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INTERNATIONAL PROGRAMME ON CHEMICAL SAFETY


ENVIRONMENTAL HEALTH CRITERIA 93


CHLOROPHENOLS OTHER THAN PENTACHLOROPHENOL


This report contains the collective views of an international group of

experts and does not necessarily represent the decisions or the stated

policy of the United Nations Environment Programme, the International

Labour Organisation, or the World Health Organization


Published under the joint sponsorship of

the United Nations Environment Programme,

the International Labour Organisation,

and the World Health Organization


World Health Organization

Geneva, 1989


The International Programme on Chemical Safety (IPCS) is a joint

venture of the United Nations Environment Programme, the International

Labour Organization, and the World Health Organization. The main

objective of the IPCS is to carry out and disseminate evaluations of

the effects of chemicals on human health and the quality of the

environment. Supporting activities include the development of

epidemiological, experimental laboratory, and risk-assessment methods

that could produce internationally comparable results, and the

development of manpower in the field of toxicology. Other activities

carried out by the IPCS include the development of know-how for coping

with chemical accidents, coordination of laboratory testing and

epidemiological studies, and promotion of research on the mechanisms

of the biological action of chemicals.


WHO Library Cataloguing in Publication Data


Chlorophenols other than pentachlorophenol


(Environmental health criteria; 93)


1. Chlorophenols I. Series


ISBN 92 4 154293 4 (NLM Classification: QV 223)

ISSN 0250-863X


(c) World Health Organization 1989


Publications of the World Health Organization enjoy copyright

protection in accordance with the provisions of Protocol 2 of the

Universal Copyright Convention. For rights of reproduction or

translation of WHO publications, in part or in toto, application

should be made to the Office of Publications, World Health

Organization, Geneva, Switzerland. The World Health Organization

welcomes such applications.


The designations employed and the presentation of the material in

this publication do not imply the expression of any opinion whatsoever

on the part of the Secretariat of the World Health Organization

concerning the legal status of any country, territory, city or area or

of its authorities, or concerning the delimitation of its frontiers or

boundaries.


The mention of specific companies or of certain manufacturers'

products does not imply that they are endorsed or recommended by the

World Health Organization in preference to others of a similar nature

that are not mentioned. Errors and omissions excepted, the names of

proprietary products are distinguished by initial capital letters.


