TOXICOLOGICAL PROFILE FOR

CHLOROPHENOLS

U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES

Public Health Service

Agency for Toxic Substances and Disease Registry

July 1999
CHLOROPHENOLS ii

DISCLAIMER

The use of company or product name(s) is for identification only and does not imply endorsement by the

Agency for Toxic Substances and Disease Registry.


















CHLOROPHENOLS 1

1. PUBLIC HEALTH STATEMENT

This public health statement tells you about chlorophenols and the effects of exposure.

The Environmental Protection Agency (EPA) identifies the most serious hazardous waste sites in

the nation These sites make up the National Priorities List (NPL) and are the sites targeted for

long-term federal cleanup activities. Chlorophenols has been found in at least 116 of the

1,467 current or former NPL sites. However, the total number of NPL sites evaluated for this

substance is not known. As more sites are evaluated, the sites at which chlorophenols are found

may increase. This information is important because exposure to this substance may harm you and

because these sites may be sources of exposure.

When a substance is released from a large area, such as an industrial plant, or from a container,

such as a drum or bottle, it enters the environment. This release does not always lead to

exposure. You are exposed to a substance only when you come in contact with it. You may be

exposed by breathing, eating, or drinking the substance or by skin contact.

If you are exposed to chlorophenols, many factors determine whether you’ll be harmed. These

factors include the dose (how much), the duration (how long), and how you come in contact with

it. You must also consider the other chemicals you’re exposed to and your age, sex, diet, family

traits, lifestyle, and state of health.

1.1 WHAT ARE CHLOROPHENOLS?

Chlorophenols are a group of chemicals in which chlorines (between one and five) have been

added to phenol. Phenol is an aromatic compound derived from benzene, the simplest aromatic

hydrocarbon, by adding a hydroxy group to a carbon to replace a hydrogen. There are five basic

types of chlorophenols: mono[one]chlorophenols, di[two]chlorophenols, tri[three]chlorophenols,

tetra[four]chlorophenols, and penta[five]chlorophenols. In all, there are 19 different

chlorophenols. Eight are discussed in this document: 2-chlorophenol, 4-chlorophenol, 2,4-

dichlorophenol, 2,4,5-trichlorophenol, 2,4,6-trichlorophenol, 2,3,4,5-tetrachlorophenol, 2,3,4,6-
CHLOROPHENOLS 2

1. PUBLIC HEALTH STATEMENT

tetrachlorophenol, and 2,3,5,6-tetraohlorophenol. Pentachlorophenol is discussed in another

document.

Except for 2-chlorophenol, which is a liquid at room temperature, all of the chlorophenols are

solids. The chlorophenols have a strong medicinal taste and odor; small amounts (at parts per

billion [ppb] to parts per million [ppm] concentrations) can be tasted in water. Very small

amounts of chlorophenols can also make fish taste bad. All the compounds discussed are or were

produced commercially.

Chlorophenols with at least two chlorines either have been used directly as pesticides or converted

into pesticides. Also, chlorophenols, especially 4-chlorophenol, have been used as antiseptics. In

addition to being produced commercially, small amounts of some chlorophenols, especially the

mono- and dichlorophenols, may be produced when waste water or drinking water is disinfected

with chlorine, if certain contaminants are present in the raw water. They are also produced during

the bleaching of wood pulp with chlorine when paper is being produced. More information on the

physical and chemical properties and on the production and use of chlorophenols is found in

Chapters 3 and 4.

1.2 WHAT HAPPENS TO CHLOROPHENOLS WHEN THEY ENTER THE

 ENVIRONMENT?

Chlorophenols can enter the environment while they are being made or used as pesticides. Most

of the chlorophenols released into the environment go into water, with very little entering the air.

The compounds that are most likely to go into the air are the mono- and dichlorophenols because

they are the most volatile (that is, have the greatest tendency to form vapors or gases). Once in

the air, sunlight helps destroy these compounds and rain washes them out of the air. Chlorophenols

stick to soil and to sediments at the bottom of lakes, rivers, or streams. However, low

levels of chlorophenols in water, soil, or sediment are broken down by microorganisms and are

removed from the environment within a few days or weeks. Further information regarding the

release and environmental fate of chlorophenols can be found in Chapters 4 and 5.
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1. PUBLIC HEALTH STATEMENT

1.3 HOW MIGHT I BE EXPOSED TO CHLOROPHENOLS?

Most people are exposed to very low levels of chlorophenols in drinking water that has been ’

disinfected with chlorine (chlorinated drinking water). Chlorophenols have been measured in

chlorinated drinking water at parts per trillion (ppt) concentrations (that is, the amount [weight]

of chlorophenols per trillion parts [volume] of water). In lakes, rivers, and streams, chlorophenols

were found in less than 1 percent of the water that was tested. Chlorophenols have been

measured in city air at concentrations of less than a part per trillion (the amount of chlorophenols

[volume] per trillion parts [volume] of air).

It has been estimated during the National Occupational Exposure Survey (NOES) from

1981-1983 that about 5,000 people in the United States are exposed to 4-chlorophenol,

2,4,5-trichlorophenol, or 2,4,6-trichlorophenol at work (NOES 1990). It has not been estimated

how many people are exposed at work to the other chlorophenols. People who make

chlorophenols or use them as pesticides are most likely to have high exposure to these chemicals.

For example, mixtures of tetrachlorophenols are used at sawmills as wood preservatives. Skim

contact while treating wood with the tetrachlorophenols is the most likely route of exposure.

Another likely route of exposure is breathing air contaminated by mono- and dichlorophenols.

Further information regarding exposure to chlorophenols can be found in Chapter 5.

1.4 HOW CAN CHLOROPHENOLS ENTER AND LEAVE MY BODY?

When chlorophenols are eaten, almost all of the compounds quickly enter the body.

Chlorophenols also rapidly enter the body through the skin. Little is known about how much of

the chlorophenols enter the body if one breathes air containing them. The monochlorophenols do

not stay inside the body very long. They are changed to less harmful products, and most leave

through the urine within 24 hours. The other chlorophenols (dichlorophenol, trichlorophenols,

tetrachlorophenols), which also leave through the urine as less harmful chemicals, can stay in the

body for several days. For further discussion about how the chlorophenols enter and leave the

body, see Chapter 2.
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1, PUBLIC HEALTH STATEMENT

1.5 HOW CAN CHLOROPHENOLS AFFECT MY HEALTH?

To protect the public from the harmful effects of toxic chemicals and to find ways to treat people

who have been harmed, scientists use many tests.

One way to see if a chemical will hurt people is to learn how the chemical is absorbed, used, and

released by the body; for some chemicals, animal testing may be necessary. Animal testing may

also be used to identify health effects such as cancer or birth defects. Without laboratory animals,

scientists would lose a basic method to get information needed to make wise decisions to protect

public health. Scientists have the responsibility to treat research animals with care and compassion. Laws 

today protect the welfare of research animals, and scientists must comply with strict animal care guidelines.

One man who splashed pure 2,4-dichlorophenol on his arm and leg died shortly after the accident.

Workers who made pesticides from chlorophenols and were exposed to chlorophenols as well as

other chemicals through breathing and through the skin developed acne and mild injury to their

livers. According to some studies, the risk of cancer was also slightly higher among workers who

had made pesticides for a long time. These workers were exposed to very high levels of other

chemicals as well as chlorophenols, so it is not certain whether the effects were caused by the

chlorophenols or the other chemicals.

Animals that were given food or drinking water containing chlorophenols at high levels developed

adverse or negative health effects. The major effects with exposure to high levels of

chlorophenols were on the liver and the immune system. Also, the animals that ate or drank

chlorophenols did not gain as much weight as the animals that ate food and drank water not

containing chlorophenols.

Feeding rats and mice high doses of 2,4-dichlorophenol for a long time did not cause cancer.

However, long-term treatment of rats and mice with high doses of 2,4,6-trichlorophenol in food

caused leukemia in rats and liver cancer in mice, suggesting that 2,4,6-trichlorophenol may be a
CHLOROPHENOLS 5

1. PUBLIC HEALTH STATEMENT

carcinogen. The Department of Health and Human Services has determined that 2,4,6-trichlorophenol

may reasonably be anticipated to be a carcinogen. The International Agency for Research on Cancer (IARC) has

determined that the chlorophenols as a group, are possibly carcinogenic to man. The Environmental Protection

Agency (EPA) has determined that 2,4,6-trichlorophenol is a probable carcinogen.

Putting chlorophenols on the skin or eyes of animals causes severe injuries. Injury is greatest with

exposure to the mono- and dichlorophenols. The signs of severe skin injury include redness,

swelling, scabbing, and scar formation. The cornea was damaged when monochlorophenols were

placed directly onto the eyes of rabbits. Further information about the health effects following

exposure to chlorophenols can be found in Chapter 2.

1.6 HOW CAN CHLOROPHENOLS AFFECT CHILDREN?

This section discusses potential health effects from exposures during the period from conception

to maturity at 18 years of age in humans. Potential effects on children resulting from exposures of

the parents are also considered.

The most likely source from which children could be exposed to chlorophenols is water that has

been disinfected with chlorine. Children could receive larger doses because they consume more

fluids per bodyweight than adults. Children may also be exposed in areas where chlorophenols

have been sprayed as pesticides or herbicides. Children playing outdoors in areas with

contaminated soil could be at risk for exposure because they often put objects or hands in their

mouths. Monochlorophenols are used as household antiseptics, and 2,4-DCP is used for

mothproofing. More complex chlorophenols are used as biocides. Biocides are substances used

to kill organisms.

We do not know whether chlorophenols cause birth defects in humans; chlorophenols have not

been shown to cause birth defects in animals, even at high doses. High levels of chlorophenols

given to pregnant female rats in the drinking water have tended to reduce the number of their
CHLOROPHENOLS 6

1. PUBLIC HEALTH STATEMENT

newborn animals and to decrease the weights of the newborn. In one study animals exposed to

chlorophenols showed delayed hardening of some bones. Section 2.6 of this profile contains

further details on animal-based developmental effects studies. We do not know whether

chlorophenols can cross the placenta or get into breast milk.

1.7 HOW CAN FAMILIES REDUCE THE RISK OF EXPOSURE TO

 CHLOROPHENOLS?

If your doctor finds that you have been exposed to significant amounts of chlorophenols, ask if

children may also be exposed. When necessary your doctor may need to ask your state

department of public health to investigate.

The chlorophenols presented in this profile exist in eight different forms, each one having different

properties and uses. Therefore, different routes exist in which a family may be exposed to chlorophenols.

Chlorophenols are primarily used as antiseptics, disinfectants, herbicides, pesticides, and wood

preservatives. People are at greater risk of exposure if they live near industrial facilities that

use or manufacture chlorophenols or waste sites that could be releasing it into the environment.

Most released chlorophenols are found in surface water or in soil near the release point. Children

should be kept from coming in contact with water or dirt in an area that could be contaminated.

You should prevent your children from eating dirt. Make sure they wash their hands frequently

and before eating. Discourage your children from putting their hands in their mouths or other

hand-to-mouth activity.

People who do not live near production or waste sites can still be exposed to chlorophenols

through other routes. Chlorophenols can be present in drinking water when chlorine is used to

disinfect it. The safe drinking water standard for 2-chlorophenol is included in Table 7-l. At low

concentrations, chlorophenols give water an unpleasant, medicinal taste.

Chlorophenols and other related chemicals are often used as herbicides and pesticides. 2,4-D and

2,4,5-T, the latter of which has been banned, are herbicides often used on food crops that can

break down to form 2,4-DCP. Children should be deterred from playing in areas where 2,4-D or
CHLOROPHENOLS 7

1. PUBLIC HEALTH STATEMENT

other chlorophenol based herbicides or pesticides have been sprayed. Children are lower to the

ground than adults and may be exposed because they often get dirt, grass, and other outdoor

material on their skin and in their mouths. Also, your children may be exposed to chlorophenols if

an unqualified person applies pesticides containing them around your home. In some cases, the

improper use of pesticides banned for use in homes has turned homes into hazardous waste sites.

Make sure that any person you hire is licensed and, if appropriate, certified to apply pesticides.

Your state licenses each person who is qualified to apply pesticides according to EPA standards

and further certifies each person who is qualified to apply “restricted use” pesticides. Ask to see

the license and certification. Also ask for the brand name of the pesticide, a Material Safety Data

Sheet (MSDS), the name of the product’s active ingredient, and the EPA registration number.

Ask whether EPA has designated the pesticide “for restricted use” and what the approved uses

are. This information is important if you or your family react to the product.

If you buy over-the-counter pesticide products to apply yourself, be sure the products are in

unopened pesticide containers that are labeled and contain an EPA registration number. Carefully

follow the instructions on the label. If you plan to spray inside, make sure the pesticide is

intended for indoor use.

If you feel sick after a pesticide has been used in your home, consult your doctor or local poison

control center.

Chlorophenols may also be present in many household products. 2,4-DCP is commonly used for

mothproofing. 4-CP is used as a disinfectant in homes, farms, hospitals, and as an antiseptic for

root canal treatment. Monochlorophenols have been used as antiseptics, although they have

largely been replaced by other chemicals. Pesticides and household chemicals should be stored

out of reach of young children to prevent unintentional poisonings. Always store pesticides and

household chemicals in their original labeled containers. Never store pesticides or household

chemicals in containers children would find attractive to eat or drink from, such as old soda

bottles.
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1. PUBLIC HEALTH STATEMENT

1.8 IS THERE A MEDICAL TEST TO DETERMINE WHETHER I HAVE BEEN

 EXPOSED TO CHLOROPHENOLS?

There is no medical test that is specific for chlorophenols to determine whether you have been

exposed to these chemicals. Compounds that have been made by your body from chlorophenols

can be measured in the urine. However, these compounds can also be found in the urine when

you are exposed to other chemicals such as lindane (an insecticide) or to 2,4-dichlorophenoxyacetic

acid (a chemical that kills weeds). More information about measuring exposure to

chlorophenols can be found in Chapter 2.

1.9 WHAT RECOMMENDATIONS HAS THE FEDERAL GOVERNMENT MADE TO

 PROTECT HUMAN HEALTH?

The federal government develops regulations and recommendations to protect public health.

Regulations can be enforced by law. Federal agencies that develop regulations for toxic

substances include the Environmental Protection Agency (EPA), the Occupational Safety and

Health Administration (OSHA), and the Food and Drug Administration (FDA).

Recommendations provide valuable guidelines to protect public health but cannot be enforced by

law. Federal organizations that develop recommendations for toxic substances include the

Agency for Toxic Substances and Disease Registry (ATSDR) and the National Institute for

Occupational Safety and Health (NIOSH).

Regulations and recommendations can be expressed in not-to-exceed levels in air, water, soil, or

food that are usually based on levels that affect animals, then they are adjusted to help protect

people. Sometimes these not-to-exceed levels differ among federal organizations because of

different exposure times (an 8-hour workday or a 24-hour day), the use of different animal

studies, or other factors.

Recommendations and regulations are also periodically updated as more information becomes

available. For the most current information, check with the federal agency or organization that

provides it. Some regulations and recommendations for chlorophenols include the following:
CHLOROPHENOLS 9

1. PUBLIC HEALTH STATEMENT

The EPA recommends that drinking water concentrations of 2-chlorophenol should not be more

than 0.04 part per million (ppm), and concentrations of 2,4-dichlorophenol should not be more

than 0.02 ppm; these are levels that can be tasted. In order for chlorophenols to be lower than

levels that can be tasted, the EPA recommends levels of 0.1 part per billion (ppb; the amount of

chlorophenols per billion parts of water) for monochlorophenols, 0.3 ppb for 2,4-dichlorophenols,

and 1 ppb for 2,4,5-trichlorophenol and 2,3,4,6-tetrachlorophenol. More information about

regulations and guidelines for chlorophenols can be found in Chapter 7.

1.10 WHERE CAN I GET MORE INFORMATION?

If you have any more questions or concerns, please contact your community or state health or

environmental quality department or

 Agency for Toxic Substances and Disease Registry

 Division of Toxicology

 1600 Clifton Road NE, Mailstop E-29

 Atlanta, GA 30333

* Information line and technical assistance

 Phone: l-800-447-1544

 Fax: (404) 639-6359

ATSDR can also tell you the location of occupational and environmental health clinics. These

clinics specialize in recognizing, evaluating, and treating illnesses resulting from exposure to

hazardous substances.
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1. PUBLIC HEALTH STATEMENT

* To order toxicological profiles, contact

 National Technical Information Service

 5285 Port Royal Road

 Springfield, VA 22161

 Phone: (800) 553-6847 or (703) 487-4650
CHLOROPHENOLS 11

2. HEALTH EFFECTS

2.1 INTRODUCTION

The primary purpose of this chapter is to provide public health officials, physicians, toxicologists, and

other interested individuals and groups with an overall perspective on the toxicology of

chlorophenols. It contains descriptions and evaluations of toxicological studies and epidemiological

investigations and provides conclusions, where possible, on the relevance of toxicity and

toxicokinetic data to public health.

A glossary and list of acronyms, abbreviations, and symbols can be found at the end of this profile.

2.2 DISCUSSION OF HEALTH EFFECTS BY ROUTE OF EXPOSURE

To help public health professionals and others address the needs of persons living or working near

hazardous waste sites, the information in this section is organized first by route of exposureinhalation, oral, and dermal; and then by health effect-death, systemic, immunological, neurological,

reproductive, developmental, genotoxic, and carcinogenic effects. These data are discussed in terms

of three exposure periods-acute (14 days or less), intermediate (15-364 days), and chronic (365 days

or more).

Levels of significant exposure for each route and duration are presented in tables and illustrated in

figures. The points in the figures showing no-observed-adverse-effect levels (NOAELs) or lowestobserved-adverse effect levels (LOAELs) reflect the actual doses (levels of exposure) used in the

studies. LOAELS have been classified into “less serious” or “serious” effects. “Serious” effects are

those that evoke failure in a biological system and can lead to morbidity or mortality (e.g., acute

respiratory distress or death). “Less serious” effects are those that are not expected to cause

significant dysfunction or death, or those whose significance to the organism is not entirely clear.

ATSDR acknowledges that a considerable amount of judgment may be required in establishing

whether an end point should be classified as a NOAEL, “less serious” LOAEL, or “serious” LOAEL,

and that in some cases, there will be insufficient data to decide whether the effect is indicative of

significant dysfunction. However, the Agency has established guidelines and policies that are used to

classify these end points. ATSDR believes that there is sufficient merit in this approach to warrant an

attempt at distinguishing between “less serious” and “serious” effects. The distinction between “less

serious” effects and “serious” effects is considered to be important because it helps the users of the
CHLOROPHENOLS 12

2. HEALTH EFFECTS

profiles to identify levels of exposure at which major health effects start to appear. LOAELs or NOAELs should

also help in determining whether or not the effects vary with dose and/or duration, and place into perspective the

possible significance of these effects to human health.

The significance of the exposure levels shown in the Levels of Significant Exposure (LSE) tables and figures

may differ depending on the user’s perspective, Public health officials and others concerned with appropriate

actions to take at hazardous waste sites may want information on levels of exposure associated with more subtle

effects in humans or animals (LOAEL) or exposure levels below which no adverse effects (NOAELs) have been

observed. Estimates of levels posing minimal risk to humans (Minimal Risk Levels or MRLs) may be of interest

to health professionals and citizens alike.

Levels of exposure associated with carcinogenic effects (Cancer Effect Levels, CELs) of chlorophenols are

indicated in Table 2-1 and Figure 2-1. Because cancer effects could occur at lower exposure levels, the figure

also shows a range for the upper bound of estimated excess risks, ranging from a risk of 1 in 10,000 to 1 in

10,000,000 (10-4-10-7), as developed by EPA.

Estimates of exposure levels posing minimal risk to humans (Minimal Risk Levels or MRLs) have been made

for chlorophenols. An MRL is defined as an estimate of daily human exposure to a substance that is likely to be

without an appreciable risk of adverse effects (noncarcinogenic) over a specified duration of exposure. MRLs

are derived when reliable and sufficient data exist to identify the target organ(s) of effect or the most sensitive

health effect(s) for a specific duration within a given route of exposure. MRLs are based on noncancerous health

effects only and do not consider carcinogenic effects. MRLs can be derived for acute, intermediate, and chronic

duration exposures for inhalation and oral routes. Appropriate methodology does not exist to develop MRLs for

dermal exposure.

Although methods have been established to derive these levels (Barnes and Dourson 1988; EPA 1990a),

uncertainties are associated with these techniques. Furthermore, ATSDR acknowledges additional uncertainties

inherent in the application of the procedures to derive less than lifetime MRLs. As an example, acute inhalation

MRLs may not be protective for health effects that are delayed in development or are acquired following

repeated acute insults, such as hypersensitivity reactions, asthma, or chronic bronchitis. As these kinds of health

effects data become available and methods to assess levels of significant human exposure improve, these MRLs

will be revised.


CHLOROPHENOLS 15

2. HEALTH EFFECTS

A User’s Guide has been provided at the end of this profile (see Appendix B). This guide should aid in the

interpretation of the tables and figures for Levels of Significant Exposure and the MRLs.

There are 19 isomers of the chlorophenols, each containing between 1 and 5 chlorines. All members of the series

are chlorine derivatives of phenol, the simplest aromatic alcohol, i.e., hydroxybenzene. They possess both acute

and chronic toxicity which varies with the number of chlorines present. However, this profile is concerned with

only eight of these isomers, chosen on the basis of the following three criteria: (1) toxicity, (2) potential for

human exposure, and (3) frequency of occurrence at NPL hazardous waste sites.

Because many of the isomers typically co-occur in the environment and have qualitatively (but not

quantitatively) similar toxicological effects, they are combined into one profile to avoid repetition across

multiple profiles. The isomers discussed include two monochlorinated compounds (2- and 4-chlorophenol, or 2-

CP and 4-CP), one dichlorinated compound (2,4-dichlorophenol, or 2,4-DCP), two trichlorinated compounds

(2,4,5- and 2,4,6-trichlorophenol, or 2,4,5-TCP and 2,4,6-TCP), and three tetrachlorinated compounds (2,3,4,5-,

2,3,4,6-, and 2,3,5,6-tetrachlorophenol, or 2,3,4,5-TeCP, 2,3,4,6-TeCP, and 2,3,5,6-TeCP). The information in

the profile is organized by isomer (mono-, di-, tri-, tetrachlorophenols), and for each isomer the available data

are then presented by duration (acute [14 days or less], intermediate [15 to 364 days], chronic [365 days or

more]). In this text, the term “chlorophenols” will refer to any two or more of these eight isomers. The most

commercially and toxicologically significant isomer, pentachlorophenol, is not included in this document

because it is the subject of a separate profile.

2.2.1 Inhalation Exposure

2.2.1.l Death

Mortality studies of workers at phenoxy herbicide factories where exposure to chlorinated phenols

(2,4,5-TCP, 2,4,6-TCP, and 2,4-DCP) occurred, have not shown increased mortality from any cause (Coggen et

al. 1991; Ott et al. 1987). Additional occupational studies that focus on cancer-related deaths are discussed in

Section 2.2.1.8. No studies were located regarding death in humans following inhalation exposure to any of the

chlorophenols discussed in this profile.

Nose-only exposure of male and female Wistar rats to 2-CP for 4 hours to a concentration of 908 ppm

(Duchosal and Biederman 1991) and whole-body exposure of Sprague-Dawley rats to 2-CP for 6 hours
CHLOROPHENOLS 16

2. HEALTH EFFECTS

at 620 ppm (Younger Labs 1975) did not result in any deaths. These studies are limited by a lack of

experimental detail. Additional studies regarding lethality in animals following inhalation exposure to

chlorophenols were not located.

2.2.1.2 Systemic Effects

No studies were located regarding musculoskeletal or renal effects in humans or animals after inhalation

exposure to any of the eight chlorophenols discussed in this profile.

The limited studies examining systemic effects following inhalation exposure to chlorophenols are described

below. The NOAEL and LOAEL values from the single reliable study are recorded in Table 2-1 and plotted in

Figure 2-1.

Respiratory Effects. No studies were located regarding respiratory effects in humans after inhalation

exposure to any of the eight chlorophenols discussed in this profile. Very limited studies of respiratory

effects in workers exposed by inhalation to one or more of the chlorophenols in conjunction with other

substances have been completed.

When compared to 260 unexposed referents, 281 workers involved in the production of sodium

trichlorophenol and its derivatives for 18 years had no increased incidence of chronic bronchitis, chronic

obstructive pulmonary disease, or altered measures of pulmonary function (Calvert et al. 1991). Exposure

occurred 15 years before pulmonary function was examined. Because trichloro-phenols are rapidly cleared,

serum 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), which was produced as a contaminant in the

manufacture of 2,4,5-TCP and its derivatives, was used to indicate that the workers had actually been

exposed. The mean lipid adjusted TCDD serum concentration in exposed workers was 200 ppt relative to 7

ppt in the controls.

