3

Evaluation of Phosgenation Reagents

The traditional classification of organic compounds, according to the nature of

functional groups and their preparations [1], emphasizes phosgene (the dichloride

of carbonic acid) as a carbonic acid derivative. Indeed, the reactivity of phosgene in

nucleophilic reactions is best understood by considering the electronic structure ofcarbonic acid and the electronic and steric effects of the substituents in its derivatives.

3.1

Definition

A phosgene equivalent or substitute is a compound able to replace phosgene as a

building block or reagent in organic syntheses, or able to specifically bring about

the basic phosgene functions as a (cyclo)carbonylating, chlorocarbonylating, chlori-

nating or dehydrating agent. The general structure 1 below illustrates the main

structural characteristic of phosgene equivalents, i.e. the presence of the carbonyl

(or carbonyl precursor) group flanked by two leaving groups.

Z1

Z2

O

1

Z1, Z

2 = halo, alkoxy, aryloxy,

midazolyl, triazolyl, etc.)

The groups Z1 and Z2 can be identical or different, thus generating symmetrical or

unsymmetrical phosgene equivalents, respectively.

3.2

Reactivity

Many phosgene equivalents have been designed in order to have the reactivity of

phosgene and the leaving group ability of various organic substituents. Formally,

and often essentially, they belong to the family of carbonic acid derivatives and,

therefore, their chemical behavior and reactivity toward nucleophiles has to be in-

terpreted in terms of this classification [1].

Phosgenations – A Handbook. L. Cotarca, H. EckertCopyright 8 2003 WILEY-VCH Verlag GmbH & Co. KGaA, WeinheimISBN: 3-527-29823-1

32

Z1

Z2

O

1

Z1, Z

2 = halo, alkoxy, aryloxy,

imidazolyl, triazolyl, etc.

+ NuZ

1Nu

O

+ Z2

Z1

Nu

O

Z2

Z1 Z

2

O

1

+ NuHZ

1Nu

O

+ HZ2

Z1

Nu

OH

Z2

Many phosgene substitutes 1, such as 1,1-carbonyldiimidazole, thionyl chloride,

bis(nitrophenyl) carbonate, di-tert-butyl dicarbonate, etc., react according to the

scheme above and the intermediates can be isolated and characterized.

The various methods in which phosgene is substituted by a structurally different

organic compound may be classified into the following two categories:

a) methods in which the specific organic compound acts as a phosgene substitute

(e.g. mimicking phosgene as a chlorine, chlorocarbonyl or carbonyl source), and

b) methods using the organic compound as an in situ phosgene source (precur-

sor).

For example, regarding the nucleophilic processes involving triphosgene and di-

phosgene, two main routes of application have been identified (see also Chapter 2):

a) as a tricoordinated carbonic acid derivative with two leaving groups (Cl, OCCl3);

the stability of intermediates (e.g. chloroformate, carbamoyl chloride, carbonate,

carbamate, N-carboxy anhydride, urea) and catalysis play important roles in

completing the nucleophilic process; and

b) as an in situ or external phosgene source, because very clean and quantitative

‘‘depolymerization’’ methods are available [2–4].

Many simple carbonic acid derivatives are highly reactive, providing useful re-

agents in synthesis and a rich and interesting chemistry [5]. For example, several

novel substituted trioxanes, such as the geminal dichlorotrioxane (C3H4O3Cl2),

tetrachlorotrioxane (C3H2O3Cl4), and trioxanone (C3H4O4), should be kinetically

stable and are likely candidates for use in synthesis. Recently, their thermodynamic

and kinetic stabilities were explored computationally [6]. Concerted ring opening

provides the most likely path for dissociation to the building-block molecules car-

bon dioxide, formaldehyde, and phosgene.

