TOXICOLOGICAL CHEMISTRY AND BIOCHEMISTRY - CHAPTER 18 ppt

These compounds have numerous industrial uses, and many of them, especially the organophosphate ester insecticides discussed later in this chapter, are economic poisons, that is, they ar

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CHAPTER 18 Organophosphorus Compounds 18.1 INTRODUCTION

Phosphorus is directly below nitrogen in the periodic table (The relationship of the chemistry

of phosphorus to that of nitrogen is somewhat like the sulfur–oxygen relationship discussed in the introduction to Chapter 17.) The phosphorus atom electron configuration is {Ne}3s23p3, and it has five outer-shell electrons, as shown by its Lewis symbol in Figure 18.1 Because of the availability

of underlying 3d orbitals, the valence shell of phosphorus can be expanded to more than eight electrons

There are many kinds of organophosphorus compounds, including those with P–C bonds and those in which hydrocarbon moieties are bonded to P through an atom other than carbon, usually oxygen These compounds have numerous industrial uses, and many of them, especially the organophosphate ester insecticides discussed later in this chapter, are economic poisons, that is, they are used to destroy pests that are harmful to crops, fruits, and vegetables Organophosphorus compounds have varying degrees of toxicity Some of these compounds, such as the nerve gases produced as military poisons, are deadly in minute quantities The organophosphate esters, a class

of compounds that contains the organophosphate ester insecticides and the organophosphate military poisons, are of particular toxicological interest because of their ability to inhibit acetylcholinesterase enzyme

18.1.1 Phosphine

Phosphine (PH3) is the hydride of phosphorus discussed as a toxic inorganic compound in Section 11.8 The formulas of many organophosphorus compounds can be derived by substituting organic groups for the H atoms in phosphine, and such an approach serves as a good starting point for the discussion of organophosphorus compounds

18.2 ALKYL AND ARYL PHOSPHINES

Figure 18.2 gives the structural formulas of the more significant alkyl and aryl phosphine compounds Methylphosphine is a colorless reactive gas that is very toxic by inhalation Dime-thylphosphine is a colorless, reactive, volatile liquid (bp, 25°C) that is toxic when inhaled or ingested Both methylphosphine and dimethylphosphine have toxic effects similar to those of phosphine, a pulmonary tract irritant and central nervous system depressant that causes fatigue, vomiting, difficult breathing, and even death Trimethylphosphine is a colorless volatile liquid (bp, 42°C) It is reactive enough to be spontaneously ignitable and probably has a high toxicity

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Triethylphosphine probably has a high toxicity and tributylphosphine is a moderately toxic liquid.

Phenylphosphine (phosphaniline) is a reactive, moderately flammable liquid (bp, 16°C) with a high toxicity by inhalation Triphenylphosphine is a crystalline solid (mp, 79°C; bp > 360°C) with a low reactivity and moderate toxicity when inhaled or ingested

The combustion of aryl and alkyl phosphines, such as trimethylphosphine, occurs as shown by the following example:

4C3H9P + 26O2→ 12CO2 + 18H2O + P4O10 (18.2.1) Such a reaction produces P4O10, a corrosive irritant toxic substance discussed in 11.8.2, or droplets

of corrosive orthophosphoric acid, H3PO4

electrons as dots.

H H H Lewis symbol of

phosphorus atom

Lewis structural formula

of phosphine

H C P H H

H H

H

H C P C H H

H H H

H C

C

C H H

H

P H H

H

P H H

C

C C C

H H

P H H

C

H

H H

H H H

P

Methylphosphine Dimethylphosphine Trimethylphosphine

Triethylphosphine Tributylphosphine

Phenylphosphine Triphenylphosphine

P

(n-C4H10)

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18.3 PHOSPHINE OXIDES AND SULFIDES

Phosphine oxides and sulfides have the general formulas illustrated below, where R represents hydrocarbon groups:

Two common phosphine oxides are triethylphosphine oxide (each R is a C2H5 group) and tribu-tylphosphine oxide (each R is a C4H9 group) The former is a colorless, deliquescent, crystalline solid (mp, 52.9°C; bp, 243°C) The latter is a crystalline solid (mp, 94°C) Both compounds probably have high toxicities when ingested

