Microchemical Journal 79 (2005) 399 404

www.elsevier.com/locate/microc

Occupational exposure to low levels of organic and inorganic substances

in a chemical plant for the production of terephtalic acid dimethyl ester
I. Iavicoli*, C. Laurini, G. Carelli
Institute of Occupational Health, Universita Cattolica del Sacro Cuore, Largo Francesco Vito, 1-00168 Rome, Italy

Accepted 17 August 2004

Available online 22 October 2004

Abstract

The aim of our study was the evaluation of personal exposure to chemical pollutants in workers employed in a plant for the production of
terephtalic acid dimethyl ester. Chemical agents have been included in the monitoring program on the basis of the industrial process. In the
plant, the oxidation of p-xylene is performed by air and the resulting acid is esterified with methyl alcohol. Purified terephtalic acid dimethyl
ester is then utilized for the production of polyethylene terephtalate. The environmental monitoring included terephtalic acid dimethyl ester,
p-toluic acid methyl ester, terephtalic acid, p-xylene, methylacetate, methylbenzoate, formic acid, acetic acid, methanol, and the catalysts
cobalt acetate and manganese (II) acetate tetrahydrate. Personal exposure to the cited airborne substances was performed in the breathing
zone of six workers. Air samplings were carried out by drawing air through glass fibre filters (terephtalic acid dimethyl ester, p-toluic acid
methyl ester and terephtalic acid aerosols), by active adsorption (methanol, formic and acetic acids vapours). p-Xylene, methylacetate and
methylbenzoate vapours were collected by passive sampling. Cellulose nitrate filters were used for cobalt and manganese salts samplings.
Analyses were performed by UV detection high-performance liquid chromatography (terephtalic acid dimethyl ester, p-toluic acid methyl
ester and terephtalic acid), flame ionization detection gas chromatography ( p-xylene, acetic acid methyl ester and benzoic acid methyl ester),
ion chromatography (formic and acetic acids) and inductively coupled plasma-mass spectrometry (cobalt and manganese). The results were
evaluated according to the threshold limit values (TLVs) of the American Conference of Governmental Industrial Hygienists (ACGIH) and
indicated that the environmental levels of the workplace pollutants were well below the threshold limit values-time weighed average (TLV-
TWA) adopted by the American Conference of Governmental Industrial Hygienists for 2002, although for three substances the TLVs were
not available.
D 2004 Elsevier B.V. All rights reserved.

Keywords: Occupational exposure; Workers; Monitoring; Terephtalic acid dimethyl ester