As regards phosgene reactions with active hydrogen substrates, mechanistic

studies were indicative of substrate activation as a result of the nucleophilicity of

chloride anion in the case of QþCl� type catalysts (e.g. quaternary ammonium

chloride). The mechanism of nucleophilic assistance by these catalysts can be ra-

3.2 Reactivity 33

tionalized in terms of an increase of the nucleophilicity of the substrate by proton

abstraction, followed by attack of the promoted anion on the electrophile (phos-

gene) [7]:

Nu H + Q Cl Nu H Cl

Cl Cl

O

Cl Nu

OQ

+ Q Cl + HCld– d–

Eckert proposed the following mechanism for phosgenation by triphosgene [8]:

Cl3C O CO O CCl3

O

Nu

+ O CCl2 + Cl

1/3

1/3

C O

Nu

+ O CCl2 +ClO CCl2 + Cl1/3+ 2/3 Nu

C O

Nu

Cl

Cl

Nu catalyst

+ nucleophilic reagentProduct + HCI

- Nu catalyst

+ nucleophilic reagent

Cl3C O C

The rate constants for the two steps of the reaction of triphosgene with substituted

anilines have been determined by conductometric measurements [9]. The first rel-

atively fast step of the reaction is the nucleophilic attack of the amine on tri-

phosgene leading to a (trichloromethyl)urethane through a six- or four-center tran-sition state, in which the carbon–nitrogen bond is formed concomitantly with the

transfer of the proton. A phosgene molecule is also produced in this reaction,

which reacts very rapidly with the amine to form an N,N 0-diarylurea. The second,

much slower step, is the nucleophilic attack of the amine on (trichloromethyl)-

urethane. Through a similar transition state, in which the proton transfer has an

even higher importance, an N,N 0-disubstituted urea and another molecule of

phosgene are formed.

By the same experimental method, the rate constants for hydrolysis and alco-

holysis of triphosgene in dioxane have been determined. The effects of the water

and alcohol concentrations, and of the temperature, as well as deuterium isotope

effects, have been studied [10]. The complex reaction scheme of triphosgene alco-

holysis has also been reported and discussed [11].

The second type of phosgene reactivity is represented by electrophilic reactions

[12]:

3 Evaluation of Phosgenation Reagents34

Cl Cl

O

+ AlCl3

or other Lewis acid

CCl

O

AlCl4

H

COCl

H

AlCl4COCl + AlCl3 + HCl

On analyzing the reactions of phosgene and phosgene equivalents, the stepwise

nature of phosgenation processes becomes apparent. It is observed that the initial

step of most of these processes involves COCl (chlorocarbonyl) transfer to the

appropriate reaction center of the molecule, with formation of the corresponding

derivative, i.e. chloroformate, carbamoyl chloride, etc. This COCl transfer is usually

followed by a nucleophilic attack to give tricoordinated derivatives, or by CO2 and/

or HCl elimination to give dicoordinated derivatives of carbonic acid. The scheme

below illustrates the reaction of amides with the phosgene equivalent triphosgene.

The dehydration of primary amides starts with chloroformylation of the substrate.

Further elimination of CO2 and HCl assisted by an appropriate amine affords the

nitrile.

R NH2

O

+Cl O O Cl

ClCl

O ClCl R NH2

O O

O Cl

Cl

Cl

OCCl3R NH2

O Cl

O

Cl

- CO2

R NH2

Cl

Cl- HClR NH

Cl

- HCl

+ HClR C N

DABCO

Amide:Triphosgene 1:1 Amide:Triphosgene 1:0.33

In the case of N-substituted formamides, the preferred dehydrating procedure is

that of Ugi, utilizing phosgene in the presence of a tertiary amine. Triphosgene

adds to the carbonyl group in exactly the same way as it does in the case of the

synthesis of a-chloroalkyl chloroformates (see Chapter 4.4 ‘‘Chlorination’’). If tri-

phosgene is catalytically decomposed by the tertiary amine, the reaction can also be

interpreted as a simple phosgenation.

3.2 Reactivity 35

HN H

O

+Cl O O Cl

ClCl

O ClCl

HN

O Cl

O

- CO2

- 2 HCl

R

HN

CCl

O

R

H

O

O

Cl

Cl

Cl

ClH

R

RN

H

ClR N C

Substrate:Triphosgene 1:1 Substrate:Triphosgene 1:0.33

2 Et3N

The above mechanism is similar to that proposed by Nakajima [13] for the dehy-

dration of primary amides under Swern conditions. There is an obvious analogy

between a sulfoxonium salt and chloroformate:

R NH2

O

R NH

OH

MeS

Me

Cl

R NH

OS

Me

Me

R N

OS

Me

Me

H Et3N

R C N

Therefore, the formation of chloroformate, or compounds of similar structure, as

key intermediates of limited (low) stability is the driving force behind many pro-

cesses involving phosgene or phosgene equivalents.