Triethylphosphine sulfide, (C2H5)3PS, is a crystalline solid (mp, 94°C) Not much is known about its toxicity, which is probably high Tributylphosphine sulfide, (C4H9)3PS, is a skin irritant with a moderate toxicity hazard When burned, both of these compounds give off dangerous fumes

of phosphorus and sulfur oxides

18.4 PHOSPHONIC AND PHOSPHOROUS ACID ESTERS

Phosphonic acid esters are derived from phosphonic acid (often erroneously called phosphorous acid), which is shown with some of its esters in Figure 18.3 Only two of the H atoms of phosphonic acid are ionizable, and hydrocarbon groups may be substituted for these atoms to give phosphonic acid esters It is also possible to have esters in which a hydrocarbon moiety is substituted for the

H atom that is bonded directly to the phosphorus atom An example of such a compound is

dimethylmethylphosphonate, shown in Figure 18.3 This type of compound has the same elemen-tal formula as triesters of the hypothetical acid P(OH)3, phosphorous acid Examples of triesters

of phosphorous acid, such as trimethylphosphite, are shown in Figure 18.3

Trimethylphosphite is a colorless liquid (bp, 233°C) It is soluble in many organic solvents, but not in water Little information is available regarding its toxicity or other hazards Tributylphos-phite is a liquid (bp, 120°C) It decomposes in water, but is probably not very toxic Triphen-ylphosphite is a white solid or oily liquid (mp, 23°C; bp, 157°C) It is a skin irritant with a moderate oral toxicity Although it is not soluble in water, it may hydrolyze somewhat to phenol, which adds

to its toxicity Tris(2-ethylhexyl)phosphite, a trialkyl phosphite in which the hydrocarbon moieties are the 2-ethylhexyl group, –CH2CH(C2H5)C4H9, is a water-insoluble compound (bp, 100°C) Its toxicity is largely unknown

Dimethylmethylphosphonate is of toxicological concern because of its widespread use; dieth-ylethylphosphonate may be a suitable substitute for it in some applications.1Methylphosphonate, (CH3O)P(O)H(OH), has a moderate oral toxicity and is a skin and eye irritant Dibutylphosphonate, (C4H9O)2P(O)H, is a liquid boiling at 115°C at 10 mmHg pressure Through ingestion and dermally,

it has a moderately high toxicity Like other organophosphonates and phosphites, it can decompose

to evolve dangerous products when heated, burned, or exposed to reactive chemicals, such as oxidants Thermal decomposition can result in the evolution of highly toxic phosphine, PH3 Combustion produces corrosive orthophosphoric acid and oxides of phosphorus

Diallylphosphonate, shown in Figure 18.3, has two alkenyl substituent groups Information is lacking on its toxicity, although compounds with allyl groups tend to be relatively toxic Incidents have been reported in which this compound has exploded during distillation

P R"

R O R'

P R"

R' R S

Phosphine oxide Phosphine sulfide

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18.5 ORGANOPHOSPHATE ESTERS 18.5.1 Orthophosphates and Polyphosphates

Figure 18.4 shows the structural formula of orthophosphoric acid as well as those of diphos-phoric and polyphosdiphos-phoric acids, produced by polymerization of orthophosdiphos-phoric acid with loss

of water These compounds form esters in which alkyl, alkenyl, and aryl hydrocarbon moieties are substituted for H; most of the more common ones are esters of orthophosphoric acid In this section,

C4H9

O P O

C4H9

O

C4H9

P OH HO

H O

H C C O P O C C H

H O

O P O H O

C C C O P O C C C

H

H H

H O

H

H H H

C

H

H H

H

C O P O

H

O P O O

Dimethylmethylphosphonate

Diallylphosphonate Trimethylphosphite

Phosphonic acid Diethylphosphonate

Diphenylphosphonate Diethylethylphosphonate

C

H

H H

H

H H

H O

C O P O C

C

H

H H H

H

H H

O

C C O P O C C H

P OH HO

O OH

P OH

P O HO

P O P OH

P O HO

Orthophosphoric Pyrophosphoric Polyphosphoric acids acid acid (n = 3 and higher)

n

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only the relatively simple organophosphate esters are discussed Many economic poisons — par-ticularly insecticides — are organophosphate esters that often contain nitrogen, sulfur, or halogens These compounds are discussed in a later section

18.5.2 Orthophosphate Esters

Some of the more significant phosphate esters are shown in Figure 18.5 Trimethylphosphate

is the simplest of the organophosphate esters; the structural formulas of the other alkyl esters of orthophosphoric acid are like those of trimethylphosphate, but with alkyl substituent groups other than methyl Comparatively little information is available about the toxicity of trimethylphosphate, although it is probably moderately toxic orally or through skin absorption A study of potential carcinogenicity of this compound to Wistar rats showed no evidence that it is carcinogenic to these test animals.2

