animal data"></A><A NAME = "SubSectionTitle:7.2.3 Relevant in vitro data"></A>7.2.3 Relevant in vitro data <PIM7.2.3>No data available.</PIM7.2.3> <A NAME = ":7.2.3 Relevant in vitro data"></A><A NAME = "SubSectionTitle:7.2.4 Workplace standards"></A>7.2.4 Workplace standards <PIM7.2.4>No data available.</PIM7.2.4> <A NAME = ":7.2.4 Workplace standards"></A><A NAME = "SubSectionTitle:7.2.5 Acceptable daily intake (ADI) and other guideline levels"></A>7.2.5 Acceptable daily intake (ADI) and other guideline levels <PIM7.2.5>No data available.</PIM7.2.5> <A NAME = ":7.2.5 Acceptable daily intake (ADI) and other guideline levels"></A><A NAME = "EndSectionTitle:7.2 Toxicity"></A><A NAME = "SectionTitle:7.3 Carcinogenicity"></A>7.3 Carcinogenicity <PIM7.3>No effect has been demonstrated with technical brodifacoum in carcinogenicity tests (ICI Ltd.).</PIM7.3> <A NAME = "EndSectionTitle:7.3 Carcinogenicity"></A><A NAME = "SectionTitle:7.4 Teratogenicity"></A>7.4 Teratogenicity <PIM7.4>Studies in rats and rabbits have demonstrated no fetotoxic embryotoxic or teratogenic effects.</PIM7.4> <A NAME = "EndSectionTitle:7.4 Teratogenicity"></A><A NAME = "SectionTitle:7.5 Mutagenicity"></A>7.5 Mutagenicity <PIM7.5>No data available.</PIM7.5> <A NAME = "EndSectionTitle:7.5 Mutagenicity"></A><A NAME = "SectionTitle:7.6 Interactions"></A>7.6 Interactions <PIM7.6>Warfarin interacts with many drugs but, although a similar pattern is expected with brodifacoum, no specific data were found.</PIM7.6> <A NAME = "EndSectionTitle:7.6 Interactions"></A><A NAME = "EndPartTitle:7. TOXICOLOGY"></A><A NAME = "PartTitle:8. TOXICOLOGICAL ANALYSES AND BIOMEDICAL INVESTIGATIONS"></A>8. TOXICOLOGICAL ANALYSES AND BIOMEDICAL INVESTIGATIONS <A NAME = "SectionTitle:8.1 Material sampling plan"></A>8.1 Material sampling plan <A NAME = "SubSectionTitle:8.1.1 Sampling and specimen collection"></A>8.1.1 Sampling and specimen collection <A NAME = "DivisionTitle:8.1.1.1 Toxicological analyses"></A>8.1.1.1 Toxicological analyses <A NAME = "EndDivisionTitle:8.1.1.1 Toxicological analyses"></A><A NAME = "DivisionTitle:8.1.1.2 Biomedical analyses"></A>8.1.1.2 Biomedical analyses <A NAME = "EndDivisionTitle:8.1.1.2 Biomedical analyses"></A><A NAME = "DivisionTitle:8.1.1.3 Arterial blood gas analysis"></A>8.1.1.3 Arterial blood gas analysis <A NAME = "EndDivisionTitle:8.1.1.3 Arterial blood gas analysis"></A><A NAME = "DivisionTitle:8.1.1.4 Haematological analyses"></A>8.1.1.4 Haematological analyses <A NAME = "EndDivisionTitle:8.1.1.4 Haematological analyses"></A><A NAME = "DivisionTitle:8.1.1.5 Other (unspecified) analyses"></A>8.1.1.5 Other (unspecified) analyses <A NAME = "EndDivisionTitle:8.1.1.5 Other (unspecified) analyses"></A><A NAME = ":8.1.1 Sampling and specimen collection"></A><A NAME = "SubSectionTitle:8.1.2 Storage of laboratory samples and specimens"></A>8.1.2 Storage of laboratory samples and specimens <A NAME = "DivisionTitle:8.1.2.1 Toxicological analyses"></A>8.1.2.1 Toxicological analyses <A NAME = "EndDivisionTitle:8.1.2.1 Toxicological analyses"></A><A NAME = "DivisionTitle:8.1.2.2 Biomedical analyses"></A>8.1.2.2 Biomedical analyses <A NAME = "EndDivisionTitle:8.1.2.2 Biomedical analyses"></A><A NAME = "DivisionTitle:8.1.2.3 Arterial blood gas analysis"></A>8.1.2.3 Arterial blood gas analysis <A NAME = "EndDivisionTitle:8.1.2.3 Arterial blood gas analysis"></A><A NAME = "DivisionTitle:8.1.2.4 Haematological analyses"></A>8.1.2.4 Haematological analyses <A NAME = "EndDivisionTitle:8.1.2.4 