Triphosgene is quantitatively converted to phosgene by catalysts such as chloride

ion [2–4]. The reaction course has been monitored by IR spectroscopy (React-IR),

which showed diphosgene to be an intermediate. The methanolysis of triphosgene

in deuterated chloroform, as monitored by 1H NMR spectroscopy, gave as pri-

mary products methyl chloroformate and methyl 1,1,1-trichloromethyl carbonate

in about a 1:1 ratio. The reaction carried out in the presence of a large excess of

Tab. 3.1. Pseudo-first-order rate constants for the reactions of

phosgene, diphosgene, and triphosgene (0.01 m) with

methanol (0.3 m) in CDCl3 at 25�C, calculated from the initial

rates [4].

Substrate kobs, sC1

MeOH, 0.3 M

MeOH, 0.3 M

ClC 5%a

MeOH, 0.3 M

ClC 10%a

Phosgene 1.7� 10�2 b b

Diphosgene 9.1� 10�4 1.0� 10�3 1.1� 10�3

Triphosgene 1.0� 10�4 2.3� 10�4 2.3� 10�4

a added as Bu4NþCl�; b too fast to be measured by NMR

3 Evaluation of Phosgenation Reagents36

Tab. 3.2. Physical properties of phosgene and phosgene equivalents and substitutes [15].

Phosgene Equivalent or

Substitute

CAS Reg.

no.

Mp [˚C] Bp [˚C]

(mmHg)

Risk (R) and

Safety (S) Phrases

Phosgene 75-44-5 �118 8.2 R: 26-34

S: 26-36/37/39-45

Diphosgene

(Trichloromethyl

chloroformate)

503-38-8 128 R: 26-34

S: 26-36/37/39-45

Triphosgene

(Bis(trichloromethyl)

carbonate)

32315-10-9 79–83 203–206 R: 20/21/22-36/

37/38

S: 23-26-27-38

Oxalyl chloride 79-37-8 �10 to �8 63–64 (763) R: 14-23/24/25-34

S: 26-36/37/39-45

Boron tribromide 10294-33-4 �46 90 R: 14-26/28-35

S: 9-26-28-36/37/

39-45

Boron trichloride 10294-34-5 �107 12.5 R: 14-26/28-34

S: 9-26-28-36/37/

39-45

Phosphorus oxychloride 10025-87-3 1.25 105.8 R: 14-22-26-35-

48/23

S: 7/8-26-36/37/

39-45

Phosphorus oxybromide 7789-59-5 56 192 R: 14-34-37

S: 7/8-26-36/37/

39-45

Thionyl chloride 7719-09-7 79 R: 14-20/22-29-35

S: 26-36/37/39-45

Thionyl bromide 507-16-4 �52 48 (20) R: 14-34-36/37

S: 26-28-36/37/

39-43-45

Phosphorus pentoxide 1314-56-3 340 R: 35

S: 22-26-45

Triphenylphosphine

dibromide

(Dibromotriphenyl-

phosphorane)

1034-39-5 235 (dec.) R: 34

S: 26-28-27-36/

37/39-45

Cyanuric chloride

(CyCl), (2,4,6-

trichloro-1,3,5-

triazine)

108-77-0 145.5–148.5 190 R: 36/37/38

S: 28

Trichloroacetyl chloride 76-02-8 �146 114–116 R: 14-22-26-35

S: 23-26-36/37/

39-45

p-Toluenesulfonylchloride, (tosyl

chloride, TsCl)

98-59-9 67–69 R: 34

S: 26-27-28-36/

37/39-45

Benzyl chloroformate 501-53-1 103 (20) R: 34-50/53

S: 26-45-60-61

3.2 Reactivity 37

Tab. 3.2 (continued)

Phosgene Equivalent or

Substitute

CAS Reg.

no.