CONTENTS


1. SUMMARY

1.1. Identity, physical and chemical properties,

analytical methods

1.2. Sources of human and environmental exposure

1.2.1. Production figures

1.2.2. Manufacturing processes

1.2.3. Uses

1.2.4. Waste disposal

1.2.5. Release of chlorophenols into the environment

1.2.6. Natural sources

1.3. Environmental transport, distribution, and transformation

1.3.1. Degradation

1.3.2. Bioaccumulation

1.3.3. Effects of physical chemical and biological

factors on degradation

1.4. Environmental levels and human exposure

1.4.1. Chlorophenol levels in the environment

1.4.2. Chlorophenol levels in food, drinking-water, and

treated wood

1.5. Kinetics and metabolism

1.6. Effects on organisms in the environment

1.7. Effects on experimental animals and in vitro systems

1.8. Effects on man

1.8.1. Non-occupational exposure

1.8.2. Occupational exposure


2. IDENTITY, PHYSICAL AND CHEMICAL PROPERTIES, ANALYTICAL METHODS


2.1. Identity

2.2. Physical and chemical properties

2.3. Conversion factors

2.4. Analytical methods

2.4.1. Sample collection and storage

2.4.2. Sample preparation and analysis


3. SOURCES OF HUMAN AND ENVIRONMENTAL EXPOSURE


3.1. Natural occurrence

3.2. Man-made sources

3.2.1. Production levels and processes

3.2.1.1 World production figures

3.2.1.2 Manufacturing processes


3.2.2. Uses

3.2.2.1 Wood treatment

3.2.2.2 Agriculture

3.2.2.3 Domestic

3.2.2.4 Water treatment

3.2.2.5 Additives

3.2.2.6 Intermediates in industrial syntheses

3.2.3. Other sources

3.3. Waste disposal

3.4. Losses of chlorophenols into the environment


4. ENVIRONMENTAL TRANSPORT, DISTRIBUTION AND TRANSFORMATION


4.1. Transport and distribution

4.1.1. Atmospheric movement

4.1.1.1 Volatilization

4.1.2. Soil movement

4.1.2.1 Adsorption

4.1.2.2 Leaching

4.1.3. Transport in aquatic environments

4.2. Degradation and bioaccumulation

4.2.1. Degradation

4.2.1.1 Abiotic degradation

4.2.1.2 Degradation by microorganisms

4.2.2. Bioaccumulation

4.3. Effects of other physical, chemical, or biological factors

4.3.1. pH

4.3.2. Lack of oxygen

4.3.3. Inorganic nutrients

4.3.4. Organic matter

4.3.5. Temperature

4.4. Persistence


5. ENVIRONMENTAL LEVELS AND HUMAN EXPOSURE


5.1. Environmental levels

5.1.1. Air

5.1.2. Water

5.1.2.1 Sediments

5.1.3. Soil

5.1.4. Food and feed, drinking-water

5.1.4.1 Food

5.1.4.2 Livestock feed

5.1.4.3 Drinking-water

5.1.5. Treated wood

5.1.6. Terrestrial and aquatic organisms

5.1.6.1 Invertebrates

5.1.6.2 Fish

5.1.6.3 Other non-human vertebrates


5.2. General population exposure

5.3. Occupational exposure


6. KINETICS AND METABOLISM


6.1. Absorption

6.2. Distribution

6.2.1. Tissue distribution following chlorophenol

exposure

6.2.2. Tissue distribution following exposure to

chemicals metabolized to chlorophenols

6.3. Metabolic transformation

6.4. Elimination and excretion


7. EFFECTS ON ORGANISMS IN THE ENVIRONMENT


7.1. Laboratory toxicity studies

7.1.1. Acute toxicity

7.1.2. Long-term toxicity

7.1.3. Organoleptic effects

7.2. Toxicity studies under natural environment conditions

7.2.1. Bacteria

7.2.2. Phytoplankton

7.2.3. Zooplankton

7.2.4. Fish

7.2.5. Effects on physical and chemical variables

7.3. Treatment levels


8. EFFECTS ON EXPERIMENTAL ANIMALS AND IN VITRO SYSTEMS


8.1. Acute studies

8.2. Skin and eye irritation; sensitization

8.3. Short-term exposure

8.4. Long-term exposure

8.5. Reproduction, embryotoxicity, and teratogenicity

8.6. Mutagenicity and related end-points

8.7. Carcinogenicity

8.8. Factors modifying toxicity; metabolism

8.9. Mechanisms of toxicity, mode of action


9. EFFECTS ON MAN


9.1. Acute toxicity

9.2. Long-term exposure

9.2.1. Effects on skin and mucous membranes

9.2.2. Systemic effects

9.2.3. Psychological and neurological effects

9.2.4. Reproductive effects


9.2.5. Carcinogenicity

9.2.5.1 Case-control studies reviewed by IARC

9.2.5.2 Cohort studies reviewed by IAC

9.2.5.3 More recent studies


10. EVALUATION OF HUMAN HEALTH RISKS AND EFFECTS ON THE ENVIRONMENT


10.1. Evaluation of human health risks

10.1.1. Exposure levels

10.1.1.1 Non-occupational exposure

10.1.1.2 Occupational exposure

10.1.2. Toxic effects

10.1.3. Risk evaluation

10.2. Evaluation of effects on the environment

10.2.1. Levels of exposure

10.2.2. Transport

10.2.3. Degradation

10.2.4. Bioaccumulation

10.2.5. Persistence

10.2.6. Toxic effects on environmental organisms

10.2.7. Risk evaluation


11. RECOMMENDATIONS


11.1. Production

11.2. Disposal

11.3. Occupational exposure

11.4. General population exposure

11.5. Recommendations for future research

11.5.1. Environmental Aspects

11.5.2. Toxicology

11.5.3. Epidemiology


12. PREVIOUS EVALUATIONS BY INTERNATIONAL BODIES


REFERENCES





WHO TASK GROUP ON ENVIRONMENTAL HEALTH CRITERIA FOR CHLOROPHENOLS

OTHER THAN PENTACHLOROPHENOL


Members


Dr U.G. Ahlborg, Unit of Toxicology, National Institute of

Environmental Medicine, Stockholm, Sweden


Dr L.A. Albert, Division of Studies on Environmental Pollution,

National Institute for Research on Biotic Resources, Vera Cruz,

Mexico (Vice-Chairman)


Dr F.A. Chandra, Toxicology and Environmental Health, Department of

Health and Social Security, London, United Kingdom


Dr A. Gilman, Industrial Chemicals and Product Safety Section, Bureau

of Chemical Hazards, Environmental Health Directorate, Department

of National Health and Welfare, Tunney's Pasture, Ottawa, Canada


Dr I. Gut, Biotransformation, Institute for Hygiene and Epidemiology,

Prague, Czechoslovakia (Chairman)