Occupational exposure of seven workers to an unspecified trichlorophenol isomer, in addition to other

chemicals, by chronic inhalation was associated with adverse upper airway and chest symptoms (cough,

chronic bronchitis, chest wheezing), altered pulmonary function (reduced expiratory flow rate of the lung,

increased closing volume of the lung, increased elastic recoil pressure of the lung), and pulmonary lesions

(interstitial densities) (Alexandersson and Hedenstierna 1982). The workers were exposed for 2-10 years

and exposure concentrations were not well characterized. The study indicates that exposure concentrations

were 0.003 mg/L (0.02 ppm) or less, and they may have varied considerably. The study was also limited
CHLOROPHENOLS 17

2. HEALTH EFFECTS

because of the small number of subjects (seven), which included three smokers. Therefore, it is not possible to

determine whether the exposure to TCP alone induced the reported respiratory effects or whether smoking

contributed to the effects. The authors (Alexandersson and Hedenstierna 1982) concluded that inhalation

exposure to trichlorophenol may cause pulmonary dysfunction and possibly fibrosis following chronicduration

exposure.

Lumber mill workers exposed to a mixture of tetrachlorophenols (specific isomers not stated) and

pentachlorophenol reported upper respiratory tract irritation more frequently than unexposed workers

(Kleinman et al. 1986). Tetrachlorophenol air concentrations ranged from 0.8 to 12.2 μg/m3

, and

pentachlorophenol concentrations were below the limit of detection (0.5 μg/m3

).

Tachypnea was observed in one of five male rats exposed (nose-only) to 2-CP at 908 ppm for 4 hours

(Duchosal and Biederman 1991). Tachypnea was not observed in any female rats exposed in the same

manner. Dark red foci observed in the lungs (right caudal, median, or left lobe) of male and female rats

exposed to 17 (2/5 males, 2/5 females) or 104 ppm (4/5 males, 2/5 females) were not found at 908 ppm

(Duchosal and Biederman 1991). No controls were used in this study. The LOAEL for tachypnea and a NOAEL

for respiratory effects identified in this limited study are presented in Table 2-l and Figure 2-l.

Cardiovascular Effects. Electrocardiograms were normal in three individuals who developed chloracne

following occupational exposure (inhalation and dermal) to chlorophenols and other compounds during the

manufacture of 2,4-DCP and 2,4,5-TCP (Bleiberg et al. 1964). No additional studies were located regarding

cardiovascular effects in humans following inhalation exposure to any of the eight chlorophenols discussed in

this profile.

No studies were located regarding cardiovascular effects in animals following inhalation exposure to any of the

eight chlorophenols discussed in this profile.

Gastrointestinal Effects. The self-reported prevalence of gastrointestinal disease was not increased

among 281 TCP production workers with elevated serum TCDD levels (Calvert et al. 1992). The workers had

been exposed to a mixture of TCPs at least 15 years prior to the survey. However, the long time lag between

exposure and examination of gastrointestinal symptoms may invalidate the study.
CHLOROPHENOLS 18

2. HEALTH EFFECTS

No studies were located regarding gastrointestinal effects in animals after inhalation exposure to any of the eight

chlorophenols discussed in this profile.

Hematological Effects. Clinical assessment of two patients occupationally exposed during the manufacture of

2,4-DCP- and 2,4,5-TCP-based herbicides revealed hematology and blood chemistry parameters (blood counts,

bleeding and clotting time, serum bilirubin, blood urea nitrogen, and others) to be within normal ranges

(Bleiberg et al. 1964).

No studies were located regarding hematological effects in animals after inhalation exposure to any of the eight

chlorophenols discussed in this profile.

Hepatic Effects. Porphyria cutanea tarda has been reported in workers employed in the manufacture of

2,4-DCP and 2,4,5-TCP (Bleiberg et al. 1964). Exposure to chlorophenols and intermediates was probably

through inhalation and dermal contact. Eleven cases of porphyria were identified, based on urinary porphyrin

excretion, in a survey of 29 workers. Elevated serum transaminase levels and evidence of liver damage, e.g.,

regeneration of liver cells and hemofuscin (a brownish-yellow pigment that results from the decomposition of

hemoglobin) deposition, were detected from liver biopsies in two cases that were studied in detail. Thus, the

exposure was probably related to liver injury. Definitive conclusions regarding the connection between the

porphyria or liver injury and exposure to chlorophenols in this group of workers cannot be made since the

workers were exposed to a variety of chlorinated compounds, including a highly volatile chlorinated phenolic

ether with six chlorines formed during the manufacturing process. The data provide an alert for potential human

risk, however. Information on exposure to other liver toxicants, including the chronic ingestion of alcohol, was

not obtained.

The results of a cross-sectional study of trichlorophenol production workers indicated an increased risk of

elevated gamma-glutamyltransferase (GGT) activity in these workers (Calvert et al. 1992). GGT is a liver

enzyme that is a potential marker of hepatobiliary disease. An interaction between alcohol consumption and

exposure was related to increased GGT activity in these production workers (Calvert et al. 1992). However, the

absence of increases in other hepatic enzymes may limit the diagnostic potential of the GGT findings in this

study.

No studies were located regarding hepatic effects in animals following inhalation exposure to any of the eight

chlorophenols discussed in this profile.
CHLOROPHENOLS 19

2. HEALTH EFFECTS

Dermal Effects. Chloracne, evidence of acquired porphyria cutanea tardia, hyperpigmentation, folliculitis,

keratosis, and hirsutism have been observed in workers employed in the manufacture of 2,4-DCP- and 2,4,5-

TCP-based herbicides (Bleiberg et al. 1964; Bond et al. 1989). As noted above in the discussion of hepatic

effects, exposure to chlorophenols may have been through either inhalation or dermal contact or both.

Furthermore, the subjects were exposed to several chlorinated compounds (e.g., dioxin) in addition to

chlorophenols; therefore, the chloracne and other dermal effects cannot be ascribed specifically to chlorophenol

exposure since chloracne is known to occur following exposure to TCDD.

No studies were located regarding dermal effects in animals following inhalation exposure to any of the eight

chlorophenols discussed in this profile.

Ocular Effects. Lumber mill workers exposed to a mixture of tetrachlorophenols (specific isomers not

stated) and pentachlorophenol reported eye irritation more frequently than unexposed workers (Kleinman et al.

1986). Tetrachlorophenol air concentrations ranged from 0.8 to 12.2 μg/m3

, and pentachlorophenol

concentrations were below the limit of detection (0.5 μg/m3

). Industrial hygienists indicated that improvements

in protective equipment were necessary at this mill, which suggests that ocular irritation could have resulted in

part from contact with contaminated surfaces (e.g., hands, clothing).

No studies were located regarding ocular effects in animals following inhalation exposure to any of the eight

chlorophenols discussed in this profile.

Body Weight Effects. No studies were located regarding body weight effects in humans following

inhalation exposure to any of the eight chlorophenols discussed in this profile.

No changes in body weight were observed during the 15-day observation period after rats were exposed (noseonly) to 2-CP at 908 ppm for 4 hours (Duchosal and Biedermann 1991). No controls were included in this study.

This NOAEL for body weight effects is recorded in Table 2-l and plotted in Figure 2-1.

2.2.1.3 Immunological and Lymphoreticular Effects

No studies were located regarding immunological and lymphoreticular effects in humans or animals after

inhalation exposure to any of the eight chlorophenols discussed in this profile.
CHLOROPHENOLS 19

2. HEALTH EFFECTS

Dermal Effects. Chloracne, evidence of acquired porphyria cutanea tardia, hyperpigmentation, folliculitis,

keratosis, and hirsutism have been observed in workers employed in the manufacture of 2,4-DCP- and 2,4,5-

TCP-based herbicides (Bleiberg et al. 1964; Bond et al. 1989). As noted above in the discussion of hepatic

effects, exposure to chlorophenols may have been through either inhalation or dermal contact or both.

Furthermore, the subjects were exposed to several chlorinated compounds (e.g., dioxin) in addition to

chlorophenols; therefore, the chloracne and other dermal effects cannot be ascribed specifically to chlorophenol

exposure since chloracne is known to occur following exposure to TCDD.

No studies were located regarding dermal effects in animals following inhalation exposure to any of the eight

chlorophenols discussed in this profile.

Ocular Effects. Lumber mill workers exposed to a mixture of tetrachlorophenols (specific isomers not

stated) and pentachlorophenol reported eye irritation more frequently than unexposed workers (Kleinman et al.

1986). Tetrachlorophenol air concentrations ranged from 0.8 to 12.2 μg/m3

, and pentachlorophenol

concentrations were below the limit of detection (0.5 μg/m3

). Industrial hygienists indicated that improvements

in protective equipment were necessary at this mill, which suggests that ocular irritation could have resulted in

part from contact with contaminated surfaces (e.g., hands, clothing).

No studies were located regarding ocular effects in animals following inhalation exposure to any of the eight

chlorophenols discussed in this profile.

Body Weight Effects. No studies were located regarding body weight effects in humans following

inhalation exposure to any of the eight chlorophenols discussed in this profile.

No changes in body weight were observed during the 15-day observation period after rats were exposed (noseonly) to 2-CP at 908 ppm for 4 hours (Duchosal and Biedermann 1991). No controls were included in this study.

This NOAEL for body weight effects is recorded in Table 2-l and plotted in Figure 2-1.

2.2.1.3 Immunological and Lymphoreticular Effects

No studies were located regarding immunological and lymphoreticular effects in humans or animals after

inhalation exposure to any of the eight chlorophenols discussed in this profile.
CHLOROPHENOLS 20

2. HEALTH EFFECTS

2.2.1.4 Neurological Effects

Lumber mill workers exposed to a mixture of tetrachlorophenols (specific isomers not stated) and

pentachlorophenol reported headaches more frequently than unexposed workers (Kleinman et al. 1986).

Monitoring of air and urinary concentrations of tetrachlorophenols suggested that exposure was principally

through the skin.

Rats exposed for 4 hours to 908 ppm 2-CP using nose-only exposure showed restlessness, a hunched posture,

and ruffled fur (Duchosal and Biedermann 1991). These effects were not observed at 104 ppm. The LOAEL and

NOAEL for neurological effects is recorded in Table 2-l and plotted in Figure 2-l.

2.2.1.5 Reproductive Effects

No studies were located regarding reproductive effects in humans or animals after inhalation exposure to any of

the eight chlorophenols discussed in this profile.

2.2.1.6 Developmental Effects

No studies were located regarding developmental health effects in humans or animals after inhalation

exposure to any of the eight chlorophenols discussed in this profile.

2.2.1.7 Genotoxic Effects

Genotoxicity studies are discussed in Section 2.5.

2.2.1.8 Cancer

A number of investigators have studied the potential association between chlorophenol-based pesticide

production and carcinogenicity (Eriksson et al. 1981, 1990; Hardell et al. 1981; Hoar et al. 1986; Honchar and

Halperin 1981; Kogevinas et al. 1992; Lynge 1985; Smith et al. 1984; Woods et al. 1987). Reports from

Sweden indicate significantly increased relative risk ratios for soft tissue sarcomas (STS) and/or nonHodgkin’s lymphomas (NHLs) in exposed workers (Eriksson et al. 1981, 1990; Hardell et al. 1981). In a

retrospective cohort study on Danish workers exposed to 2,4-DCP and 4- chloro-o-tolyloxy-acetic
CHLOROPHENOLS 22

2. HEALTH EFFECTS

The composite human results represent studies from a variety of occupational settings, with various degrees of

exposure to chlorophenols, dioxins, intermediates, and final products, such as chlorophenoxy pesticides. The

data are not sufficiently sensitive to support a relationship, per se, between any of the chlorophenol exposures

and tumor incidence. However, taken in composite, the human study results do suggest a possible concern for

increased tumorigenic risk in farm workers and production workers exposed to chlorophenols or their end-use

products (Woods et al. 1987).

No studies were located regarding cancer in animals after inhalation exposure to any of the eight chlorophenols

discussed in this profile.

2.2.2 Oral Exposure

2.2.2.1 Death

No studies were located regarding death in humans after oral exposure to any of the eight chlorophenols

discussed in this profile.

The lowest reported LD50 for a chlorophenol isomer was 89 mg/kg for male mice treated with 2,3,5,6 TeCP in

ethanol (Ahlborg and Larsson 1978). The highest reported LD50 was 2,960 mg/kg for male rats treated with

2,4,5-TCP in corn oil (McCollister et al. 1961). The range of LD50 values indicates that the chlorophenols are

slightly or moderately toxic according to the classification scheme of Hodge and Sterner (1949). Ahlborg and

Larssen (1978) examined the acute oral toxicity of the TeCPs in both ethanol and propylene glycol. The LD50s

were higher when propylene glycol was used as the vehicle rather than ethanol (e.g., the LD50 for 2,3,4,6-TeCP

in female mice was 131 when administered in ethanol and 735 mg/kg when administered in propylene glycol).

The Ahlborg and Larssen (1978) study highlights the importance of vehicle effects in acute gavage studies, and

because vehicles were different across studies and chlorophenol isomers, it is not possible to make definitive

conclusions about which isomer is more toxic following a single oral dose.

In the only known toxicity study involving repeated dosing of monochlorophenols, groups of male and female

ICR mice received daily gavage doses of 35, 69, or 175 mg/kg/day 2-CP in corn oil for 14 days. No exposurerelated deaths occurred at the two lower treatment levels. All mice exposed at 175 mg/kg/day died,
CHLOROPHENOLS 23

2. HEALTH EFFECTS

suggesting a steep dose-response relationship between the mid- and high-treatment doses (Borzelleca et

al.1985a).

In repeated-dose studies of 2,4-DCP in corn oil, 4 out of 34 pregnant Fischer-344 rats treated by gavage at 750

mg/kg/day on gestation days 6-15 died (Rodwell et al. 1989), while all non-pregnant rats treated with 2,000

mg/kg/day in the diet for 14 days survived (NTP 1989). Although pregnant rats may be more susceptible, the

difference in effect may also be a result of differences in the rate of exposure between gavage and dietary

dosing.

All rats and mice exposed to 2,4-DCP in the diet for 13 weeks at doses of 2,000 or 2,600 mg/kg/day survived

(NTP 1989). However, all mice died when exposed to 5,200 mg/kg/day for 3 weeks (NTP 1989). In a 2-year

study, decreased survival was not observed in rats fed 2,4-DCP in the diet at doses up to 440 mg/kg/day or in

mice fed 2,4-DCP in the diet at doses up to 1,300 mg/kg/day for 103 weeks (NTP 1989).

No deaths were observed among rats treated by gavage (18 doses in olive oil) or in the diet with 2,4,5-TCP at

doses up to 1,000 mg/kg/day for 90 days (McCollister et al. 1961). In addition, no deaths were observed in

rabbits treated with 20 gavage doses of 500 mg/kg/day 2,4,5-TCP over 28 days (McCollister et al. 1961).

Deaths were observed during the first 4 weeks of treatment among female rats (3/40) and male rats (8/25)

exposed to 2,4,6-TCP in corn oil by gavage for 11 weeks at 1,000 but not at 500 mg/kg/day (Blackbum et

al.1986). The females were treated 2 weeks prior to pregnancy and then throughout gestation. No deaths were

observed in rats treated by gavage with 2,4,6-TCP in corn oil at 720 mg/kg/day for 90 days (Bercz et al. 1990).

In a 7-week dietary study, 1 of 5 rats died at 1,075 mg/kg/day and 4 of 10 mice died at 4,095 mg/kg/day, with no

deaths observed at 735 mg/kg/day among rats or at 2,795 mg/kg/day among mice (NCI 1979). In a chronic

study, no increased mortality trend was observed in rats or mice treated with 2,4,6-TCP in the diet at

concentrations up to 500 mg/kg/day for 106-107 weeks for rats and 1,356 mg/kg/day for 105 weeks for mice

(NCI 1979).

No deaths were observed in rats treated by gavage with 200 mg 2,3,4,6-TeCP/kg/day during gestation (RTI

1987) or among male and female rats treated at 200 mg/kg/day for 90 days (American Biogenics 1988). In both

studies the 2,3,4,6-TeCP was given in olive oil.
CHLOROPHENOLS 24

2. HEALTH EFFECTS

The LD50 values and all reliable LOAEL values for death in each species and duration category are recorded in

Table 2-2 and plotted in Figure 2-2.

2.2.2.2 Systemic Effects

The highest NOAEL values and all reliable LOAEL values for systemic effects in each species and duration

category for oral exposures to chlorophenols are recorded in Table 2-2 and plotted in Figure 2-2.

Respiratory Effects. No studies were located regarding respiratory effects in humans after oral exposure to any

of the eight chlorophenols discussed in this profile.

Lung hemorrhaging occurred in rats treated with a single lethal gavage dose of 2,4-DCP (Wil Research

Laboratories 1982). Nasal lesions were noted in male but not female rats exposed to 210 mg/kg/day for

103 weeks. Nasal lesions were not observed in mice fed as much as 1,300 mg/kg/day for the same exposure

period (NTP 1989). This effect may, therefore, be specific to the male rat or may have been a result of aspiration

while eating. Histopathological changes have not been observed in the lungs of rats or mice orally exposed to

2,4-DCP (Borzelleca et al. 1985a; NTP 1989), 2,4,5-TCP (McCollister et al. 1961), 2,4,6-TCP (Bercz et al.

1990; Blackburn et al. 1986; NCI 1979), or 2,3,4,6-TeCP (American Biogenics 1988).

Cardiovascular Effects. No studies were located regarding cardiovascular effects in humans after oral

exposure to any of the eight chlorophenols discussed in this profile.

No change in heart weight was noted in mice fed 2,4-DCP at doses up to 230 mg/kg/day for 6 months

(Kobayashi et al. 1972). Histopathological examinations of the heart have not revealed any effects in rats fed

2,4-DCP at 2,000 mg/kg/day or in mice fed 2,4-DCP at 2,600 mg/kg/day for 13 weeks (NTP 1989). Studies on

rats exposed to 2,4-DCP at doses as high as 440 mg/kg/day and mice exposed to as much as 1,300 mg/kg/day

for 103 weeks also showed no histological changes in the heart (NTP 1989).

Heart weight changes were not observed in rats treated with 18 gavage doses of 1,000 mg 2,4,5-TCP/kg, nor

were.histological changes observed in the hearts of rats treated with 2,4,5-TCP in the diet at doses up to1,000

mg/kg/day for 98 days (McCollister et al. 1961).
























CHLOROPHENOLS 49

2. HEALTH EFFECTS

Heart weight did not increase in rats exposed orally to 2,4,6-TCP over an intermediate (10 or 13 weeks)

exposure period to doses as high as 1,000 mg/kg/day (Bercz et al. 1990; Blackburn et al. 1986). No treatmentrelated lesions were evident upon histopathologic examination of the hearts of rats and mice exposed to doses as

high as 720 and 1,356 mg/kg/day of 2,4,6-TCP, respectively for 90 days (Bercz et al.1990) or 105 weeks (NCI

1979).

No changes in heart weight or histology were observed in rats treated with 2,3,4,6-TeCP for 90 days

(American Biogenics 1988).

Gastrointestinal Effects. No studies were located regarding gastrointestinal effects in humans after oral

exposure to any of the eight chlorophenols discussed in this profile.

Mild catarrhal enteritis was observed in female Sprague-Dawley albino rats given a single gavage dose of 316-

5,000 mg/kg/day 2,4-DCP in corn oil and sacrificed 24 hours later (Henke and Lockwood 1978). No pathology

reports were provided for rats that were sacrificed on day 7 or day 14. In another study, gross necropsy revealed

reddened hind, stomach and intestines in Fischer-344 rats given a single gavage dose of 2,400 mg/kg/day 2,4-

DCP in corn oil. Both studies demonstrated that this compound can be irritating to the gastrointestinal tract (Wil

Research Laboratories 1982). The observation of gastrointestinal effects at lower doses in Sprague-Dawley

compared to Fischer-344 rats suggests that Sprague-Dawley rats may be more sensitive to the acute

gastrointestinal effects of 2,4-DCP. No significant histopathological changes were observed in the

gastrointestinal tracts of Fischer-344 rats fed 2,000 mg/kg/day 2,4-DCP or mice fed 2,600 mg/kg/day 2,4-DCP

for 13 weeks, or in rats fed 440 mg/kg/day 2,4-DCP or mice fed 1,300 mg/kg/day 2,4-DCP for 103 weeks (NTP

1989).

In a 90-day study, no significant histopathological changes were observed in the gastrointestinal tracts of rats

treated by gavage with 2,4,6-TCP at 720 mg/kg/day (Bercz et al. 1990). Histopathologic examination of the

stomach and intestines of rats and mice exposed to 2,4,6-TCP for 2 years at doses as high as 500 and 1,356

mg/kg/day, respectively, revealed no treatment-related lesions (NCI 1979).

Wistar rats administered a single gavage dose of 632 mg/kg 2,3,4,6-TeCP had mucosal hyperemia of the

stomach and severe necrosis of the intestine (Hattula et al. 1981). At a dose of 432 mg/kg, mild necrosis was

observed in the intestines of 1/10 rats, with no effects observed at 410 mg/kg. Focal necrosis of the small

intestines was observed in Wistar rats treated by gavage for 55 days with 100 mg/kg/day 2,3,4,6- TeCP. No
CHLOROPHENOLS 50

2. HEALTH EFFECTS

effects were observed at 10 mg/kg/day (Hattula et al. 1981). In contrast, no histopathological changes were

observed in the gastrointestinal tracts of Sprague-Dawley rats treated with 2,3,4,6-TeCP at 200 mg/kg/day for 90

days (American Biogenics 1988). 2,3,4,6-TeCP was administered in olive oil in both the Hattula et al. (1981)

(concentrations not reported) and American Biogenics (1988) studies (maximum concentration of 20 mg/mL).

Because olive oil was used as a vehicle for both studies, the differences in effects to the gastrointestinal tract

may likely be due to the dissimilar dosing solution concentrations and rodent strains.

Hematological Effects. No studies were located regarding hematological effects in humans after oral

exposure to any of the eight chlorophenols discussed in this profile.

Groups of 12 male and 12 female mice, administered once daily by gavage with up to 69 mg/kg/day 2-CP or up

to 638 mg/kg/day 2,4-DCP for 14 days, showed no adverse effects on standard hematological parameters,

including total and differential white blood cells, red blood cells, platelets, hematocrit, hemoglobin, and

coagulation measures relative to unexposed controls (Borzelleca et al. 1985a). However, when groups of 20

male and 20 female mice were dosed with up to 383 mg/kg/day of 2,4-DCP (male), and 49 mg/kg/day (female)

in drinking water for 90 days, the number of white blood cells was increased in the high-dose males (Borzelleca

et al. 1985c). No changes in red or white blood cell counts were noted in mice exposed to 2,4-DCP at doses up

to 230 mg/kg/day for 6 months (Kobayashi et al. 1972). After 13 weeks of prenatal exposure and up to 15 weeks

of postnatal exposure to 2-CP in drinking water, rat weanlings showed no adverse effects on red cell count,

hematocrit, mean corpuscular volume, white cell count, or hemoglobin concentration; the highest exposure dose

was 50 mg/kg/day (Exon and Koller 1982). Chronic prenatal/postnatal exposure to either 50 mg/kg/day 2-CP or

30 mg/kg/day 2,4-DCP resulted in increased erythrocyte count, packed cell volume, and hemoglobin

concentration. The increases for erythrocyte count and hemoglobin (>10%) were statistically significant (p≤

0.05) (Exon and Koller 1985). However, the investigators suggested that the increase may be secondary to

effects on liver enzymes or on hematopoietic stem cells and did not consider these effects biologically

significant,

In an NTP study (NTP 1989), bone marrow atrophy was observed in male rats treated with 2,4-DCP in the diet

at 1,000 mg 2,4-DCP/kg/day for 13 weeks and in female rats at 500 mg/kg/day. The atrophy resulted in

depletion of both erythroid and myeloid elements, with no effects observed at 250 mg/kg/day. No hematological

effects were noted in mice treated with 2,4-DCP in the diet for 13 weeks at doses up to 2,600 mg/kg/day or in

rats or mice treated with 2,4-DCP for 103 weeks (rats, 440 mg/kg/day; mice, 1,300 mg/kg/day) (NTP 1989).
CHLOROPHENOLS 51

2. HEALTH EFFECTS

Treatment of rats with 2,4,5-TCP in the diet at doses up to 1,000 mg/kg/day for 98 days resulted in no

changes in hematocrit, hemoglobin, or white blood cell counts(McCollister et al. 1961). Administration of up to

720 mg/kg/day 2,4,6-TCP to rats for 90 days resulted in no adverse effects on erythrocyte count, leukocyte

count, corrected leukocyte count, hemoglobin, hematocrit, platelet count, or a differential analysis of leukocytes

(Bercz et al. 1990). Rats exposed orally for 7 weeks to 2,4,6-TCP exhibited a “moderate to marked increase” in

splenic hematopoiesis (NCI 1979). A high incidence of bone marrow hyperplasia and leukocytosis occurred in

rats chronically exposed to 2,4,6-TCP in their diet at 250 mg/kg/day (NCI 1979). Further discussion of these

hematological effects in rats can be found in Section 2.2.2.8. No hematological effects were evident in mice

exposed chronically to 2,4,6-TCP in their diet at doses up to 1,300 mg/kg/day (NCI 1979).

Treatment of rats by gavage with doses of 200 mg/kg/day 2,3,4,6-TeCP for 90 days significantly (p<0.05)

reduced hemoglobin and hematocrit in both sexes (American Biogenics 1988). Although the effects were

statistically significant, the investigators did not consider the effects to be toxicologically significant because the

group mean data were within the normal range of reference control data for the laboratory where the study was

conducted. In addition, no gross or histopathologic evidence was found to support the decreases in hemoglobin

and hematocrit.