Mp [˚C] Bp [˚C]

(mmHg)

Risk (R) and

Safety (S) Phrases

Ethyl chloroformate 541-41-3 �81 93 R: 11-22-26-34

S: 9-16-26-28-33-

36/37/39-45

1-Chloroethyl

chloroformate

50893-53-3 118–119 R: 23/24/25-34

S: 26-27-36/37/

39-45

Phenyl chloroformate 1885-14-9 38 74–75 (13) R: 26-34

S: 26-28-36/37/

39-45

Phenyl

chlorothionoformate

1005-56-7 81–83 (6) R: 34

S: 26-27-28-36/

37/39-45

Bis(4-nitrophenyl)

carbonate

5070-13-3 136–138 R: 36/38

S: 26-36

Di-t-butyl dicarbonate 24424-99-5 23 56–57 (0.5) R: 10-36/37/38

S: 16-26-36

Ethylene carbonate 96-49-1 37–39 243–244 (740) R: 36

S: 26-37/39

Chloroethylene

carbonate

3967-54-2 121–123 (18) R: 34

S: 26-36/37/39-45

Dimethyl carbonate 616-38-6 2–4 90 R: 11

S: 9-16

Diethyl carbonate 105-58-8 126–128 R: 11

S: 9-16

Diphenyl carbonate 102-09-0 79–82 301–302 R: 21/22

S: 36

1,1-Carbonyldiimidazole

(CDI)

530-62-1 117–122 R: 34-20/21/22

S: 26-27-36/37/

39-45

1,1-Carbonylbis(2-

methylimidazole)

13551-83-2 218–220 R: 36/37/38

S: 26-37/39

Ethyl acetoacetate 141-97-9 �43 181 R: 36/37/38

S: 26-36

Acetic anhydride 108-24-7 �73 140 R: 10-20/22-34

S: 26-36/37/39-45

Isatoic anhydride 118-48-9 233 (dec.) R: 36-43

S: 24-26-37

Trifluoroacetic acid

anhydride (TFAA)

407-25-0 �65 39.5–40 R: 34-14-20/21/22

S: 23-26-27-36/

37/39-45

Trifluorometh-

anesulfonic

anhydride (triflic

anhydride, Tf2O)

358-23-6 81–83 (745) R: 14-34

S: 26-27-36/37/

39-45

3 Evaluation of Phosgenation Reagents38

Tab. 3.2 (continued)

Phosgene Equivalent or

Substitute

CAS Reg.

no.

Mp [˚C] Bp [˚C]

(mmHg)

Risk (R) and

Safety (S) Phrases

1,1-Dichlorodimethyl

ether

4885-02-3 85 R: 10-23/24/25-

36/37/38-40

S: 16-26-36/37/

39-45

Dimethoxymethane

(formaldehyde acetal,

methylal)

7149-92-0 �105 41–42 R: 11-19-36/37/38

S: 16-33-26-36

Diethoxymethane 462-95-3 87–88 R: 11-19-36/37/38

S: 16-26-36/37/39

Phosgene iminium

chloride

(Dichloromethylene)-

dimethylammonium

chloride (Vilsmeier

reagent/Viehe’s salt)

33842-02-3 183–187 (dec.) R: 14-34

S: 26-28-36/37/

39-45

(Chloromethylene)-

dimethylammonium

chloride (Vilsmeier

reagent)

3724-43-4 132 (dec.) R: 61-20/21-36

S: 26-36/37/39-

45-53

Pyridine–phosgene

adduct 1-[2-

(Chloroformyl)-2-

azacyclohexa-3,5-

dienyl]pyridinium

chloride (2-DHPP)

117371-69-4 84–87 (dec.)

Benzotriazol-1-

yloxytripyrrolidino

phosphonium

hexafluoro-

phosphate (PyBOP)

128625-52-5 154–156 (dec.) R: 36/37/38

S: 26-37/39

Benzotriazol-1-yloxy

tris(dimethylamino)-

phosphonium

hexafluoro-

phosphate (BOP

reagent)

56602-33-6 >130 (dec.) R: 20/21/22-36/

37/38

S: 26-36

Carbon monoxide, CO 630-08-0 �205 �191.5 R: 61-12-23-48/23

S: 53-45

Carbon dioxide, CO2 124-38-9 �78.5 (sublim.) R: 61-23-48/23

S: 38

Trimethylsilyl

isocyanate

1118-02-1 90–92 R: 10-20/21/22-

36/37/38

S: 23-38-16-36/

37/39

Chlorosulfonyl

isocyanate

1189-71-5 �44 107 R: 14-23/24/25-35

S: 3/7-26-36/37/

39-45

3.2 Reactivity 39

methanol (0.3 m, 30 equiv.) was found to be a pseudo-first-order process with a kobsof 1.0� 10�4 s�1. Under the same conditions, values of kobs of 0.9� 10�3 s�1 and

1.7� 10�2 s�1 for the methanolysis of diphosgene and phosgene, respectively,

were determined. The experimental data suggest that, under these conditions, the

maximum concentration of phosgene during the methanolysis of triphosgene and

diphosgene was lower than 1� 10�5m. Methyl 1,1,1-trichloromethyl carbonate

Tab. 3.2 (continued)

Phosgene Equivalent or

Substitute

CAS Reg.

no.