Dr R. Jones, Health and Safety Executive, Bootie, Merseyside, United

Kingdom


Dr J. Kangas, Kuopio Regional Institute of Occupational Health,

Kuopio, Finland


Dr E. Lynge, Danish Cancer Registry, Institute of Cancer Epidemiology,

Copenhagen, Denmark


Dr U.G. Oleru, Department of Community Health, College of Medicine,

University of Lagos, Lagos, Nigeria


Dr J.K. Selkirk, Division of Toxicology Research and Testing,

Carcinogenesis and Toxicological Evaluation Branch, National

Institute of Environmental Health Sciences, Research Triangle

Park, NC, USA


Dr A. van der Gen, Leiden University, Leiden, Netherlands


Observer


Dr S. Lambert (European Chemical Industry Ecology and Toxicology

Centre), Rhône Poulenc, Décines Charpieu, France


Secretariat


Dr G.C. Becking, Team Leader, International Programme on Chemical

Safety, Interregional Research Unit, World Health Organization,

Research Triangle Park, NC, USA (Secretary)


Dr T. Kauppinen, International Agency for Research on Cancer, Lyons,

France


Mr R. Newhook, Bureau of Chemical Hazards, Environmental Health

Directorate, Department of National Health and Welfare, Tunney's

Pasture, Ottawa, Canada (Temporary Adviser, Rapporteur)


NOTE TO READERS OF THE CRITERIA DOCUMENTS


Every effort has been made to present information in the criteria

documents as accurately as possible without unduly delaying their

publication. In the interest of all users of the Environmental Health

Criteria documents, readers are kindly requested to communicate any

errors that may have occurred to the Manager of the International

Programme on Chemical Safety, World Health Organization, Geneva,

Switzerland, in order that they may be included in corrigenda, which

will appear in subsequent volumes.


***


A detailed data profile and a legal file can be obtained from the

International Register of Potentially Toxic Chemicals, Palais des

Nations, 1211 Geneva 10, Switzerland (Telephone no. 7988400-7985850).


ENVIRONMENTAL HEALTH CRITERIA FOR CHLOROPHENOLS OTHER THAN

PENTACHLOROPHENOL


A WHO Task Group on Environmental Health Criteria for

Chlorophenols other than Pentachlorophenol met at the Monitoring and

Assessment Research Centre, London, United Kingdom, on 21-25 March,

1988. Dr M. Hutton opened the meeting and welcomed the members on

behalf of the host institute and on behalf of the United Kingdom

Department of Health and Social Security, who sponsored the meeting.

Dr G.C. Becking addressed the meeting on behalf of the three

Cooperating Organizations of the IPCS (UNEP, ILO, and WHO). The Task

Group reviewed and revised the draft criteria document and made an

evaluation of the risks for human health and the environment from

exposure to chlorophenols other than pentachlorophenol.


The drafts of this document were prepared by Mr R. NEWHOOK and

Dr A. GILMAN, Health Protection Branch, Ottawa, Canada. Dr G. BECKING,

IPCS Interregional Research Unit, was responsible for the overall

scientific content of the document and Mrs M.O. HEAD, Oxford, England,

for the editing.


The efforts of all who helped in the preparation and finalization

of the document are gratefully acknowledged.


***


Partial financial support for the publication of this criteria

document was kindly provided by the United States Department of Health

and Human Services, through a contract from the National Institute of

Environmental Health Sciences, Research Triangle Park, North Carolina,

USA -- a WHO Collaborating Centre for Environmental Health Effects.

The United Kingdom Department of Health and Social Security generously

supported the costs of printing.


1. SUMMARY


1.1 Identity, Physical and Chemical Properties, Analytical Methods


Chlorophenols (CPs) are organic chemicals formed from phenol

(1-hydroxybenzene) by substitution in the phenol ring with one or more

atoms of chlorine. Nineteen congeners are possible, ranging from

monochlorophenols to the fully chlorinated pentachlorophenol (PCB).

Chlorophenols, particularly trichlorophenols (T3CP), tetrachloro-

phenols (T4CP), and PCP, are also available as sodium or potassium

salts.


Chlorophenols are solids at room temperature, except for 2-MCP,

which is a liquid. The aqueous solubility of chlorophenols is low, but

the sodium or potassium salts of chlorophenols are up to four orders

of magnitude more soluble in water than the parent compounds. The

acidity of chlorophenols increases as the number of chlorine sub-

stitutions increases. The n-octanol/water partition coefficients

of chlorophenols increase with chlorination, indicating a propensity

for the higher chlorophenols to bioaccumulate. Taste and odour

thresholds are quite low.


Technical grade chlorophenol products are heterogeneous mixtures

of chlorophenols, unreacted precursors, and a variety of dimeric

microcontaminants. As a result of the semiquantitative nature of the

reaction of chlorine with molten phenol, commercial formulations of

chlorophenols contain substantial quantities of other chlorophenols.