Musculoskeletal Effects. No studies were located regarding musculoskeletal effects in humans after oral

exposure to any of the eight chlorophenols discussed in this profile.

Ninety-day (up to 2,600 mg/kg/day) and 2-year (up to 1,300 mg/kg/day) exposure of rats and mice to

2,4-DCP did not result in any histopathological changes in the muscle or ribs (NTP 1989). Single dose and 55-

day exposure to 2,3,4,6-TeCP produced no adverse histopathological effects on muscle in Wistar rats (Hattula et

al. 1981). The highest single and intermediate-duration exposure levels were 632 mg/kg and 100 mg/kg/day,

respectively (Hattula et al. 1981).

Hepatic Effects. No studies were located regarding hepatic effects in humans after oral exposure to any of the

eight chlorophenols discussed in this profile.

Treatment of mice by gavage with 2-CP in corn oil at doses up to 69 mg/kg/day for 14 days resulted in a

significant decrease in liver weights in females with no effects on serum glutamic-oxaloacetic transaminase

(SGOT); serum glutamic-pyruvic transaminase (SGPT); liver microsomal proteins; cytochrome P-450;
CHLOROPHENOLS 52

2. HEALTH EFFECTS

cytochrome b5; or activities of liver aminopyrine demethylase, aniline hydroxylase, or arylhydrocarbon

hydroxylase (Borzelleca et al. 1985a). The study authors did not consider the change in liver weight to be

adverse because biologically or statistically significant compound-related adverse effects were not observed.

In Sprague-Dawley rats, twice daily administration of as little as 0.32 mg/kg 4-CP for 2 weeks

(0.64 mg/kg/day) resulted in significant activation of hepatic enzymes including cytochrome P-450

(Phomchirasilp et al. 1989b). Microsomal protein and cytochrome P-450 levels were also elevated in the

treated rats. The magnitude of increases over 2 weeks in liver microsomal protein and cytochrome P-450

content declined at doses above 0.64 mg/kg/day. Following additional experiments in which treatment was

given two times per day, both a 2-week exposure to 2.58 mg/kg/day and an 8-week exposure to 0.64

mg/kg/day resulted in a foamy cytoplasm and the clustering of mitochondria and endoplasmic reticulum.

The electron microscopic changes were not observed in the livers of rats treated at 1.28 mg/kg/day for 2

weeks. In separate studies, similar treatment doses of 4-CP had no effect on relative liver weights,

microsomal zoxazolamine 6-hydroxylase activity, or measures of serum lipid and lipidlipoprotein

concentrations, but did increase fasting glucose levels (Phomchirasilp et al. 1989a). Light microscopy was

not reported in this study. Based on the electron microscopic changes following 2 weeks of exposure, 2.58

mg/kg/day is considered a LOAEL and 1.28 mg/kg/day is considered a NOAEL. As described in footnote

“b” of Table 2-2, an acute duration oral MRL of 0.01 mg/kg/day was calculated for the chlorophenols

based on 4-CP. The LOAEL for 4-CP was the lowest LOAEL among all the acute-duration LOAELs for

all the chlorophenols discussed in this profile.

Sprague-Dawley rats dosed at 20 mg/kg/day of 2,4-DCP in the drinking water had increased liver weights

(Exon et al. 1984), an effect that could indicate hyperplasia or enzyme induction. No histopathological

changes were observed in the livers of Fischer-344 rats fed 2,4-DCP in the diet at doses up to 2,000

mg/kg/day for 13 weeks or 400 mg/kg/day for 103 weeks (NTP 1989). Liver weights or liver enzymes

released to the serum were not measured in the NTP (1989) study. Mice fed 325 mg/kg/day of 2,4-DCP for

13 weeks had dose-related increases in hepatocellular necrosis (not further described) (NTP 1989). When

mice were fed 383 or 230 mg/kg/day for 90 days or 6 months, respectively, no effects were noted on

SGOT or SGPT activity (these enzymes are released into the bloodstream as a result of liver injury)

(Borzelleca et al. 1985a; Kobayashi et al. 1972). One of 10 mice exposed to 230 mg/kg/day 2,4-DCP for 6

months had hepatocellular hyperplasia. No liver effects were observed at 100 mg/kg/day (Kobayashi et al.
CHLOROPHENOLS 53

2. HEALTH EFFECTS

1972). Diffuse syncytial alterations occurred in male mice given 800 mg/kg/day 2,4-DCP in the diet for 103

weeks (NTP 1989). The number of cells affected was small, and the affected cells were scattered within the

histologic sections.

When guinea pigs were administered 40 mg/kg 2,4-DCP perorally 3 times a week for 2 weeks, lipid

peroxidation was increased in the liver (Clerhata et al. 1996). A high intake of ascorbic acid

(50 mg/animal/day) significantly decreased lipid peroxidation in the liver in comparison to guinea pigs with low

ascorbic acid intake (2 mg/kg/day). 2,4-DCP accumulation was also decreased in the liver of animals with high

ascorbic acid intake.

The pretreatment of rats with 2,4,5- or 2,4,6-TCP by gavage at doses up to 400 mg/kg/day for 14 days had no

effect on ethylp-nitrophenylphosphonothionate detoxification (Carlson 1978). 2,4,5-TCP but not 2,4,6-TCP at

400 mg/kg/day decreased microsomal NADPH-reductase activity and cytochrome P-450 activity.

Histologic changes in the liver were not observed when rats were treated by gavage with 2,4,5-TCP in corn oil

at doses up to 1,000 mg/kg/day for 18 or 24 days (McCollister et al. 1961). Slight pathologic changes, which

were not further described, were noted in the livers of rabbits treated by gavage with 2,4,5-TCP in 5% gum

acacia solution for 20 or 28 days (McCollister et al. 1961). Over a 98-day period, a dose of 300 mg/kg/day given

to rats in the diet resulted in mild centrilobular degeneration and focal necrosis, with no effects observed at 100

mg/kg/day (McCollister et al. 1961).

Increased liver weight and midzonal vacuolation of hepatocytes were evident in rats exposed orally for

7 weeks to 2,300 mg/kg/day 2,4,6-TCP (NCI 1979). Increased relative liver weights were found in groups of

male rats exposed to 240 and 720 mg/kg/day of 2,4,6-TCP for 90 days and groups of female rats exposed to 720

mg/kg/day of 2,4,6-TCP for 90 days (Bercz et al. 1990). No treatment-related histopathological evidence of

tissue damage was noted. Clinical chemistry results included increased serum albumin and total protein

concentrations, which the investigators attributed to either an altered hydration status or dysfunctional hepatic

activity (Bercz et al. 1990). The investigators considered 240 mg/kg/day as a LOAEL for hepatic effects and the

next lower dose, 80 mg/kg/day, as a NOAEL for acute duration exposure. In contrast, increased liver weight and

histopathologic lesions were not evident in rats exposed to 2,4,6-TCP over intermediate or chronic periods at

doses up to 1,000 and 500 mg/kg/day, respectively (Blackburn et al. 1986; NCI 1979).
CHLOROPHENOLS 54

2. HEALTH EFFECTS

Microscopic examination revealed hepatic hyperplasia and other signs of hepatocellular damage (e.g., liver cell

abnormalities, focal areas of cellular alteration) in mice exposed chronically to 2,4,6-TCP in the diet at doses as

low as 650 mg/kg/day (NCI 1979). It is possible these lesions were precursors of the hepatocellular adenomas

and carcinomas also observed in this study. More information relating to these hepatic neoplasms can be found

in Section 2.2.2.8.

Concentration-related increases in absolute liver weight occurred in rats exposed perinatally to 3 or

30 mg/kg/day 2,4,6-TCP for 15 weeks (Exon and Koller 1985). The investigators did not examine functional or

anatomical hepatic parameters.

The different effects of 2,4,6-TCP in rats and mice may, in part, be a result of the different methodologies used

for exposure, variations in experimental design, and/or possible differences in gastrointestinal absorption

because of the nature of the vehicle. In the intermediate oral studies by Bercz et al. (1990) and Blackburn et al.

(1986), 2,4,6-TCP was administered in corn oil by gavage. Interpretation of the Blackburn et al. (1986) data is

further complicated by the investigators’ failure to report sample sizes used in the statistical analysis. The NCI

(1979) studies used administration of 2,4,6-TCP in the diet, while 2,4,6-TCP was administered in drinking water

in the Exon and Koller (1985) study, therefore, a direct comparison is not very meaningful.

For both acute- (one dose) and intermediate-duration (55 days) administration of 2,3,4,6-TeCP in Wistar rats,

the most severe effects occurred in the liver (Hattula et al. 1981). In the single dose study, various adverse

histopathological effects occurred at unspecified dose levels up to a maximum dose of 632 mg/kg. Intermediateduration (55 days) administration of 100 mg/kg/day resulted in both Level III (large confluative necroses with

dilated and thrombosed veins) and Level II (bile duct proliferation, focal necrosis, and polymorphonuclear

leukocyte infiltration) hepatic damage. At 50 mg/kg/day, 1 out of 10 rats showed Level III damage. The

NOAEL for hepatic effects following 55 days of exposure was 10 mg/kg/day (Hattula et al. 1981). The number

of animals used in the 55-day study was not stated.

In a study sponsored by the EPA (American Biogenics 1988), increased liver weights and centrilobular

hypertrophy were observed in rats treated by gavage with 2,3,4,6-TeCP at 100 or 200 mg/kg/day for 90 days. No

effects were observed at 25 mg/kg/day.
CHLOROPHENOLS 55

2. HEALTH EFFECTS

Renal Effects. No studies were located regarding renal effects in humans after oral exposure to any of the eight

chlorophenols discussed in this profile.

In mice, daily administration of 35 or 69 mg/kg/day 2-CP for 14 days had no adverse effects on measures of

renal function, including blood urea nitrogen (BUN), total protein, albumin/globulin ratio, or electrolyte

balance (Borzelleca et al. 1985a). No significant compound-related adverse effects were noted at necropsy.

In the same study, a dose of 175 mg/kg/day was lethal to all exposed mice.

Except for renal tubular necrosis in mice that died following treatment with 2,4-DCP in the diet for 3 weeks

at 5,200 mg/kg/day (NTP 1989), kidney effects have not been observed in animals treated with 2,4-DCP.

Based on histological examinations, the reported NOAELs for kidney effects are 2,000 and 440 mg/kg/day

for rats fed 2,4-DCP in the diet for 13 and 103 weeks, respectively (NTP 1989), and 230,2,600, and 1,300

for mice fed 2,4-DCP in the diet for 90 days, 13 weeks, and 103 weeks, respectively (Kobayashi et al. 1972;

NTP 1989). Treatment of mice with 2,4-DCP in drinking water at doses up to 491 mg/kg/day had no effect

on kidney weights or clinical chemistry values including urine protein, phosphorus, calcium, sodium,

chloride, potassium, or creatinine levels (Borzelleca et al. 1985a). Histopathological examinations were not

completed because the clinical chemistry was negative.

Treatment of rats with 2,4,5-TCP at 1,000 mg/kg/day by gavage for 18 days resulted in a significant

increase in kidney weight, with no histopathologic changes or changes in BUN (McCollister et al. 1961).

Slight pathologic changes (not further described) were observed in rabbits given 20 gavage doses of 100 or

500 mg/kg/day, with no effects noted at 10 mg/kg/day (McCollister et al. 1961). In a go-day study, 2,4,5-

TCP administered in the diet at 300 mg/kg/day resulted in mild degenerative changes in the renal

epithelium of the convoluted tubules and in proliferation of the interstitial tissue (McCollister et al. 1961).

No kidney effects were observed at 100 mg/kg/day.

Administration of 720 mg/kg/day 2,4,6-TCP in corn oil by gavage for 90 days resulted in increased absolute

and relative kidney weights in male, but not female, Sprague-Dawley rats and decreased urinary pH in both

sexes. No other effects on clinical parameters of renal function were observed (Bercz et al. 1990). Renal

weight did not increase in Long-Evans rats administered 2,4,6-TCP in corn oil by gavage at doses as high as

1,000 mg/kg/day for 11 weeks, 5 days per week (Blackburn et al. 1986). Strain differences and daily

treatment as opposed to treatment five times per week may account for the differences in renal effects in the

Bercz et al. (1990) and Blackburn et al. (1986) studies. No treatment-related lesions were evident upon
CHLOROPHENOLS 56

2. HEALTH EFFECTS

histopathologic examination of the kidney in rats and mice exposed to dietary 2,4,6-TCP for 2 years at doses as

high as 500 and 1,356 mg/kg/day, respectively (NCI 1979).

A single dose or 55day exposure to 2,3,4,6-TeCP, at doses up to 632 mg/kg or 100 mg/kg/day, respectively, had

no adverse effect on the histological appearance of the kidneys of rats (Hattula et al. 1981). Increased kidney

weights without any histopathologic changes were observed in rats treated by gavage with 2,3,4,6-TeCP at 100

mg/kg/day for 90 days (American Biogenics 1988). No renal effects were observed at 25 mg/kg/day.

Endocrine Effects. No studies were located regarding endocrine effects in humans after oral exposure to any of

the eight chlorophenols discussed in this profile.

Histopathologic examinations did not reveal any changes in the endocrine glands (adrenals, pituitary, thyroid,

pancreas) of rats or mice treated with 2,4-DCP in the diets at doses up to 2,000 (rats) or

2,600 (mice) mg/kg/day for 13 weeks, or at doses up to 440 (rats) or 1,300 (mice) mg/kg/day for 103 weeks

(NTP 1989). Histopathologic changes of the adrenals were not observed in rats treated with 2,4,5-TCP in the

diet at 1,000 mg/kg/day for 98 days (McCollister et al. 1961).

Female rats treated by gavage with 720 mg/kg/day of 2,4,6-TCP for 90 days had slightly, but statistically

significant, elevated adrenal weights compared to untreated controls (Bercz et al. 1990). Because no

histopathological changes were noted, this dose is considered a NOAEL. Adrenal gland weights were not

increased in male rats treated by gavage with 2,4,6-TCP at 1,000 mg/kg/day for 11 weeks (Blackburn et al.

1986), providing further support that the adrenal glands are not a target of 2,4,6-TCP toxicity. However,

differences between male and female rats could be due to endocrine differences between males and females.

Histopathologic changes were not observed in the adrenal glands, thyroid, pancreas, or parathyroid glands in rats

or mice treated with 2,4,6-TCP in the diet at doses of 500 (rats) or 1,356 (mice) mg/kg/day for 105 weeks (NCI

1979). Treatment of rats by gavage with 2,3,4,6-TeCP for 90 days at doses up to 200 mg/kg/day had no effect on

the histologic appearance of the adrenal glands, pituitary, pancreas, or thymus (American Biogenics 1988).

Dermal Effects. No studies were located regarding dermal effects in humans after oral exposure to any of the

eight chlorophenols discussed in this profile.
CHLOROPHENOLS 57

2. HEALTH EFFECTS

Pregnant rats given 750 mg/kg 2,4-DCP by gavage experienced hair loss (Rodwell et al. 1989). No

histological changes in the skin were found in rats or mice given as much as 2,000 or 2,600 mg/kg/day,

respectively, for up to 13 weeks, nor for these same species fed up to 440 or 1,300 mg/kg/day for up to

103 weeks (NTP 1989). Upon histopathologic examination of the skin, no treatment-related effects were

observed in rats or mice exposed chronically to oral doses of 2,4,6-TCP as high as 500 or 1,356 mg/kg/day,

respectively (NCI 1979).

Ocular Effects. No studies were located regarding ocular effects in humans after oral exposure to any of the

eight chlorophenols discussed in this profile.

Histopathologic examination of the eyes did not reveal any adverse effect in rats or mice either treated with 2,4-

DCP (NTP 1989) in the diet or treated by gavage with 2,3,4,6-TeCP (American Biogenics 1988) for

intermediate or chronic durations. Ophthalmoscopic examinations did not reveal any treatment-related effects in

rats treated by gavage with 2,4,6-TCP at doses up to 720 mg/kg/day for 90 days (Bercz et al. 1990).

Body Weight Effects. No studies were located regarding body weight effects in humans after oral

exposure to any of the eight chlorophenols discussed in this profile.

In a 14-day study, both sexes of mice receiving 69 mg/kg/day 2-CP had unspecified body weight decrements

(Borzelleca et al. 1985a); the NOAEL was 35 mg/kg/day. No effects on body weight were observed in rats

treated with 2-CP in drinking water at doses of 50 mg/kg/day during gestation and lactation as well as 15-weeks

postweaning (Exon and Koller 1981,1982). Single-day gestational exposure of gravid Sprague-Dawley rats to

1,000 mg/kg 4-CP resulted in a significant body weight loss (Kavlock 1990). By 72 hours after dosing, the body

weight difference was no longer statistically significant, and lower levels did not produce any body weight gain

inhibition in gravid Sprague-Dawley rats. The NOAEL for the body weight effect for 4-CP was 667 mg/kg/day.

Additional results from this study are discussed in Section 2.2.2.6.

Studies with rats and mice fed 2,4-DCP for acute, intermediate, and chronic durations revealed dose-related

decreases in food intake and body weight (NTP 1989). These effects are believed to be due to the bad taste of

2,4-DCP. Body weights were not affected in mice treated with 2,4-DCP in the diet at doses up to 230 mg/kg/day

(Kobayshi et al. 1972) or in drinking water at doses up to 491 mg/kg/day (Borzelleca et al.1985a). To improve

palatability in drinking water, Borzelleca et al. (1985a) used a 1:9 emulphor:water
CHLOROPHENOLS 58

2. HEALTH EFFECTS

solution which is a modified vegetable oil. Body weights of pregnant animals treated on gestation days

6-l5 were reduced at 375 but not 200 mg/kg/day (Rodwell et al. 1989).

Treatment of rats by gavage with 2,4,5-TCP for 18 or 24 days at 1,000 mg/kg/day had no effect on body weight

(McCollister et al. 1961). In contrast, treatment with 2,4,5-TCP in the diet at 1,000 mg/kg/day for 90 days

resulted in a 24% decrease in body weight gain in female but not in male rats (McCollister et al. 1961). No

effects on food intake were measured.

Treatment of rats with 2,4,6-TCP by gavage at 1,000 mg/kg/day for 2 weeks before mating and throughout

gestation resulted in reduced body weights through gestation day 14 (Blackburn et al. 1986). Body weights on

gestation day 21 were not significantly different from those of the controls. No effect on body weight was

observed in rats treated by gavage with 2,4,6-TCP at 1,000 mg/kg/day for 90 days (Bercz et al. 1990) or 11

weeks (Blackburn et al. 1986), suggesting that pregnant animals may be more sensitive to effects on body

weight following treatment with 2,4,6-TCP. No effect on body weight was observed in mice treated with 2,4,6-

TCP in drinking water at 30 mg/kg/day for 24-25 weeks (Exon and Koller 1985). Body weights were

significantly reduced in rats treated with 2,4,6-TCP in the diet for 7 weeks at 735 but not at 500 mg/kg/day and

250 mg/kg/day for 105 weeks (NCI 1979). Body weights were also significantly decreased in mice fed 2,600

mg/kg/day 2,4,6-TCP in the diet for 7 weeks and at 658 mg/kg/day for 105 weeks (NCI 1979). No effects on

body weight were observed in mice fed 1,300 mg/kg/day 2,4,6-TCP for 7 weeks (NCI 1979). Food intake data

were not provided in the NCI (1979) study. The fact that 2,4,6-TCP affected body weight following dietary

intake but had little effect at similar doses following gavage treatment suggests that 2,4,6-TCP may have caused

the food to be less palatable and reduced food intake in mice at the concentrations used in the NCI (1979) study.

Therefore, decreased body weight may be an effect of decreased food intake rather than an effect of 2,4,6-TCP

treatment.

Body weight was significantly decreased in rats treated by gavage with 2,3,4,6-TeCP at 100 mg/kg/day

(American Biogenics 1988) for 90 days, but not 100 mg/kg/day for 55 days (Hattula et al. 1981).

2.2.2.3 Immunological and Lymphoreticular Effects

No studies were located regarding immunological and lymphoreticular effects in humans after oral exposure to

any of the eight chlorophenol isomers discussed in this profile.
CHLOROPHENOLS 59

2. HEALTH EFFECTS

Rats fed 50 mg/kg/day 2-CP for up to 16 weeks and mice fed 69 mg/kg/day 2-CP for 14 days showed no

changes in humoral or cell-mediated immunological assays (Borzelleca et al. 1985a; Exon and Koller

1983,1985). Indices assessed in the Exon and Koller (1983, 1985) studies include antibody production, delayed

type hypersensitivity, and phagocytic activity of peritoneal exudate cells. Female mice exposed to 69 mg/kg/day

for 14 days had statistically significant decreases in spleen weight but no gross abnormalities in spleen

morphology (Borzelleca et al. 1985a). Spleen and thymus weights were not significantly affected in rats that

received 50 mg 2,4-DCP kg/day in drinking water for 16 weeks (Exon and Koller 1983, 1985). Perinatal

exposure of young rats to 2-CP at doses up to 50 mg/kg/day produced no treatment-related effects on humoral or

cell-mediated immunity, thymus weights, or spleen weights (Exon and Koller 1983, 1985).

Histopathological examination of lymph nodes, spleen, and thymus did not reveal any effects in rats or

mice treated with 2,4-DCP in the diet at doses up to 2,000 (rats) and 2,600 mg/kg/day (mice) for 13 weeks, or

440 (rats) and 1,300 mg/kg/day (mice) for 103 weeks (NTP 1989). Bone marrow atrophy was observed in rats

treated at 500 but not 250 mg/kg/day for 13 weeks (NTP 1989). Because both erythroid and myeloid elements

were affected, this study is also discussed in Section 2.2.2.2 under Hematological Effects. No changes in spleen

weight were observed in mice treated with 2,4-DCP in the diet at 230 mg/kg/day for 6 months (Kobayashi et al.

1972), and no changes in spleen or thymus weight were noted in mice treated with 2,4-DCP in the drinking

water at doses up to 491 mg/kg/day for 90 days.

As shown in Table 2-2 and Figure 2-2, immune system effects have been reported in animals at low doses of

2,4-DCP. Decreased delayed-type hypersensitivity occurred in rats during 15-week-duration exposure to 3

mg/kg/day of 2,4-DCP in drinking water, and increased serum antibodies to key hole limpert nemocyanin were

found in the blood of rats during similar exposures to 30 mg/kg/day (Exon and Koller 1985; Exon et al. 1984).

Macrophage function, measured by the in vitro phagocytosis of sheep red blood cells, showed no effect from

2,4-DCP treatment. These results suggest that the immune system is quite sensitive to 2,4-DCP. No immune

system effects occurred with exposure to 0.3 mg/kg/day (Exon et al. 1984). Based on the NOAEL of 0.3

mg/kg/day, an intermediate-duration oral MRL of 0.003 mg/kg/day was calculated for the chlorophenols as

described in the footnote in Table 2-2. The LOAEL for 2,4-DCP was the lowest among all the intermediateduration LOAELs for all the chlorophenols discussed in this profile.
CHLOROPHENOLS 60

2. HEALTH EFFECTS

No changes in spleen weight or histological appearance were observed in rats treated with 2,4,5-TCP in the diet

at doses of 1,000 mg/kg/day for 98 days (McCollister et al. 1961) or in rats treated by gavage with 720

mg/kg/day 2,4,6-TCP for 90 days (Bercz et al. 1990). Spleen weights were significantly increased in rats

exposed to 2,4,6-TCP in the drinking water both pre- and postnatally at doses of 30 mg/kg/day, while no

significant effects on immune function (antibody levels, delayed-type hypersensitivity, macrophage numbers)

were observed (Exon and Koller 1985). Treatment of rats and mice with 2,4,6-TCP in the diet for 2 years at

doses up to 500 mg/kg/day for rats and 1,356 mg/kg/day for mice did not reveal any significant gross or

histopathological changes in the spleen, lymph nodes, or thymus (NCI 1979).

Administration of a single gavage dose 632 mg/kg of 2,3,4,6-TeCP in Wistar rats resulted in “slight stasis” in

the spleens of rats (Hattula et al. 1981); the toxicological significance of this finding is unknown. No

histological changes were observed in the spleen, lymph nodes, or thymus of rats treated with 2,3,4,6-TeCP by

gavage at doses up to 200 mg/kg/day for 90 days (American Biogenics 1988).

The highest NOAEL values and all reliable LOAEL values for immunological and lymphoreticular effects in

rats and mice for each exposure duration are recorded in Table 2-2 and plotted in Figure 2-2.

2.2.2.4 Neurological Effects

No studies were located regarding neurological effects in humans after oral exposure to any of the eight

chlorophenol isomers discussed in this profile.

In most acute animal studies involving 2-, 4-CP and 2,4-DCP exposure, a common syndrome of effects

precedes death (Borzelleca et al. 1985a, 1985b; Kobayashi et al. 1972; Spencer and Williams 1950; Wil

Research Laboratories 1982). This syndrome includes restlessness, tremors, convulsions, dyspnea and/or

tachypnea, and collapse or coma. In many of these studies, the major effects associated with exposure to high

doses of many phenolic compounds are myoclonic convulsions, or spasmodic twitching of a group of muscles.