1. Introduction threshold limit value-short-term exposure limit (TLV-STEL)

Raw materials, intermediates or the finished product
present in the terephtalic acid dimethyl ester production
cycle can become airborne and thus be absorbed by workers
following inhalation.
The raw materials of the process are p-xylene and
methanol. The American Conference of Governmental
Industrial Hygienists (ACGIH) has established both thresh-
old limit values-time weighed average (TLV-TWA) and
* Corresponding author. Tel.: +39 6 30154486; fax: +39 6 3053612.
E-mail address: iavicoli.ivo@rm.unicatt.it (I. Iavicoli).
0026-265X/$ - see front matter D 2004 Elsevier B.V. All rights reserved.
doi:10.1016/j.microc.2004.08.007
[1] for these two substances that are potentially toxic in
humans.
The inhalation of p-xylene vapours can determine
subacute and acute effects such as headache, lack of muscle
coordination, dizziness, change in ones sense of balance,
dyspnea, confusion, stomach discomfort, chest pain, CNS
disturbances, mild changes in liver function and focal
hepatic necrosis [2,3]. Other effects include increased
leucocyte phagocytosis, enzymatic activity alterations,
decreased T-lymphocytes or glycogen, and increased eryth-
rocyte and leucocyte numbers in urine [2,3].
Exposure to methanol vapours can lead, in humans, to
conjunctivitis, headache, vomiting, dizziness, vertigo, res-
400 I. Iavicoli et al. / Microchemical Journal 79 (2005) 399404
piratory difficulty, abdominal pain, giddiness, insomnia,
gastric disturbances, and bilateral blindness [35]. Visual
disturbances were also reported by Humperdink [6] and in
two studies reviewed by Rowe and McCollister [7].
No data are available about the inhalatory toxicity in man
of terephtalic acid dimethyl ester, p-toluic acid dimethyl
ester and methylbenzoate. Consequently, neither the
ACGIH nor other regulatory institutions have set exposure
limits for these substances.
In Italy, after issuing of the Legislative Decree no. 25
of 2nd February 2002 [8] which brings into effect the 98/
24/EC Directive concerning the protection of health and
safety from chemical agents during work [9], the
approach of risk assessment of occupational exposure to
chemical agents has changed considerably since, on
account of the field of application (art. 60-bis) and indeed
the definition of chemical agents (art. 60-ter), environ-
mental monitoring has to be extended to all the
substances of the industrial cycle that workers might
come into contact with. Moreover, the risk assessment
must be integrated with the biological monitoring of
exposure when appropriate biological indexes are avail-
able (art. 60-quater).
The aim of our study was to assess the risk of exposure to
chemical agents in a plant for the production of terephtalic
acid dimethyl ester. Besides p-xylene, methanol (raw
materials) and terephtalic acid dimethyl ester (finished
product), environmental monitoring also included the most
important process intermediates such as p-toluic acid methyl
ester, terephtalic acid, formic acid, acetic acid, methylace-
tate, methylbenzoate, and the catalysts cobalt acetate and
manganese (II) acetate tetrahydrate.
2. Materials and methods
2.1. Chemical plant
The chemical plant for the production of terephtalic acid
dimethyl ester under study is situated in an industrial area of
Southern Italy, only a few kilometers from the city of
Naples.
Oxidation of p-xylene is performed by atmospheric
oxygen and the acids obtained are esterified with methanol.
For further purification, pure terephtalic acid dimethyl ester
is separated and used for the production of polyethylene
terephtalate polymer.
In short, the chemical plant is made up of the following
sections.
2.1.1. p-Xylene oxidation
p-Xylene is oxidized to p-toluic acid which, esterified
with methanol in the next section, is then recycled to obtain
terephtalic acid monomethyl ester. The process therefore
involves oxidation of the p-xylene methyl groups in two
successive steps.
2.1.2. Acids esterification
Esterification occurs in a plate column where the acid
compounds are esterified by an excess of gaseous
methanol.
2.1.3. Methanol distillation
Excess methanol used in esterification is recovered by
rectification and put back into the production cycle.
Light esters are recovered from the bottom of the
rectification.
2.1.4. Esters fractionation
Esters are fractionated in two distillation columns; three
fractions are obtained:
(a) p-toluic ester, which is recycled to oxidizers;
(b) raw terephtalic acid dimethyl ester, to be purified by
crystallization;
(c) other heavy products, to be treated in the methanolysis
reactors.
2.1.5. Methanolysis
By this process terephtalic acid dimethyl ester is
recovered from heavy oxidation products. Subsequently,
the heavy products are treated with water to recover the
catalyst which is then sent to the oxidizers.
2.1.6. Crystallization of raw terephtalic acid dimethyl ester
Raw terephtalic acid dimethyl ester undergoes purifica-
tion in order to eliminate isoterephtalic acid dimethyl ester
and o-terephtalic acid dimethyl ester formed by esterifica-
tion of m- and o-xylene, the major impurities of p-xylene.
Terephtalic acid dimethyl ester is dissolved in methanol,
crystallized and separated from the liquid phase by
centrifugation.
2.1.7. Rectification of terephtalic acid dimethyl ester
Terephtalic acid dimethyl ester undergoes final rectifica-
tion to increase its purity by eliminating traces of acid
compounds. On leaving the rectification column, pure
terephtalic acid dimethyl ester is stored, after stabilization
with methyl alcohol.
2.1.8. Methanol distillation
Methanol used in the crystallization is rectified, recov-
ered and recycled.
2.2. Tasks and duties
The plant is run by eight shift workers and three day
workers. Environmental monitoring was carried out for five
shift workers and one day worker.
2.2.1. Shift manager
Responsible for controlling staff, the plant and the
production cycle.
 I. Iavicoli et al. / Microchemical Journal 79 (2005) 399404 401