Mp [˚C] Bp [˚C]

(mmHg)

Risk (R) and

Safety (S) Phrases

(Methoxycarbonyl-

sulfamoyl)

triethylammonium

betaine (Burgess

reagent)

29684-56-8 76–79 R: 36/37/38

S: 26-37/39

1,3-Dicyclohexyl-

carbodiimide (DCC)

538-75-0 34–35 122–124 (6) R: 22-24-41-43

S: 24-26-37/39-45

1,3-Diisopropyl-

carbodiimide

693-13-0 145–148 R: 10-26-36/37/

38-41-42/43

S: 16-23-26-36/

37/39-45

1,3-Bis(2,2-dimethyl-1,3-

dioxolan-4-ylmethyl)-

carbodiimide [Bis-4-

(2,2-dimethyl-1,3-

dioxolyl)methyl

carbodiimide

(BDDC)]

159390-26-8 R: 36/37/38

S: 26-36

2-Chloro-1,3-

dimethylimi-

dazolium chloride

(CDC)

95–100 (dec.) See [14]

2-Chloro-1,3-

dimethylimi-

dazolium hexafluoro-

phosphate

101385-69-7 231–233 R: 36/37/38

S: 26-36

2-Chloro-1,3-dimethyl-

imidazolium tetra-

fluoroborate

153433-26-2 175–177 R: 36/37/38

S: 26-36

Diethyl azodicarboxylate

(DEAD)

1972-28-7 106 (13) R: 20/21/22-36/

37/38-40-44

S: 15-23-26-36

Diphenylphosphoryl

azide

26386-88-9 157 (0.17) R: 23/24/25-36/

37/38

S: 26-28-36/37/

39-45

3 Evaluation of Phosgenation Reagents40

has also been synthesized independently and characterized by the APCI-MS tech-

nique.

3.3

Physical Properties

Phosgene equivalents are gaseous, liquid or solid compounds. The main physical

properties of phosgene and some phosgene equivalents are presented in Table 3.2.

The potential danger in the handling of the phosgene equivalents is associated

with the vapor pressures of the compounds. Very few specific data are available. In

the case of the chlorinated phosgene substitutes, diphosgene and triphosgene, the

vapor pressures are significantly lower and a value as low as 0.15 Torr has been

reported for triphosgene (Table 3.3).

3.4

Physiological Data

While searching for significant data to describe the potential workplace health

hazards associated with the use of phosgene equivalents, we were surprised by the

lack of quantitative data for monitoring exposure to these compounds. The reason

for this is definitely the still limited use of phosgene equivalents in industrial pro-

cesses. The best approach to prevent erroneous and hazardous use of these mate-

rials is to first gain thorough knowledge of the material data sheets, which are easily

accessible and available [18]. Some threshold limit value/time-weighted average (TLV-TWA) data are collected in Table 3.4. The class representative, phosgene, has a TLV

of 0.1 ppm, but other phosgene equivalents have values ranging from 0.005 ppm

(hexamethylene diisocyanate) to 5000 ppm (carbon dioxide). It should be noted

that aliphatic isocyanates have even lower TLVs and that suitable safety measures

have to be taken before working with these reagents [20].

Tab. 3.3. Vapor pressures of phosgene and some important substitutes [15–19].

Phosgenation reagent Vapor pressure

(Pa)

Vapor pressure

(Torr)

Temp.

(˚C)

Ref.

Phosgene 162000 1215 20 15

Diphosgene 1370 10.3 20 16

Triphosgene 20 0.15 20 16

Diethyl carbonate 1100 8.3 20 15

Dimethyl carbonate 13300 100 37 17

Acetic anhydride 500 3.8 20 15

Triflic anhydride 1060 8 20 18

Phosphoryl chloride 5300 40 27 15

Thionyl chloride 12900 97 20 19

3.4 Physiological Data 41

Tab. 3.4. TLV-TWAa data for phosgene and some important substitutes [20].