The relationship between chlorophenol exposure and the onset of convulsions is discussed further in Sections

2.4 and 2.5. In general, the sensitivity of these clinical signs (particularly convulsions) decreases with increasing

chlorination.

In an LD50 study, single oral doses (unspecified) of 2-CP or 4-CP caused restlessness, motor weakness,

tremors, convulsion, or central nervous system depression in rats and mice (Borzelleca et al. 1985a, 1985b).
CHLOROPHENOLS 61

2. HEALTH EFFECTS

The actual doses used in the study (Borzelleca et al. 1985b) were not stated. A single oral dose of 514 mg/kg 4-

CP produced seizures immediately followed by death in male ICR mice (Phornchirasilp et al. 1989b). Single

doses of 2-CP >300 mg/kg resulted in distress and twitching in rabbits (Spencer and Williams 1950).

Administration of 4-CP produced similar effects at higher, unspecified doses. In male and female ICR mice,

repeated administration of 35 and 69 mg/kg/day 2-CP for 44 days resulted in hyperactivity and decreased brain

weight, respectively (Borzelleca et al. 1985a); although, the brain tissue appeared grossly normal (Borzelleca et

al. 1985a).

Mice treated with 2,4-DCP in the diet at 5,200 mg/kg/day for 14 days were lethargic and 1 out of 5 males died

(NTP 1989). Hunched posture was observed in rats treated with 2,4-DCP in the diet at 2,000 mg/kg/day for 13

weeks (NTP 1989) with no histopathological changes in the brain, sciatic nerve, or spinal cord. In mice treated

with 2,4-DCP in the diet at doses up to 2,600 mg/kg/day for 13 weeks, no histopathological changes were

observed in the brain, sciatic nerve, or spinal cord (NTP 1989). No effect on brain weight was observed in mice

treated with 2,4-DCP in the drinking water at doses up to 491 mg/kg/day (Borzelleca et al.1985a). No clinical

signs of neurological effects were reported in rats or mice fed doses up to 440 mg/kg/day for rats and 1,300

mg/kg/day for mice, and histopathologic examination of the brains of these animals did not reveal any effects

(NTP 1989).

No changes in brain weight or histological appearance of the brain were observed in rats treated with

2,4,5-TCP in the diet at doses up to 1,000 mg/kg/day for 98 days (McCollister et al. 1961).

Histopathologic examination of the brain (cerebrum and cerebellum) of rats and mice exposed repeatedly to oral

2,4,6-TCP at doses as high as 720 and 1,356 mg/kg/day, respectively, revealed no treatment-related effects

(Bercz et al. 1990; NCI 1979). Similarly, in Wistar rats exposed acutely to up to 632 mg/kg 2,3,4,6-TeCP, or

repeatedly to 200 mg/kg/day 2,3,4,6-TeCP for 90 days, no histopathological effects in the brain were observed

(American Biogenics 1988).

The highest NOAEL and all LOAEL values for neurological effects in each species and duration category are

recorded in Table 2-2 and plotted in Figure 2-2.
CHLOROPHENOLS 62

2. HEALTH EFFECTS

2.2.2.5 Reproductive Effects

No studies were located regarding reproductive effects in humans after oral exposure to any of the eight

chlorophenol isomers discussed in this profile.

A teratogenicity study in which pregnant rats were treated with 2,4-DCP by gavage on gestation days 6-15 at

doses that caused maternal deaths and decreased body weight gain showed neither postimplantation loss nor

changes in the numbers of resorptions and viable fetuses (Rodwell et al. 1989). No reproductive organ pathology

was observed in rats or mice of either sex fed up to 2,000 or 2,600 mg/kg/day 2,4-DCP, respectively, for 13

weeks (NTP 1989). Reproductive organ pathology was also not observed in male rats fed 440 and female rats

fed 250 mg/kg/day 2,4-DCP and male mice fed 1,300 and female mice fed 8,210 mg/kg/day 2,4-DCP for 2 years

(NTP 1989). Sperm from male mice fed 500 mg/kg/day 2,4-DCP for 90 days in drinking water were not

impaired in their ability to fertilize ova (Seyler et al. 1984).

Using identical experimental protocols, investigators have studied the reproductive effects of 2-CP, 2,4-DCP,

and 2,4,6-TCP in Sprague-Dawley female rats (Exon and Koller 1985). Groups of rats received uncontaminated

drinking water or one of three concentrations of a chlorophenol in drinking water, beginning at weaning and

extending through mating and parturition. The total exposure duration for each group was approximately 13

weeks. The only consistent concentration-related effect observed in all three experiments was a marginal

decrease (p<0.10) in litter size. In all cases, the individual conceptus, rather than the litter, was the unit of

statistical analysis. For 2-CP, 2,4-DCP, and 2,4,6-TCP, the highest concentration in water corresponded to

50,30, and 30 mg/kg/day, respectively; these doses are considered LOAELs for reproductive effects. No

significant reproductive effects were observed at 5 mg/kg/day 2-CP and 3 mg/kg/day for 2,5-DCP and 2,4,6-

TCP.

In a study designed to look at reproductive function, Blackburn et al. (1986) treated female rats with

2,4,6-TCP by gavage at doses up to 1,000 mg/kg/day for 2 weeks before mating and throughout gestation and

treated male rats with 2,4,6-TCP at doses up to 1,000 mg/kg/day for 10 weeks. The treated females were mated

with untreated males, and the treated males were mated with untreated females. 2,4,6-TCP had no effects on

breeding success, litter size, or litter survival when either sex was treated. Treatment of males had no effect on

sperm count, motility, or morphology, nor were there any changes in weights of the testes, prostate, or seminal

vesicles. Although treatment-related deaths occurred in both sexes at 1,000 mg/kg/day, this dose can be

considered a NOAEL for 2,4,6-TCP reproductive effects in rats.
CHLOROPHENOLS 63

2. HEALTH EFFECTS

In 90-day studies, gavage treatment of rats with either 2,4,5-TCP at doses up to 1,000 mg/kg/day

(McCollister et al. 1961) or with 2,4,6-TCP up to 720 mg/kg/day (Bercz et al. 1990) had no effect on the weight

of the testes or ovaries. Treatment of rats with 2,4,6-TCP in the diet for 2 years had no effects on the histologic

appearance of the testis and prostate or of the uterus or ovaries (NCI 1979).

In a study designed to examine developmental effects, pregnant rats were treated by gavage with

2,3,4,6-TeCP at doses up to 200 mg/kg/day on gestation days 6-l 5 (RTI 1987). An increased trend in

percent preimplantation loss with dose suggested an effect on the process of implantation or early

postimplantation viability. Because this study was not designed to examine the preimplantation/ implantation

phase of reproduction, the investigators suggested that the effect requires confirmation. Therefore, a LOAEL or

NOAEL for reproductive effects in female rats exposed to 2,3,4,6-TeCP is not clearly defined by this study. No

histopathological changes were observed in the testes, ovaries, or uterus and cervix of rats treated by gavage

with 2,3,4,6-TeCP at doses up to 200 mg/kg/day for 90 days (American Biogenics 1988).

The highest NOAEL values and all reliable LOAEL values are listed in Table 2-2 and plotted in Figure 2-2.

2.2.2.6 Developmental Effects

No studies were located regarding developmental effects in humans after oral exposure to any of the eight

chlorophenol isomers discussed in this profile.

No significant changes in offspring body or liver weights were observed in rats treated with 2-CP in drinking

water at doses up to 50 mg/kg/day throughout gestation and up to 91 days post partum (Exon and Keller 1981,

1983, 1985). Groups of 6-13 female Sprague-Dawley rats receiving a single dose of 333,667, or 1,000 mg/kg 4-

CP on gestational day 11 showed no adverse changes in litter sizes, perinatal loss, pup weight, or litter biomass

(Kavlock 1990). The only treatment-related effect was a transient decrease in maternal body weight at 1,000

mg/kg.

Oral exposure of pregnant rats to 750 mg/kg/day 2,4-DCP for 10 gestational days induced a slight decrease in

fetal weight and a statistically significant delayed ossification of sternal and vertebral arches and led to a slight

insignificant increase in early embryonic deaths (0.8/average litter controls; 1.2/litter 750 mg/kg/day) (Rodwell

et al. 1989). Maternal death occurred at this dose level, indicating that 2,4-DCP was not selectively toxic to

embryos or fetuses. The authors indicated that, although the number of deaths and fetal weights
CHLOROPHENOLS 64

2. HEALTH EFFECTS

differed from that of the concurrent controls, values were not different from the historical control data from their

laboratory. No evidence of malformations in the offspring was found in this study. At 375 mg/kg/day, maternal

body weight was reduced, with no effects observed at 200 mg/kg/day.

No effect on immune function parameters (antibody production, delayed type hypersensitivity response,

phagocytic activity) was noted in 6-week-old rats treated with 2,4-DCP in the drinking water at doses up to 30

mg/kg/day throughout gestation (Exon and Koller 1985; Exon et al. 1984). Spleen weights were significantly

increased at 30 mg/kg/day, although no histological changes in the spleen were observed.

Gavage administration of 650 mg/kg/day 2,4,5-TCP during organogenesis (days 6-15 of gestation) produced no

fetotoxicity, malformations, or structural terata in the offspring of Sprague-Dawley rats (Chernoff et al. 1990).

Treatment resulted in statistically insignificant increases in maternal lethality and decrements in maternal weight

gain (Chernoff et al. 1990). In another developmental study, groups of mice received either a single gavage dose

of 800-900 mg/kg 2,4,5-TCP on 1 day of gestation (any of gestation days S-15), or 250-300 mg/kg/day on any 3

days of gestation (gestation days 7-9, 10-12, or 13-15) (Hood et al. 1979). With the exception of a significant

increase in the incidence of prenatal mortalities and resorptions in dams dosed on day fourteen, 2,4,5-TCP had

no effect on resorption incidence or pup survival. 2,4,5-TCP administration did not affect mean fetal weight or

the incidence of gross malformations, skeletal malformations, or cleft palates (Hood et al. 1979).

In a study designed to examine reproductive effects, a 10-11% decrease in litter weights was observed in litters

of female rats treated by gavage with 2,4,6-TCP at 500 mg/kg/day for 2 weeks before mating and throughout

gestation (Blackburn et al. 1986). No effects on litter weights were observed at 100 mg/kg/day, and no effects

on survival to postnatal day 42 were observed. No effects on body weight were observed among offspring of

male rats treated by gavage with 2,4,6-TCP at 1,000 mg/kg/day for 10 weeks before mating (Blackburn et al.

1986). Because comprehensive examinations of offspring were not completed, this study is not sufficient to

conclude that developmental effects do not occur following exposure to 2,4,6-TCP.

Maternal exposure of rats to 500 mg/kg/day 2,4,6-TCP produced a transient reduction in the body weight of

offspring (Blackbum et al. 1986). No developmental effects were noted in the offspring of female rats exposed

to 2,4,6-TCP throughout gestation (Blackbum et al. 1986; Exon and Koller 1985). In addition, no developmental

effects were noted in the offspring of male rats treated with 2,4,6-TCP and untreated females (Blackbum et al.

1986). These studies were limited by the lack of reporting on the number of animals from
CHLOROPHENOLS 65

2. HEALTH EFFECTS

which group means were calculated (Blackburn et al. 1986) and by a lack of reporting on maternal toxicity

(Exon and Koller 1985).

In a developmental study in which female Sprague-Dawley rats orally received purified 2,3,4,6-TeCP

throughout organogenesis, the only effect on the fetus was delayed ossification of the skull bones (Schwetz et al.

1974). The reported incidences were 14/173 (8%) and 18/104 (17%) at 0 and 30 mg/kg/day, respectively. When

analyzed by litter, no statistical difference for delayed ossification was observed. Therefore, 30 mg/kg/day

2,3,4,6-TeCP is considered a NOAEL for developmental effects in rats. In a follow-up study, pregnant CD rats

received 0,25, 100, or 200 mg/kg/day, in olive oil, every day during organogenesis (RTI 1987). Administration

of the two highest doses resulted in corrected maternal body weight gain (dam body weight-gravid uterus

weight) inhibitions of 13% and 26%, respectively, with no effects at 25 mg/kg/day. Measurement of food intake

indicated that these effects were not related to decreased food consumption, Minor variations between dose

groups in fetal malformation and aberrations were not dose related. The investigators also noted a dose-related

trend for 2,3,4,6-TeCP-mediated effects on implantation or postimplantation viability. No further evidence of

maternal or fetotoxic effects were observed (RTI 1987). Based on maternal toxicity, this study identifies 100

mg/kg/day as a LOAEL and 25 mg/kg/day as a NOAEL for developmental effects.

The highest NOAEL value and all LOAEL values from each reliable study for developmental effects for each

exposure duration category are recorded in Table 2-2 and plotted in Figure 2-2.

2.2.2.7 Genotoxic Effects

No studies were located regarding genotoxic effects in humans after oral exposure to any of the eight

chlorophenols discussed in this profile.

In ICR mice, daily gavage administration of 69 mg/kg/day 2-CP or 638 mg/kg/day 2,4-DCP in corn oil for 14

days did not increase sister chromatid exchange (SCE) rates in testicular or bone marrow cells (Borzelleca et al.

1985a). Further details were not provided. Ninety-day exposure,of mice to 2,4DCP in drinking water at doses up

to 500 mg/kg/day also had no effect on SCE in bone marrow and testicular cells (Borzelleca et al. 1985a). A

single gavage dose of 2,4,5-TCP (164 mg/kg), 2,4,6-TCP (164 mg/kg), or 2,3,4,6-TeCP (28 or 193 mg/kg) given

to rats did not damage deoxyribonucleic acid (DNA) as measured by the fraction of DNA eluted from white

blood cells or livers (Kitchin and Brown 1988).
CHLOROPHENOLS 66

2. HEALTH EFFECTS

Other genotoxicity studies are discussed in Section 2.5.

2.2.2.8 Cancer

No studies were located regarding cancer in humans after oral exposure to any of the eight chlorophenol isomers

discussed in this profile.

In the one oral carcinogenicity study located, groups of Sprague-Dawley rats received prenatal, postnatal, or

both pre- and postnatal exposure to 2-CP (Exon and Koller 1985). The exposure concentrations were 0,5, 50,

and 500 ppm in drinking water (0, 0.5, 5, 50 mg/kg/day). Under all exposure conditions, 2-CP administration

had no effect on the incidence, latency, or types of tumors relative to the untreated controls. Additional groups

of gravid dams received ethylurea and nitrite, precursors of the carcinogenic initiator ethylnitrosourea (ENU), on

gestation days 14 and 21. No consistent effects on either tumor incidence or latency occurred in rats treated with

ENU and then treated either prenatally or postnatally with 2-CP. The groups of males receiving ENU and both

prenatal and postnatal 2-CP had increased tumor incidence and decreased tumor latency relative to a control

group receiving ENU only. The investigators indicate that the combined changes were marginally statistically

significant (p< 0.10) in comparison to a group receiving the initiator ENU only. ENU-exposed female rats also

exposed pre- and postnatally to 2-CP showed no consistent, concentration-related effects on either tumor

incidence or latency (Exon and Koller 1985). Findings in the combined-exposure male treatment groups indicate

that 2-CP may be either a cocarcinogen or a tumor promotor. However, an analysis of incidence and latency data

suggests that the effects may not be concentration related. No effects on tumorigenicity were found in similar

studies with 2,4-DCP given in drinking water at 0.3,3, or 30 mg/kg/day. It is not clear whether a maximum

tolerated dose was achieved in these studies (Exon and Koller 1985).

Chronic carcinogenicity bioassays in rats and mice treated with 2,4-DCP in the diet at doses up to

440 mg/kg/day for rats and 1,300 mg/kg/day for mice did not provide any evidence that 2,4-DCP is

carcinogenic (NTP 1989). In contrast, carcinogenicity bioassays with rats and mice provide evidence that

chronic oral exposure to 2,4,6-TCP is associated with leukemia and liver cancer (NCI 1979). In male rats,

chronic oral exposure to 2,4,6-TCP in the diet produced a significant dose-related increase in the incidence of

monocytic leukemia (NCI 1979). An increased incidence of leukemia also occurred in female rats; however, the

increase was not significant compared to the controls. In addition, leukocytosis and monocytosis as well as

hyperplasia of the bone marrow were induced in treated male and female rats that did not develop
CHLOROPHENOLS 67

2. HEALTH EFFECTS

leukemia. In rats with leukemia, there were large numbers of circulating monocytes in the blood that ranged

from well-differentiated monocytes to immature and blast forms. Monocytes were often observed in the liver,

spleen, lymph tissue, and bone marrow and occasionally in the lungs, adrenals, and other organs.

In both male and female B6C3Fl mice treated chronically with 2,4,6-TCP in the diet, a significant

doserelated increase in the incidence of hepatocellular adenomas and carcinomas (not further described) was

noted (NCI 1979). Liver damage, including individual liver cell abnormalities, focal areas of cellular

alteration and focal and nodular areas of hyperplasia were commonly present in the treated mice. Significant

limitations of this study included the failure to report the dioxin content of the 2,4,6-TCP formulation,

changes in the dosing regimen of mice, and no testing of organ function. Another limitation was the failure

to compare the incidence of liver tumors to historical controls as well as concurrent controls. Hepatocellular

carcinoma has a high natural incidence in this strain of mouse which tends to vary from one study to the

next.

A single oral dose of 2,4,6-TCP (200 mg/kg) did not significantly increase skin tumors in mice treated

dermally with a tumor promoter (12-O-tetradecanoylphorbol-13-acetate [TPA]) relative to TPA alone,

suggesting that 2,4,6-TCP does not act systemically as an initiator (Bull et al. 1986). Other studies also

examined the possible carcinogenic effects of 2,4,6-TCP, but contained limitations that preclude a

conclusion (Bionetics Research Labs 1968; Innes et al. 1969; Stoner et al. 1986). The limitations included

early termination of the experiment (24 weeks) (Stoner et al. 1986), only one treatment group (Bionetics

Research Labs 1968; Innes et al. 1969), a small number of treated animals (Bionetics Research Labs 1968;

Innes et al. 1969), and a change in dosing regimen and method of exposure (Bionetics Research Labs 1968;

Innes et al. 1969).

The Cancer Effect Levels (CELs) are recorded in Table 2-2 and plotted in Figure 2-2.

2.2.3 Dermal Exposure

2.2.3.1 Death

A worker who splattered pure 2,4-DCP on portions of his right arm and leg while disposing of industrial

waste collapsed and experienced a seizure within 20 minutes of the accident and died shortly thereafter.

Postmortem examination revealed blood and urine 2,4-DCP concentrations of 24.3 and 5.3 mg/L,

respectively. The identity of 2,4-DCP was confirmed by mass spectrometry. The investigators did not
CHLOROPHENOLS 68

2. HEALTH EFFECTS

estimate an absorbed dose (Kintz et al. 1992), but assuming a blood volume of 5 liters and a body weight of 70

kg, the dose would be approximately 2 mg/kg as a minimum. A screen for other drugs including ethanol,

organic solvents, tranquilizers, and drugs of abuse was negative.

Limited data were located on the lethal effects of dermally applied chlorophenols in experimental animals.

Results of a contract laboratory study indicate that the dermal LD50 of 2-CP in rabbits is between 1,000 and

1,580 mg/kg (Younger Lab 1975). Antemortem observations included increasing weakness, tremors, collapse,

and coma. Gross necropsy in the rabbit studies indicated hemorrhage in the lungs, Liver discoloration,

gastrointestinal inflammation, darkened spleens and kidneys, and enlarged gall bladders. The study data do not

clearly indicate whether mortality resulted from any of these effects. Conclusions from this study are limited by

small test groups and/or the lack of information regarding experimental methodology.

A dermal LD50 of 1,415 mg/kg has been reported for male rabbits exposed to 2,4-DCP for 24 hours (Carreon et

al. 1980b). Because there were only two rabbits per dose group, the 95% confidence interval on this value is

very large (236-8,455 mg/kg). Unoccluded dermal application of 2,000 mg/kg 2,3,4,5-TeCP or 2,3,5,6-TeCP

resulted in 1 out of 20 and 2 out of 20 deaths, respectively, in Sprague-Dawley rats (Shen et al. 1983). The

purity of each test compound was >99%. Because these preliminary studies indicated that the dermal LD50

values for 2,3,4,5-TeCP and 2,3,5,6-TeCP were greater than 2,000 mg/kg, further testing of these compounds

was not completed. The LD50 for commercial tetrachlorophenol, consisting primarily of the 2,3,4,6-isomer (at

least 90%), was 485 mg/kg in males and 565 mg/kg in females. Clinical signs preceding death for all

tetrachlorophenol isomers included initial hyperactivity followed by hypoactivity, neuromuscular weakness, and

convulsions (Shen et al. 1983).

The LD50 values and dermal doses of chlorophenols associated with death are recorded in Table 2-3.

2.2.3.2 Systemic Effects

No studies were located regarding respiratory, cardiovascular, hematological, musculoskeletal, hepatic, or renal

effects in humans or animals after dermal exposure to any of the eight chlorophenols discussed in this profile.

The systemic effects that were observed after dermal exposure to chlorophenols are discussed below.

Gastrointestinal Effects. No studies were located regarding gastrointestinal effects in humans after

dermal exposure to any of the eight chlorophenols discussed in this profile.


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2. HEALTH EFFECTS

Diarrhea was observed in one of two female rabbits the day after a dermal exposure to a single dose of

398 mg/kg/day 2,4-DCP (Hencke and Lockwood 1978). This limited study suggests that either dermally applied

2,4-DCP, or the stress of being exposed to a skin irritant, can result in gastrointestinal effects in rabbits.

Dermal Effects. Chloracne and evidence of acquired porphyria, hyperpigmentation, and hirsutism have been

observed in workers employed in the manufacture of 2,4-DCP- and 2,4,5-TCP-based herbicides (Bleiberg et al.

1964; Bond et al. 1989). The chloracne incidence was greatest in young employees exposed in trichlorophenol

production and in chlorophenol production and finishing procedures (Bond et al. 1989). In this study, workers

exposed to the highest concentration of the contaminant TCDD were at the greatest risk of developing

chloracne.

The results of animal studies indicate that monochlorophenols are corrosive to epithelial tissue (Bioassay

Systems 1981; Rhodia 1978). Severe effects have been reported at exposure levels of 242-2,000 mg/kg of 2-CP

or 4-CP applied directly to rabbit skin. Corrosion (not further described) is typically accompanied by other signs

of severe skin injury, including erythema, edema, and discoloration. A single dermal application of a lower dose

(100 mg/kg) of 4-CP to one ear of a mouse did not increase ear weight relative to the untreated ear (Dohi et al.

1989). Because of the inadequacies of the test methodologies used, few conclusions regarding dose-response

relationships or comparative isomeric potency can be made.

Dermal lesions were caused by a single direct application of as little as 200 mg/kg 2,4-DCP to bare

abdominal skin of New Zealand White rabbits (Carreon et al. 1980a, 1980b; Hencke and Lockwood 1978;

Younger Labs 1976). The dose-related dermal damage observed was described as mild-to-moderate erythema

and mild-to-marked edema, followed by necrosis and scabbing. No NOAEL values were identified in these

studies.

Dermal application of 20 mL/kg (32 g/kg) 2,3,4,5-TeCP on the shaved skin of female rats resulted in

dermatosis associated with scar formation. Rats treated with the sodium hydroxide extracted fraction of

2,3,4,5-TeCP had no dermatological lesion, indicating that the adverse effects were attributable to the

chlorophenol rather than contaminants, such as dioxins (Shen et al. 1983).

Ocular Effects. Lumber mill workers exposed to a mixture of tetrachlorophenols (specific isomers not

stated) and pentachlorophenol reported eye irritation more frequently than unexposed workers (Kleinman et
CHLOROPHENOLS 72

2. HEALTH EFFECTS

al. 1986). The eye irritation was likely a direct effect of the tetrachlorophenols, resulting from contact with the

airborne chemicals or contact with contaminated surfaces (e.g., hands, clothing).

Monochlorophenols produce effects ranging from slight hyperemia to severe corrosion when applied to the

corneas of rabbits. Rabbits administered 0.6 mg/kg 4-CP (a 1% solution) showed slight hyperemia (Harrison and

Madonia 1971). At 1.2 mg/kg, rabbits had more severe hyperemia with edematous swelling, corneal cloudiness,

and exudation. The maximum response occurred 5 hours after application. Inflammation was no longer apparent

at 96 hours. Severe discomfort and corrosion was reported to occur 1 minute after the application of 33 mg/kg

undiluted 2-CP to rabbit eyes (Younger Labs 1975). Although the results are inadequate for an assessment of

comparative potencies across isomers, the available data indicate that 2-CP and 4-CP produce rapid and severe

cornea1 destruction at relatively low concentrations.

Severe cornea1 damage occurred in the eyes of rabbits after a single direct application of 0.1 mL 2,4-DCP

(Hencke and Lockwood 1978). Careful washing of the eye 30 seconds after application did not prevent this

damage.

2.2.3.3 Immunological and Lymphoreticular Effects

No studies were located regarding immunological and lymphoreticular effects in humans following dermal

exposure to any of the eight chlorophenols discussed in this profile.