2.2.2. Foreman
Controls the furnaces, compressors and centrifuges and
carries out all the actions to guarantee their correct
functioning; intervenes in all parts of the plant on request
of the shift manager; informs the shift manager of the need
to stock up on raw and secondary materials.
2.2.3. External oxidation workers (2)
Control (intervening when necessary) oxidation, ester-
ification, methanol distillation, raw ester distillation, meth-
anolysis, terephtalic acid dimethyl ester rectification,
catalyst recovery and distillation filtrate sections.
2.2.4. External crystallization worker
Controls and intervenes in the crystallization and
intermediate storage areas.
2.2.5. Technological worker (day worker)
Provides the maintenance staff with practical assistance
to eliminate loss of steam and assists workers responsible
for cleaning the chemical plant. He is in charge of filling
cisterns with terephtalic acid dimethyl ester for sale outlet.
timetable extended from 8:00 a.m. to 5:00 p.m., with an
hour for lunch.
Terephtalic acid dimethyl ester, p-toluic acid methyl ester
and terephtalic acid were collected on binder-free, type AE,
25 mm diameter, cat. no. 225-702 (SKC, Pittsburgh, PA,
USA) glass fibre membrane, at the flow rate of 2 L/min with
AirChek 52 (SKC) pump. p-Xylene, methylacetate, meth-
ylbenzoate were sampled through a cat. no. 575-002 (SKC)
active carbon passive sampler. Methanol was collected on
cat. no. 226-82 (SKC) Anasorb 747 CSC vial at the flow
rate of 50 mL/min, while formic and acetic acids were
sampled with cat. no. 226-09 active carbon vial at the flow
rate of 100 mL/min. These three pollutants were sampled
with a PocketPump (SKC) fitted with cat. no. 224-26-01
(SKC) double-adjustable low flow holders. Cobalt acetate
and manganese acetate were collected by filtering air
through 25-mm, 0.8-Am pore size, cat. no. 600-60121
(SKC) mixed cellulose esters at the flow rate of 2 L/min. For
the linear velocity of sample flow of polluting airborne
particulates, we adhered to current Italian legislation [8].
2.4. Analysis

2.3. Sampling
The aim of the environmental survey, which had a
duration of four consecutive days in January 2003, was to
measure individual exposure to the substances listed in
Table 1. For each of these, we have indicated the physical
state (s, solid or v, vapour), CAS registry number and risk
and safety phrases.
During the survey, climatic data were obtained from a
meteorological station situated a few hundred meters from
the plant. Air was sampled in the breathing zone of the
workers. For shift workers, sampling took place over a
continuous 77.5 h period, while for day worker the
duration was similar, but samplings were suspended
during the lunch break and were resumed immediately
afterwards. The 6:00 a.m. to 2:00 p.m shift (the first
shift) was chosen for the samplings. A day workers
Terephtalic acid dimethyl ester, p-toluic acid methyl ester
and terephtalic acid were extracted from the fibre glass filter
in 5 ml acetonitrile (HPLC grade, Carlo Erba Reagenti,
Rodano, Italy), under sonication for 15 min. Recovery was
measured by spiking five filters with 100 Al of an
acetonitrile solution containing 97.1 Ag terephtalic acid
dimethyl ester (TCI, Tokyo, Japan) and 118.3 Ag p-toluic
acid methyl ester (TCI), and 50 Al of an aqueous solution
containing 111 Ag terephtalic acid (ChemService, West
Chester, PA, USA). The filters were dried in a silica gel
dryer overnight. Five clean filters were extracted to
determine limits of detection (LoDs). Terephtalic acid
dimethyl ester and p-toluic acid methyl ester standards
were prepared in acetonitrile at 3.88 and 4.73 mg/l,
respectively, while terephtalic acid standard was prepared
in water at 111 mg/l. Blanks, standards, spikes and samples
(20 Al) were analysed by HPLC, using a mixture of water/