Phosgene Substitute CAS Reg. No. TLV-TWAa (ppm)

Phosgene 75-44-5 0.1

Phosphorus oxychloride 10025-87-3 0.1

Thionyl chloride 7719-09-7 1b

Ethyl chloroformate 541-41-3 0.1

Benzyl chloroformate (Z-Cl) 501-53-1 1

Acetic anhydride 108-24-7 5

Methyl isocyanate 822-06-0 0.005

Isophorone diisocyanate 4098-71-9 0.005

Dimethyl carbonate (DMC) 616-38-6 200

N,N 0-Dicyclohexylcarbodiimide (DCC),

in solution

538-75-0 50

Diethyl azodicarboxylate (DEAD) 1972-28-7 50

Carbon monoxide, CO 630-08-0 25

Carbon dioxide, CO2 124-38-9 5000

aThreshold Limit Value/Time-Weighted Average (TLV-TWA) is the time-

weighted average concentration for a conventional 8-hour working day

and a 40-hour working week, to which it is believed that nearly all

workers may be repeatedly exposed, day after day, without adverse

effect.bThreshold Limit Value/Time-Weighted Average-Ceiling (TLV-C) is theconcentration that should not be exceeded during any part of the

working exposure.

3.5

References

1 H. Hagemann (Ed.), Houben-Weyl:Methoden der Organischen Chemie, Bd.E4: Kohlensaeure-Derivate, Thieme,

Stuttgart, 1983.

2 H. Eckert, B. Gruber, N. Dirsch, to

Dr. Eckert GmbH, German Patent DE19740577, 1999; Chem. Abstr. 1999,130, 211406; WO 9914159, 1999, Eur.Patent EP 1017623, 2002.

3 L. Cotarca, Org. Proc. Res. & Dev.1999, 5, 377.

4 L. Pasquato, G. Modena, L. Cotarca,

S. Mantovani, P. Delogu, J. Org.Chem. 2000, 65, 8224–8228.

5 A. F. Hegarty, Derivatives of CarbonDioxide, in Comprehensive OrganicChemistry, vol. 2 (Ed.: D. R. Barton),

Pergamon Press, Oxford, 1979, p.

1067.

6 M. L. Shirel, P. Pulay, J. Am. Chem.Soc. 1999, 121, 8544–8548.

7 J.-R. Gauvreau, G. Martin, T.

Malfroot, J.-P. Senet, J. Chem. Soc.,Perkin. Trans. 2 1984, 1971–1974.

8 H. Eckert, B. Forster, Angew.Chem. Int. Ed. Engl. 1987, 26, 894–895.

9 L. Cotarca, R. Bacaloglu, C.

Csunderlik, N. Marcu, A.

Tarnaveanu, J. Prakt. Chem. 1987,

329, 1052–1062.10 L. Cotarca, R. Bacaloglu, C.

Csunderlik, N. Marcu, A.

Tarnaveanu, J. Prakt. Chem. 1985,

327, 881–886.11 M. Milea, Ph.D. Thesis, Polytechnic

University, Timisoara, 2002.

12 J.-P. Senet, The Recent Advances inPhosgene Chemistry, vol. 1, 1997, SNPE,p. 16–17.

13 N. Nakajima, M. Ubukata, Tetra-hedron Lett. 1997, 38, 2099–2102.

3 Evaluation of Phosgenation Reagents42

14 T. Isobe, T. Ishikawa, J. Org. Chem.

1999, 64, 6984–6989.15 International Chemical Safety Cards

(ICSCS), NIOSH, National Institutefor Occupational Safety and Health(WHO), 1998; http://www.cdc.gov/niosh/ipcsngrm/ngrm0000.html

16 Ubichem, Triphosgene, CD-ROM,

1999.

17 W. V. Steele, R. D. Chiroco, S. E.

Knipmeyer, A. Nguyen, N. K. Smith,

J. Chem. Eng. Data 1997, 42, 1008–1020, 1037–1052.

18 http://www.msdsonline.com19 K. Arii, Sci. Rep. Tohoku Imp. Univ.

Ser. 1, vol. 22, 1933, p. 182–199.20 Documentation of the Threshold Limit

Values and Biological Exposure Indices,American Conference of

Governmental Industrial Hygienists,

ACGIH, 2002, p. 4.

3.5 References 43