The murine local lymph node assay, which is predictive of skin sensitization potential, was completed in mice

treated with 2,4,5-TCP (Kimber and Weisberger 1991). A single dermal exposure of 50 mL of 2,4,5-TCP was

applied on one shaved flank; 5 days later the mice were given 3 daily doses (140-560 mg/kg/day) applied to the

ear. A positive response was observed at all doses, suggesting that 2,4,5-TCP can be a skin sensitizer. This study

is limited since only three mice were used in each group and a statistical analysis of the data was not completed.

2.2.3.4 Neurological Effects.

An industrial waste worker who accidentally splashed pure 2,4-DCP on portions of his right arm and leg,

experienced a seizure within 20 minutes of the exposure, and died shortly thereafter (Kintz et al. 1992). Lumber

mill workers exposed to a mixture of tetrachlorophenols (specific isomers not stated) and
CHLOROPHENOLS 73

2. HEALTH EFFECTS

pentachlorophenol reported headaches more frequently than unexposed workers (Kleinman et al. 1986).

Industrial hygiene observations of inadequate use of protective equipment to prevent skin exposure led the

investigators to suggest that exposure was principally through the skin, with some possibility of oral ingestion.

Rabbits given single applications of 250 mg/kg 2,4-DCP or more became lethargic (Carreon et al. 1980a, 1980b;

Younger Labs 1976), and two rabbits in the 2,000-mg/kg group and one in the 4,000-mg/kg group became

anorexic (Carreon et al. 1980b). Small sample sizes weaken the validity of these data, but the lethargy observed

in this study is in keeping with the signs of central nervous system depression seen in rats and mice orally

exposed to 2,4-DCP. In a single-dose dermal study of the tetrachlorophenols in rats, clinical signs observed

before death were hyperactivity, neuromuscular weakness, convulsions, and death (Shen et al. 1983). Both

2,3,5,6-TeCP and 2,3,4,5-TeCP that had dermal LD50 values >than 2,000 mg/kg were less toxic than 2,3,4,5-

TeCP that had a dermal LD50 of 468 mg/kg in males and 565 mg/kg in females.

No NOAEL values were identified for neurological effects. The lowest LOAEL values for neurological effects

in rabbits are recorded in Table 2-2.

2.2.3.5 Reproductive Effects

No studies were located regarding reproductive effects in humans or animals after dermal exposure to any of the

eight chlorophenol isomers discussed in this profile.

2.2.3.6 Developmental Effects

No studies were located regarding developmental effects in humans or animals after dermal exposure to any of

the eight chlorophenol isomers discussed in this profile.

2.2.3.7 Genotoxic Effects

Genotoxicity studies are discussed in Section 2.5.
CHLOROPHENOLS 74

2. HEALTH EFFECTS

2.2.3.8 Cancer

Numerous authors have studied the possible relationship between occupational chlorophenol exposure and the

expression of oncogenicity. For all of these studies, the workers were exposed by both the inhalation and dermal

routes. The description and results of these studies were provided in Section 2.2.1.8.

Results of case-control studies have suggested increased risks for soft tissue sarcoma, malignant lymphoma, and

acute myeloid leukemia in slaughterhouse workers exposed occupationally to a number of chemicals, including

2,4,6-TCP, by dermal exposure during the treatment of animal pelts (Pearce et al. 1988; Smith et al. 1984).

Workers in these studies were also exposed to potentially oncogenic viruses (including bovine leukemia virus).

Because of the confounding exposures to various agents, no conclusions can be made from these studies as to

the causal agent for these cancers.

In 15-week mouse initiation-promotion studies, 2-CP and 2,4-DCP, but not 2,4,6-TCP, showed tumor

promoting activity (Boutwell and Bosch 1959). One application of the known tumor initiator 9,10-dimethyl-1,2-

benzanthracene (DMBA) to the middorsal region of mice was followed by twice weekly dermal applications of

25 μL of a 20% solution of either 2-CP, 2,4-DCP, or 2,4,6-TCP. Compared to DMBA treatment alone, 2-CP and

2,4-DCP increased the number of skin tumors, with no effect from 2,4,6-TCP exposure (Boutwell and Bosch

1959). In a study in which no initiator was used, 2-CP applied to the backs of mice twice per week for 12 weeks

resulted in papillomas in 46% of the mice (Boutwell and Bosch 1959). No carcinomas were observed. The

significance of these results is limited by the lack of appropriate vehicle control groups, irritation, and the

reporting of only gross pathological effects (EPA 1980a).

2,4,6-TCP did not have initiating activity in an initiation-promotion study in mice (Bull et al. 1986). Mice were

treated with a dermal dose of 200 mg/kg/day 2,4,6-TCP followed 2 weeks later by 20 weeks (3 times per week)

of dermal 12-0-tetradecanoylphorbol-13-acetate (TPA) treatment.

2.3 TOXICOKINETICS

Tri- and tetrachlorophenol are rapidly absorbed and excreted following occupational exposure, which

involves both the inhalation and dermal routes. Studies using human cadaver tissue also suggest rapid

absorption after dermal application. Data on the absorption of chlorophenols by the oral route are limited
CHLOROPHENOLS 75

2. HEALTH EFFECTS

to animal studies. Based on the results of these studies and the physical properties of chlorophenols, the

gastrointestinal absorption of chlorophenols should be rapid and virtually complete. Data are insufficient to

quantitatively estimate the absorption rate or to compare absorption following administration in food versus

administration in water.

Limited evidence from animal studies suggests rapid clearance of chlorophenols from all body tissues.

Intravenous administration of 2,4-DCP to rats resulted in short-lived deposition in the kidney, liver, brain, and

fat. The extent of plasma protein binding, which is a major determinant of both the body burden and elimination

kinetics, increases with increasing chlorination. Increased plasma protein binding decreases the clearance rate of

higher chlorinated phenols (Pekari et al. 1991).

Few systematic metabolic studies were located for chlorophenols. In general, rapid Phase II metabolism to

glucuronide and sulfate conjugates seems to be the predominant route of metabolism. The relative proportion of

these conjugates may be species-, dose-, and route-related. The most important Phase I metabolites are

apparently quinone and semiquinone reactive intermediates. Prominent urinary metabolites after 2,4,6-TCP

administration in rats are other trichlorophenols. In at least one in vitro study, no evidence of dioxin precursors

was found.

After occupational exposure to chlorophenols in a lumber treatment facility, elimination rates were inversely

proportional to the degree of chlorination probably because of increased plasma protein binding with increased

chlorination. Elimination half-lives of 18 hours and 4.2 days were recorded for 2,4,6-TCP and 2,3,4,6-TeCP,

respectively. Elimination occurred according to a two-compartment open model. In rats orally administered

radiolabelled 2,4,6-TCP, 92.5% of the administered radioactivity appeared in the urine and 6.4% appeared in the

feces within 3 days after exposure cessation.

2.3.1 Absorption

Absorption of chlorophenols has not been studied in children.

2.3.1.l Inhalation Exposure

The identification of 2,4,6-TCP and 2,3,4,6-TeCP in the serum and urine of workers exposed while treating

lumber indicates that 2,4,6-TCP and 2,3,4,6-TeCP are absorbed through inhalation (Pekari et al. 1991). No
CHLOROPHENOLS 76

2. HEALTH EFFECTS

airborne chlorophenol concentrations were provided. Although inhalation exposure was possible, a study of

pullers at a timber mill (Fenske et al. 1987) suggests that 95% of the estimated exposure is by the dermal route.

No studies were located regarding the absorption of chlorophenols in animals after inhalation exposure to any of

the eight chlorophenol isomers discussed in this profile.

2.3.1.2 Oral Exposure

No studies were located regarding oral absorption in humans of any of the eight chlorophenol isomers

discussed in this profile. These isomers have moderately high lipophilicity and pKas >5.0; consequently,

intestinal ahsorption should be favored (Ambre 1990). Based on chemical properties and on limited animal data,

absorption through the gastrointestinal tract after oral intake in humans is expected to be both rapid and virtually

complete.

The animal data indicating rapid and complete absorption are based solely on studies reporting recovery of all or

most of the orally administered chlorophenols in the urine. Spencer and Williams (1950) recovered ≥100% of a

single oral dose of 2- or 4-CP (emulsified in water) given to rabbits. Five days after three daily gavage

treatments of rats with radiolabelled 2,4,6-TCP (vehicle not reported), 82.3% of the administered radioactivity

was recovered in the urine (Korte et al. 1978). In a 15-day study of 25 μg/day radiolabelled 2,4,6-TCP, 92% of

the administered radioactivity was recovered in the urine of the treated rats (Bahig et al. 1981).

2.3.1.3 Dermal Exposure

In vivo and in vitro data indicate that the chlorophenols are readily absorbed following dermal exposure. In an

industrial accident, 20 minutes after a worker was splashed with a pure solution of 2,4-DCP on less than 10% of

his body (arm and leg), he collapsed and shortly thereafter died (Kintz et al. 1992). Postmortem blood and urine

concentrations of 2,4-DCP were 24.3 and 5.3 mg/L, respectively. Using a fluorescent tracer, and measures of

urinary excretion of TeCP in lumber mill workers exposed to a wood preservative (20% TeCP, 3%

pentachlorophenol, <0.4% other CPs), Fenske et al. (1987) estimated that 30-100% of the 2,3,4,6-TeCP

deposited on the skin is absorbed. Absorption occurred through the hands and forearms despite the use of

chemical-resistant gloves. Fenske et al. (1987) also indicate that the skin regions with
CHLOROPHENOLS 77

2. HEALTH EFFECTS

greatest exposure, the hands and forearms, were in frequent contact with wood so that abrasion may have

reduced the barrier properties of the stratum corneum.

The results of diffusion experiments using hydrated human cadaver epidermis also indicate that the

chlorophenols readily cross the skin at low concentrations. The permeability coefficients determined in

excised human abdominal epidermis were 5 .5, 6.1, 10.0, and 9.9 cm miN- 1x104

 for 2-CP, 4-CP, 2,4-DCP, and

2,4,6-TCP (Roberts et al. 1977). 2-CP and 4-CP were reported to damage the skin, determined by an increase in

the permeability coefficient at aqueous concentrations of 0.8 and 0.75% (w/v), respectively, while no damage

was observed with 2,4-DCP and 2,4,6-TCP at concentrations up to saturation. In a study using abdominal skin

exposed to air, absorption of 2,3,4,6-TeCP over 24 hours was 33% from an aqueous medium (1.54% 2,3,4,6-

TeCP) and 63% from a diesel-oil-based medium (0.96 2,3,4,6-TeCP) (Horstman et al. 1989). These values were

determined by assuming that the amount of the applied dose that was not recovered from the skin’s surface was

the amount absorbed. The actual amounts recovered in the skin and receiving solutions were 9.5 and 3.9% for

the aqueous- and oil-based medium, respectively. The authors attribute low recovery to difficulties in extracting

2,3,4,6-TeCP from the skin.

Dermal absorption can be inferred from in vivo animal studies resulting in death and/or adverse systemic effects

following dermal exposure to 2-CP (Younger Labs 1975) and 2,4-DCP (Carreon et al. 1980a, 1980b; Hencke

and Lockwood 1978; Younger Labs 1976).

Chlorophenols are also readily permeable in rodent skin in vitro preparations. At solution pHs between 5.0 and

5.74, the apparent 2-CP, 2,4-DCP, and 2,4,6-TCP permeability constants for a hairless mouse skin preparation

over a concentration range of 0.05-0.5% varied from 0.14 to 0.36 cm/hour in whole skin and from 0.136 to

0.276 cm/hour in skin stripped of the stratum corneum (Huq et al. 1986). The investigators proposed that

permeability is probably greater in the more highly vascularized human tissue because the extensive network of

surface capillaries in humans reduces the thickness of the diffusional barrier. They further stated that dermally

absorbed phenolic compounds are potentially more toxic than orally absorbed compounds because Phase II

detoxification reactions are more rapid after oral exposure. In another in vitro diffusion study of 4-CP, 87.4 to

90.5% of the applied dose crossed rat epidermal preparations in 72 hours, indicating extensive absorption

(Hughes et al. 1993). Those phenols (both chlorophenols and other substituted phenols) with log Kow, values

between 1.4 and 3.5 showed the greatest amount of permeability through the dermal membrane. Although

specific data were not identified, dermal absorption of
CHLOROPHENOLS 78

2. HEALTH EFFECTS

chlorophenols should also be greater for the neutral acid form than for the phenolate anion as ions do not readily

cross cell membranes.

2.3.1.4 Other Routes of Exposure

No studies were located regarding absorption in humans exposed to any of the eight chlorophenol isomers by

other routes.

An experiment with rabbits indicated that 2,4,6-TCP is absorbed through the cornea to a minor degree

following ocular application (Ismail et al. 1977).

2.3.2 Distribution

Distribution of chlorophenols has not been studied in children.

2.3.2.1 Inhalation Exposure

No studies were located regarding the tissue distribution in humans or animals exposed by inhalation to any of

the eight chlorophenol isomers discussed in this profile.

2.3.2.2 Oral Exposure

No studies were located regarding the tissue distribution in humans exposed orally to any of the eight

chlorophenol isomers discussed in this profile.

Chlorophenols do not appear to accumulate in animals following oral exposure. For example, liver 2-CP

concentrations were 2.2,3.2, and 0.8 ppm, and kidney 2-CP concentrations were 2.6,2.4, and 2.2 ppm in female

rats exposed to 2-CP in the drinking water for 16 weeks at 5,50, and 500 ppm, respectively (Exon and Koller

1982). The investigators did not provide an explanation for the low value (0.8 ppm) found in the livers of rats

receiving the high dose and did not indicate whether these values were wet or dry weight concentrations.

Radioactivity was not recovered in the liver, lung, and subcutaneous fat of rats given three daily gavage doses of

radiolabelled 2,4,6-TCP (Korte et al. 1978) or in unspecified tissues of rats given radiolabelled 2,4,6-TCP by

gavage for 15 days (Bahig et al. 1981).
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2. HEALTH EFFECTS

The highest concentrations of 2,3,4,6-TeCP were found in the spleen followed by the kidneys and liver

24 hours after a single oral dose was given to rats (Hattula et al. 1981). In a 55day study in which rats were

treated by gavage with 2,3,4,6-TeCP at 10,50, or 100 mg/kg/day, tissue levels, measured 24 hours after the last

dose, were dose related. For all doses, the concentrations of 2,3,4,6-TeCP in the brain and muscle were lower

than those found in the kidney, liver, and spleen. At the 100 mg/kg/day dose, the kidney had the highest 2,3,4,6-

TeCP concentrations (5.1 ppm) followed by the spleen (3.2 ppm), liver (2.2 ppm), brain (1.2 ppm), and muscle

(0.46 ppm) (Hattula et al. 1981). At the 10 mg/kg/day dose, 2,3,4,6-TeCP was not detected in the brain or

muscle (detection limit not stated), while low levels were found in the spleen (0.04 ppm), kidney (0.03 ppm),

and liver (0.01 ppm).

2.3.2.3 Dermal Exposure

Concentrations of 2,4-DCP were 24.3, 5.3, 18.7, and 1.2 mg/L in the blood, urine, bile, and stomach contents of

a worker who collapsed (within 20 minutes) and died shortly after being splashed with pure 2,4-DCP on his

right arm and leg (Kintz et al. 1992).

No studies were located regarding the tissue distribution in animals dermally exposed to any of the eight

chlorophenol isomers discussed in this profile.

2.3.2.4 Other Routes of Exposure

A study in which laboratory animals were given intravenous 2,4-DCP provides some insight regarding

distribution patterns anticipated in humans (Somani and Khalique 1982). Intravenously administered

2,4-DCP rapidly distributes to the kidney, liver, fat, and brain in rats, with the highest concentrations in the

kidney and liver. Elimination from these tissues is also rapid; the elimination half-time for plasma is

approximately 10 minutes (Somani and Khalique 1982). The results of in vitro binding studies using human

serum proteins indicate that both 2,4-DCP and 2,4,6-TCP strongly bind to serum proteins, including albumin

and globulin (Judis 1982). The percentage of the compound bound to albumin was slightly greater for 2,4,6-TCP

(94.1%) than for 2,6-DCP (87.7%).

In rabbits, following ocular exposure, radiolabelled 2,4,6-TCP was distributed to various compartments of the

eye (Ismail et al. 1977). At 30 minutes post exposure, the applied radioactivity was detected in the cornea (4%),

aqueous humor (0.37%), lens (0.037%), iris (0.18%), choroid (0.04%), vitreous (0.01%), conjunctiva
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(2.14%), limbus (0.96%), and sclera (0.35%). At 60 minutes post exposure the respective percentages were 2.4,

0.17, 0.03, 0.10, 0.13, 0.01, 2.49, 0.88, and 0.53%.

Peak concentrations of 2,4,6-TCP were observed in all tissues assayed (blood, liver, kidney, muscle, fat, and

brain) 30 minutes after rats were given a single intraperitoneal injection of 25 mg/kg 2,4,6-TCP (Pekari et al.

1986). The highest concentration observed was in the kidneys, 329 ± 117 nmol/g tissue, a concentration

approximately 2, 7, 10, 13, and 26 times the concentrations found in the blood, liver, fat, muscle, and brain,

respectively.

2.3.3 Metabolism

Both human and animal studies indicate that sulfation and glucuronidation are the main metabolic pathways of

chlorophenols. Among sawmill workers, virtually all the absorbed tri- and tetrachlorophenols were excreted in

the urine as conjugated metabolites (Pekari et al. 1991). Sulfate conjugation was predominant.

A number of rabbit studies (Azouz et al. 1953; Bray et al. 1952a, 1952b; Spencer and Williams 1950) have

shown that metabolism of the monochlorophenols is principally via conjugation. In the latter study, groups of 6

rabbits were treated by gavage with 171.3 mg/kg of 2-CP or 4-CP emulsified in water as a single dose. For both

isomers, the 24-hour urine analysis indicated that between 78.1 and 88.3% of the administered dose was

excreted as the glucuronide, and between 12.8 and 20.6% of the administered dose was excreted as the ethereal

sulfate. A total of 101.7 and 101.1% of the administered 2-CP or 4-CP doses, respectively, was accounted for as

urinary glucuronide and sulfate conjugates. Metabolism was further investigated in 4 rabbits, each treated by

gavage with an average dose of 395 mg/kg/day of 4-CP. After 36 hours, 54.1% of the administered dose

appeared in the urine as the glucuronide conjugate, and 10.4% of the administered dose appeared in the ethereal

sulfate fraction. Only 0.1% of the administered dose was excreted as 4-chlorocatechol. The low total recovery

(64.5%) in the latter experiment limits conclusions. Other rabbit studies indicated that chlorocatechols

constituted only 1.5-4.5% of the administered doses of 300 mg/kg 2-CP or 500 mg/kg 4-CP (Azouz et al. 1953).

In a limited study in dogs (Coombs and Hele 1926) about half of an oral dose of 2- or 4-CP was excreted in the

urine as the ethereal sulphate. No evidence for metabolism to mercapturic acid was found.

In contrast to the study in dogs, Phornchirasilp et al. (1989a) has proposed that in mice 4-CP is metabolized by

P-450 enzymes to intermediates that react with glutathione to form glutathionyl adducts. This pathway
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was proposed based on the observation that 4-CP treatment of mice depleted liver thiol stores. The depletion of

liver thiol stores was prevented by a P-450 inhibitor (SKP 525-A) suggesting that P-450 activity is required for this

effect.

A study in rats found that glucuronides and other unspecified conjugates were formed following a single

intravenous dose of 2,4-DCP (10 mg/kg) (Somani and Khalique 1982). One hour after dosing, only small

amounts of 2,4-DCP were found in the tissues studied (plasma, liver, kidneys, fat, brain). Although other

unspecified conjugates were found in the fat, glucuronide conjugates were not found in the fat at any time

interval. Two minor metabolites of 2,4-DCP, both dichloromethoxy phenols, have been identified in studies

using isolated perfused rat livers (Somani et al. 1984). The extent to which the dichloromethoxy phenols are

formed in vivo has not been determined (Somani et al. 1984).

2,4-DCP has been shown to be metabolized into two major metabolites identified as 2-chloro-1,4-

hydroxyquinone and 2-chloro- 1,4-benzoquinone by microsomal fractions and whole cells of yeast

Saccharomyces cerevisiae expressing human cytochrome P-450 3A4 (Mehmood et al. 1997). Another

metabolite, 1,2,4-hydroxybenzene, was also detected during biotransformation by whole cells but was not

observed in microsomal fractions. Thus, human CYP3A4 can remove either or both chlorine atoms from the

aromatic ring of 2,4-DCP molecule, forming 2-chloro-1,4-hydroxyquinone and 1,2,4-hydroxybenzene,

respectively. 2-chloro-1,4-hydroxyquinone was probably acted on by dehydrogenase from yeast microsomes,

forming 2-chloro-1,4-benzoquinone (Mehmood et al. 1997).

Little information was located on the metabolism of trichlorophenols. In general, 2,4,6-TCP undergoes

biotic isomerization to other trichlorophenol isomers and conjugation with glucuronic acid (Bahig et al.

1981). Male rats eliminated 63% of a gavage dose of 2,4,6-TCP in the urine as 4 trichlorophenol isomers

and 28% as conjugates. Three of the trichlorophenol isomers were identified as 2,4,6-TCP (parent

compound), 2,3,6-TCP, and 2,4,5-TCP; the fourth isomer was not identified. Glucuronic acid accounts

for approximately 80% of the conjugates detected in urine (Bahig et al. 1981).

In vitro studies using rat liver microsomes have shown that 2,4,5-TCP can be metabolized to 3,4,6-trichlorocatechol,

2,5-dichlorohydroquinone, and a dihydroxydichlorobenzene (not further characterized) (Butte et al. 1988; Juhl et al.

1991). Metabolites were also dimerized to a dihydroxyhexachlorobiphenyl, a dihydroxypentachlorodiphenyl ether,

two hydroxypentachlorodiphenyl ethers, a hydoxyhexachlorodiphenyl ether, and a Hydroxyhexachlorodioxin or

hydroxyhexachlorodiphenoquinone (Butte et al. 1988). Metabolites generated following incubation
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of 2,4,6-TCP with rat liver S-9 fraction were 2,6-dichloro-1,4-hydroquinone and two isomers of

hydroxypentachlorodiphenyl ether (Juhl et al. 1989). The 2,6-dichloro-1,4-semiquinone free

radical was also identified. Although in vivo these metabolites may be minor, in vitro they were responsible for

DNA damage (Juhl et al. 1989, 199l).

Metabolism of 2,4,6-TCP by the skin has not been detected (Huq et al. 1986). Therefore, Huq et al. (1986) have

suggested that 2,4,6-TCP absorbed through the skin could be more toxic than a similar ingested dose because the

ingested compound is partially converted to glucuronide conjugates.

In a study in rats, a majority (70%) of intraperitoneally administered 2,4,6-TCP detected in the blood was in

conjugated form 30 minutes after dosing. The authors speculated that the chemical was conjugated with glucuronic

acid (Pekari et al. 1986). The average percentage of the metabolites of 2,4,6-TCP conjugated in the blood over the

course of the study was 83±11%.

A study of the metabolism of the TeCP isomers following intraperitoneal injection in rats, indicates that much of

the dose is excreted in the urine unchanged (Ahlborg and Larrson 1978). Following treatment with 2,3,4,5- and

2,3,4,6-TeCP, a trichlorohydroquinone was identified in the urine as a minor metabolite. Following treatment with

2,3,5,6-TeCP, about 35% of the recovered dose (total recovery 98.7%) was tetrachloro-p-hydroquinone, while the

remaining was the unchanged parent compound (Ahlborg and Larrson 1978).

Metabolism of chlorophenols has not been studied in children. In humans, activity of UDP-glucuronosyltransferase

(responsible for glucuronide conjugates) does not reach adult levels until about 6-8 months of age, although the

development of this activity is isoform specific. Activity of sulfotransferases (responsible for sulfate conjugates)

seems to develop earlier, although again, it is isoform specific. The activity of some sulfotransferase isoforms may

be greater than that of adults during infancy and early childhood (Leeder and Kearns 1997). Since chlorophenols

are detoxified in the liver by conjugation with glucuronic acid and sulfate, the toxicity of chlorophenols may be

different in children.

2.3.4 Excretion

Excretion of chlorophenols has not been studied in children.
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2.3.4.1 Inhalation Exposure

After occupational exposure by combined dermal and inhalation routes to a chlorophenol dipping solution,

maximal urinary concentrations were 1-11.8 μmol/L 3.4-17.3 μmol/L, and 0.2-0.9 μmol/L for tri-, tetra-, and

pentachlorophenol, respectively (Pekari et al. 1991). Elimination half-lives were 18 hours, 4.2 days, and 16

days, respectively. The renal clearance rate of 2,3,4,6-TeCP was approximately five times faster than the

clearance rate of pentachlorophenol; this finding reflects the increased plasma protein binding of the higher

chlorinated compound (Pekari et al. 1991). The clearance rate of 2,4,6-TCP could not be calculated because of

highly variable serum concentrations (Pekari et al. 1991).

No animal studies were located regarding the excretion of any of the eight chlorophenol isomers after

inhalation exposure.

2.3.4.2 Oral Exposure

The limited available data indicate that orally administered monochlorophenols are rapidly absorbed and

excreted in the urine, primarily as glucuronide and sulfate conjugates, in rats, rabbits, and dogs (Bray et al.