Table 1
Air pollutants, physical state, CAS registry number, risk and safety phrasesa
Substance Physical state solid/vapour (S/V) CAS registry number Risk phrases Safety phrases
Terephtalic acid dimethyl ester S 120-61-6
p-Toluic acid methyl ester S 99-75-2
Terephtalic acid S 100-21-0
p-Xylene V 106-42-3 10-20/21-38 (2)-25
Methylacetate V 79-20-9 11-36-66-67 (2)-16-26-29-33
Methylbenzoate V 93-58-3
Formic acid V 64-18-6 35 (1/2)-23-26-45
Acetic acid V 64-19-7 10-35 23-26-45
Methanol V 67-56-1 11-23/24/25-39/23/23/24/25 1/2-7-16-36/37-45
Cobalt acetate trihydrate S 71-48-7
Manganese (II) acetate tetrahydrate S 6156-78-1
a
Ministry of Health. Decree 14th June 2002. Adoption of 2001/59/EC Council Directive with XXVIII adapting to technical progress the 67/548/EEC
Council Directive concerning the classification, packaging and labeling of dangerous substances. Gazzetta Ufficiale N. 244 17th October 2002.
402 I. Iavicoli et al. / Microchemical Journal 79 (2005) 399404
acetonitrile as the mobile phase at the flow rate of 1.5 ml/
min; programme: time 0 min, H2O/acetonitrile=100%:0%;
time 2 min, H2O/acetonitrile=100%:0%; time 10 min, H2O/
acetonitrile=0%:100%; time 12 min, H2O/acetonitrile=
100%:0%; time 20 min, H2O/acetonitrile=100%: 0%.
Quantification was obtained by the external standard
method. Analyses were performed using a mod. Vista
(Varian, Walnut Creek, CA, USA) liquid chromatograph
fitted with an Ultra C18 5 Am, 2504.6 mm (Supelco,
Bellefonte; PA, USA) column and a Polychrom mod. 9060
(Varian) detector operating at 240 nm. Samples, standards,
blanks and spikes were injected into the liquid chromato-
graph after filtering through a 0.2-Am GyroDisk membrane
(Orange Scientific, Waterloo, Belgium).
p-Xylene, methyl acetate and methylbenzoate were
analysed by flame ionization detection gas chromatography.
The analytes were desorbed for 4 h at room temperature with
2 ml of carbon sulfide (J.T. Baker, Instra-Analyzed, Deventer,
Holland). Extraction efficiency was measured by adding to
the adsorbent 2 ml of carbon sulfide containing p-xylene (RS
grade, Carlo Erba Reagenti), methylacetate (ChemService)
and methylbenzoate (RPE grade, Carlo Erba Reagenti) at
concentrations of 0.43, 0.47 and 0.38 mg/l, respectively. Five
clean adsorbents were also extracted to determine LoDs.
Analyses were performed using a mod 3400 (Varian) gas
chromatograph and a mod. 8100 (Varian) autosampler.
Quantification was calculated by external standard method
with correction for extraction efficiency. A 60 m, i.d. 0.53
mm, Rtx-VMS (Restek, Bellefonte, PA, USA) column was
used with flame ionization detection. An isotherm pro-
gramme was used: 40 8C for 4 min (step 1); programmed
temperature (step 2): up to 180 8C at 4 8C/min; programmed
temperature (step 3): up to 240 8C at 10 8C/min. The carrier
and makeup gas was nitrogen at flows of 4 and 26 ml/min,
respectively.
Formic and acetic acids were analyzed by ion chroma-
tography using the OSHA-ID168SG method with a mod.
2100iSP ion chromatograph fitted with P580 (Dionex,
Sunnyvale, CA, USA) pump. Formic and acetic acid
standards were supplied by ChemService.
Methanol was determined by flame ionization gas
chromatography using the OSHA 91 method. Standards
and instruments were supplied by ChemService and Varian
(see above), respectively.
Cobalt acetate and manganese acetate were analysed by
