Ikeda, Masayuki

Ikeda, Masayuki

Address: Kyoto Industrial Health Association, 67, Nishinokyo-Kitatsuboicho, Nakagyo-ku, Kyoto 604

Country: Japan

Phone: 81 75 823 0533

Fax: 81 75 823 802 0038

E-mail: mbh02572@niftyserve.or.jp

Past position(s): Professor, Kyoto University Faculty of Medicine

Education: MD, 1957, Kyoto University; PhD, 1963, Kyoto University

Areas of interest: Biological monitoring of industrial and environmental chemicals; risk evaluation of chemicals

Monday, 28 February 2011 20:21

Organic Solvents

Introduction

Organic solvents are volatile and generally soluble in body fat (lipophilic), although some of them, e.g., methanol and acetone, are water soluble (hydrophilic) as well. They have been extensively employed not only in industry but in consumer products, such as paints, inks, thinners, degreasers, dry-cleaning agents, spot removers, repellents, and so on. Although it is possible to apply biological monitoring to detect health effects, for example, effects on the liver and the kidney, for the purpose of health surveillance of workers who are occupationally exposed to organic solvents, it is best to use biological monitoring instead for “exposure” monitoring in order to protect the health of workers from the toxicity of these solvents, because this is an approach sensitive enough to give warnings well before any health effects may occur. Screening workers for high sensitivity to solvent toxicity may also contribute to the protection of their health.

Summary of Toxicokinetics

Organic solvents are generally volatile under standard conditions, although the volatility varies from solvent to solvent. Thus, the leading route of exposure in industrial settings is through inhalation. The rate of absorption through the alveolar wall of the lungs is much higher than that through the digestive tract wall, and a lung absorption rate of about 50% is considered typical for many common solvents such as toluene. Some solvents, for example, carbon disulphide and N,N-dimethylformamide in the liquid state, can penetrate intact human skin in amounts large enough to be toxic.

When these solvents are absorbed, a portion is exhaled in the breath without any biotransformation, but the greater part is distributed in organs and tissues rich in lipids as a result of their lipophilicity. Biotransformation takes place primarily in the liver (and also in other organs to a minor extent), and the solvent molecule becomes more hydrophilic, typically by a process of oxidation followed by conjugation, to be excreted via the kidney into the urine as metabolite(s). A small portion may be eliminated unchanged in the urine.

Thus, three biological materials, urine, blood and exhaled breath, are available for exposure monitoring for solvents from a practical viewpoint. Another important factor in selecting biological materials for exposure monitoring is the speed of disappearance of the absorbed substance, for which the biological half-life, or the time needed for a substance to diminish to one-half its original concentration, is a quantitative parameter. For example, solvents will disappear from exhaled breath much more rapidly than corresponding metabolites from urine, meaning they have a much shorter half-life. Within urinary metabolites, the biological half-life varies depending on how quickly the parent compound is metabolised, so that sampling time in relation to exposure is often of critical importance (see below). A third consideration in choosing a biological material is the specificity of the target chemical to be analysed in relation to the exposure. For example, hippuric acid is a long-used marker of exposure to toluene, but it is not only formed naturally by the body, but can also be derived from non-occupational sources such as some food additives, and is no longer considered a reliable marker when toluene exposure is low (less than 50 cm3/m3). Generally speaking, urinary metabolites have been most widely used as indicators of exposure to various organic solvents. Solvent in blood is analysed as a qualitative measure of exposure because it usually remains in the blood a shorter time and is more reflective of acute exposure, whereas solvent in exhaled breath is difficult to use for estimation of average exposure because the concentration in breath declines so rapidly after cessation of exposure. Solvent in urine is a promising candidate as a measure of exposure, but it needs further validation.

Biological Exposure Tests for Organic Solvents

In applying biological monitoring for solvent exposure, sampling time is important, as indicated above. Table 1 shows recommended sampling times for common solvents in the monitoring of everyday occupational exposure. When the solvent itself is to be analysed, attention should be paid to preventing possible loss (e.g., evaporation into room air) as well as contamination (e.g., dissolving from room air into the sample) during the sample handling process. In case the samples need to be transported to a distant laboratory or to be stored before analysis, care should be exercised to prevent loss. Freezing is recommended for metabolites, whereas refrigeration (but no freezing) in an airtight container without an air space (or more preferably, in a headspace vial) is recommended for analysis of the solvent itself. In chemical analysis, quality control is essential for reliable results (for details, see the article “Quality assurance” in this chapter). In reporting the results, ethics should be respected (see chapter Ethical Issues elsewhere in the Encyclopaedia).