Triethylphosphate, (C2H5O)3PO, is a liquid (fp, –57°C; bp, 214°C) It is insoluble in water, but soluble in most organic solvents Like other phosphate esters, it damages nerves and is a cholinesterase inhibitor It is regarded as moderately toxic Two other alkyl phosphates with toxicities probably similar to that of triethylphosphate are tributylphosphate, (n-C4H9O)3PO, and

tris(2-ethylhexyl)-phosphate, (C8H17O)3PO

Triallylphosphate is the phosphate triester of allyl alcohol and contains unsaturated C=C bonds

in its structure This compound is a liquid (fp, –50°C) It is regarded as having a high toxicity and produces abnormal tissue growth when administered subcutaneously It has been known to explode during distillation

Tetraethylpyrophosphate

O

O O P O

O

O O P O

CH3

H3C

CH3

H C O P O C H

O H H

H H O H

H

H C

C H H

H H

O

H H H

H H

H H O

C H

C H H

Tri- o-cresylphosphate, TOCP

Triphenylphosphate

Trimethylphosphate

Triallylphosphate

C

O C

H H H

H

H H

H C O

H

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18.5.3 Aromatic Phosphate Esters

Triphenylphosphate is a colorless, odorless, crystalline solid (mp, 49°C; bp, 245°C) It is moderately toxic A similar, but much more toxic, compound is tri-o-cresyl-phosphate (TOCP),

an aryl phosphate ester with a notorious record of poisonings.3 Before its toxicity was fully recognized, TOCP was a common contaminant of commercial tricresylphosphate Tricresylphos-phate is an industrial chemical with numerous applications and consists of a mixture of phosTricresylphos-phate esters in which the hydrocarbon moieties are meta and para cresyl substituents It has been used

as a lubricant, gasoline additive, flame retardant, solvent for nitrocellulose, plasticizer, and even a cooling fluid for machine guns Although modern commercial tricresylphosphate contains less than 1% TOCP, contaminant levels of up to 20% in earlier products have resulted in severe poisoning incidents

Pure TOCP is a colorless liquid (fp, –27°C; bp, 410°C) It produces pronounced neurological effects and causes degeneration of the neurons in the body’s central and peripheral nervous systems, although fatalities are rare Early symptoms of TOCP poisoning include nausea, vomiting, and diarrhea, accompanied by severe abdominal pain Normally a 1- to 3-week latent period occurs after these symptoms have subsided, followed by manifestations of peripheral paralysis, as evi-denced by “wrist drop” and “foot drop.” In some cases, the slow recovery is complete, whereas in others partial paralysis remains

The most widespread case of TOCP poisoning occurred in the U.S in 1930 when approximately 20,000 people were affected by the ingestion of alcoholic Jamaican ginger (“Jake”) adulterated by 2% TOCP The peculiar manner in which the victims walked, including “foot drop,” slapping the feet on the floor, high stepping, and unsteadiness, gave rise to the name of “jake leg” to describe the very unfortunate condition

A major incident of TOCP poisoning affected 10,000 people in Morocco in 1959 The victims had eaten food cooked in olive oil adulterated with TOCP-contaminated lubricating oil A number

of cases of permanent paralysis resulted from ingestion of the contaminated cooking oil

It is believed that metabolic products of TOCP inhibit acetylcholinesterase Apparently other factors are involved in TOCP neurotoxicity A study of tri-o-cresylphosphate poisoning in China has described a number of symptoms.4 Initial pain in the lower leg muscles was followed by paralysis and lower limb nerve injury Patients with mild poisoning recovered after several months, but more severely poisoned ones suffered permanent effects Despite the devastating effects of TOCP, the percentage of virtually complete recovery in healthy subjects is relatively high

18.5.4 Tetraethylpyrophosphate

Tetraethylpyrophosphate (TEPP) was the first organophosphate compound to be used as an insecticide This compound was developed in Germany during World War II and was substituted for nicotine as an insecticide It is a white to amber hygroscopic liquid (bp, 155°C) that readily hydrolyzes in contact with water Because of its tendency to hydrolyze and its extremely high toxicity to mammals, TEPP was used for only a very short time as an insecticide, although it is a very effective one It was typically applied as an insecticidal dust formulation containing 1% TEPP The toxicity of TEPP to humans and other mammals is very high; it has a toxicity rating of 6, supertoxic TEPP is a very potent acetylcholinesterase inhibitor (The inhibition of acetylcholinest-erase by organophosphate insecticides is discussed in Section 18.7.)