Haematological analyses"></A><A NAME = "DivisionTitle:8.1.2.5 Other (unspecified) analyses"></A>8.1.2.5 Other (unspecified) analyses <A NAME = "EndDivisionTitle:8.1.2.5 Other (unspecified) analyses"></A><A NAME = ":8.1.2 Storage of laboratory samples and specimens"></A><A NAME = "SubSectionTitle:8.1.3 Transport of laboratory samples and specimens"></A>8.1.3 Transport of laboratory samples and specimens <A NAME = "DivisionTitle:8.1.3.1 Toxicological analyses"></A>8.1.3.1 Toxicological analyses <A NAME = "EndDivisionTitle:8.1.3.1 Toxicological analyses"></A><A NAME = "DivisionTitle:8.1.3.2 Biomedical analyses"></A>8.1.3.2 Biomedical analyses <A NAME = "EndDivisionTitle:8.1.3.2 Biomedical analyses"></A><A NAME = "DivisionTitle:8.1.3.3 Arterial blood gas analysis"></A>8.1.3.3 Arterial blood gas analysis <A NAME = "EndDivisionTitle:8.1.3.3 Arterial blood gas analysis"></A><A NAME = "DivisionTitle:8.1.3.4 Haematological analyses"></A>8.1.3.4 Haematological analyses <A NAME = "EndDivisionTitle:8.1.3.4 Haematological analyses"></A><A NAME = "DivisionTitle:8.1.3.5 Other (unspecified) analyses"></A>8.1.3.5 Other (unspecified) analyses <A NAME = "EndDivisionTitle:8.1.3.5 Other (unspecified) analyses"></A><A NAME = ":8.1.3 Transport of laboratory samples and specimens"></A><A NAME = "EndSectionTitle:8.1 Material sampling plan"></A><A NAME = "SectionTitle:8.2 Toxicological analyses and their interpretation"></A>8.2 Toxicological analyses and their interpretation <A NAME = "SubSectionTitle:8.2.1 Tests on toxic ingredient(s) of material"></A>8.2.1 Tests on toxic ingredient(s) of material <A NAME = "DivisionTitle:8.2.1.1 Simple qualitative test(s)"></A>8.2.1.1 Simple qualitative test(s) <A NAME = "EndDivisionTitle:8.2.1.1 Simple qualitative test(s)"></A><A NAME = "DivisionTitle:8.2.1.2 Advanced qualitative confirmation test(s)"></A>8.2.1.2 Advanced qualitative confirmation test(s) <A NAME = "EndDivisionTitle:8.2.1.2 Advanced qualitative confirmation test(s)"></A><A NAME = "DivisionTitle:8.2.1.3 Simple quantitative method(s)"></A>8.2.1.3 Simple quantitative method(s) <A NAME = "EndDivisionTitle:8.2.1.3 Simple quantitative method(s)"></A><A NAME = "DivisionTitle:8.2.1.4 Advanced quantitative method(s)"></A>8.2.1.4 Advanced quantitative method(s) <A NAME = "EndDivisionTitle:8.2.1.4 Advanced quantitative method(s)"></A><A NAME = ":8.2.1 Tests on toxic ingredient(s) of material"></A><A NAME = "SubSectionTitle:8.2.2 Tests for biological specimens"></A>8.2.2 Tests for biological specimens <A NAME = "DivisionTitle:8.2.2.1 Simple qualitative test(s)"></A>8.2.2.1 Simple qualitative test(s) <A NAME = "EndDivisionTitle:8.2.2.1 Simple qualitative test(s)"></A><A NAME = "DivisionTitle:8.2.2.2 Advanced qualitative confirmation test(s)"></A>8.2.2.2 Advanced qualitative confirmation test(s) <A NAME = "EndDivisionTitle:8.2.2.2 Advanced qualitative confirmation test(s)"></A><A NAME = "DivisionTitle:8.2.2.3 Simple quantitative method(s)"></A>8.2.2.3 Simple quantitative method(s) <A NAME = "EndDivisionTitle:8.2.2.3 Simple quantitative method(s)"></A><A NAME = "DivisionTitle:8.2.2.4 Advanced quantitative method(s)"></A>8.2.2.4 Advanced quantitative method(s) <A NAME = "EndDivisionTitle:8.2.2.4 Advanced quantitative method(s)"></A><A NAME = "DivisionTitle:8.2.2.5 Other dedicated method(s)"></A>8.2.2.5 Other dedicated method(s) <A NAME = "EndDivisionTitle:8.2.2.5 Other dedicated method(s)"></A><A NAME = ":8.2.2 Tests for biological specimens"></A><A NAME = "SubSectionTitle:8.2.3 Interpretation