Table 1. Some examples of target chemicals for biological monitoring and sampling time

Solvent

Target chemical

Urine/blood

Sampling time1

Carbon disulphide

2-Thiothiazolidine-4-carboxylicacid

Urine

Th F

N,N-Dimethyl-formamide

N-Methylformamide

Urine

M Tu W Th F

2-Ethoxyethanol and its acetate

Ethoxyacetic acid

Urine

Th F (end of last workshift)

Hexane

2,4-Hexanedione

Hexane

Urine

Blood

M Tu W Th F

confirmation of exposure

Methanol

Methanol

Urine

M Tu W Th F

Styrene

Mandelic acid

Phenylglyoxylic acid

Styrene

Urine

Urine

Blood

Th F

Th F

confirmation of exposure

Toluene

Hippuric acid

o-Cresol

Toluene

Toluene

Urine

Urine

Blood

Urine

Tu W Th F

Tu W Th F

confirmation of exposure

Tu W Th F

Trichloroethylene

Trichloroacetic acid

(TCA)

Total trichloro- compounds (sum of TCA and free and conjugated trichloroethanol)

Trichloroethylene

Urine

Urine

Blood

Th F

Th F

confirmation of exposure

Xylenes2

Methylhippuric acids

Xylenes

Urine

Blood

Tu W Th F

Tu W Th F

1 End of workshift unless otherwise noted: days of week indicate preferred sampling days.
2 Three isomers, either separately or in any combination.

Source: Summarized from WHO 1996.

 

Anumber of analytical procedures are established for many solvents. Methods vary depending on the target chemical, but most of the recently developed methods use gas chromatography (GC) or high-performance liquid chromatography (HPLC) for separation. Use of an autosampler and data processor is recommended for good quality control in chemical analysis. When a solvent itself in blood or in urine is to be analysed, an application of headspace technique in GC (headspace GC) is very convenient, especially when the solvent is volatile enough. Table 2 outlines some examples of the methods established for common solvents.

Table 2. Some examples of analytical methods for biological monitoring of exposure to organic solvents

Solvent

Target chemical

Blood/urine

Analytical method

Carbon disulphide

2-Thiothiazolidine-4-
carboxylic acid

Urine

High performance liquid chromatograph with ultraviolet detection

(UV-HPLC)

N,N-Dimethylformamide

N-Methylformamide

Urine

Gas chromatograph with flame thermionic detection (FTD-GC)

2-Ethoxyethanol and its acetate

Ethoxyacetic acid

Urine

Extraction, derivatization and gas chromatograph with flame ionization detection (FID-GC)

Hexane

2,4-Hexanedione

Hexane

Urine

Blood

Extraction, (hydrolysis) and FID-GC

Head-space FID-GC

Methanol

Methanol

Urine

Head-space FID-GC

Styrene

Mandelic acid

Phenylglyoxylic acid

Styrene

Urine

Urine

Blood

Desalting and UV-HPLC

Desalting and UV-HPLC

Headspace FID-GC

Toluene

Hippuric acid

o-Cresol

Toluene

Toluene

Urine

Urine

Blood

Urine

Desalting and UV-HPLC

Hydrolysis, extraction and FID-GC

Headspace FID-GC

Headspace FID-GC

Trichloroethylene

Trichloroacetic acid
(TCA)

Total trichloro-compounds (sum of TCA and freeand conjugated trichloroethanol)

Trichloroethylene

Urine

Urine

Blood

Colorimetry or esterification and gas chromatograph with electron capture detection (ECD-GC)

Oxidation and colorimetry, or hydrolysis, oxidation, esterification and ECD-GC

Headspace ECD-GC

Xylenes

Methylhippuric acids (three isomers, either separately orin combination)

Urine

Headspace FID-GC

Source: Summarized from WHO 1996.

Evaluation

A linear relationship of the exposure indicators (listed in table 2) with the intensity of exposure to corresponding solvents may be established either through a survey of workers occupationally exposed to solvents, or by experimental exposure of human volunteers. Accordingly, the ACGIH (1994) and the DFG (1994), for example, have established the biological exposure index (BEI) and the biological tolerance value (BAT), respectively, as the values in the biological samples which are equivalent to the occupational exposure limit for airborne chemicals—that is, threshold limit value (TLV) and maximum workplace concentration (MAK), respectively. It is known, however, that the level of the target chemical in samples obtained from non-exposed people may vary, reflecting, for example, local customs (e.g., food), and that ethnic differences may exist in solvent metabolism. It is therefore desirable to establish limit values through the study of the local population of concern.