18.6 PHOSPHOROTHIONATE AND PHOSPHORODITHIOATE ESTERS

The general formulas of phosphorothionate and phosphorodithioate esters are shown in Figure 18.6, where R represents a hydrocarbon or substituted hydrocarbon moiety Many of the

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organophosphate insecticides are sulfur-containing esters of these general types, which often exhibit

higher insect:mammal toxicity ratios than do their nonsulfur analogs Esters containing the P=S

(thiono) group are not as effective as their analogous compounds that contain the P=O functional

group in inhibiting acetylcholinesterase In addition to their lower toxicities to nontarget organisms,

thiono compounds are more stable toward nonenzymatic hydrolysis The metabolic conversion of

P=S to P=O (oxidative desulfuration) in organisms is responsible for the insecticidal activity and

mammalian toxicity of phosphorothionate and phosphorodithioate insecticides

An example of a simple phosphorothionate is tributylphosphorothionate, in which the R groups

(above) are n-C4H9 groups It is a colorless liquid (bp, 143°C) The compound is a cholinesterase

inhibitor, as are some of its metabolic products Examples of phosphorothionate and

phospho-rodithioate esters with more complex formulas synthesized for their insecticidal properties are

discussed in the following section

18.7 ORGANOPHOSPHATE INSECTICIDES

The organophosphate insecticides were originally developed in Germany during the 1930s and

1940s, primarily through the efforts of Gerhard Schrader and his research group The first of these

was tetraethylpyrophosphate, discussed in Section 18.5 Its disadvantages — including high toxicity

to mammals — led to the development of related compounds, starting with parathion, O,O-

diethyl-O-p-nitrophenylphosphorothionate, which will be discussed in some detail

18.7.1 Chemical Formulas and Properties

Many insecticidal organophosphate compounds have been synthesized Unlike the organohalide

insecticides that they largely displaced, the organophosphates readily undergo biodegradation and

do not bioaccumulate However, the neurotoxic characteristics of organophosphates pose dangers

in their handling and use, so that once-popular compounds of this type have now been phased out

or their uses severely curtailed

An enormous variety of organophosphate ester compounds have been synthesized and used as

pesticides They can be categorized as phosphates, phosphorothiolates, phosphorothioates, and

phosphorodithioates, depending on the number and bonding configurations of S atoms bound to

the central P atom (Figure 18.7) In the generic formulas of these classes of compounds shown in

Figure 18.7, the R groups are frequently methyl (–CH3) or ethyl (–C2H5) groups and Ar is a moiety

of a more complex structure, frequently aromatic In some insecticides, three or even all four of

the atoms bound directly to P are S atoms

18.7.2 Phosphate Ester Insecticides

Figure 18.8 shows some organophosphate insecticides based on the phosphate esters These

compounds do not contain sulfur One of the more significant of these compounds is paraoxon,

hydrocarbon or substituted hydrocarbon moiety.

S

O R

R O P O R S

O R

Phosphorothionate Phosphorodithioate

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which, as noted previously, is a metabolic activation product of parathion It has been synthesized directly and was made by Schrader in 1944 along with parathion One of the most toxic organo-phosphate insecticides, paraoxon has a toxicity rating of six It is alleged to have been provided to

chemical warfare agents in South Africa’s former apartheid government Naled is a bromine-containing phosphate ester insecticide Mevinphos is considered to be an extremely dangerous

chemical It is still used, however.5 Dichlorvos has a toxicity rating of four and is deactivated by

enzymes in the livers of mammals Its tendency to vaporize has enabled its use in pest strips In

2002, the company that had been using dichlorvos in Vapona fly killer and moth killer strips announced that it would no longer do so because of concerns over its potential carcinogenicity.6

distin-guished by the numbers and orientations of the sulfur atoms around the phosphorus.

Phosphoramidothioic acid, O,S-dimethyl ester, a phosphorothiolate

Dicrotophos, a phosphate (no sulfur)

H C C O P O

N

H H

C

H

S

Cl Cl Cl

H

O

H

H H

Dursban, a phosphorothioate

H H

H H H

S O H

Dimethoate, a phosphorodithioate

C H H

O H

P O C H

H

O C C

C

H

C NCH3

CH3 H

O

R O P O Ar O

O R

CH3 H

H

O C

H

Cl Cl

H H

O

H

H H

H

C

C H H O

H

General formula

Mevinphos Dichlorvos

C Br Cl Cl Br

H O

H

H C O

H

O P O H

C C

H

Naled Paraoxon

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18.7.3 Phosphorothionate Insecticides

Figure 18.9 gives the structural formulas of some typical phosphorothionate esters and the general formula of this type of organophosphate insecticide

