Difenacoum

Structural formula
	Simplified structural formula - mixture of several stereoisomers
General
Surname	Difenacoum
other names	Diphenacoum; 3- (3-biphenyl-4-yl-1,2,3,4-tetrahydro-1-naphthyl) -4-hydroxy-coumarin; 3- (3- (1,1'-Biphenyl) -4-yl-1,2,3,4-tetrahydro-1-naphthalenyl) -4-hydroxy-2 H -1-benzopyran-2-one;
Molecular formula	C 31 H 24 O 3
Brief description	white solid
External identifiers / databases
EC number	259-978-4
ECHA InfoCard	100,054,508
PubChem	54676884
ChemSpider	10469075
Wikidata	Q424775
properties
Molar mass	444.53 g mol −1
Physical state	firmly
density	1.25 g cm −3
Melting point	215 - 217 ° C (decomposition)
solubility	practically insoluble in water (2.5 mg l −1 at 20 ° C); soluble in acetone and chloroform;
safety instructions
H and P phrases	H: 300-310-330-360D-372-410
	P: ?
Toxicological data	0.68 mg kg −1 ( LD 50 , rat , oral , mixture of isomers) ; 2.5–5.0 mg kg −1 ( LD 50 , mouse , oral , 1 R 3 R isomer) ; 0.8–1.5 mg kg −1 ( LD 50 , mouse , oral , 1 S 3 S isomer) ; 2.5–5.0 mg kg −1 ( LD 50 , mouse , oral , 1 S 3 R isomer) ; 0.3–0.9 mg kg −1 ( LD 50 , mouse , oral , 1 R 3 S isomer) ;
	As far as possible and customary, SI units are used. Unless otherwise noted, the data given apply to standard conditions .

Difenacoum is a mixture of several isomeric chemical compounds from the group of 4-hydroxycoumarins .

Extraction and presentation

Difenacoum can be obtained by a condensation reaction of 4-hydroxycoumarin and 3- (biphenyl-4-yl) -1,2,3,4-tetrahydro-1-naphthol. Laboratory syntheses of the individual isomers proceed using stereoisomeric starting materials and intermediates.

properties

Difenacoum is a flammable solid that is practically insoluble in water. It decomposes at temperatures above 215–217 ° C. It is available as a mixture of several toxicologically active isomers, with the cis isomer being present in the technical product at 50-80%.

Stereochemistry

Difenacoum is a chiral compound that contains two asymmetrically substituted carbon atoms. This gives four stereoisomers, with the (1 S , 3 S ) and (1 R , 3 R ) isomers and the (1 S , 3 R ) and (1 R , 3 S ) isomers forming corresponding pairs of enantiomers . The melting points for the (1 R , 3 S ), (1 S , 3 R ) isomer pair are 216 ° C. and for the (1 R , 3 R ), (1 S , 3 S ) isomer pair, 213 ° C.

use

Difenacoum is an anticoagulant (prevents blood coagulation so that after ingestion of the active ingredient the animal dies of internal bleeding) of the second generation and is used as a rodenticide in various forms against rats and mice. Due to the identified risks of the active ingredient (potentially persistent, bioaccumulating and toxic), Difenacoum was included in the annex of the Biocides Directive for only five years. Resistance to difenacoum is documented in Denmark, Germany and Great Britain. However, they are less than against the anticoagulant warfarin , Coumatetralyl , Chlorophacinone and bromadiolone .

Admission

As a biocidal product

In accordance with European legislation (Directive 98/8 / EC on the placing of biocidal products on the market) and with the resolution of July 29, 2008, a decision has been made to add the active ingredient Difenacoum to the corresponding list from April 1, 2010 (Annex I of Directive 98 / 8 / EG) for product type 14 (rodenticides). The sale of biocidal products that contain the active ingredient difenacoum is therefore still permitted in the EU (Switzerland has adopted this provision). However, this permit was subject to certain conditions:

The nominal concentration of the active ingredient in the products must not exceed 75 mg / kg and only ready-to-use products may be approved.
The products must contain an aversive substance and, if necessary, a dye. Products must not be used as an adhesive poison.
Appropriate measures must be implemented to reduce the risk to humans, non-target animals and the environment. For example, the restriction to use by specialist staff, the definition of a maximum package size and the obligation to use secure, stable bait boxes.
The authorization is initially limited to March 31, 2015, an extension of this period is linked to a new risk assessment.

As a pesticide

In accordance with European legislation (Directive 91/414 / EEC of July 15, 1991 on the placing of plant protection products on the market) and Directive 2009/70 / EC of June 25, 2009 of the EU Commission, it was decided to add the active substance difenacoum to Annex I of the Directive 91/414 / EEC (positive list of the active substances permitted in plant protection products). The sale of plant protection products with the active ingredient difenacoum is therefore still permitted in the EU. However, this permit was subject to certain conditions:

The nominal concentration of the active ingredient in the products must not exceed 50 mg / kg.
Applications are only permitted in the form of prepared baits that are in protected and secured bait boxes.
Approval is restricted to professional users.
The permit is initially limited to December 30, 2019.

In Germany, Austria and Switzerland and no pesticides are approved that contain this active ingredient.

safety instructions

Difenacoum is very toxic if ingested, in contact with the skin or if inhaled.