In evaluating the results, non-occupational exposure to the solvent (e.g., via use of solvent-containing consumer products or intentional inhalation) and exposure to chemicals which give rise to the same metabolites (e.g., some food additives) should be carefully excluded. In case there is a wide gap between the intensity of vapour exposure and the biological monitoring results, the difference may indicate the possibility of skin absorption. Cigarette smoking will suppress the metabolism of some solvents (e.g., toluene), whereas acute ethanol intake may suppress methanol metabolism in a competitive manner.

 

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As in many other countries, risk due to exposure to chemicals is regulated in Japan according to the category of chemicals concerned, as listed in table 1. The governmental ministry or agency in charge varies. In the case of industrial chemicals in general, the major law that applies is the Law Concerning Examination and Regulation of Manufacture, Etc. of Chemical Substances, or Chemical Substances Control Law (CSCL) for short. The agencies in charge are the Ministry of International Trade and Industry and the Ministry of Health and Welfare. In addition, the Labour Safety and Hygiene Law (by the Ministry of Labour) provides that industrial chemicals should be examined for possible mutagenicity and, if the chemical in concern is found to be mutagenic, the exposure of workers to the chemical should be minimized by enclosure of production facilities, installation of local exhaust systems, use of protective equipment, and so on.

Table 1. Regulation of chemical substances by laws, Japan

Category Law Ministry
Food and food additives Foodstuff Hygiene Law MHW
Pharmaceuticals Pharmaceuticals Law MHW
Narcotics Narcotics Control Law MHW
Agricultural chemicals Agricultural Chemicals Control Law MAFF
Industrial chemicals Chemical Substances Control Law MHW & MITI
All chemicals except for radioactive substances Law concerning Regulation of
House-Hold Products Containing
Hazardous Substances
Poisonous and Deleterious
Substances Control Law
Labour Safety and Hygiene Law
MHW

MHW

MOL
Radioactive substances Law concerning Radioactive Substances STA

Abbreviations: MHW—Ministry of Health and Welfare; MAFF—Ministry of Agriculture, Forestry and Fishery; MITI—Ministry of International Trade and Industry; MOL—Ministry of Labour; STA—Science and Technology Agency.

Because hazardous industrial chemicals will be identified primarily by the CSCL, the framework of tests for hazard identification under CSCL will be described in this section.

The Concept of the Chemical SubstanceControl Law

The original CSCL was passed by the Diet (the parliament of Japan) in 1973 and took effect on 16 April 1974. The basic motivation for the Law was the prevention of environmental pollution and resulting human health effects by PCBs and PCB-like substances. PCBs are characterized by (1) persistency in the environment (poorly biodegradable), (2) increasing concentration as one goes up the food chain (or food web) (bioaccumulation) and (3) chronic toxicity in humans. Accordingly, the Law mandated that each industrial chemical be examined for such characteristics prior to marketing in Japan. In parallel with the passage of the Law, the Diet decided that the Environment Agency should monitor the general environment for possible chemical pollution. The Law was then amended by the Diet in 1986 (the amendment taking effect in 1987) in order to harmonize with actions of the OECD regarding health and the environment, the lowering of non-tariff barriers in international trade and especially the setting of a minimum premarketing set of data (MPD) and related test guidelines. The amendment was also a reflection of observation at the time, through monitoring of the environment, that chemicals such as trichloroethylene and tetrachloroethylene, which are not highly bioaccumulating although poorly biodegradable and chronically toxic, can pollute the environment; these chemical substances were detected in groundwater nationwide.

The Law classifies industrial chemicals into two categories: existing chemicals and new chemicals. The existing chemicals are those listed in the “Existing Chemicals Inventory” (established with the passage of the original Law) and number about 20,000, the number depending on the way some chemicals are named in the inventory. Chemicals not in the inventory are called new chemicals. The government is responsible for hazard identification of the existing chemicals, whereas the company or other entity that wishes to introduce a new chemical into the market in Japan is responsible for hazard identification of the new chemical. Two governmental ministries, the Ministry of Health and Welfare (MHW) and the Ministry of International Trade and Industry (MITI), are in charge of the Law, and the Environment Agency can express its opinion when necessary. Radioactive substances, specified poisons, stimulants and narcotics are excluded because they are regulated by other laws.