Insecticidal parathion is a phosphorothionate ester first licensed for use in 1944 Pure parathion

is a yellow liquid that is insoluble in kerosene and water, but stable in contact with water Among its properties that make parathion convenient to use as an insecticide are stability in contact with neutral and somewhat basic aqueous solutions, low volatility, and toxicity to a wide range of insects

It was applied as an emulsion in water, dust, wettable powder, or aerosol Even before it was banned for general use, it was not recommended for applications in homes or animal shelters because of its toxicity to mammals

Parathion has a toxicity rating of six (supertoxic), and methylparathion (which has methyl groups instead of the ethyl groups shown in Figure 18.9) is regarded as extremely toxic As little

as 120 mg of parathion has been known to kill an adult human, and a dose of 2 mg has killed a child Most accidental poisonings have occurred by absorption through the skin Since its use began, several hundred people have been killed by parathion One of the larger poisoning incidents occurred

in Jamaica in 1976 from ingestion of parathion-contaminated flour Of 79 people exposed, 17 died

In the body, parathion is converted to paraoxon (structure in Figure 18.8), which is a potent inhibitor of acetylcholinesterase Because this conversion is required for parathion to have a toxic effect, symptoms develop several hours after exposure, whereas the toxic effects of TEPP or

R O P O Ar

O R

S

H H

C

H S

N

C

CH3

H3C H

CH3

S

H H

H

H C H

Cl

H H

S

O

C

H

Parathion General formula

CH3

H H

S

O

H

HFenitrothion

H C C O P O

H H

S

O

C

H

Cl

CH3

Toclofos-methyl

S O

H3C

CH3

Cl

CH3

Coumaphos

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paraoxon develop much more rapidly Symptoms of parathion poisoning in humans include skin twitching, respiratory distress, and, in fatal cases, respiratory failure due to central nervous system paralysis Parathion and methylparathion are now essentially banned from use in the U.S

For many years diazinon was one of the leading insecticides for residential use, including use

on lawns and gardens In December 2000, the U.S Environmental Protection Agency (EPA) announced stringent curbs on diazinon use that banned sales of this product by the end of 2004 This ban was put in place because of evidence of water pollution and bird poisonings by diazinon and because it was a leading cause of accidental insecticide poisonings There has also been concern that diazinon in water adversely affects the sense of “smell” of salmon and their ability to avoid predators.7

Fenitrothion is a broad-spectrum insecticide effective against a number of insects It has been

widely used in Australia for locust control In January 2002, nine workers were hospitalized in Melbourne, Australia, as the result of exposure to fenitrothion.8 The incident occured when a forklift ran over and punctured three cans of the insecticide Symptoms reported included irritated skin, stinging eyes, and nausea According to an official at the scene, fenitrothion “works its way into the eyes, armpits, and up the nose.” Because of the applications for which it is used, residential and dietary exposures to fenitrothion are considered to be negligible in the U.S

Coumaphos is of interest because it is the most effective pesticide against varroa mites and

small hive beetles in beehives and is an ingredient of insecticide strips hung in the hives to kill the mites.9 There is some concern regarding this use because of coumaphos detected in honey The U.S EPA has granted extensions for the use of coumaphos in beehives, including one to run from February 2, 2002, to February 1, 2003

Another phosphorothionate insecticide, chlorpyrifos methyl,

is used to protect stored grain from insects Because of concerns about its acute, subchronic, and developmental toxicity potential, the U.S EPA has placed a ban on sales of this insecticide after December 31, 2004 The relatively long period from announcing the ban until it takes effect was allowed to enable agricultural interests to find a suitable substitute

18.7.4 Phosphorodithioate Insecticides

Figure 18.10 shows the general formula of phosphorodithioate insecticides and structural

for-mulas of some examples In 2002, dimethoate was canceled for residential use in the U.S., and some of the crop uses of disulfoton were discontinued Azinphos-methyl and phosmet are among

the older organophosphate insecticides, having first been licensed in the mid-1960s In late 2001, the U.S EPA canceled 28 crop uses for azinphos-methyl and announced that seven crop uses, including those on peaches, almonds, walnuts, and cotton, were to be phased out over the next 4 years Three uses of phosmet were voluntarily withdrawn by the manufacturer, and uses on nine crops, including blueberries, grapes, pears, and plums, were allowed for five more years These measures were taken to reduce consumer exposure and particularly to reduce hazards to workers.10

Malathion is the best-known phosphorodithioate insecticide It shows how differences in

structural formula can cause pronounced differences in the properties of organophosphate pesticides

Chlorpyrifos methyl

C O P O

N H

H

S

O

H

H Cl

Cl Cl

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