of toxicological analyses"></A>8.2.3 Interpretation of toxicological analyses <A NAME = ":8.2.3 Interpretation of toxicological analyses"></A><A NAME = "EndSectionTitle:8.2 Toxicological analyses and their interpretation"></A><A NAME = "SectionTitle:8.3 Biomedical investigations and their interpretation"></A>8.3 Biomedical investigations and their interpretation <A NAME = "SubSectionTitle:8.3.1 Biochemical analysis"></A>8.3.1 Biochemical analysis <A NAME = "DivisionTitle:8.3.1.1 Blood, plasma or serum"></A>8.3.1.1 Blood, plasma or serum <A NAME = "EndDivisionTitle:8.3.1.1 Blood, plasma or serum"></A><A NAME = "DivisionTitle:8.3.1.2 Urine"></A>8.3.1.2 Urine <A NAME = "EndDivisionTitle:8.3.1.2 Urine"></A><A NAME = "DivisionTitle:8.3.1.3 Other fluids"></A>8.3.1.3 Other fluids <A NAME = "EndDivisionTitle:8.3.1.3 Other fluids"></A><A NAME = ":8.3.1 Biochemical analysis"></A><A NAME = "SubSectionTitle:8.3.2 Arterial blood gas analyses"></A>8.3.2 Arterial blood gas analyses <A NAME = ":8.3.2 Arterial blood gas analyses"></A><A NAME = "SubSectionTitle:8.3.3 Haematological analyses"></A>8.3.3 Haematological analyses <A NAME = ":8.3.3 Haematological analyses"></A><A NAME = "SubSectionTitle:8.3.4 Interpretation of biomedical investigations"></A>8.3.4 Interpretation of biomedical investigations <A NAME = ":8.3.4 Interpretation of biomedical investigations"></A><A NAME = "EndSectionTitle:8.3 Biomedical investigations and their interpretation"></A><A NAME = "SectionTitle:8.4 Other biomedical (diagnostic) investigations and their interpretation"></A>8.4 Other biomedical (diagnostic) investigations and their interpretation <A NAME = "EndSectionTitle:8.4 Other biomedical (diagnostic) investigations and their interpretation"></A><A NAME = "SectionTitle:8.5 Overall interpretation of all toxicological analyses and toxicological investigations"></A>8.5 Overall interpretation of all toxicological analyses and toxicological investigations <PIM8.5>Collect a sample of the product blood/urine/faeces.<NL> <NL> Biomedical analysis<NL> <NL> Prothrombin time (PT) monitoring is essential. For the first 5 to 6 days it should be done at least daily, and repeated even if results were normal uponadmission. Prothrombin time may initially be normal, even in a severe poisoning because vitamin K-dependent clotting factors have a long half-life and are still circulating several hours after brodifacoum starts its effect.<NL> <NL> Activated partial thromboplastin time (PTT) is abnormal.<NL> <NL> Coagulation tests in general may be normal (e.g. coagulation time, thromboelastogram).<NL> <NL> Haemoglobin: Red blood count<NL> Urinalysis (haematuria): Stools<NL> <NL> Toxicological analysis<NL> <NL> Although a sensitive HPLC technique exists, it is not clinically useful.<NL> <NL> Other investigations<NL> <NL> Specific organ evaluation for bleeding as clinically indicated.</PIM8.5> <A NAME = "EndSectionTitle:8.5 Overall interpretation of all toxicological analyses and toxicological investigations"></A><A NAME = "EndPartTitle:8. TOXICOLOGICAL ANALYSES AND BIOMEDICAL INVESTIGATIONS"></A><A NAME = "PartTitle:9. CLINICAL EFFECTS"></A>9. CLINICAL EFFECTS <A NAME = "SectionTitle:9.1 Acute poisoning"></A>9.1 Acute poisoning <A NAME = "SubSectionTitle:9.1.1 Ingestion"></A>9.1.1 Ingestion <PIM9.1.1>Ingestion of brodifacoum is initially asymptomatic, and may continue as such even with prolonged alterations in prothrombin time. No gastrointestinal tract or other symptomatology occurs.