When the alkaline hydrolysis of chlorobenzenes is used to manufacture

chlorophenols, the technical product can contain unreacted

chlorobenzene.


A number of other compounds are present as microcontaminants in

technical tri- and tetrachlorophenol preparations, as a result of the

elevated reaction temperatures used. These include the polychlorinated

dibenzo- p-dioxins (PCDDs), polychlorinated dibenzofurans (PCDFs),

polychlorinated phenoxyphenols ("predioxins"), polychlorinated

diphenyl ethers, polychlorinated benzenes, and polychlorinated

biphenyls. Lower chlorophenol preparations do not contain detectable

levels of dioxins, presumably because their manufacture does not occur

at sufficiently high temperatures. Tri- and tetrachloro-dibenzo-

p-dioxins predominate in T3CP formulations, while the hexa, hepta,

and octa congeners are the major PCDD contaminants in technical T4CP

and PCP. 2,3,7,8-Tetra-chlorodibenzo- p-dioxin (2,3,7,8-TCDD) occurs

primarily as a contaminant of 2,4,5,-T3CP, though it is present at

low µg/litre concentrations in T4CP, PCP, and Na-PCP. Chlorophenol

formulations contain a similar array of PCDFs. Phenoxyphenols may

comprise as much as 1-5% of the formulation.


A large number of sampling and analytical methods have been

developed for the determination of chlorophenols in different media.

Sensitive methods, such as gas chromatography, high-performance liquid

chromatography, and mass spectrometry are increasingly used.


1.2 Sources of Human and Environmental Exposure


1.2.1 Production figures


Recent data on production levels of chlorophenols other than PCP

are not readily available. Around 1975, the combined global production

of all chlorophenols approached 200 million kg; slightly more than

half of this quantity consisted of non-PCP chlorophenols, primarily

2,4-dichlorophenol (2,4-DCP), 2,4,5-trichlorophenol (2,4,5-T3CP),

and 2,3,4,6-tetrachlorophenol (2,3,4,6-T4CP). Consumption has since

declined in some countries as a consequence of health-based concerns

(particularly for 2,4,5-T3CP), and the use of alternative wood

preservatives. Some European countries and the USA are major producers

and consumers of chlorophenols.


1.2.2 Manufacturing processes


The compounds 2-MCP, 4-MCP, 2,4-DCP, 2,3,4-T3CP, 2,4,6-T3CP,

2,3,4,6-T4CP, and PCP have been made by direct stepwise chlorination

of phenol or lower chlorinated phenols at a high temperature; a

catalyst is necessary if the last two chlorophenols are being

produced. Alternatively, some chlorophenols (2,5-DCP, 3,4-DCP,

2,4,5-T3CP, 2,3,4,5-T4CP and PCP) can be produced by the alkaline

hydrolysis of the appropriate chlorobenzene.


Both methods yield contaminants that are themselves potential

health hazards, including polychlorinated dibenzo- p-dioxins (PCDDs),

polychlorinated dibenzofurans (PCDFs), and 2-phenoxyphenols.


1.2.3 Uses


Chlorophenols are toxic for a wide range of organisms, a property

that accounts for many of their uses. Large quantities of higher

chlorophenols are used in pressure treatment in the wood preservation

industry; in addition, substantial amounts of the sodium salts of

T4CP, PCP, and T3CP are used to surface-treat fresh-cut logs and

lumber against sapstain fungi and surface mould. Large quantities of

lower chlorophenols serve as intermediates in the production of

pesticides, such as T4CP, PCP, 2,4-D, and 2,4,5-T. The use of 2,4,5-T

has been discontinued in a number of countries. Lesser amounts of

chlorophenols are used as wood preservatives in agricultural and

domestic applications, and as additives to inhibit microbial growth in

a wide array of products, such as adhesives, oils, textiles, and

pharmaceutical products.


1.2.4 Waste disposal


As a result of process design, the quantities of chlorophenolic

wastes generated are reportedly small. Available treatment methods for

such waste should prove satisfactory, if they are carefully applied.

Gravity separation is the primary treatment method most often used to

recover oil and the associated chlorophenol for recycling and

treatment. Organisms during secondary treatment degrade roughly 90% of

most chlorophenol waste, provided that they are acclimated to the

waste, and precautions are taken against shock loadings. Adsorption

onactivated carbon as a final clean-up step removes almost 100% of

remaining waste chlorophenols in waste-streams. Incineration appears

to be an effective means of disposal, if the temperatures are high

enough and residence times long enough to ensure complete combustion

and prevent the formation of PCDDs and PCDFs in the incinerator.