1952a, 1952b; Coombs and Hele 1926; Spencer and Williams 1950). Most of the administered dose is excreted

in the urine within 24 hours. More comprehensive data, including the kinetics of tissue uptake and distribution,

are limited to 4-CP (discussed below). Data are insufficient to identify differences in the excretion of

monochlorophenol isomers between animal species.

At oral doses of 150-450 mg/kg, excretion of the glucuronide conjugate of orally administered 4-CP in

rabbits followed first-order kinetics (Bray et al. 1952a). The velocity constant kg, or the rate of glucuronide

excretion relative to remaining body burden, was 0.41 hour-1. The investigators noted that the value of kg for 4-

CP is apparently not related to the electron withdrawing influence of the substituent group (Bray et al.1952a).

Male rats administered radiolabelled 2,4,6-TCP by gavage for 3 days and observed for 5 days after dosing

eliminated a total of 82.3% of the total dose in the urine and 22.2% in the feces (Korte et al. 1978). In a second

study using male rats, radiolabelled 2,4,6-TCP was administered by gavage for 15 days, with sacrifice 3 days

after administration ended. A total of 92.5% of the administered dose was excreted in the urine, and 6.4% was

excreted unchanged in the feces (Bahig et al. 1981). Four trichlorophenol isomers
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were detected in the urine and comprised 63% of the total urinary radioactivity. These isomers were the

unchanged parent compounds, 2,3,6-TCP, 2,4,5-TCP, and an unidentified compound. The metabolites identified

in the polar fraction were trichlorophenol conjugates with glucuronic acid; these products accounted for 28% of

the radioactivity eliminated in the urine (Bahig et al. 1981). Free trichlorophenol was identified in the feces. The

excretion of radioactivity declined rapidly after dosing ended. By the third day postexposure, only 4.3% of the

radioactivity in a daily dose was detected in the urine and 1.9% was detected in the feces (Bahig et al.1981).

2.3.4.3 Dermal Exposure

As discussed in Section 2.3.4.1, combined dermal and inhalation exposure to a chlorophenol-containing wood

treatment solution resulted in the urinary excretion of tri-, tetra-, and pentachlorophenol. Rate constants of

elimination were inversely proportional to the extent of chlorination (Pekari et al. 1991).

No animal studies were located regarding the excretion of any of the eight chlorophenol isomers after dermal

exposure.

2.3.4.4 Other Routes of Exposure

A study in rats showed rapid clearance from the kidney, liver, fat, brain, and plasma of both the parent

compound and metabolites after intravenous administration of 10 mg/kg/day 2,4-DCP in an aqueous solution

(Somani and Khalique 1982). Half-lives for 2,4-DCP and its conjugates ranged from 4 to 30 minutes in these

tissues, with the highest values in kidney, followed by the liver, fat, plasma, and brain (Somani and Khalique

1982). No detectable amounts were found in the brain at 60 minutes. These data suggest that 2,4-DCP does not

accumulate in body tissues and is quickly excreted.

In rats administered 2,4,6-TCP by intraperitoneal injection, the majority (70%) of 2,4,6-TCP associated

radioactivity detected in the blood 30 minutes after dosing was in a conjugated form (Pekari et al. 1986). The

authors speculated that it was conjugated with glucuronic acid. The biological half-life of conjugated 2,4,6-TCP

was 1.4 hours in blood and ranged from 1.4 to 1.8 hours in other tissues. Elimination of approximately 90% of

the administered dose in the urine occurred within 4-6 hours. Only trace amounts of trichlorophenol were

detected in tissues 10 hours after dosing (Pekari et al. 1986).
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Ahlborg and Larrson (1978) studied the urinary excretion of TeCPs in rats following intraperitoneal injection of a

single dose. The slowest rate of excretion was observed following treatment with 2,3,4,5-TeCP. During the 72

hours after administration, about 60% of the dose was recovered in the urine; the majority of it was excreted

unchanged. In contrast, following treatment with 2,3,4,6-TeCP, 95.9% of the dose was excreted in the urine in 72

hours, and 98.7% of the administered 2,3,5,6-TeCP was excreted in the urine within 24 hours after dosing. The

investigators (Ahlborg and Larsson 1978) did not provide an explanation regarding the slower excretion of 2,3,4,5-

TeCP compared to the excretion of 2,3,4,6-TeCP and 2,3,5,6-TeCP.

2.3.5 Physiologically based Pharmacokinetic (PBPK)/Pharmacodynamic (PD) Models

Physiologically based pharmacokinetic (PBPK) models use mathematical descriptions of the uptake and

disposition of chemical substances to quantitatively describe the relationships among critical biological processes

(Krishnan et al. 1994). PBPK models are also called biologically based tissue dosimetry models. PBPK models are

increasingly used in risk assessments, primarily to predict the concentration of potentially toxic moieties of a

chemical that will be delivered to any given target tissue following various combinations of route, dose level, and

test species (Clewell and Andersen 1985). Physiologically based pharmacodynamic (PBPD) models use

mathematical descriptions of the dose-response function to quantitatively describe the relationship between target

tissue dose and toxic end points.

PBPK/PD models refine our understanding of complex quantitative dose behaviors by helping to delineate

and characterize the relationships between: (1) the external/exposure concentration and target tissue dose of

the toxic moiety, and (2) the target tissue dose and observed responses (Andersen et al. 1987; Andersen and

Krishnan 1994). These models are biologically and mechanistically based and can be used to extrapolate the

pharmacokinetic behavior of chemical substances from high to low dose, from route to route, between

species, and between subpopulations within a species. The biological basis of PBPK models results in more

meaningful extrapolations than those generated with the more conventional use of uncertainty factors.

The PBPK model for a chemical substance is developed in four interconnected steps: (1) model

representation, (2) model parametrization, (3) model simulation, and (4) model validation (Krishnan and

Andersen 1994). In the early 1990s, validated PBPK models were developed for a number of

toxicologically important chemical substances, both volatile and nonvolatile (Krishnan and Andersen 1994;

Leung 1993). PBPK models for a particular substance require estimates of the chemical substance-specific

physicochemical parameters, and species-specific physiological and biological parameters. The numerical
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estimates of these model parameters are incorporated within a set of differential and algebraic equations that

describe the pharmacokinetic processes. Solving these differential and algebraic equations provides the predictions

of tissue dose. Computers then provide process simulations based on these solutions.

The structure and mathematical expressions used in PBPK models significantly simplify the true complexities of

biological systems. If the uptake and disposition of the chemical substance(s) is adequately described, however,

this simplification is desirable because data are often unavailable for many biological processes. A simplified

scheme reduces the magnitude of cumulative uncertainty. The adequacy of the model is, therefore, of great

importance, and model validation is essential to the use of PBPK models in risk assessment.

PBPK models improve the pharmacokinetic extrapolations used in risk assessments that identify the maximal (i.e.,

the safe) levels for human exposure to chemical substances (Andersen and Krishnan 1994). PBPK models provide

a scientifically-sound means to predict the target tissue dose of chemicals in humans who are exposed to

environmental levels (for example, levels that might occur at hazardous waste sites) based on the results of studies

where doses were higher or were administered in different species. Figure 2-3 shows a conceptualized

representation of a PBPK model.

If PBPK models for chlorophenols exist, the overall results and individual models are discussed in this

section in terms of their use in risk assessment, tissue dosimetry, and dose, route, and species extrapolations.

There are no PBPK models for chlorophenols.

2.4 MECHANISMS OF ACTION

2.4.1 Pharmacokinetic Mechanisms

Chlorophenols have moderately high lipophilicity. They are weak organic acids with pKa values that range from

5.4 to 8.9 (Shiu et al. 1994); consequently, absorption should be favored in the stomach and the intestine.

Absorption through the gastrointestinal tract is by simple diffusion and is expected to be both rapid and virtually

complete. The chlorophenols are also readily absorbed after dermal exposure. Dermal absorption should also be

greater for the neutral acid form than for the phenolate anion as ions do not readily cross cell membranes. Dermally

absorbed doses of chlorophenols are potentially more toxic than orally absorbed doses (Huq et al. 1986). The

chlorophenols were not metabolized or conjugated during

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their diffusive transport through the skin (Huq et al. 1986); however, they are partially converted to more easily

eliminated, less toxic glucuronide conjugates after oral ingestions.

After a single oral dose of 2,3,4,6-TeCP to rats, the kidney had the highest tissue concentration, followed by the

spleen, liver, brain, and muscle (Hattula et al. 1981). When administered intravenously to rats, 2,4-DCP rapidly

distributes to the kidney, liver, fat, and brain, with the highest concentrations in the kidney and liver (Somani

and Khalique 1982). 2,4-DCP and 2,4,6-TCP strongly bind to serum proteins, including albumin and globulin

(Judis 1982).

2.4.2 Mechanisms of Toxicity

Chlorophenols uncouple mitochondrial oxidative phosphorylation and produce convulsions. Within

20 minutes of being accidentally splashed with 2,4-DCP on his right arm and leg, a worker experienced seizures,

collapsed, and died shortly thereafter (Kintz et al. 1992). Lethargy, tremors, convulsions, and/or central nervous

system depression have been reported in chlorophenol-exposed animals (Borzelleca et al. 1985a; Deichmann

and Mergard 1948). Within the series including phenols and chlorinated phenols, convulsive effects decreased

with increasing chlorination. Limited data were located on the mechanism of phenol- or chlorophenol-induced

convulsions. Phenol administration in cats facilitated effects on central synaptic transmission at both excitatory

and inhibitory synapses (Banna and Jabbur 1970). The authors proposed that certain phenols increase the

amount of neurotransmitter released during synaptic transmission, resulting in convulsions. After intraperitoneal

injection of several chlorophenols, convulsions predominated in those mice receiving the 2- and 4-CP

compounds (Farquh&son et al. 1958). Because these compounds have pK values of 8.65 or higher and would

not be in the ionic form at physiologic pH, the investigators attributed the observed effect to the chlorophenol

rather than to the ion.

Particularly for the higher chlorophenols, the primary toxic mechanism associated with exposure is the

uncoupling of mitochondrial oxidative phosphorylation (Farquharson et al. 1958; Weinbach and Garbus 1965).

Although the kinetics of chlorophenol-induced uncoupling have primarily been studied in in vitro mitochondrial

preparations, the associated metabolic effects (such as increased body temperature and dyspnea) have been

verified in vivo (Farquharson et al. 1958). The ability of chlorophenols to uncouple oxidative phosphorylation

increases with increasing chlorination. Toxic manifestations include central nervous system depression followed

by increased respiration, hyperthermia, a blood pressure rise, progressive euromuscular weakness, and cyanosis.

The results of a number of in vitro studies (Cascorbi and Ahlers
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1989; Izushi et al. 1988; Mitsuda et al. 1963; Narasimhan et al. 1992; Shannon et al. 1991; Stockdale and

Selwyn 1971) indicate a concentration-dependent triphasic effect of chlorophenols on phosphorylation and

cellular respiration. At low concentrations, uncoupling produces stimulation of state 4 (resting state) respiration

as a result of increased adenosine triphosphatase (ATPase) activity in the absence of a phosphate acceptor.

Inhibition of state 3 (active) respiration is also observed. At moderate concentrations, resting respiration is

neither stimulated nor inhibited. Significant inhibition of respiration, associated with a breakdown of the

electron transport process and decreased ATPase activity, occurs at very high concentrations. These

concentrations are also associated with mitochondrial swelling and disruption of the mitochondrial matrix

structure. Investigators have cited two independent mechanisms to explain these effects on cellular metabolism.

Uncoupling activity has been attributed to a protonophoric effect (a disruption of the energy gradient across the

mitochondrial membrane resulting from distribution of chlorophenols in the phospholipid bilayer of the

membrane), whereas inhibition of cellular respiration has been attributed to a direct action on intracellular

proteins.

The results of these and other studies also illustrate that higher order chlorophenols have the greatest effects on

cellular metabolism. In general, investigators have found that 2-CP and 4-CP are less than 7% as potent as

tetrachlorophenol in uncoupling oxidative phosphorylation and inhibiting cellular respiration (Cascorbi and

Ahlers 1989; Janik and Wolf 1992; Narasimhan et al. 1992; Weinbach and Garbus 1965). Within the

chlorophenol series, two physicochemical parameters, the a-Hammett constant, a measure of electron

withdrawing ability, and the octanol-water partition coefficient (log Kow), accounted for 98% of the variability in

the inhibition of ATPase activity (Cascorbi and Ahlers 1989).

Corrosive skin damage resulting from high concentration phenol exposure has been attributed to protein

denaturation by protein-solute complexes (Roberts et al. 1977). In this study, various concentrations of 2-CP and

4-CP were applied to samples of human abdominal skin maintained in a diffusion chamber. The estimated

threshold concentrations for damage (the aqueous concentration at which the transmembrane permeability

coefficient began to increase) were 0.8% and 0.75%, respectively, for these two isomers. The investigators

proposed that the extent of damage was related to the concentration of the solute partitioned into the stratum

corneum, the diffusivity of the solute, and the pK of the applied phenolic compound.

In a study in rats, Kitchin and Brown (1988) examined the effects of single gavage doses of 2,4,5-TCP, 2,4,6-

TCP, and 2,3,4,6-TeCP on markers of carcinogenic initiation (alkaline elution for DNA damage in liver and

blood), promotion of carcinogenesis (ornithine decarboxylase activity in the liver), and hepatic cell damage
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(serum alanine aminotransferase [SGPT] activity). At a dose one-fifth the LD50 (164 mg/kg for 2,4,5 and 2,4,6-

TCP; 28 mg/kg for 2,3,4,6-TeCP), no effects were observed. 2,4,6-TCP and 2,3,4,6-TeCP were also tested at

higher equimolar concentrations (2,4,6-TCP, 500 mg/kg; 2,3,4,6-TeCP, 193 mg/kg). At the high dose, both

compounds resulted in a significant increase in liver ornithine decarboxylase activity. No effects on alkaline

elution of DNA or on SGPT activity were observed, suggesting that 2,4,6-TCP and 2,3,4,6-TeCP were weak

promoters.

2.4.3 Animal-to-Human Extrapolations

Extrapolating animal toxicity data to predict human risk from chlorophenol exposure appears to be

reasonable because of the similarity in metabolic pathways and effects. However, the one case of human death

following dermal exposure indicates that animals may be more resistant to the toxic effects of 2,4-

dichlorophonol than humans.

2.5 RELEVANCE TO PUBLIC HEALTH

Issues relevant to children are explicitly discussed in 2.6 Children’s Susceptibility and 5.6 Exposures of

Children.

Overview.

Chlorophenols are used as intermediates in the production of dyes and chlorinated pesticides. Because of its

biocidal properties, 4-CP is also used as a dental antiseptic. Runoff from pesticide degradation, contaminated

food intake, and the chlorination of both drinking water and waste water are the environmental sources of

human exposure to chlorophenols. A chlorophenol-containing waste site may result in groundwater

contamination with subsequent introduction into the drinking water supplies. Dermal exposure can occur in

occupational settings. Much lower levels of dermal exposure can occur through showering and bathing with

water containing chlorophenols. In addition, the environmental dechlorination of the higher chlorophenols can

result in exposure to the lower chlorophenols.

Exposed pesticide production workers may be at increased risk for soft tissue sarcoma, Hodgkin’s disease, and

non-Hodgkin’s lymphoma. Although these results have been found in several occupational studies, the majority

of studies find no, or only slightly, increased cancer risk associated with exposure. Possible
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confounding variables in the positive studies included recall and selection bias. Another major health

concern in workers is the development of chloracne, which is probably attributable to the presence of other

chlorinated dioxins as contaminants in CP-containing pesticides.

The results of animal studies partially support the human data. 2,4,6-TCP was a carcinogen in 2-year rat and

mouse studies. Other studies suggest that chlorophenols, rather than being initiators, may be tumor promoters.

This is supported by genotoxicity data that suggest that the chlorophenols are not directly mutagenic. The EPA

has classified 2,4,6-TCP as a class B2 carcinogen. Hepatic effects, ranging from enzyme induction to

generalized necrosis, are also found in animals. Although 2,4-DCP has been shown to effect cell-mediated

immunity in laboratory studies, the toxicological relevance of this finding to individuals exposed near hazardous

waste sites is unknown. The higher chlorinated phenols have shown equivocal reproductive and developmental

effects only at doses producing maternal toxicity. These findings indicate a possible concern for pregnant

women exposed in the workplace or through contaminated environmental media. Observations of corrosion and

death after skin application of high doses of chlorophenols reinforces the dermal health hazard concern for

workers.

Minimal Risk Levels for Chlorophenols

Exposures to chlorophenols at hazardous waste sites are most likely to be to a mixture of chlorophenols rather

than to a single compound. Unfortunately, no information regarding effects following exposure to a mixture of

chlorophenols was identified. As a conservative approach, duration-specific MRLs for the chlorophenols as a

class were developed based on the single compound with the lowest LOAEL and, therefore, should protect

against effects following exposure to all chlorophenols as well as exposure to mixtures of chlorophenols if

effects of multiple chlorophenols are additive.

Inhalation

The inhalation data for chlorophenols is limited to a single acute study of 2-CP in which rats were exposed

(nose-only) to 17, 104, or 908 ppm for 4 hours (Duchosal and Biederman 1991). Restlessness and hunched

posture were observed at the high concentration. Dark red foci were observed at the two lower concentrations.
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but not at the high concentration. No controls were used in this study. Because of the lack of a clear

doseresponse relationship and the absence of controls, this study was not considered appropriate for the

derivation of an inhalation MRL.

Oral

• An MRL of 0.01 mg/kg/day has been derived for acute-duration oral exposure to chlorophenols. This MRL

is based on electron microscopic changes (foamy cytoplasm and clustering of rnitochondria and

endoplasmic reticulum) observed in the hepatocytes of rats treated with 4-CP at 2.58 mg/kg/day but not at

1.28 mg/kg/day (Phornchirasilp et al. 1989b). The rats were treated by gavage two times per day with the 4-

CP in corn oil. There are no additional studies that examine liver effect following oral exposure to 4-CP.

• An MRL of 0.003 mg/kg/day has been derived for intermediate-duration oral exposure to chlorophenols.

This MRL is based on a decrease in delayed type hypersensitivity observed in rats treated with 2,4-DCP in

the drinking water throughout gestation and 10 weeks after weaning at 3 mg/kg/day but not at 0.3

mg/kg/day (Exon and Keller 1985; Exon et al. 1984).

Chronic

No chronic duration oral MRLs were derived for any of the chlorophenols because the NOAELs identified in

the chronic studies were greater than LOAELs identified in the intermediate duration studies.

Death. No data were found on death following inhalation or ingestion of chlorophenols. The only report of

death in humans following exposure to chlorophenols is a single case in which a man died shortly after being

splashed on less than 10% of his body with 2,4-DCP (Kintz et al. 1992). Postmortem blood and urine

concentrations were 24.3 and 5.3 mg/L, respectively. Most data from acute inhalation, oral, and dermal lethality

animal studies suggest that chlorophenols are lethal only at high exposure levels. Acute lethality generally

occurs at oral doses greater than 100 mg/kg (Ahlborg and Larsson 1978; Bercz et al. 1990; Blackburn et al.

1986; Borzelleca et al. 1985a, 1985b; Carreon et al. 1980a; Kobayashi et al. 1972; NTP 1989; Rodwell et al.

1989). The range of oral LD50 values, 89 mg/kg for male mice treated with 2,3,5,6- TeCP in ethanol (Ahlborg

and Larsson 1978) to 2,960 mg/kg for male rats treated with 2,4,5-TCP in corn oil (McCollister et al. 1961),

indicates that the chlorophenols are slightly or moderately toxic according to the
CHLOROPHENOLS 93

2. HEALTH EFFECTS

classification scheme of Hodge and Sterner (1949). The use of different vehicles in oral studies makes it difficult

to draw any conclusions about which of the chlorophenols are the most toxic. For example, in studies of the

TeCPs, oral LD50s in rats were lower when the compounds were given in 40% ethanol rather than propylene

glycol (Ahlborg and Larssen 1978).

More limited dermal LD50 data indicate a range of 485 mg/kg for 2,3,4,6-TeCP in rats (Shen et al. 1983) to

1,414 mg/kg/day for 2,4-DCP in rabbits (Carreon et al. 1980b). The range of LD50s following intraperitoneal

injection exposure was 48 mg/kg for 2,3,5,6-TeCP given to mice in 40% ethanol (Ahlborg and Larsson 1978) to

430 mg/kg for 2,4-DCP given to rats in olive oil (Farquharson et al. 1958).

Typical signs of severe acute intoxication include ataxia, fatigue, disorientation, tachycardia, and increased

respiratory rate followed by dyspnea, myoclonic convulsions, and coma (Borzelleca et al. 1985a, 1985b;

Farquharson et al. 1958; Kobayashi et al. 1972). Convulsions are a diagnostic feature of intoxication with

certain phenolic compounds, including the lower chlorinated phenols. The mechanism of action of this effect is

poorly understood. Furthermore, an adequate dose-response relationship for this end point has not been

established. Convulsions have been reported after both oral and dermal administration, indicating that the effect

is not route specific.

Given the high doses of chlorophenols required to produce death in laboratory animals, death in humans

exposed through contaminated drinking water is unlikely. The taste and odor thresholds of the chlorophenols,

which are in the ppb range (Burttschell et al. 1959), would make the likelihood of intoxication via drinking

water quite remote because of the unpleasant taste and odor of the contaminated water. In the occupational

setting, exposure to more highly concentrated chlorophenols could result in death following inhalation, oral, or

dermal exposure as suggested by the case report by Kintz et al. (1992).

Systemic Effects. No data regarding the systemic toxicological effects of exposure to chlorophenols in

humans, in isolation from other contaminants, were located in the literature. The discussion provided below will

describe systemic effects in humans occupationally exposed to a variety of airborne contaminants (including

chlorophenols), laboratory animal studies, and supporting data.

Respiratory Effects. In a small cross-sectional study on workers involved in 2,4,5,-TCP production, no

adverse effects on pulmonary function or the incidence of pulmonary lesions were observed (Calvert et al.

1991). Lumber mill workers exposed to a mixture of tetrachlorophenols (specific isomers not stated) and
CHLOROPHENOLS 94

2. HEALTH EFFECTS

pentachlorophenol reported upper respiratory tract irritation more frequently than unexposed workers

(Kleinman et al. 1986). Acute inhalation exposure of laboratory animals to monochlorophenols has resulted in

hemorrhage in the lungs and tachypnea (Duchosal and Biedermann 1991). Rats and mice exposed to high oral

doses of 2,4-DCP or 2,4,6-TCP had no adverse effects on lung weight or histopathology (Bercz et al. 1990;

Blackburn et al. 1986; NCI 1979; NTP 1989).

The limited data are insufficient to predict the respiratory response of humans exposed either acutely or chronically

to chlorophenols.

Cardiovascular Effects. No studies were located regarding cardiovascular effects in humans after exposure by any

route to any of the eight chlorophenols discussed in this profile. Animal studies have not reported histological

changes in the heart following exposure to 2,4-DCP, 2,4,5-TCP, or 2,4,6-TCP (Bercz et al 1990; Blackburn et al.

1986; NCI 1979; NTP 1989), providing limited evidence that these compounds are not cardiovascular toxicants.

Gastrointestinal Effects. Symptomology of gastrointestinal effects has not been reported in production

workers exposed to trichlorophenols and other chlorinated organics (Calvert et al. 1992). Single gavage doses of

432 mg/kg or more 2,3,4,6-TeCP has produced intestinal cell necrosis in rats (Hattula et al. 1981). The results of

other animal studies, however, did not indicate damage to the intestinal tract after exposure to large oral doses of

chlorophenols (NCI 1979; NTP 1989).

Hematological Effects. Adequate data for the assessment of hematological effects in chlorophenol-exposed

humans were not located. Results from oral acute- to chronic-duration animal studies indicate that 2-CP has no

adverse effects on standard hematological end points at doses up to 50 mg/kg/day (Borzelleca et al. 1985a; Exon

and Koller 1985). Consequently, under the conditions of these studies, the hematological system does not appear to

be a target organ at moderately high exposure concentrations.

Results of chronic oral studies in rats indicate that various hematopoietic effects, such as bone marrow

atrophy, hyperplasia, and leukocytosis, occur in rats exposed chronically to 500 mg/kg/day or more 2,4-DCP or

2,4,6-TCP (NCI 1979; NTP 1989). Furthermore, the results of the NCI (1979) studies indicate that 2,4,6- TCP is

associated with an increased incidence of leukemia in rats.
CHLOROPHENOLS 95

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Musculoskeletal Effects. No studies were located regarding musculoskeletal effects in humans.

Intermediate and chronic oral exposure of animals to 2,4-DCP (NTP 1989) or 2,3,4,6-TeCP (Hattula et al. 1981)

did not result in any histopathologic changes in muscle.

Hepatic Effects. Chlorophenol-exposed manufacturing workers have been diagnosed with porphyria,

elevated serum transaminase levels, regenerative hepatocellular activity, and hemofuscin deposition (Bleiberg et al.

1964). In another group of production workers, elevated GGT activity has been associated with an interaction

between 2,4,5-TCP exposure and alcohol consumption (Calvert et al. 1992). These data indicate a concern for

hepatic effects in individuals exposed to chlorophenols.