<NL> <NL> Coagulation disturbances may become evident a few days after ingestion, and may be detected only by laboratory studies. In severe poisoning, gum-bleeding, epistaxis, petechiae, ecchymoses, haematomata, blood in urine and faeces, and genital haemorrhage may occur. Internal bleeding and cerebral haemorrhage may complicate the patient's prognosis.</PIM9.1.1> <A NAME = ":9.1.1 Ingestion"></A><A NAME = "SubSectionTitle:9.1.2 Inhalation"></A>9.1.2 Inhalation <PIM9.1.2>No data available.</PIM9.1.2> <A NAME = ":9.1.2 Inhalation"></A><A NAME = "SubSectionTitle:9.1.3 Skin exposure"></A>9.1.3 Skin exposure <PIM9.1.3>The commercial product is not irritating to the skin. Animal studies showed that the pure substance is absorbed through the skin.</PIM9.1.3> <A NAME = ":9.1.3 Skin exposure"></A><A NAME = "SubSectionTitle:9.1.4 Eye contact"></A>9.1.4 Eye contact <PIM9.1.4>Slightly irritant.</PIM9.1.4> <A NAME = ":9.1.4 Eye contact"></A><A NAME = "SubSectionTitle:9.1.5 Parenteral exposure"></A>9.1.5 Parenteral exposure <PIM9.1.5>No data available.</PIM9.1.5> <A NAME = ":9.1.5 Parenteral exposure"></A><A NAME = "SubSectionTitle:9.1.6 Other"></A>9.1.6 Other <PIM9.1.6>No data available.</PIM9.1.6> <A NAME = ":9.1.6 Other"></A><A NAME = "EndSectionTitle:9.1 Acute poisoning"></A><A NAME = "SectionTitle:9.2 Chronic poisoning"></A>9.2 Chronic poisoning <A NAME = "SubSectionTitle:9.2.1 Ingestion"></A>9.2.1 Ingestion <PIM9.2.1>Ingestion of brodifacoum may be repeated, leading to severe poisoning (Basehore & Mowry, 1987).</PIM9.2.1> <A NAME = ":9.2.1 Ingestion"></A><A NAME = "SubSectionTitle:9.2.2 Inhalation"></A>9.2.2 Inhalation <PIM9.2.2>No data available.</PIM9.2.2> <A NAME = ":9.2.2 Inhalation"></A><A NAME = "SubSectionTitle:9.2.3 Skin exposure"></A>9.2.3 Skin exposure <PIM9.2.3>No data available.</PIM9.2.3> <A NAME = ":9.2.3 Skin exposure"></A><A NAME = "SubSectionTitle:9.2.4 Eye contact"></A>9.2.4 Eye contact <PIM9.2.4>No data available.</PIM9.2.4> <A NAME = ":9.2.4 Eye contact"></A><A NAME = "SubSectionTitle:9.2.5 Parenteral exposure"></A>9.2.5 Parenteral exposure <PIM9.2.5>No data available.</PIM9.2.5> <A NAME = ":9.2.5 Parenteral exposure"></A><A NAME = "SubSectionTitle:9.2.6 Other"></A>9.2.6 Other <PIM9.2.6>No data available.</PIM9.2.6> <A NAME = ":9.2.6 Other"></A><A NAME = "EndSectionTitle:9.2 Chronic poisoning"></A><A NAME = "SectionTitle:9.3 Course, prognosis, cause of death"></A>9.3 Course, prognosis, cause of death <PIM9.3>The course of poisoning is characteristically long. Alterations of coagulation parameters and clinical symptoms of bleeding may be maintained for several days if no treatment is provided.<NL> <NL> The prognosis is poor in cases with internal bleeding or intracerebral haemorrhage, and also in patients with previous haematological illnesses or renal insufficiency.<NL> <NL> Death is uncommon (Basehore & Mowry, 1987).</PIM9.3> <A NAME = "EndSectionTitle:9.3 Course, prognosis, cause of death"></A><A NAME = "SectionTitle:9.4 Systematic description of clinical effects"></A>9.4 Systematic description of clinical effects <A NAME = "SubSectionTitle:9.4.1 Cardiovascular"></A>9.4.1 Cardiovascular <PIM9.4.1>No direct cardiotoxic effects have been described in man.</PIM9.4.1> <A NAME = ":9.4.1 Cardiovascular"></A><A NAME = "SubSectionTitle:9.4.2 Respiratory"></A>9.4.2 Respiratory <PIM9.4.2>No effects have been reported but theoretically haemoptysis would be a possibility.