1.2.5 Release of chlorophenols into the environment


Patterns of losses to the environment appear similar in most

industrialized countries. The majority of chlorophenol wastes are

released in spills and leaching from treated lumber (PCP, NaPCP,

NaT4CP), and as contaminants or breakdown products of agricultural

pesticides (2,4-DCP, 2,4,5-T3CP). Substantial amounts of

chlorophenol wastes (NaT4CP, NaPCP) are released from sawmills,

planer mills, and the incineration of wood wastes. Significant amounts

of chlorophenols can be formed and subsequently released into the

environment from the chlorine bleaching process in pulp and

paper-mills, the chlorination of waste-water and drinking-water, and

the incineration of municipal waste. A significant amount of wastes is

discharged from manufacturing sites. Losses during storage and

transport are negligible. No estimates are available of the quantities

of chlorophenols released as a result of the disinfection of

waste-waters with chlorine, volatilization, or domestic uses of

products containing these compounds.


1.2.6 Natural sources


While some chlorophenols and related organohalogens occur

naturally, as metabolites of certain flora and fauna, these sources

are thought to make a negligible contribution to overall environmental

levels.


1.3 Environmental Transport, Distribution, and Transformation


Chlorophenols adsorb strongly on acidic soils, and those with a

high organic content. Leaching is more significant in basic and

mineral soils. Studies to date have not addressed the quantitative

contribution of these processes to the transport of chlorophenols

in situ.


Adsorption appears to play an important role in surface waters.

Chlorophenols that are not degraded in the water body are incorporated

into the sediments, most likely because they adsorb on sediment

particulates. They may persist in sediments for years. However, it is

not known how important this process is for lower chlorophenols, since

they should be adsorbed to a lesser extent than the T4CPs and PCP

studied to date.


While a large part of the chlorophenols entering natural waters is

probably degraded, they are nonetheless fairly persistent and, thus,

may be transported considerable distances by water.


Although chlorophenols are principally water and soil

contaminants, some atmospheric movement occurs, and low levels of PCP

have been found in rain, snow, and outdoor air. No corresponding

measurements have been made for other chlorophenols, but it is highly

probable that they too are transported in this manner.


1.3.1 Degradation


Chlorophenol residues are removed from the environment by both

biological and non-biological degradation. Laboratory studies have

shown that ultraviolet radiation can break down chlorophenols in a

matter of hours to days, and the shifts in the ratio of PCP to some of

its breakdown products in situ suggest that this process is

important in exposed habitats.


A large number of bacteria and fungi from different habitats are

able to degrade chlorophenols in the laboratory, sometimes eliminating

tens of mg/litre in a matter of hours or days. Degradation is

generally slowest for the higher chlorinated phenols, and for those

with a chlorine in the "meta" position. Previous exposure to a given

chlorophenol or a related compound enables a microorganism to

metabolize it immediately and/or at a faster rate, presumably by

inducing the necessary enzymes. In general, anaerobic biodegradation

of these compounds is much slower than aerobic metabolism.

Considerable overlap appears to exist in the rates of biodegradation

of the compounds in different habitats.


But chlorophenols should only persist in environments where the

rates of these transformations are minor. The persistence of

chlorophenols other than PCP has not been studied under controlled

conditions, but spills and applications of PCP as a herbicide

reportedly disappear in a matter of weeks or months.


1.3.2 Bioaccumulation


Bioaccumulation of chlorophenols appears to be moderate, and most

bioconcentration factors (BCFs) fall roughly between 100 and 1000. The

biocentration factor is usually a positive function of the chlorine

number, and there are no obvious relationships between it and the type

of organism (algae, plants, invertebrates, fish). Once exposure is

discontinued, chlorophenols clear rapidly from biota, indicating that

the bioaccumulation observed in field studies is the result of

long-term exposure rather than persistence.


1.3.3 Effects of physical, chemical, and biological factors on

degradation


Both the rate of evaporation and the extent of adsorption of PCP

(and undoubtedly other chlorophenols) are inversely related to pH. In

contrast, the rates of photolysis of 4-MCP and 2,4-DCP both increase

with pH, and shortage of oxygen, inorganic nutrients, or organic

matter may all influence the biodegradation rate of various lower

chlorophenols. Higher temperatures increase the rates of evaporation,

photolysis, and microbial degradation of chlorophenols, although the

last process obviously has an upper limit.


1.4 Environmental Levels and Human Exposure


1.4.1 Chlorophenol levels in the environment


Data on levels of chlorophenols other than PCP in the environment

are not available for air. Levels of PCP in outdoor air range from 1

to several ng/m3. Work-place air concentrations of chlorophenols are

much higher. Facilities in which chlorophenols are used, such as

sawmills, often have air levels of several tens of µg/m3, while in

manufacturing facilities, concentrations may be in the mg/m3 range.