Acute exposure concentrations of up to 69 mg/kg/day 2-CP for 14 days in mice produced no changes in hepatic

microsomal P-450 enzyme levels (Borzelleca et al. 1985a). In contrast, 2-week administration of 0.64 mg/kg/day 4-

CP in Sprague-Dawley rats increased microsomal demethylase activities, microsomal protein, and cytochrome P450 content (Phornchirasilp et al. 1989a). Electron microscopic changes in hepatocytes (foamy cytoplasm,

clustering of mitochondria and endoplasmic reticulum) occurred at ≥ 2.58 mg/kg/day, and 1.28 mg/kg/day was

considered a NOAEL. The discrepancies in results between these two studies may be related to species differences

but is most likely due to a 10-fold difference in test material volume measured on a body weight basis.

Animal data regarding the hepatic effects of the higher chlorinated phenols are conflicting. Mouse studies

indicate that chronic exposure to 2,4-DCP is associated with liver necrosis (NTP 1989). There is

inconclusive evidence that 2,4-DCP causes hepatocellular hyperplasia in rats and mice and diffuse

syncytial alterations in mice exposed for long periods. A possible mechanism for the observed diffuse

syncytial alterations was demonstrated in an in vitro study (Onfelt 1987) in which 2,4-DCP interfered with

normal cell division by disrupting spindle formation. Interference of 2,4-DCP with oxidative

phosphorylation, as demonstrated in an in vitro study with isolated mitochondria (Stockdale and Selwyn

1971), may be a mechanism for any or all of these liver effects since it can deplete the energy stores

available to affected cells.

Hepatic effects observed in rats and mice following intermediate and chronic oral exposure to 2,4,6-TCP

include alterations in hepatocytes, increased liver weight, and hepatic hyperplasia (Exon and Koller 1985;

NCI 1979). The latter effect may possibly be a precursor to hepatic adenomas and carcinomas also

observed in mice chronically exposed to 2,4,6-TCP (NCI 1979). Exposure to mid- to high-oral doses of

2,4,6-TCP has resulted in increased relative liver weights (Bercz et al. 1990; NCI 1979) and midzonal
CHLOROPHENOLS 96

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vacuolation of hepatocytes (NCI 1979). In intermediate-duration oral studies, administration of as low as 50

mg/kg/day was associated with massive hepatocellular necrosis and venous thrombosis in l/10 rats (Hattula et al.

1981).

The mechanism for the observed hepatic alterations is difficult to determine. Various hepatic microsomal drugmetabolizing enzymes were not induced in an acute study in which rats were given several intraperitoneal

injections of 2,4,6-TCP (Denomme et al. 1983). Acute oral dosing with as much as 400 mg/kg had no effect on

enzyme activities and protein levels that are indicative of either increased metabolic activity or hepatotoxicity

(Carlson 1978). Hepatic ornithine decarboxylase activity, a potential marker of tumor promoting capabilities, was

elevated over control levels only after administration of lethal doses of 2,4,6-TCP or 2,3,4,6-TeCP (Kitchin and

Brown 1988). Despite the inability to specifically ascertain the mechanistic basis of observed hepatotoxic effects,

the available in vivo data are adequate to indicate that individuals exposed to sufficient levels of chlorophenols near

hazardous waste sites are potentially at risk for liver effects ranging from increased enzyme activity to generalized

necrosis.

Renal Effects. No data on the renal effects of chlorophenols in humans were located. In animal studies, either no or

mild renal effects are evident at oral exposure levels of 720-2,600 mg/kg/day (Bercz et al. 1990; Blackburn et al.

1986; NCI 1979; NTP 1989). Renal tubular necrosis occurred only at lethal exposure concentrations (NTP 1989).

The current data suggest that renal toxicity may only occur at doses unlikely in occupational or environmental

settings.

Endocrine Effects. There are no reports of endocrine effects in humans occupationally exposed to chlorophenols.

Histopathological changes have not been observed in endocrine glands (adrenal gland, pituitary, thyroid,

parathyroids, pancreas) in animals exposed to chlorophenols for intermediate and chronic durations, providing

limited evidence that endocrine glands are not a target of chlorophenol toxicity (American Biogenics 1988; Bercz

et al. 1990; Blackburn et al. 1986; McCollister et al. 1961; NCI 1979; NTP 1989). An in vitro study examining the

binding of chlorophenols to human transthyretin (a carrier of thyroid hormone) found that increasing chlorination

resulted in greater affinity for the thyroxine (T4) binding site of the carrier (van den Berg 1990). The affinities of 2-

CP, 2,4,5-TCP, and 2,4,6-TCP compared to T4 were 0.004, 0.15, and 0.33, respectively. Tetrachlorophenols were

not tested. Based on the results of this in vitro study, van den Berg (1990) suggests that chlorophenols may reduce

plasma T4 levels through competition with T4 binding on transthyretin and other T4 carriers (e.g., thyroid binding

globulin, albumin).
CHLOROPHENOLS 97

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Dermal Effects. Chloracne and evidence of acquired porphyria cutanea tarda, hyperpigmentation, and

hirsutism have been observed in factory workers who were concurrently exposed to chlorophenols in

phenoxy-based herbicides and, potentially, to dioxins (TCDD) (Bleiberg et al. 1964; Bond et al. 1989). In at

least one study, chloracne incidence was positively correlated with TCDD exposure (Bond et al. 1989). The

results of dermal studies with rats and rabbits indicate that chlorophenols can produce various effects, ranging

from mild erythema to severe corrosion of the skin (Bioassay Systems 1981; Carreon et al. 1980a, 1980b;

Hencke and Lockwood 1978; Rhodia 1978; Shen et al. 1983). The reports describing dermal effects are very

limited and do not provide details of the effects observed; additionally, dose-response relationships are not

clearly defined. The lowest dose resulting in direct dermal effects was 242 mg/kg/day 2-CP applied to the skin

of rabbits (Bioassay Systems 1981).

Dermal exposure may be a special concern because wood treatment workers had measurable tetrachlorophenol

levels on the hands and volar surface of the forearm, despite the use of gloves when handling timber (Fenske et

al. 1987).

Ocular Effects. Eye irritation was reported among lumber mill workers exposed to a mixture of

tetrachlorophenols (specific isomers not stated) and pentachlorophenol (Kleinman et al. 1986). The eye irritation

was likely a direct effect of the tetrachlorophenols. The results of ocular toxicity studies in rabbits indicate that

2-CP concentrations as low as 1% can result in mild hyperemia (Rhodia 1978). The extent of tissue damage is

concentration-related. Application of a 2% solution resulted in severe hyperemia with edema and cloudy

swelling (Rhodia 1978), while administration of undiluted 2-CP produced edema with severe tissue erythema

and corrosion (Younger Labs 1975). Severe cornea1 damage in rabbits occurred after the direct application of

0.1 mL 2,4-DCP in the eye (Hencke and Lockwood 1978). Consequently, moderately high vapor concentrations

of 2-CP, 2,4-DCP, and possibly other chlorophenols in industry or at hazardous waste sites have the potential to

produce ocular irritation and/or damage in unprotected individuals.

Body Weight Effects. Effects on body weight have not been reported in humans occupationally exposed to

chlorophenols. Body weight loss has been observed in animals exposed to chlorophenols following acute,

intermediate, and chronic duration exposure (American Biogenics 1988; Borzelleca et al. 1985a; Kavlock 1990;

McCollister et al. 1961; NCI 1979; NTP 1989; Rodwell et al. 1989). When chlorophenols are administered in

the diet, changes in body weight may be in part a result of decreased food intake because of reduced palatability

(NTP 1989), although body weight decreases have also been observed following gavage administration

(American Biogenics 1988). The lowest dose associated with body weight decrease was
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2. HEALTH EFFECTS

20 mg 2,3,4,6-TeCP given to rats by gavage for 90 days (American Biogenics 1988). The observation that a TeCP

has the greatest effect on body weight is consistent with the observation that TeCPs are more potent in uncoupling

oxidative phosphorylation than the monochlorophenols (Cascorbi and Ahlers 1989; Narasimhan et al. 1992).

Immunological and Lymphoreticular Effects. No human data were located regarding immunological or

lymphoreticular effects of chlorophenols. The results of one animal study indicate that neither humoral nor cellmediated immunity is affected by oral exposure to 2-CP at doses up to 50 mg/kg/day (Exon and Koller 1985). In

contrast, combined pre- and postnatal exposure to 2,4-DCP at 3 mg/kg/day both stimulated antibody production

and inhibited a delayed type hypersensitivity response (Exon and Koller 1985). Combined pre- and postnatal

exposure to 2,4,6-TCP in drinking water at doses up to 30 mg/kg/day did not significantly affect humoral or cellmediated immunity in rats (Exon and Koller 1985). As discussed under hematological effects, bone marrow

atrophy affecting both erythroid and myeloid elements has been observed in rats treated with 2,4-DCP in the diet at

500 mg/kg/day for 13 weeks (NTP 1989). Histological examination of lymph nodes, spleen, and thymus in

chlorophenol-exposed animals has not revealed any effects in intermediate and chronic duration studies

(McCollister et al. 1961; NCI 1979; NTP 1989).

Because of limited animal data and knowledge regarding the toxicological significance of many immunological

findings, the relevance to public health of immunological effects following exposure to the chlorophenols cannot

be determined specifically. However, animal evidence indicates that 2,4-DCP may have an effect on the immune

system.

Neurological Effects. Lumber mill workers exposed to a mixture of tetrachlorophenols (specific isomers not

stated) and pentachlorophenol reported headaches more frequently than unexposed workers (Kleinman et al. 1986).

In animals exposed to chlorophenols by the inhalation, oral, or dermal routes, convulsions (a sign of exposure to

high doses of some phenolic compounds) decrease with increasing chlorination. In oral and dermal acute lethality

studies, convulsions were noted only as antecedents of death (Borzelleca et al. 1985a, 1985b; Deichmann and

Mergard 1948). Consequently, adequate information about dose-response relationships or isomeric potencies were

not determined. The mechanisms for these effects are not known, although interference with oxidative energy

metabolism in the central nervous system has been suggested, based on in vitro studies with rat brain and nerve

tissues (Farquharson et al. 1958). After intraperitoneal injection in mice, the median doses producing convulsions

were 99 and 116 mg/kg, respectively, for 2-CP and 4-CP (Angel and Rogers 1972). Although this administration

route has limited relevance for human exposure, the
CHLOROPHENOLS 99

2. HEALTH EFFECTS

data do suggest that humans exposed at hazardous waste sites via drinking water are likely to be at minimal risk

of developing convulsions.

Reproductive Effects. No data were located regarding the reproductive effects of chlorophenols in

humans. Studies on the reproductive toxicity of chlorophenols in rats suggest that 2-CP, 2,4-DCP, and

2,4,6-TCP, administered on days 6 through 15 of gestation, may reduce liter size (Exon and Koller 1985).

However, at the highest dose tested (about 30 mg/kg/day 2,4-DCP and 2,4,6-TCP, and 50 mg/kg/day 2-CP) litter

sizes were reduced compared to controls only at the p≤0.1 level. A study designed to assess the reproductive

toxicity of 2,4,6-TCP found no effect on male or female reproductive functions at doses that caused death and

reduced body weight (Blackburn et al. 1986). An increasing trend for preimplantation loss was observed in

pregnant rats treated with 2,3,4,6-TeCP on gestation days 6-15 (RTI 1987). Because this study was not designed

to examine the preimplantation/ implantation phase of reproduction, the issue of whether 2,3,4,6-TeCP affects

implantation still needs to be resolved. Histological changes in the testes or ovaries have not been observed in

rats or mice exposed to 2,4-DCP, 2,4,5- or 2,4,6-TCP, or 2,3,4,6-TeCP in intermediate- and chronic-duration

studies (American Biogenics 1988; Bercz et al. 1990; McCollister et al. 1961; NCI 1979; NTP 1989).

Developmental Effects. No data were located regarding developmental effects in humans following

exposure to chlorophenols. The results of developmental studies in animals do not clearly show a selective

effect on development at doses lower than those causing maternal toxicity. At maternally toxic doses (750

mg/kg/day) reduced fetal body weight and delayed ossification were observed in the offspring of rats treated

with 2,4-DCP on gestation days 6-15 (Rodwell et al. 1989). No developmental effects were noted in rats treated

with 2,3,4,6-TeCP even at a dose that caused a 26% reduction in maternal body weight gain. The lack of a

specific developmental effect for 2-CP, 2,4,6-TCP (Fu et al. 1990), 4-CP, and 2,3,4,5-TeCP (Mayura et al. 1991)

is supported by studies using the in vitro hydra assay which showed that the compounds were equally toxic to

adult and developing organisms.

In vitro exposure of rat embryos indicates that the chlorophenols can directly affect development. Exposure of

rat embryos to 6 mM 4-CP or 2,3,4,5-TeCP resulted in a significant decrease in crown-rump length, somite

number, and DNA and protein content (Mayura et al. 1991). The effects of 2,3,4,5-TeCP on development were

much greater than 4-CP. 2,3,4,5-TeCP but not 4-CP also resulted in a significant reduction in yolk sac diameter.

4-CP exposure (195-781 nM) of rat embryos reduced measures of growth (somite number, crown rump length,

DNA content) and increased structural defects (hind limb bud absence,
CHLOROPHENOLS 100

2. HEALTH EFFECTS

hypoplasia of first arch, tail defects) (Oglesby et al. 1992). The effects of 4-CP were ameliorated by coculture

with hepatocytes, suggesting that 4CP, rather than a metabolite, was responsible for the effects on development.

In summary, the in vivo data suggest marginal effects of chlorophenol exposure on maternal and fetal toxicity

and no evidence of teratogenicity. The more highly chlorinated compounds may present the greatest health risk

to pregnant women exposed occupationally or through contaminated drinking water.

Genotoxic Effects. Studies regarding genotoxic effects in humans were not available. 2-CP and 4-CP

have been tested in one in vivo and several in vitro genotoxicity assays. Acute administration of up to

69 mg/kg/day 2-CP in mice was not associated with any changes in bone marrow or testicular sister

chromatid exchange (SCE) frequency (Table 2-4). Similarly, oral administration of up to 638 mg/kg/day (14

days) or 500 mg/kg/day (90 days) had no effect on SCEs in the testes or bone marrow (Borzelleca et al. 1985a).

No further details were provided.

In mammalian in vitro systems, 2-CP induced slight-to-moderate increases in c-mitosis (indicating disturbances

of the spindle function) and aneuploidy in cultured Chinese hamster lung cells (Onfelt 1987; see Table 2-5). The

increase in aneuploidy, compared to controls, was statistically significant (p<0.025) by the chisquare test. The

results of prokaryotic genotoxicity assays for 2-CP and 4-CP were primarily negative for mutagenicity. In

standard Salmonella typhimurium reverse mutation assays with strains TA98, TA100, TA1535, TA1537, and

TA1538, treatment generally did not produce an increased number of revertants (DeMarini et al. 1990; Haworth

et al. 1983; Rapson et al. 1980). Negative findings occurred both in the presence and absence of metabolic

activation. In one study, 4-CP had a marginally positive response in strain TA1537 (Seuferer et al. 1979).

Neither 2-CP nor 4-CP, either with or without the S9 protein fraction, showed positive gene expression in a umu

test system (Ono et al. 1992; Sakagami et al. 1988). 2-CP and 4-CP were negative in a prophage induction assay

with Escherichia coli (DeMarini et al. 1990). 4-CP induced an increased number of revertants in S. typhimurium

strains TA97 TA98, TAlOO, and TA104 (Strobe1 and Grummt 1987). The effects were most pronounced in

strain TA97, in the presence of metabolic activation. Interpretation of these data is confounded by the absence of

concentration-effect relationships.

2,4-DCP was negative for SCE induction in the testes and bone marrow after drinking water administration in

rats (Borzelleca et al. 1985a; see Table 2-4). As shown in Table 2-5, the compound was mostly negative for

mutagenic activity in S. typhimurium assays (Haworth et al. 1983; Probst et al. 1981; Rapson et al. 1980;







CHLOROPHENOLS 108

2. HEALTH EFFECTS

Rasanen et al. 1977; Simmon et al. 1977) but was positive with activation in a prophage induction assay (DeMarini

et al. 1990) and positive without activation in a umu test system (Ono et al. 1992). In mammalian cells (Table 2-5),

2,4-DCP was negative for gene mutation in Chinese hamster V79 cells (Hattula and Knuutinen 1985) but produced

chromosomal aberrations in Chinese hamster V79 cells (Onfelt 1987) and induced unscheduled DNA synthesis in

rat hepatocytes (Probst et al. 1981).

2,4,5-TCP did not increase DNA damage in mice given a single oral dose (164 mg/kg) as indicated by

alkaline elution of DNA from white blood cells and the liver (Kitchin and Brown 1988). 2,4,5-TCP was

predominantly negative in standard S. typhimurium reversion bioassays (George et al. 1992; Rasanen et al. 1977)

but was positive both with and without activation in a umu test system (Ono et al. 1992) and with (DeMarini et al.

1990) and without activation (George et al. 1992) in prophage induction assays (Table 2-5). 2,4,5-TCP did induce

chromosome aberrations in Chinese hamster ovary cells both with and without metabolic activation (Armstrong et

al. 1993).

2,4,6-TCP has been evaluated for genotoxicity in a variety of in vitro and in viva assays. As summarized in Tables

2-4 and 2-5, the results of these various assays have been both positive and negative, with the majority of studies

reporting negative results. According to Kitchin and Brown (1988), short-term in vitro tests with chlorinated

phenols often show weakly positive or no effects. Five different assays have reported positive results. In vitro,

2,4,6-TCP has demonstrated genotoxic activity without metabolic activation in bacteria (Bacillus subtilis), yeast

(Saccharomyces cervisiae), and mammalian cells (Chinese hamster V79 cells, mouse lymphoma L5178Y TK +/-

cells) (Fahrig et al. 1978; Hattula and Knuutinen 1985; Kinae et al. 1981; McGregor et al. 1988). In vivo, 2,4,6-

TCP has demonstrated genotoxic activity in somatic cells of mice in the spot test (Fahrig et al. 1978). 2,4,6-TCP

has tested positive for chromosomal aberrations in Chinese hamster ovary cells both with and without metabolic

activation (Armstrong et al. 1993). Positive results for mutations in Chinese hamster V-79 cells reported by Hattula

and Knuutinen (1985) were in contrast to the negative results reported by Jansson and Jansson (1992). Additional

negative results occurred in bacteria (S. typhimurium without activation), yeast (S. cervisie), and mammalian ovary

cells (Fahrig et al. 1978; Galloway et al. 1987; Haworth et al. 1983; Kinae et al. 1981; Lawlor et al. 1979; Rasanen

et al. 1977). In vivo tests using insect systems (Drosophila melanogaster) were also negative (Valencia et al. 1985).

An increase in DNA damage was not observed in the white blood cells or livers of mice given a single oral dose of

2,3,4,6-TeCP (193 mg/kg) (Kitchin and Brown 1988). 2,3,4,6-TeCP did test positive for mutation in Chinese

hamster V79 cells (Hattula and Knuutinen 1985). All three tetrachlorophenol isomers have
CHLOROPHENOLS 109

2. HEALTH EFFECTS

tested negative for mutation in standard S. typhimurium strains (Rasanen et al. 1977; Zeiger et al. 1988). 2,3,4,5-

and 2,3,4,6-TeCP, but not 2,3,5,6-TeCP, tested positive in a prophage induction assay (DeMarini et al. 1990), and

2,3,4,6-TeCP was positive both with and without activation in a umu test system (Ono et al. 1992).

The preponderance of the evidence from in vivo (Borzelleca et al. 1985a; Kitchen and Brown 1988; Valencia et al.

1985) and in vitro studies with prokaryotes (DeMarini et al. 1990; George et al. 1992; Haworth et al. 1983; Kinae

et al. 1979; Ono et al. 1992; Probst et al. 1981; Rapson et al. 1980; Rasanen et al. 1977; Sakagami et al. 1988;

Simmon et al. 1977; Zeiger et al. 1988) suggests that as a class the chlorophenols are not directly mutagenic. In

contrast, a more limited number of in vitro studies with eukaryotic cells have generally been positive for

chromosomal aberrations (Armstrong et al. 1993; Jansson and Jansson 1992; Onfelt 1987; Probst et al. 1981)

suggesting that chromosome malsegregation may be the mechanism of genotoxicity for the chlorophenols. The

lack of effect in the in vivo studies may be a result of the rapid urinary excretion of chlorophenols in these singledose studies (Borzelleca et al. 1985a; Kitchin and Brown 1988).

Cancer. Numerous cohort and case-control studies of wood finishing and chlorophenoxy herbicide workers

exposed to higher chlorophenols are available (Coggon et al. 1991; Eriksson et al. 1981, 1990; Hardell et al.

1987; Hoar et al. 1986; Honchar and Halperin 1981; Kogevinas et al. 1992; Lynge 1985; Ott et al. 1980;

Pearce et al. 1988; Smith et al. 1984; Woods et al. 1987). The results of these studies vary, but some suggest

a relationship between chlorophenol exposure and increased incidence of soft-tissue sarcomas, lung

cancers, malignant lymphomas, non-Hodgkin’s lymphomas, and nasal/nasopharyngeal cancers. The

conclusions from these studies are limited by small cohort sizes, coexposure to other contaminants

(including TCDD), and the lack of adequate control groups.

Chronic oral studies of 2,4-DCP in rats and mice (Exon and Koller 1985; NTP 1989) have not resulted in

any significant carcinogenic effect, even following both pre- and postnatal exposure (Exon and Koller

1985). A positive result in a dermal initiation promotion study suggests that 2,4-DCP can act as a promoter

(Boutwell and Bosch 1959).

The data available are inadequate regarding cancer in humans following exposure to 2,4,6-TCP. Animal

data suggest that humans may be at risk of cancer following exposure to 2,4,6-TCP (NCI 1979). A

significant dose-related increase in the incidence of leukemia occurred in male rats chronically exposed to
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2,4,6-TCP in the diet (NCI 1979). Both female and male mice treated chronically with 2,4,6-TCP in the diet had

significantly increased incidences of hepatocellular carcinomas and adenomas when compared to the controls (NCI

1979).

The carcinogenicity of 2,4,6-TCP following both intraperitoneal and subcutaneous exposure has been

evaluated in studies with mice. No significant increase in the incidence of pulmonary tumors was noted in mice

given repeated intraperitoneal injections of 2,4,6-TCP over an intermediate exposure period and followed over a

24-week observation period (Stoner et al. 1986). No significant increase in the incidence of injection-site tumors or

systemic tumors was observed in mice 18 months after a single subcutaneous injection of 2,4,6-TCP (Bionetics

Research Labs 1968). These intraperitoneal and subcutaneous studies are limited because the duration of exposures

was less than lifetime. In addition, although the intraperitoneal and subcutaneous routes of administration are

valuable research methods, their relevance to human exposure pathways is limited.

IARC (1987) considers chlorophenols as a group to have limited evidence for human carcinogenicity (group 2B).

The Department of Health and Human Services (NTP 1994) considers that 2,4,6-TCP may reasonably be

anticipated to be a carcinogen. Based on the positive NCI (1979) cancer bioassays with rats and mice, EPA (IRIS

1994) has classified 2,4,6-TCP as a B2 agent (probable human carcinogen). This category applies to those chemical

agents for which there is sufficient evidence of carcinogenicity in animals and inadequate evidence of

carcinogenicity in humans. EPA (IRIS 1994) has calculated a cancer potency factor (q1* or slope factor) for 2,4,6-

TCP of 0.02 (mg/kg/day) for both oral and inhalation exposure. This cancer potency factor is equivalent to a

drinking water unit risk value and an inhalation unit risk value of 3.1x10-7 (μg/L)-1 and 3.1x10-6 (μg/m3

)

-1,

respectively (IRIS 1994). The drinking water concentration of 2,4,6-TCP associated with an excess lifetime cancer

risk of 10-4, 10-5, and 10-6 is 300 μg/L, 30 μg/L , and 3 μg/L, respectively. The air concentration of 2,4,6-TCP

associated with an excess lifetime cancer risk of 10-4, 10-5, and 10-6 is 30 μg/m3

, 3 μg/m3, and 0.3 μg/m3,

respectively (IRIS 1994).

The mechanism(s) by which 2,4,6-TCP induces cancer in animals are not known. However, it has recently been

suggested that 2,4,6-TCP causes cancer either by suppressing the immune system, by acting as a weak clastogen,

and/or by acting as a weak initiator or promoter of carcinogenesis (Kitchin and Brown 1988). According to Kitchin

and Brown (1988), two positive results (direct V-79, Bacillus subtilus) support the idea that 2,4,6-TCP may be an

initiator. However, three negative results in the Ames test, hepatocyte mediated V-79, and alkaline elution in vivo

fail to support the idea that 2,4,6-TCP is an initiator. 2,4,6-TCP was also
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not an initiator following a single oral, dermal, or subcutaneous dose given to mice followed by 20 weeks of

three times per week skin applications of the promotor 12-O-tetradecanoylphorbol-13-acetate (Bull et al. 1986).

Supporting evidence for 2,4,6-TCP as a promotor includes the observation that ornithine decarboxylase and

cytochrome P-450 induction occurs at high doses.