</PIM9.4.2> <A NAME = ":9.4.2 Respiratory"></A><A NAME = "SubSectionTitle:9.4.3 Neurological"></A>9.4.3 Neurological <A NAME = "DivisionTitle:9.4.3.1 Central Nervous System (CNS)"></A>9.4.3.1 Central Nervous System (CNS) <PIM9.4.3.1>Intracerebral haemorrhage has been described as a secondary complication (Basehore & Mowry, 1987).</PIM9.4.3.1> <A NAME = "EndDivisionTitle:9.4.3.1 Central Nervous System (CNS)"></A><A NAME = "DivisionTitle:9.4.3.2 Peripheral nervous system"></A>9.4.3.2 Peripheral nervous system <PIM9.4.3.2>No effects have been reported.</PIM9.4.3.2> <A NAME = "EndDivisionTitle:9.4.3.2 Peripheral nervous system"></A><A NAME = "DivisionTitle:9.4.3.3 Autonomic nervous system"></A>9.4.3.3 Autonomic nervous system <PIM9.4.3.3>No effects have been reported.</PIM9.4.3.3> <A NAME = "EndDivisionTitle:9.4.3.3 Autonomic nervous system"></A><A NAME = "DivisionTitle:9.4.3.4 Skeletal and smooth muscle"></A>9.4.3.4 Skeletal and smooth muscle <PIM9.4.3.4>Muscular haematoma may occur, especially on the elbows, knees and buttocks (CCINFOdisc, 1989).</PIM9.4.3.4> <A NAME = "EndDivisionTitle:9.4.3.4 Skeletal and smooth muscle"></A><A NAME = ":9.4.3 Neurological"></A><A NAME = "SubSectionTitle:9.4.4 Gastrointestinal"></A>9.4.4 Gastrointestinal <PIM9.4.4>Haematemesis and melena may occur. Abdominal and flank pain have been reported after intra-abdominal bleeding (Jones et al., 1984).</PIM9.4.4> <A NAME = ":9.4.4 Gastrointestinal"></A><A NAME = "SubSectionTitle:9.4.5 Hepatic"></A>9.4.5 Hepatic <PIM9.4.5>Although the liver is the site of metabolism of brodifacoum, no observable clinical effects are apparent, except coagulopathy.</PIM9.4.5> <A NAME = ":9.4.5 Hepatic"></A><A NAME = "SubSectionTitle:9.4.6 Urinary"></A>9.4.6 Urinary <A NAME = "DivisionTitle:9.4.6.1 Renal"></A>9.4.6.1 Renal <PIM9.4.6.1>Haematuria may be clinically evident or detected only by the laboratory (Jones et al., 1984). Urinary tract haemorrhage has been reported (Hollinger & Pastoor, 1993).</PIM9.4.6.1> <A NAME = "EndDivisionTitle:9.4.6.1 Renal"></A><A NAME = "DivisionTitle:9.4.6.2 Others"></A>9.4.6.2 Others <PIM9.4.6.2>No data available.</PIM9.4.6.2> <A NAME = "EndDivisionTitle:9.4.6.2 Others"></A><A NAME = ":9.4.6 Urinary"></A><A NAME = "SubSectionTitle:9.4.7 Endocrine and reproductive systems"></A>9.4.7 Endocrine and reproductive systems <PIM9.4.7>No data available.</PIM9.4.7> <A NAME = ":9.4.7 Endocrine and reproductive systems"></A><A NAME = "SubSectionTitle:9.4.8 Dermatological"></A>9.4.8 Dermatological <PIM9.4.8>Petechial rashes may be seen.</PIM9.4.8> <A NAME = ":9.4.8 Dermatological"></A><A NAME = "SubSectionTitle:9.4.9 Eye, ears, nose, throat: local effects"></A>9.4.9 Eye, ears, nose, throat: local effects <PIM9.4.9>Epistaxis and gum bleeding.</PIM9.4.9> <A NAME = ":9.4.9 Eye, ears, nose, throat: local effects"></A><A NAME = "SubSectionTitle:9.4.10 Haematological"></A>9.4.10 Haematological <PIM9.4.10>Coagulation is impaired after ingestion of significant quantities of brodifacoum. The usual haematological symptoms are: gum bleeding, epistaxis, ecchymoses, haematoma, and haematuria; there may be internal bleeding.</PIM9.4.10> <A NAME = ":9.4.10 Haematological"></A><A NAME = "SubSectionTitle:9.4.11 Immunological"></A>9.4.11 Immunological <PIM9.4.11>No data available.</PIM9.4.11> <A NAME = ":9.4.11 Immunological"></A><A NAME = "SubSectionTitle:9.4.12 Metabolic"></A>9.4.12 Metabolic <A NAME = "DivisionTitle:9.4.12.1 Acid-base disturbances"></A>9.4.12.1 Acid-base disturbances <PIM9.4.12.1>No data available.