ICP-MS, using the OSHA ID125G method after digestion
of the filters in an MDS-2000 microwave oven (CEM,
Matthews, NC, USA) with ultra pure concentrated HNO3
(6970% J.T. Baker Instra-Analyzed) and dilution to 5 ml
with deionized water (Nuovo RD 30 Elettracqua, Genova,
Italy and Milli-Q, Millipore, Bedford, MA, USA). Calibra-
tion was performed by using working standards of cobalt
and manganese obtained by serial dilutions of 1000 mg/L
standards (HPS, Charleston, SC, USA). Analyses were
carried out by means of mod. Elan 6000 (Sciex-Perki-
nElmer, Norwalk, UK) ICP-MS.
3. Results
The results of environmental measurements of pollutants
are shown in Table 2 and are expressed as means and
concentration range. To calculate mean values, the LoD/2
value were used in cases where some levels were below the
LoD. Relative detection limits were deduced from LoDs,
extraction parameters and the volume of air sampled. These
are indicated in Table 2 for all substances as bb Q, except for
terephtalic acid dimethyl ester and methylbenzoate whose
LoDs were found to be 0.0003 and 0.1 mg/m3, respectively.
Relative data for each substance that has an established
threshold limit value-time weighted average (TLV-TWA)
have also been reported by referring to the American
Conference of Governmental Industrial Hygienists (ACGIH)
standards for the year 2002.
On account of the low solubility of terephtalic acid in
acetonitrile, the standard solutions had to be prepared in
water, but recovery (98,0F1.8%) with acetonitrile of small
amounts, such as those collected during air samplings, was
not affected. Recoveries of terephtalic acid dimethyl ester
and p-toluic ester were 101.8F2.0% and 97.7F2.3%,
respectively. Relative detection levels were b0.0005 mg/m3
(terephtalic acid dimethyl ester), b0.0001 mg/m3 ( p-toluic
acid methyl ester) and b0.0008 mg/m3 (terephtalic acid).
4. Discussion and conclusion
The sampling strategy took into account the remarkable
differences of the physico-chemical properties of the
substances examined. In fact, while some of them, such as
terephtalic acid dimethyl ester, p-toluic acid methyl ester
and terephtalic acid dimethyl ester are solid, others, such as
p-xylene, methylacetate, methylbenzoate, formic acid,
acetic acid and methyl alcohol, were present in the work-
places as vapours. This made it necessary not only to adopt
different sampling systems for airborne particulates and
vapours, but also compelled us to use different vapour
sorbents.
In order to reduce the number of sampling devices worn
by workers, we opted for a passive sampling system for the
collection of p-xylene, methylacetate and methylbenzoate,
and an active sampling system for formic and acetic acids,
and methyl alcohol. To sample formic and acetic acids and
methyl alcohol, the double-adjustable low flow holders was
particularly useful since it enabled us to use a single pump
to sample formic and acetic acids with two vials.
With regard to sampling of cobalt and manganese
acetate-based catalyst, on account of the very limited
duration of the three loading operations, 3.33, 2.93 and
2.83 min, respectively, we decided to perform extra
samplings during the second shift.
It should be remembered that the melting point of p-
toluic acid methyl ester is 33 8C and that during our
environmental survey the air temperature never exceeded
 I. Iavicoli et al. / Microchemical Journal 79 (2005) 399404 403