Residues of all chlorophenol isomers have been found in fresh and

marine waters. In relatively undeveloped areas, levels are often

undetectable in receiving waters, and only occasionally exceed

1 µg/litre close to industrial sources of chlorophenols. In receiving

waters from heavily industrialized regions, ambient levels are

somewhat higher, but still median concentrations do not exceed

1 µg/litre, while the maximum concentrations in surface waters and

ground waters can reach several µg/litre. As a result of spills,

isolated levels as high as 61 000 µg/litre of chlorophenols (T4CP +

PCP) in ground water, and 18 090 µg/litre in surface waters have been

reported.


Levels of some chlorophenols in effluents from chemical and wood

preservation industries may reach several thousand µg/litre, though

typical levels are in the low µg/litre range, and dilution apparently

reduces these to the observed low ambient levels.


Chlorophenol concentrations in sediments are generally higher than

those in the overlying water. Levels in sediments from waters not

receiving large chlorophenol inputs generally contain less than 1 µg

of the individual chlorophenols/kg dry sediment. The maximum levels of

all chlorophenol isomers in fresh-water sediments in industrialized

regions seldom exceed 50 µg/kg. However, in some instances, thousands

of µg chlorophenols/kg have been detected in fresh-water sediments

adjacent to point sources (spillage sites and effluent discharges).


In waters receiving chlorophenolic wastes, invertebrates generally

contain from trace levels to 20 µg of chlorophenols from the

surrounding environments/kg wet tissue, though levels approaching

200 µg/kg have been observed in some instances. Fish can contain

similar whole-body levels of chlorophenols, usually concentrated in

the liver and viscera. For example, liver tissues from sculpins

inhabiting polluted waters contained up to 1600 µg/kg wet weight. In

birds, muscle tissues exhibited only trace to moderate (50 µg/kg wet

weight) levels of chlorophenols, however, higher concentrations have

been found in single samples of liver, brain, kidney, and eggs. For

instance, a level of 1017 µg 2,4-DCP/kg (fresh weight) was found in

the kidney of an eagle.


1.4.2 Chlorophenol levels in food, drinking-water, and treated wood


Quantities of T4CP range from trace to several µg/kg in carrots,

potatoes (also 2,4-DCP), turnips, cabbages, beets, and raw milk,

though contamination from treated wood storage containers can elevate

these levels considerably. Recent restrictions on the agricultural use

of chlorophenols have reduced this contamination. T4CP has been

detected in poultry, but no reports of residues in other meat have

been found.


Drinking-water supplies are characterized by relatively low

concentrations of chlorophenols. While a variety of congeners have

been detected, these are usually present in the range of 10-3 to

10-1 µg/litre.


Concentrations of PCP or T4CP in treated wood are predictably

high, and can reach several hundred mg/kg of wood dust or shavings.


1.5 Kinetics and Metabolism


The lower chlorophenols are readily absorbed across the skin of

both laboratory animals and human beings. The results of studies on

rats further suggest that absorption via the skin is greater for the

sodium salts than for the parent molecules (2,3,5,6-T4CP and its salt

were used). Ingested chlorophenols are also readily taken up from the

gastrointestinal tract. The absorption of inhaled lower chlorophenols

by experimental animals has not been studied.


Experimental animals accumulate chlorophenols mostly in the liver

and kidney, and to a lesser extent in the brain, muscle, and fat

tissues. The higher levels in the liver and kidney may reflect their

greater circulating blood volume, as well as the role these organs

play in the detoxification and elimination of these compounds. Related

compounds, such as trichlorophenyl acetate, 2,4-D, Nemacide, Silvex,

2,4,5-T, and lindane, yield similar tissue distributions of

chlorophenol metabolites.


In the animals studied to date, most chlorophenols were rapidly

conjugated to glucuronates or sulfates in the liver. This binding, and

also dechlorination and methylation, serve to detoxify these

compounds. At present, the only chlorinated phenol that is known to be

metabolized to a more toxic substance is 2,3,5,6,-T4CP, which gives

rise to tetrachloro- p-hydroquinone. The corresponding quinone has

been shown to bind covalently to protein and DNA.


Chlorophenols are eliminated by test mammals primarily through the

urine (roughly 80-90%), in both free and bound forms. Smaller amounts

are eliminated in faecal matter. A single dose of chlorophenols is

virtually eliminated within one to several days. Elimination rates

appear to be even more rapid for some tissues.