</PIM9.4.12.1> <A NAME = "EndDivisionTitle:9.4.12.1 Acid-base disturbances"></A><A NAME = "DivisionTitle:9.4.12.2 Fluid and electrolyte disturbances"></A>9.4.12.2 Fluid and electrolyte disturbances <PIM9.4.12.2>No data available. </PIM9.4.12.2> <A NAME = "EndDivisionTitle:9.4.12.2 Fluid and electrolyte disturbances"></A><A NAME = "DivisionTitle:9.4.12.3 Others"></A>9.4.12.3 Others <PIM9.4.12.3>No data available.</PIM9.4.12.3> <A NAME = "EndDivisionTitle:9.4.12.3 Others"></A><A NAME = ":9.4.12 Metabolic"></A><A NAME = "SubSectionTitle:9.4.13 Allergic reactions"></A>9.4.13 Allergic reactions <PIM9.4.13>No data available.</PIM9.4.13> <A NAME = ":9.4.13 Allergic reactions"></A><A NAME = "SubSectionTitle:9.4.14 Other clinical effects"></A>9.4.14 Other clinical effects <PIM9.4.14>No data available.</PIM9.4.14> <A NAME = ":9.4.14 Other clinical effects"></A><A NAME = "SubSectionTitle:9.4.15 Special risks"></A>9.4.15 Special risks <PIM9.4.15>One case of abortion has been reported by Lipton & Klaas (1984). Data on breast milk secretion are not available and therefore breast feeding should not be recommended. Individuals with bleeding diatheses may be at higher risk.</PIM9.4.15> <A NAME = ":9.4.15 Special risks"></A><A NAME = "EndSectionTitle:9.4 Systematic description of clinical effects"></A><A NAME = "SectionTitle:9.5 Others"></A>9.5 Others <A NAME = "EndSectionTitle:9.5 Others"></A><A NAME = "SectionTitle:9.6 Summary"></A>9.6 Summary <A NAME = "EndSectionTitle:9.6 Summary"></A><A NAME = "EndPartTitle:9. CLINICAL EFFECTS"></A><A NAME = "PartTitle:10. MANAGEMENT"></A>10. MANAGEMENT </S><A NAME = "SectionTitle:10.1 General principles"></A>10.1 General principles <PIM10.1>In all cases of brodifacoum ingestion, the patient (especially children) should be clinically monitored by daily laboratory studies for at least 4 or 5 days.<NL> <NL> Gastric lavage or emesis is indicated if the ingested amount is uncertain or possibly toxic. Administration of activated charcoal and cathartics is useful. If initial coagulation disorders have been detected, the prothrombin time should be monitored (for at least 60 days). The treatment is based upon the administration of vitamin K1. Fresh frozen plasma or whole blood should be given in severe cases of poisoning in order to provide clotting factors.<NL> <NL> Clinical observation should be very strict in order to diagnose any possibility of bleeding.</PIM10.1> <A NAME = "EndSectionTitle:10.1 General principles"></A><A NAME = "SectionTitle:10.2 Life supportive procedures and symptomatic treatment"></A>10.2 Life supportive procedures and symptomatic treatment <PIM10.2>Life-saving procedures are indicated if serious complications arise.<NL> <NL> Symptomatic treatment for bleeding is the administration of fresh frozen plasma or fresh whole blood for correcting coagulopathy.</PIM10.2> <A NAME = "EndSectionTitle:10.2 Life supportive procedures and symptomatic treatment"></A><A NAME = "SectionTitle:10.3 Decontamination"></A>10.3 Decontamination <PIM10.3>If more than 24 hours have elapsed decontamination measures are not effective.<NL> <NL> Emesis or gastric lavage may be effective if attempted within 3 to 6 hours of ingestion.<NL> <NL> Administration of activated charcoal and cathartics may be considered.</PIM10.3> <A NAME = "EndSectionTitle:10.3 Decontamination"></A><A NAME = "SectionTitle:10.4 Enhanced elimination"></A>10.4 Enhanced elimination <PIM10.4>Enhancement of elimination is not indicated.