Test System Under CSCL

The flow scheme of examination is depicted in figure 1, which is a stepwise system in principle. All chemicals (for exceptions, see below) should be examined for biodegradability in vitro. In case the chemical is readily biodegradable, it is considered “safe”. Otherwise, the chemical is then examined for bioaccumulation. If it is found to be “highly accumulating,” full toxicity data are requested, based on which the chemical will be classified as a “Class 1 specified chemical substance” when toxicity is confirmed, or a “safe” one otherwise. The chemical with no or low accumulation will be subject to toxicity screening tests, which consist of mutagenicity tests and 28-day repeated dosing to experimental animals (for details, see table 2). After comprehensive evaluation of the toxicity data, the chemical will be classified as a “Designated chemical substance” if the data indicate toxicity. Otherwise, it is considered “safe”. When other data suggest that there is a great possibility of environmental pollution with the chemical in concern, full toxicity data are requested, from which the designated chemical will be reclassified as “Class 2 specified chemical substance” when positive. Otherwise, it is considered “safe”. Toxicological and ecotoxicological characteristics of “Class 1 specific chemical substance,” “Class 2 specific chemical substance” and “Designated chemical substance” are listed in table 3 together with outlines of regulatory actions.

Figure 1. Scheme of examination

TOX260F1

Table 2. Test items under the Chemical Substance Control Law, Japan

Item Test design
Biodegradation For 2 weeks in principle, in vitro, with activated
sludge
Bioaccumulation For 8 weeks in principle, with carp
Toxicity screening
Mutagenicity tests
Bacterial system
Chromosome aberration


Ames’ test and test with E. coli, ± S9 mix
CHL cells, etc., ±S9 mix
28-day repeated dosing Rats, 3 dose levels plus control for NOEL,
2 weeks recovery test at the highest dose level in addition

Table 3. Characteristics of classified chemical substances and regulations under the Japanese Chemical Substances Control Law

Chemical substance Characteristics Regulation
Class 1
specified chemical substances
Nonbiodegradability
High bioaccumulation
Chronic toxicity
Authorization to manufacture or import necessary1
Restriction in use
Class 2
specified chemical substances
Nonbiodegradability
Non- or low bioaccumulation Chronic toxicity
Suspected environmental pollution
Notification on scheduled manu-facturing or import quantity
Technical guideline to prevent pollution/heath effects
Designated chemical substances Nonbiodegradability
Non- or low bioaccumulation
Suspected chronic toxicity
Report on manufacturing or import quantity
Study and literature survey

1 No authorization in practice.

Testing is not required for a new chemical with a limited use amount (i.e., less than 1,000 kg/company/year and less than 1,000 kg/year for all of Japan). Polymers are examined following the high molecular-weight compound flow scheme, which is developed with an assumption that chances are remote for absorption into the body when the chemical has a molecular weight of greater than 1,000 and is stable in the environment.

Results of Classification of Industrial Chemicals,as of 1996

In the 26 years from the time CSCL went into effect in 1973 to the end of 1996, 1,087 existing chemical items were examined under the original and amended CSCL. Among the 1,087, nine items (some are identified by generic names) were classified as “Class 1 specified chemical substance”. Among those remaining, 36 were classified as “designated”, of which 23 were reclassified as “Class 2 specified chemical substance” and another 13 remained as “designated”. The names of Class 1 and 2 specified chemical substances are listed in figure 2. It is clear from the table that most of the Class 1 chemicals are organochlorine pesticides in addition to PCB and its substitute, except for one seaweed killer. A majority of the Class 2 chemicals are seaweed killers, with the exceptions of three once widely used chlorinated hydrocarbon solvents.

Figure 2. Specified and designated chemical substances under the Japanese Chemical Substances Control Law

TOX260T4

In the same period from 1973 to the end of 1996, about 2,335 new chemicals were submitted for approval, of which 221 (about 9.5%) were identified as “designated”, but none as Class 1 or 2 chemicals. Other chemicals were considered “safe” and approved for manufacturing or import.

 

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Contents

Preface
Part I. The Body
Part II. Health Care
Part III. Management & Policy
Part IV. Tools and Approaches
Part V. Psychosocial and Organizational Factors
Part VI. General Hazards
Part VII. The Environment
Part VIII. Accidents and Safety Management
Part IX. Chemicals
Part X. Industries Based on Biological Resources
Part XI. Industries Based on Natural Resources
Part XII. Chemical Industries
Part XIII. Manufacturing Industries
Part XIV. Textile and Apparel Industries
Part XV. Transport Industries
Part XVI. Construction
Part XVII. Services and Trade
Part XVIII. Guides