1.6 Effects on Organisms in the Environment


The available information on the effects of chlorophenols in the

environment centres primarily on aquatic organisms. Considerable

overlap exists in the concentrations that are toxic for bacteria,

phytoplankton, plants, invertebrates, and fish, most of the EC50 and

LC50 values falling in the several mg/litre range. Toxicity generally

increases with the degree of chlorination of the phenol ring. However,

chlorophenols with chlorine in the 3 and 5 positions ("meta"

chlorophenols) are often more toxic than expected solely on the basis

of their chlorine number. Species-specific sensitivity can override

these general patterns. Furthermore, particularly in the case of the

higher chlorophenols, acute toxicity is a strong inverse function of

pH, reflecting the degree of ionization of the chemical. In long-term

studies, sublethal levels of 2,4-DCP reduced both growth and survival

of fathead minnows. In one study, exposure to a concentration of only

0.5 µg 2,4,6-T3CP/litre was fetotoxic in trout.


Fish kills have resulted from PCP spills, some of which have also

involved T4CP. In controlled field studies, exposure to large

quantities (100-5000 µg/litre) of chlorophenols (4-MCP, 2,4-DCP,

2,4,6-T3CP) generally impaired algal primary production and

reproduction, altered algal species composition dramatically, and


reduced zooplankton biomass and production. These studies shed little

light on the hazard, if any, presented by the low-level contamination

observed in most environments. The low concentrations of several

chlorophenols typically found in moderately contaminated waters have

been reported to impair the flavour of fish.


1.7 Effects on Experimental Animals and In Vitro Systems


In rats, lethal doses of lower chlorinated phenols resulted in

tremors and convulsions (except for T4CP and some T3CPs), hypotonia,

and, after death, a rapid onset of rigor mortis. Acute LD50s for rats

for all lower chlorophenols and routes of administration ranged from

130 to 4000 mg/kg body weight. The range of toxicity of the compounds

generally occurred in the following order: T4CPs > MCP > DCPs >

T3CPs, when the toxicant was administered either orally or by

subcutaneous injection. When injected intraperitoneally, the

toxicities of MCP, DCPs, and T3CPs were similar, while T4CP was 2-3

times more toxic. In studies on dermal exposure, 2,3,5,6-T4CP was the

most toxic of the T4CP isomers. These variations according to route

of administration may reflect differences in the rate of absorption of

the compounds. Acute effects are attributable to the parent

chlorophenol itself rather than to the microcontaminants.


Some reports have indicated that lower chlorinated phenols cause

mild irritation of the eye in rats. This effect increases with the

number of chlorine atoms on the phenol ring. Skin sensitization has

not been shown for the chlorophenols.


Short-term exposures of rats and mice to 2,4-DCP at hundreds of

mg/kg have been consistently associated with increased spleen and

liver weights and, in some instances, with haematological or

immunological effects. The very few studies concerning exposure to

various tri- and tetrachlorophenols have also identified

exposure-related changes in the weight or histology of the liver and,

in some instances, of the spleen or kidney. In one study, combined

pre- and postnatal exposure to 2-MCP and 2,4-DCP resulted in

haematological changes in exposed rats, but only 2,4-DCP elicited

immune responses.


Several lower chlorophenols appear to be mildly fetotoxic, though

the data are inconsistent in this regard. While female rats exposed to

2-MCP, 2,4-DCP, or 2,4,6-T3CP in the drinking-water produced smaller

litters with an increased frequency of stillborn offspring in one

study, similar or higher exposures in other studies did not have any

effects on these and other reproductive parameters. A dose of 30 mg/kg

body weight per day of pure or technical 2,3,4,6-T4CP delayed

ossification of fetal skull bones, but was not embryolethal.


Birth defects did not arise as a result of daily exposure of rats

to concentrations of up to 500 mg 2-MCP/litre, 300 mg 2,4-DCP/litre

(both in the drinking-water), 1000 mg 2,4,6-T3CP/kg body weight and

30 mg 2,3,4,6-T4CP/kg body weight (both by gavage).


Limited information indicates that 2,4,6-T3CP (in yeast and

mammalian test systems) and 2,3,4,6-T4CP (Chinese hamster cell

cultures) elicited weak mutagenic responses, but were not clastogenic.

Most of the other chlorophenols that have been tested have been found

to be non-mutagenic in the few test systems used (primarily

bacterial).


Exposure of rats and mice (both sexes) to 2,4-DCP for 2 years at

doses as high as 440 and 1300 mg/kg body weight per day, respectively,

proved negative with respect to carcinogenicity. In a test with a

similar design, 2,4,6-T3CP at doses of up to 10 000 mg/kg body

weight per day caused cancer in mice (hepatocellular carcinomas or

adenomas) and male rats (lymphomas, leukaemia). The 2,4,6-T3CP used

was commercial grade and was not analysed for impurities, such as

PCDDs and PCDFs.