</PIM10.4> <A NAME = "EndSectionTitle:10.4 Enhanced elimination"></A><A NAME = "SectionTitle:10.5 Antidote treatment"></A>10.5 Antidote treatment <A NAME = "SubSectionTitle:10.5.1 Adults"></A>10.5.1 Adults <PIM10.5.1>Phytomenadione (vitamin K1) should be administered. If prothrombin time is significantly reduced vitamin K1 should be administered intravenously starting with 10 mg each 6 h (40 mg/day). The intramuscular route may be chosen under appropriate clinical settings. The dosage should be adjusted according to the prothrombin time. </PIM10.5.1> <A NAME = ":10.5.1 Adults"></A><A NAME = "SubSectionTitle:10.5.2 Children"></A>10.5.2 Children <PIM10.5.2>Indication and dosage is the same as in adults.</PIM10.5.2> <A NAME = ":10.5.2 Children"></A><A NAME = "EndSectionTitle:10.5 Antidote treatment"></A><A NAME = "SectionTitle:10.6 Management discussion"></A>10.6 Management discussion <PIM10.6>There is no consensus on the appropriate administration schemes for vitamin K. Some authors give oral vitamin K prophylactically in cases where ingestion is uncertain. The usual route for treatment is intravenous, although in somecases it has been given intramuscularly or subcutaneously. The use of phenobarbital as a hepatic microsomal enzyme inducer is controversial.</PIM10.6> <A NAME = "EndSectionTitle:10.6 Management discussion"></A><A NAME = "EndPartTitle:10. MANAGEMENT"></A><A NAME = "PartTitle:11. ILLUSTRATIVE CASES"></A>11. ILLUSTRATIVE CASES <A NAME = "SectionTitle:11.1 Case reports from literature"></A>11.1 Case reports from literature <PIM11.1>Lipton & Klaas (1984) reported a case of a psychotic 31-year-old woman who ingested thirty 50 g packages of commercial rodenticide containing brodifacoum. Five days later, she was admitted to hospital with slash marks on both wrists and blood clots in the gums. Laboratory results were: haemoglobin 12.2 g/dL, Ht 37.9%, WBC 5.6/mm3, platelets 390.000, prothrombin time 72s (control = 12 s), activated partial thromboplastin time greater than 100s (normal = 25 to 35s), fibrinogen 380 mg/dL. Urinalysis was negative for blood and protein. Treatment was started with 25 mg of vitamin K1 and fresh frozen plasma. The dose of vitamin K1 was increased to 125 mg per day after little improvement in the prothrombin time. Phenobarbital was also administered as an hepatic enzyme inducer. This case was complicated by a complete and apparently spontaneous abortion.<NL> <NL> Basehore & Mowry (1987) reported a patient who, following chronic ingestion of the rodenticide, was admitted to hospital with nose-bleeding, haematuria and multiple ecchymoses. Laboratory studies showed: prothrombin time = 60 seconds (normal = 12.4), partial prothrombin time = 79.2 seconds (normal = 27), bleeding time 15 minutes. Treatment was started with vitamin K1 and frozen fresh plasma. The patient was discharged 9 days afterwards with almost normal prothrombin time and partial thromboplastin time and prescribed oral phytomenadione. Three weeks later, he presented with status epilepticus; intradural haemorrhage was diagnosed by CAT-Scan. Prothrombin time was again over 60 seconds. He deteriorated and died 4 hours after admission.</PIM11.1> <A NAME = "EndSectionTitle:11.1 Case reports from literature"></A><A NAME = "EndPartTitle:11. ILLUSTRATIVE CASES"></A><A NAME = "PartTitle:12. ADDITIONAL INFORMATION"></A>12. ADDITIONAL INFORMATION <A NAME = "SectionTitle:12.1 Specific preventive measures"></A>12.1 Specific preventive measures <PIM12.1>As any other pesticide, these rodenticides should be kept out of the reach of children and irresponsible persons. Use of superwarfarin, such as brodifacoum, should be restricted to agronomical application and not widely advertised or sold without restriction for household use.