Individual evidence

↑ ^a ^b ^c ^d ^e ^f ^g ^h Entry on Difenacoum in the GESTIS substance database of the IFA , accessed on January 10, 2017(JavaScript required) .
↑ Health and Safety Guide (HSG) for Difenacoum , accessed on December 1, 2014.
↑ Entry on 3- (3-biphenyl-4-yl-1,2,3,4-tetrahydro-1-naphthyl) -4-hydroxycoumarin in the Classification and Labeling Inventory of the European Chemicals Agency (ECHA), accessed on February 1, 2016 Manufacturers or distributors can expand the harmonized classification and labeling .
↑ ^a ^b ^c ^d ^e van Heerden, PS; Bezuidenhoudt, BCB; Ferreira, D .: Efficient Asymmetric Synthesis of the Four Diastereomers of Diphenacoum and Brodifacoum in Tetrahedron 53 (1997) 6045-6056, doi: 10.1016 / S0040-4020 (97) 00254-8 .
↑ Joseph Sherma; Analytical Methods for Pesticides and Plant Growth Regulations, p. 152; ISBN 978-0-12-784316-2 .
↑ Jung, J.-C .; Park, O.-S .: Synthesic Approaches and Biological Activities of 4-Hydroxycoumarin Derivatives in Molecules 14 (2009) 4790-4803, doi: 10.3390 / molecules14114790 .
↑ ^a ^b Directive 98/8 / EC of the European Parliament: Assessment Report - Difenacoum. September 17, 2009, accessed on July 1, 2017 (English, PDF; 913 kB).
↑ van Heerden, PS; Bezuidenhoudt, BCB; Ferreira, D .: Improved synthesis for the rodenticides, diphenacoum and brodifacoum in J. Chem. Soc. , Perkin Trans. 1, 1997, 1141-1146, doi: 10.1039 / A607269K .
^ Federal Institute for Occupational Safety and Health: Difenacoum ( Memento from June 23, 2013 in the Internet Archive ).
↑ Directive 98/8 / EC of February 16, 1998 on the placing of biocidal products on the market In: Official Journal of the European Communities. L 123, p. 1 of April 24, 1998.
↑ Directive 2008/81 / EC of 29 July 2008 amending Directive 98/8 / EC of the European Parliament and the Council to include the active substance difenacoum in Annex I . In: Official Journal of the European Communities. L 201, p. 46 of July 30, 2008.
↑ Directive 91/414 / EEC of July 15, 1991 on the placing of plant protection products on the market . In: Official Journal of the European Communities. L 230 of August 19, 1991.
↑ Directive 2009/70 / EC of the Commission of June 25, 2009 amending Directive 91/414 / EEC of the Council to include the active substances difenacoum, didecyldimethylammonium chloride and sulfur . In: Official Journal of the European Communities. L 165/59 of June 26, 2009.
^ Directorate-General for Health and Food Safety of the European Commission: Entry on Difenacoum in the EU pesticide database; Entry in the national registers of plant protection products in Switzerland , Austria and Germany ; accessed on March 12, 2016.

[GESTIS-1] ↑ ^a ^b ^c ^d ^e ^f ^g ^h Entry on Difenacoum in the GESTIS substance database of the IFA , accessed on January 10, 2017(JavaScript required) .

[2] Health and Safety Guide (HSG) for Difenacoum , accessed on December 1, 2014.

[CLP_100.054.508-3] Entry on 3- (3-biphenyl-4-yl-1,2,3,4-tetrahydro-1-naphthyl) -4-hydroxycoumarin in the Classification and Labeling Inventory of the European Chemicals Agency (ECHA), accessed on February 1, 2016 Manufacturers or distributors can expand the harmonized classification and labeling .

[Heerden1-4] van Heerden, PS; Bezuidenhoudt, BCB; Ferreira, D .: Efficient Asymmetric Synthesis of the Four Diastereomers of Diphenacoum and Brodifacoum in Tetrahedron 53 (1997) 6045-6056, doi: 10.1016 / S0040-4020 (97) 00254-8 .

[5] Joseph Sherma; Analytical Methods for Pesticides and Plant Growth Regulations, p. 152; ISBN 978-0-12-784316-2 .

[6] Jung, J.-C .; Park, O.-S .: Synthesic Approaches and Biological Activities of 4-Hydroxycoumarin Derivatives in Molecules 14 (2009) 4790-4803, doi: 10.3390 / molecules14114790 .

[eu-7] Directive 98/8 / EC of the European Parliament: Assessment Report - Difenacoum. September 17, 2009, accessed on July 1, 2017 (English, PDF; 913 kB).

[Heerden2-8] van Heerden, PS; Bezuidenhoudt, BCB; Ferreira, D .: Improved synthesis for the rodenticides, diphenacoum and brodifacoum in J. Chem. Soc. , Perkin Trans. 1, 1997, 1141-1146, doi: 10.1039 / A607269K .

[baua-9] Federal Institute for Occupational Safety and Health: Difenacoum ( Memento from June 23, 2013 in the Internet Archive ).

[10] Directive 98/8 / EC of February 16, 1998 on the placing of biocidal products on the market In: Official Journal of the European Communities. L 123, p. 1 of April 24, 1998.

[11] Directive 2008/81 / EC of 29 July 2008 amending Directive 98/8 / EC of the European Parliament and the Council to include the active substance difenacoum in Annex I . In: Official Journal of the European Communities. L 201, p. 46 of July 30, 2008.

[12] Directive 91/414 / EEC of July 15, 1991 on the placing of plant protection products on the market . In: Official Journal of the European Communities. L 230 of August 19, 1991.

[13] Directive 2009/70 / EC of the Commission of June 25, 2009 amending Directive 91/414 / EEC of the Council to include the active substances difenacoum, didecyldimethylammonium chloride and sulfur . In: Official Journal of the European Communities. L 165/59 of June 26, 2009.

[PSM-14] Directorate-General for Health and Food Safety of the European Commission: Entry on Difenacoum in the EU pesticide database; Entry in the national registers of plant protection products in Switzerland , Austria and Germany ; accessed on March 12, 2016.