Studies on rats on the carcinogenicity of 2-MCP or 2,4-DCP

(500 µg/litre and 300 µg/litre, respectively, for 15-24 months) were

inadequate. Some chlorophenols appeared to be promoters (MCPs,

2,4-DCP, and 2,4,5-T3CP); others did not.


Exposure of female rats to 2,4-DCP in the drinking-water, at

0-300 mg/litre, altered the major immune function in offspring exposed

prenatally and postnatally, but not in rats exposed only in utero.

In contrast, in a similar study, a concentration of 2-MCP as high as

500 mg/litre did not have any adverse effects on the immune systems of

rats.


The major effects observed with lethal exposures to chlorophenols

indicated a general effect on the nervous system. Long-term studies

implicated the liver and kidney as organs that accumulate high

concentrations of chlorophenols and are often adversely affected by

exposure to chlorophenols, perhaps reflecting their roles in the

detoxification and elimination of xenobiotics. On the basis of the

suppression of cell-mediated immunity in rats exposed to 2,4-DCP, it

can be assumed that the thymus and spleen may be target organs.


The toxicology of chlorophenols is complicated by the presence of

PCDD and PCDF microcontaminants in technical grade products.

Assessment of toxicity studies with chlorophenols requires a knowledge

of the types, levels, and effects of the microcontaminants that are

present in the formulation studied, because some PCDDs and PCDFs are

extremely toxic.


The major mode of action in the acute toxicity of chlorophenols

involves the uncoupling of oxidative phosphorylation and the

inhibition of the electron transport system. These effects are related

to the number of chlorine atoms on the molecule and to a lesser extent

by their positions on the molecule. PCP is 40 times more potent than

2,4-DCP as an uncoupler. The chlorophenate ion is evidently

responsible for the uncoupling reaction, while the undissociated

molecule causes convulsions.


Other enzyme systems are also inhibited by exposure to

chlorophenols in vitro, though, in some instances, such inhibition

is not observed with in vivo exposures.


1.8 Effects on Man


1.8.1 Non-occupational exposure


Low (usually 10 mg/kg) levels of the lower chlorinated phenols are

found in the serum, urine, and adipose tissues of the general

population. The major identifiable sources of these chlorophenols are

food and drinking-water. Chlorophenol levels in the ambient atmosphere

have not been measured.


In the only instance of acute exposure of the general population

to chlorophenols, an explosion at a manufacturing plant contaminated

an area, with a population of 37 000 persons, with sodium hydroxide,

2,4,5-T3CP, and TCDD. However, the effects, if any, of the released

2,4,5-T3CP were masked by those of TCDD. Clinical symptoms

attributed to TCDD were recorded in the exposed individuals. No toxic

effects have been attributed to the low concentrations of

chlorophenols typical of most non-occupational exposures. However,

undesirable organoleptic effects are produced by chlorophenols at very

low concentrations.


1.8.2 Occupational exposure


Worker exposure is a major concern in industries in which

chlorophenols are used extensively, as respiratory and dermal

absorption of these compounds results in measurable levels in the

blood and urine of exposed workers. In the manufacture of

chlorophenols, clinical symptoms associated with exposure include eye,

nose, and airway irritation, dermatitis, chloracne, and porphyria.

Abnormal liver function tests, changes in brain wave activity, and

slowed visual reaction time have been reported in association with

high-level exposure.


In sawmill workers, Na-T4CP exposures have caused numerous cases

of dermatitis and respiratory irritation. Eye, nose, and airway

irritation from exposure to T3CP have been reported by gas mask

testers.


Conflicting results have come from epidemiological studies

relating cancer incidence and mortality to chlorophenol exposure in

the work place. Associations between soft-tissue sarcoma, malignant

lymphoma, and nasal and nasopharyngeal cancer, have been shown in some

epidemiological studies, but not in others. Exposure levels have not

been accurately determined in these studies, and the conflicting

results remain unresolved, at present.


2. IDENTITY, PHYSICAL AND CHEMICAL PROPERTIES, ANALYTICAL METHODS


2.1 Identity


Chlorophenols are organic chemicals formed from phenol

(1-hydroxybenzene) by substitution in the phenol ring with one or more

atoms of chlorine. Nineteen congeners are possible, ranging from

mono-chlorophenols to the fully substituted pentachlorophenol.a

However, this document does not deal with pentachlorophenol, which has

been evaluated previously (WHO, 1987b). The chlorophenols

(particularly trichlorophenols and tetrachlorophenols) are also used

in the form of sodium or potassium salts. The CAS number, name,

chemical (molecular) formula, commercial uses, and common synonyms and

trade names for each chlorophenol congener, are presented in Table 1.

The general chemical structure for the chlorophenol congeners is shown

below.


  1   2   3   4   5   6   7   8   9   ...   18

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