</PIM12.1> <A NAME = "EndSectionTitle:12.1 Specific preventive measures"></A><A NAME = "SectionTitle:12.2 Other"></A>12.2 Other <PIM12.2>No data available.</PIM12.2> <A NAME = "EndSectionTitle:12.2 Other"></A><A NAME = "EndPartTitle:12. ADDITIONAL INFORMATION"></A><A NAME = "PartTitle:13. REFERENCES"></A>13. REFERENCES <PIM13.>Bachman KA & Sullivan TJ (1983) Dispositional and pharmacodynamics characteristics of brodifacoum in warfarin-sensitive rats. Pharmacology, 27(5): 251-288.<NL> <NL> Basehore LM & Mowry JM (1987) Death following ingestion of superwarfarin rodenticide: A case report. Vet & Human Toxicology, 29 (6 Dec.).<NL> <NL> Budivari S (ed) (1996) The Merck Index, An Encyclopedia of Chemicals, Drugs and Biologicals, 12th ed., Merck & Co., Inc., Whitehouse Station, NJ, USA.<NL> <NL> CCINFO (1989)<NL> <NL> Chong L, Chan W, Ho C (1986) A case of superwarfarin poisoning. Scand J Haematol, 36: 314-315.<NL> <NL> Fitzgerald K & Bronstein AC (1987). Comparison of first and second generation anticoagulant rodenticide poisonings: fourteen canine cases. Abstracts from the AACT/AAPCC/ABMT/CAPCC scientific meetings. Sept. 27.<NL> <NL> Hoffman RS, Smilkstein MJ, Goldfrank LR (1988) "Evaluation of coagulation factor abnormalities in long-acting anticoagulant overdose". J Toxicol Clin Toxicol, 26 (3-4): 48. <NL> <NL> Hollinger B & Pastoor TP (1993). Case management and plasma half-life in a case of brodifacoum poisoning. Arch Intern Med, 153 (16):1925-8<NL> <NL> Jones E, Growe GH, Naiman SC (1984) Prolonged anticoagulation in rat poisoning. JAMA, 252: 3005-3007.<NL> <NL> ICI Ltd. - Technical Information<NL> <NL> Lipton RA & Klaas EM (1984) Human ingestion of superwarfarin rodenticide resulting in a prolonged anticoagulant effect. JAMA, Dec 7., vol. 252, No. 21.<NL> <NL> Park BK et al. (1979) A study of the effect of anticoagulants on (3H) vitamin K1 metabolism and prothrombin complex activity in the rabbit. Biochem Pharmacol, 28 (8): 1323-9.<NL> <NL> Smolinske SC, Sherger DS, Kearus PS & Rumack BH (1987) Long acting coagulant rodenticide ingestion in children. Vet & Hum Toxicology, 29 (6 Dec.).</PIM13.> <A NAME = "EndPartTitle:13. REFERENCES"></A><A NAME = "PartTitle:14. AUTHOR(S), REVIEWER(S), DATE(S) (INCLUDING UPDATES), COMPLETE ADDRESS(ES)"></A>14. AUTHOR(S), REVIEWER(S), DATE(S) (INCLUDING UPDATES), COMPLETE ADDRESS(ES) <PIM14.>Authors: Dr C. Dell Acqua<NL> Dr J. Pronczuk<NL> CIAT<NL> Piso 7, Hospital de Clinicas<NL> Av. Italia s/n<NL> Montevideo<NL> Uruguay<NL> <NL> Tel: 598-2-470300 and 598-2-804000<NL> Fax: 598-2-470300<NL> <NL> Date: February 1990<NL> <NL> Peer<NL> review: London, United Kingdom, March 1990.<NL> <NL> Informal Consultation, post JMPR meeting, September 1991<NL> <NL> Original<NL> Editor: Dr S. Chaplin, Newcastle-upon-Tyne, United Kingdom<NL> (September 1991)<NL> <NL> Update: International Programme on Chemical Safety (May 1992)<NL> <NL> Editor: Mrs J. Dum閚il, International Programme on Chemical Safety<NL> (July 1999)<NL> <NL> </PIM14.> <A NAME = "EndPartTitle:14. AUTHOR(S), REVIEWER(S), DATE(S) (INCLUDING UPDATES), COMPLETE ADDRESS(ES)"></A> </PRE> <script src="/scripts/google_analytics.js" type="text/javascript"></script> </BODY> <PRE> </PRE> <PRE> See Also: <A HREF="../../eintro/eintro/abreviat.htm">Toxicological Abbreviations</A> <A HREF="../../hsg/hsg/hsg093.htm">Brodifacoum (HSG 93, 1995)</A> </PRE> </HTML>

CINXE.COM

Brodifacoum (PIM 077)