200 Ag/m3*
this value (maximum temperature=13 8C), and the temper-

b0.112.5
Mn ature in the control room, where monitored workers was
always below 21 8C. This confirms that the sampling device

4.2
20 Ag/m3 (i.e. fibre filter) used for collecting p-toluic acid methyl ester
was adequate. It should be noted that during other periods of

0.351.4
the year, when air temperature is above the melting point of

1.1
Co

p-toluic acid methyl ester, further investigation would be

necessary to ascertain whether this substance is present in
24.5 mg/m3

b0.050.29

b0.050.60

b0.050.51

b0.050.50

0.070.33
Acetic acid

the workplace as a vapour or aerosol, or in both physical

0.12

0.22

0.30

0.24
0.11

states. The latter event would require a different and,

probably, more complex sampling system.
Analyses were carried out using Occupational Safety and
262 mg/m3
Methanol

Health Administration (OSHA) methods, when available.

0.33.8

b0.12.7

b0.11.8

b0.11.4

0.10.6
0.43

To analyze terephtalic acid dimethyl ester, p-toluic acid

0.8
1.6

1.0

0.3

methyl ester and terephtalic acid, we developed a HPLC

method with UV detection.
b0.0020.088

b0.0020.130

b0.0020.026

0.0030.044

b0.0020.013
Airborne organic (mg/mg3) and inorganic (Ag/m3) pollutant levels (mean, range) in the breathing zone of six workers; n= number of measurements
Formic acid

Recovery from fibre filters of terephtalic acid, terephtalic

9.4 mg/m3

acid dimethyl ester and p-toluic acid methyl ester were close
0.036
0.022

0.008

0.007

0.006

to 100% and their relative detection levels in air were lower

than 1 Ag/m3, enabling the measurement of very low
environmental levels.
Methylbenzoate

As regards the sampling of methylbenzoate, in the

absence of validated methods, we used the same passive
0.33.7

0.22.2

0.36.9

0.43.5

0.33.4

sampling system employed for methylacetate and p-xylene.

1.1
1.3

2.3

1.6

1.4

The equivalent sampling rate for this substance was

calculated according to the dimensional parameters of the

Methylacetate

sampler and the diffusion coefficient derived by Hirschfel-

606 mg/m3

b0.10.7

b0.10.4

b0.10.9

b0.10.3

b0.10.6

ers method [10].

0.2
0.5

0.4

0.1

0.3

The environmental levels show a relatively wide

variability, with a maximum/minimum level ratio that
frequently exceeds 10, and this result is in keeping with
434 mg/m3
p-Xylene

b0.11.7

b0.14.3

b0.10.4

b0.10.3

0.10.4

occupational activities performed out of doors. Moreover,

1.1
0.7

0.2

0.2

0.2

on the first day of sampling, a dysfunction resulted in the

partial closing down of the chemical plant. Consequently,
workers spent more time in the plant than normal. For this
b0.00080.004

b0.00080.004

b0.00080.006
0.0010.014

0.0010.013

reason, we have reported only the mean and range of

Terephtalic

10 mg/m3

concentrations and have omitted the standard deviation.

0.005
0.005

0.002

0.002

0.003
acid

The substances examined did not include products such

as those derived from p-xylene isomers, i.e. m- and o-
xylene, which were present in the process in very small
b0.00010.020

b0.00010.013

b0.00010.022
0.0010.030

0.0030.020
p-Toluic acid
methyl ester

quantities. We did not therefore determined terephtalic acid

monomethyl ester, isoterephtalic acid dimethyl ester and o-
0.003
0.006

0.009

0.008

0.009

terephtalic acid dimethyl ester.

Workplace levels were well below ACGIH TLV-TWA

even if for three of the substancesterephtalic acid
Terephtalic acid
dimethyl ester

dimethyl ester, p-toluic acid methyl ester and methylben-

0.0030.006

0.0010.007

0.0030.020

0.0020.010

0.0070.106

* Intended change to 30 Ag/m3.

zoate exposure limits were not established. In the literature,

0.003
0.004

0.009

0.005

0.039

to our knowledge, no data are available for the effects on

humans following exposure to these substances.

The environmental levels of the pollutants with a TLV-
4
n

TWA were two orders of magnitude below their respective

External workers

(crystallization)
External worker

limits. For solid state substances with no TLV-TWA, the

Catalyst loader
Technological
Shift foreman

mean of resulting levels was a few Ag/m3 (terephtalic acid

(oxidation)
1st operator
TLV-TWA

workera

dimethyl ester, 4 Ag/m3; p-toluic acid methyl ester, 6 Ag/

Substance
Table 2

m3), while for the only vaporous substance (methylben-

Job

zoate), it was 1.3 mg/m3. As regards cobalt and manganese

404 I. Iavicoli et al. / Microchemical Journal 79 (2005) 399404
acetate, in the absence of a short-term exposure level
(STEL) and on the basis of the duration of the exposure, we
can estimate a mean weighted exposure for 8 h of 0.0064
and 0.025 Ag/m3 (as a metal), respectively. These values are
several orders of magnitude below the TLV-TWA estab-
lished for these two metals.
In conclusion, even if it is difficult to make a hygiene
assessment of the three substances that do not have an
established TLV-TWA, all the other substances investigated
were well below their respective ACGIH levels. To the best
of our knowledge, this is the first study that investigates
occupational exposure in workers employed in a plant for
the synthesis of terephtalic acid dimethyl ester This fact
makes our findings of particular interest in the field of
prevention and in that of Industrial Hygiene.
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