2.6 CHILDREN’S SUSCEPTIBILITY

This section discusses potential health effects from exposures during the period from conception to maturity at

18 years of age in humans, when all biological systems will have fully developed. Potential effects on offspring

resulting from exposures of parental germ cells are considered, as well as any indirect effects on the fetus and

neonate due to maternal exposure during gestation and lactation. Relevant animal and in vitro models are also

discussed.

Children are not small adults. They differ from adults in their exposures and may differ in their susceptibility to

hazardous chemicals. Children’s unique physiology and behavior can influence the extent of their exposure.

Exposures of children are discussed in section 5.6 Exposures of Children.

Children sometimes differ from adults in their susceptibility to hazardous chemicals, but whether there is a

difference depends on the chemical (Guzelian et al. 1992; NRC 1993). Children may be more or less susceptible

than adults to health effects and the relationship may change with developmental age (Guzelian et al. 1992;

NRC 1993). Vulnerability often depends on developmental stage. There are critical periods of structural and

functional development during both pre-natal and post-natal life and a particular structure or function will be

most sensitive to disruption during its critical period(s). Damage may not be evident until a later stage of

development. There are often differences in pharmacokinetics and metabolism between children and adults. For

example, absorption may be different in neonates because of the immaturity of their gastrointestinal tract and

their larger skin surface area in proportion to body weight (Morselli et al. 1980; NRC 1993); the gastrointestinal

absorption of lead is greatest in infants and young children (Ziegler et al. 1978). Distribution of xenobiotics may

be different; for example, infants have a larger proportion of their bodies as extracellular water and their brains

and livers are proportionately larger (Widdowson and Dickerson 1964; Foman et al. 1982; Owen and Brozek

1966; Altman and Dittmer 1974; Foman 1966). The infant also has an immature blood-brain barrier (Adinolfi

1985; Johanson 1980) and probably an immature blood-testis barrier (Setchell and Waites 1975). Many

xenobiotic metabolizing enzymes have distinctive developmental patterns and at various stages of growth and

development, levels of particular enzymes may be higher or
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lower than those of adults and sometimes unique enzymes may exist at particular developmental stages (feeder

and Kearns 1997; Komori 1990; Vieira et al. 1996; NRC 1993). Whether differences in xenobiotic metabolism

make the child more or less susceptible also depend on whether the relevant enzymes are involved in activation

of the parent compound to its toxic form or in detoxification. There may also be differences in excretion,

particularly in the newborn who has a low glomerular filtration rate and has not developed efficient tubular

secretion and resorption capacities (Altman and Dittmer 1974; West et al. 1948; NRC 1993). Children and

adults may differ in their capacity to repair damage from chemical insults. Children also have a longer lifetime

in which to express damage from chemicals; this potential is particularly relevant to cancer.

Certain characteristics of the developing human may increase exposure or susceptibility while others may

decrease susceptibility to the same chemical. For example, the fact that infants breathe more air per kilogram of

body weight than adults may be somewhat counterbalanced by their alveoli being less developed, so there is a

disproportionately smaller surface area for absorption (NRC 1993).

No direct information is available regarding the health effects of chlorophenols observed in children.

However, health effects observed in adults are also expected to be of potential concern in children. Although no

direct information is available on the effects of chlorophenols on the developmental process in humans, studies

in animals indicate few developmental effects. No significant changes in offspring body or liver weights were

observed in rats treated with 2-CP in drinking water at doses up to 50 mg/kg/day throughout gestation and up to

91 days post par-turn (Exon and Koller 1981, 1985). No adverse changes in litter sizes, perinatal loss, pup

weight, or litter biomass were observed when female rats received a single dose of 4-CP as high as 1,000 mg/kg

on gestational day 11 (Kavlock 1990). Oral exposure of pregnant rats to a maternal toxic dose of 750 mg/kg/day

2,4-DCP for 10 gestational days induced a slight decrease in fetal weight and a statistically significant delayed

ossification of sternal and vertebral arches and led to a slight insignificant increase in early embryonic deaths

(Rodwell et al. 1989). No effects on immune function parameters were observed in 6-week old rats treated with

2,4-DCP in the drinking water at doses up to 30 mg/kg/day throughout gestation (Exon and Koller 1985; Exon

et al. 1984). Gavage administration of 650 mg/kg/day 2,4,5-TCP during organogenesis (days 6-15 of gestation)

produced no fetotoxicity, malformations, or structural terata in the offspring of rats (Chemoff et al. 1990).

Administration of 800-900 mg/kg 2,4,5-TCP in mice on 1 day of gestation or 250-300 mg/kg/day on any 3 days

of gestation had no effect on resorption incidence, pup survival, mean fetal weight, gross malformations,

skeletal malformation, or cleft palates (Hood et al. 1979). Similarly, maternal exposure of rats to 500 mg/kg/day

2,4,6-TCP only produced a
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transient reduction in the body weight of offspring (Blackburn et al. 1986). When female Sprague-Dawley rats

orally received purified 2,3,4,6-TeCP throughout organogenesis, the only effect on the fetus was delayed

ossification of the skull bones (Schwetz et al. 1974). However, this effect was not statistically significant when

analyzed by litters. In a follow-up study in pregnant rats receiving 0,25, 100, or 200 mg/kg/day every day during

organogenesis, the two highest doses resulted in inhibition of maternal body weight gain. There was also a doserelated trend for 2,3,4,6-TeCP-mediated effects on implantation or postimplantation viability. Chlorophenols do

not appear to be teratogenic in animals (Rodwell et al. 1989; Exon and Koller 1981; Schwetz et al. 1974).

Prior maternal exposure to chlorophenols is unlikely to affect the fetus or a nursing neonate. The relative

rapid metabolism and excretion of chlorophenols (Keith et al. 1980) should limit their potential to accumulate

in maternal tissue; chlorophenols do not appear to accumulate in animals after oral exposure (Korte et al.

1978; Bahig et al. 1981). The accumulation of 2-CP in tissues of dams was found to be minimal (Exon and

Koller 1982). However, 2,3,4,6-TeCP was detected in adipose tissues from people not occupationally exposed

to chlorophenols (Mussalo-Rauhamaa et al. 1989), probably due to the relatively higher octanolwater partition

coefficient of TeCP. Chlorophenols and/or their metabolites might cross the placenta as it has been shown in a

reproductive study in rats that transplacental exposure to 2-CP can be feto- or embryotoxic at a high dose,

resulting in a significant increase in the number of still births (Exon and Koller 1982), although it is possible

that these could be indirect effects of the fetus. In another study, an increase in delayed ossification of the

fetal skull bones was observed when pregnant Sprague-Dawley rats were treated with TeCP, supporting that

chlorophenols might cross the placenta. No studies are available that measured chlorophenols in breast milk.

As a class, the chlorophenols are not directly genotoxic although a limited number of in vitro studies with

eukaryotic cells have been positive for chromosomal aberrations. There is no information to indicate that

parental exposure may affect children via damage to germ cells.

Metabolism of chlorophenols has not been studied in children. However, sulfation and glucuronidation are the

main metabolic pathways for chlorophenols in both human and animal studies. The conjugated metabolites

are then eliminated in urine. In humans, activity of UDP-glucuronosyltransferase (responsible for glucuronide

conjugates) does not reach adult levels until about 6-8 months of age, although the development of this

activity is isoform specific. Activity of sulfotransferases (responsible for sulfate conjugates) seems to develop

earlier, although again it is isoform specific. The activity of some sulfotransferase isoforms may be
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greater than that of adults during infancy and early childhood (Leeder and Kearns 1997). In rats, while

sulfation is almost at adult levels at birth, UDP-glucuronosyltransferase activity towards different xenobiotics

varies with maturation (Weiss 1960; Young and Lietman 1978). It is possible that chlorophenols might be

eliminated at a slower rate in children, resulting in increased susceptibility of children to their toxicity.

2.7 BIOMARKERS OF EXPOSURE AND EFFECT

Biomarkers are broadly defined as indicators signaling events in biologic systems or samples. They have been

classified as markers of exposure, markers of effect, and markers of susceptibility (NAS/NRC 1989).

Due to a nascent understanding of the use and interpretation of biomarkers, implementation of biomarkers as

tools of exposure in the general population is very limited. A biomarker of exposure is a xenobiotic substance or

its metabolite(s), or the product of an interaction between a xenobiotic agent and some target molecule(s) or

cell(s) that is measured within a compartment of an organism (NAS/NRC 1989). The preferred biomarkers of

exposure are generally the substance itself or substance-specific metabolites in readily obtainable body fluid(s)

or excreta. However, several factors can confound the use and interpretation of biomarkers of exposure. The

body burden of a substance may be the result of exposures from more than one source. The substance being

measured may be a metabolite of another xenobiotic substance (e.g., high urinary levels of phenol can result

from exposure to several different aromatic compounds). Depending on the properties of the substance (e.g.,

biologic half-life) and environmental conditions (e.g., duration and route of exposure), the substance and all of

its metabolites may have left the body by the time samples can be taken. It may be difficult to identify

individuals exposed to hazardous substances that are commonly found in body tissues and fluids (e.g., essential

mineral nutrients such as copper, zinc, and selenium). Biomarkers of exposure to chlorophenols are discussed in

Section 2.7.1.

Biomarkers of effect are defined as any measurable biochemical, physiologic, or other alteration within an

organism that, depending on magnitude, can be recognized as an established or potential health impairment or

disease (NAS/NRC 1989). This definition encompasses biochemical or cellular signals of tissue dysfunction

(e.g., increased liver enzyme activity or pathologic changes in female genital epithelial cells), as well as

physiologic signs of dysfunction such as increased blood pressure or decreased lung capacity. Note that these

markers are not often substance specific. They also may not be directly adverse, but can indicate potential health

impairment (e.g., DNA adducts). Biomarkers of effects caused by chlorophenols are discussed in Section 2.7.2.
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A biomarker of susceptibility is an indicator of an inherent or acquired limitation of an organism’s ability to

respond to the challenge of exposure to a specific xenobiotic substance. It can be an intrinsic genetic or other

characteristic or a preexisting disease that results in an increase in absorbed dose, a decrease in the biologically

effective dose, or a target tissue response. If biomarkers of susceptibility exist, they are discussed in Section 2.9,

“Populations That Are Unusually Susceptible.”

2.7.1 Biomarkers Used to Identify or Quantify Exposure to Chlorophenols

There are no biomarkers of exposure or effect that have been validated in children or adults exposed as

children. The only known biomarkers of chlorophenol exposure are the hydrolyzed urinary extracts of the parent

compounds and dechlorinated derivatives. However, these extracts are not unique to chlorophenol exposure. For

example, conjugated forms of higher chlorophenols have been observed after laboratory administration of

hexachlorocyclohexanes (Engst et al. 1976; Koransky et al. 1975), indicating that urinary chlorophenol levels are

not specific to chlorophenol exposure. Similarly, the presence of chlorophenols or their metabolites in urine is not

necessarily diagnostic for chlorophenol exposure because these compounds are also detectable in urine after

exposure to certain other pesticides, such as lindane (Karapally et al. 1973), VC-13 (Shafik et al. 1973), 2,4-

dichloro-phenoxyacetic acid, and 2,4,5-trichlorophenoxyacetic acid (Hill et al. 1989). Finally, metabolic

dechlorination of higher chlorophenols to lower chlorophenols occurs under some conditions (Renner and Mucke

1986). Studies to determine the importance of these processes on urinary chlorophenol formation, as either

conjugated or unconjugated metabolites, have not been conducted. Consequently, the value of assessing urinary

chlorophenol concentrations as measures of potential exposure in workers or residents near hazardous waste sites

cannot currently be determined.

2.7.2 Biomarkers Used to Characterize Effects Caused by Chlorophenols

No unique biomarkers of effects are available for chlorophenols. As discussed in Section 2.2, the clinical

signs associated with high acute levels of monochlorophenol administration include myoclonic convulsions

(Angel and Rogers 1972; Borzelleca et al. 1985a, 1985b; Farquharson et al. 1958) and dermal and ocular

lesions (Bioassay Systems 1981; Rhodia 1978; Younger Labs 1975). Both myoclonic convulsions and

epithelial tissue corrosion are commonly observed after exposure to numerous phenolic compounds and are

therefore not necessarily diagnostic of monochlorophenol exposure. Increasing chlorination results in clinical

signs of metabolic derangement, such as hyperthermia and blood pressure decrements (Angel and Rogers

1972; Farquharson et al. 1958). These clinical signs are not specific to chlorophenols; they occur
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following exposure to any agent that uncouples mitochondrial oxidative phosphorylation such as nitrophenol

(Ahlborg and Thunburg 1980). Other effects of chlorophenols, including effects on the immune system (Exon et al.

1984) and on reproduction (Exon and Koller 1985), are also not specific to chlorophenols.

For more information on biomarkers for renal and hepatic effects of chemicals see ATSDR/CDC Subcommittee

Report on Biological Indicators of Organ Damage (1990) and for information on biomarkers for neurological

effects see OTA (1990).

2.8 INTERACTIONS WITH OTHER SUBSTANCES

Data regarding the interaction of chlorophenols with other chemical substances in humans or animals were not

located. Substances that result in effects similar to those for the chlorophenols have the potential to interact with

these compounds. For example, chlorophenols may interact with other carcinogens, promoters, neurotoxic agents,

and liver, renal, dermatologic, and ocular toxins.

Factors interfering with Phase II conjugation reactions would inhibit the detoxification of chlorophenols. The

results of recent experimentation indicate that the polycyclic aromatic hydrocarbon (PAH), 3-methylcholanthrene

(3-MC), stimulates the glucuronidation of phenolic substrates through the induction of glucuronylsyltransferase

(Jansen et al. 1992; Wishart 1978a, 1978b). The enzymes induced have a spectrophotometric peak of 448

nanometers (cytochrome P-448) and are characteristically distinct from the phenobarbital-type induced enzymes

that have an absorbance maximum at 450 nanometers. These findings suggest that other toxic and/or carcinogenic

PAHs, such as benzo(a)pyrene, can significantly enhance the metabolism of phenols. The relationship between

PAH particulate and solid material, commonly associated with incinerators and hazardous waste sites, and

chlorophenol metabolism has not been studied. In general, the ability of another chemical to affect the toxicity of

chlorophenols may depend on its affinity for the cytochrome P-448 substrate binding site.

Chlorophenols are toxic to the liver. Exposure to hepatotoxic drugs such as acetaminaphen (Tylenol) and

chlorophenols may result in additive effect. However, there are no studies that indicate such interaction.

Using an in vitro rat liver microsomal preparation, Arrhenius et al. (1977) noted that 2,4-DCP, 2,4,6-TCP, and

2,3,4,6-TeCP in the concentration range of 0.03-3 mM shifted the metabolism of aromatic amines from Coxygenation to n-oxygenation. The carcinogenic metabolites of aromatic amines can be formed by M-
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oxygenation. Therefore, Arrhenius et al. (1977) suggested that the chlorophenols should be considered as possible

synergists for the carcinogenicity of aromatic amines.

2.9 POPULATIONS THAT ARE UNUSUALLY SUSCEPTIBLE

A susceptible population will exhibit a different or enhanced response to chlorophenols than will most

persons exposed to the same level of chlorophenols in the environment. Reasons include genetic make-up,

developmental stage, age, health and nutritional status (including dietary habits that may increase

susceptibility, such as inconsistent diets or nutritional deficiencies), and substance exposure history

(including smoking). These parameters may result in decreased function of the detoxification and excretory

processes (mainly hepatic, renal, and respiratory) or the preexisting compromised function of target organs

(including effects or clearance rates and any resulting end-product metabolites). For these reasons we expect the

elderly, with declining organ function, and the youngest of the population, with immature and developing organs,

will generally be more vulnerable to toxic substances than healthy adults. Populations who are at greater risk due to

their unusually high exposure are discussed in Section 5.7, Populations With Potentially High Exposure.

No specific population that would be particularly susceptible to chlorophenol intoxication has been identified.

Because of the extensive hepatic conjugation and renal clearance of these compounds, individuals with liver or

kidney dysfunction may be the most sensitive population. The results of recent studies indicate that individuals

with cirrhosis of the liver (Macdonald et al. 1992; Ohta 1991) or hepatitis (Ohta 1991) show impaired Phase II

conjugation. Chronic renal failure is associated with the inability to clear conjugated metabolites, resulting in

elevated, steady-state whole body concentrations of glucuronide and sulfate metabolites (Martin et al. 1991).

Patients with acute tubular necrosis, with or without cirrhosis, show markedly elevated urinary β-glucuronidase

concentrations (Solis-Herruzo et al. 1986) and, theoretically, a high body burden of unconjugated metabolites.

These data suggest that chlorophenol-exposed individuals with preexisting liver or kidney disease may be at

increased risk from exposure.

Individuals with Gilbert’s disease or Crigler-Najjar syndrome, inherited deficiencies of bilirubin UDPglucuronyl

transferase (UGT), may have increased sensitivity to the effects of chlorophenol exposure (de Morais and Wells

1988; de Morais et al. 1992). Considerable progress in understanding the genetic control of these abnormalities has

recently been made (Jansen et al. 1992). Patients with Type I Crigler-Najjar syndrome may be at the greatest risk

following exposure to phenolic compounds. This form of the syndrome
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is characterized by unconjugated hyperbilirubinemia and apparently results from a deficiency in the 3-

Mcinducible form of the phenolic UGT. Defects in cytochrome P-450 induction occur in Type II (partial

hyperbilirubinemia) Crigler-Najjar syndrome and Gilbert disease; consequently, these patients may not be as

sensitive to increased plasma concentrations of chlorophenol.

Cigarette smokers are at potentially increased risk from chlorophenol exposure (Alvares 1978; Bock et al.

1987). The incomplete combustion products of smoking, such as PAHs, induce P-448 metabolism, resulting in

the potential formation of reactive metabolites and an increased conjugation rate (see Sections 2.3.3 and 2.7).

Alternatively, PAHs may accelerate the detoxification of chlorophenol. Consequently, definitive statements

about the relationship between cigarette smoking and chlorophenol metabolism cannot be made at the present

time.

Evidence from rat studies (Exon et al. 1985) suggests that at least one part of the immune system (delayed

hypersensitivity) is sensitive to 2,4-DCP. Persons with immune system deficiencies, therefore, may be more

susceptible to the adverse effects of 2,4-DCP exposure.

Fetuses or neonates may also be at increased risk. In humans, activity of UDP-glucuronosyltransferase

(responsible for glucuronide conjugates) does not reach adult levels until about 6-8 months of age, although the

development of this activity is isoform specific. Activity of sulfotransferases (responsible for sulfate conjugates)

seems to develop earlier, although again, it is isoform specific. The activity of some sulfotransferase isoforms

may be greater than that of adults during infancy and early childhood (Leeder and Kearns 1997). This

conclusion is also supported by data from rat hepatic bioassays in which UGT activities toward phenolic

substrates reached adult levels between days 16 and 20 of gestation (Wishart 1978a). Enzymatic activity toward

bilirubin is negligible during this gestational period (the “late foetal” group), but surges between gestation day

20 and postnatal day 2 (the “postnatal” group). The differences in fetal and neonatal detoxification systems,

compared to the mature organism, may result in a slower elimination of the chlorophenols, which may serve to

increase the toxicity of these compounds.

Further discussion of the susceptibility of children is in Section 2.6 Children’s Susceptibility.
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2. HEALTH EFFECTS

2.10 METHODS FOR REDUCING TOXIC EFFECTS

This section will describe clinical practice and research concerning methods for reducing toxic effects of

exposure to chlorophenols. However, because some of the treatments discussed may be experimental and

unproven, this section should not be used as a guide for treatment of exposures to chlorophenols. When specific

exposures have occurred, poison control centers and medical toxicologists should be consulted for medical

advice.

2.10.1 Reducing Peak Absorption Following Exposure

Following high-dose oral exposure to chlorophenols, administration of water for dilution may be warranted

(Bronstein and Currance 1988). Although Ellenhorn and Barceloux (1988) recommend the use of ipecac/lavage,

activated charcoal, and cathartics for gastric contamination from chlorophenols, Bronstein and Currance (1988)

recommend against emesis because of possible aspiration into the lungs. This is more important for the liquid

chlorophenols than for the solid species.

Specific decontamination procedures for chlorophenols after skin or eye contact are not available. However,

general approaches for minimizing absorption can be extrapolated from literature on phenol or

pentachlorophenol. After dermal contact, rinsing with water (Gosselin et al. 1984) or washing with soap

(Bronstein and Currance 1988) may be the procedures of choice. The case reported by Kintz et al. (1992) in

which death occurred in a worker dermally exposed to 2,4-DCP on less than 10% of his body indicated that

washing with water may not be sufficient, especially if contaminated clothing is not removed. Attempts to

decontaminate phenols with alcohol, vegetable oils, glycerin, or polyethylene glycol, with or without methanol,

have met with variable success (Gosselin et al. 1984). After flushing a contaminated eye with water, irrigation is

sometimes used. This technique is suggested for adults with an intact lid who have no evidence of edema

(Bronstein and Currance 1988). For children, irrigation of each eye with normal saline, using large bore

intravenous tubing, is sometimes recommended (Bronstein and Currance 1988). In more advanced cases, the use

of proparacaine hydrochloride may follow eye irrigation (Bronstein and Currance 1988).

2.10.2 Reducing Body Burden

The limited experimental data suggest that orally administered chlorophenols are rapidly conjugated and

excreted in the urine (see Sections 2.3.3 and 2.3.4). The efficacy of drug therapy to accelerate Phase II
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detoxification reactions is not known. For example, supplying substrates for glucuronidation and sulfur

conjugation may increase the excretion of the chlorophenols. Based on studies involving pentachlorophenol

exposure, the utility of either exchange transfusions or forced diuresis is equivocal (Robson et al. 1969; Young

and Haley 1978).

A high intake of ascorbic acid has been shown to reduce accumulation of 2,4-DCP and decrease liquid

peroxidation in the liver of guinea pigs compared to animals with low ascorbic acid intake (Derhata et al. 1996).

2.10.3 Interfering with the Mechanism of Action for Toxic Effects

The mechanism of toxic action for 2-CP or 4-CP is not known. Although these chemicals may be weak

uncouplers of oxidative phosphorylation, inconsistent findings of increased metabolic rate after exposure

suggest that this mechanism may not be the mechanism of greatest consequence (Angel and Rogers 1972;

Farquharson et al. 1958; Weinbach and Garbus 1965). Convulsive seizures, of unknown origin, are the most

characteristic clinical signs of acute overdose (Angel and Rogers 1972; Borzelleca et al. 1985a). Treatment for

the prevention of seizures includes the common anticonvulsant sequence of diazepam, phenytoin, and

phenobarbital (Bronstein and Currance 1988; Ellenhorn and Barceloux 1988). The use of anticonvulsants on

infants and children must be closely monitored to prevent overdosage and toxic effects of drugs.

No methods to directly reduce the adverse effects of chlorophenol-induced stimulation of mitochondrial

respiration were located.

2.11 ADEQUACY OF THE DATABASE

Section 104(I)(5) of CERCLA, as amended, directs the Administrator of ATSDR (in consultation with the

Administrator of EPA and agencies and programs of the Public Health Service) to assess whether adequate

information on the health effects of chlorophenols is available. Where adequate information is not available,

ATSDR, in conjunction with the National Toxicology Program (NTP), is required to assure the initiation of a

program of research designed to determine the health effects (and techniques for developing methods to

determine such health effects) of chlorophenols.
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The following categories of possible data needs have been identified by a joint team of scientists from

ATSDR, NTP, and EPA. They are defined as substance-specific informational needs that if met would

reduce the uncertainties of human health assessment. This definition should not be interpreted to mean that all

data needs discussed in this section must be filled. In the future, the identified data needs will be evaluated and

prioritized, and a substance-specific research agenda will be proposed.

2.11.1 Existing Information on Health Effects of Chlorophenols

The existing data on health effects of inhalation, oral, and dermal exposure of humans and animals to

chlorophenols are summarized in Figure 2-4. The purpose of this figure is to illustrate the existing information

concerning the health effects of chlorophenols. Each dot in the figure indicates that one or more studies provide

information associated with that particular effect. The dot does not necessarily imply anything about the quality

of the study or studies, nor should missing information in this figure be interpreted as a “data need.” A data

need, as defined in ATSDR’s Decision Guide for Identifying Substance-Specific Data Needs Related to

Toxicological Profiles (ATSDR 1989), is substance-specific information necessary to conduct comprehensive

public health assessments. Generally, ATSDR defines a data gap more broadly as any substance-specific

information missing from the scientific literature.

Humans are potentially exposed to chlorophenols occupationally, through municipal solid waste combustion,

and as a result of the disinfection of drinking water. The chlorophenol by-products of manufacturing activities

may be the greatest single source of concern at NPL hazardous waste sites. Workers in phenoxy pesticide

production, wood preservation, dye manufacturing, and alcohol denaturation may be at some risk from

chlorophenol exposure. Exposure potential in most of these industries is greater for the higher chlorinated

phenols, which, based on the results of animal studies, are more toxic than the dichlorophenols and the

monochlorophenols (Borzelleca et al. 1985a). Results of human studies involving exposure to higher

chlorophenols suggest that occupational dermal exposure is a more significant concern than inhalation exposure

(Kleinman et al. 1986).

Except for the single death following dermal 2,4-DCP exposure (Kintz et al. 1992) no health effects data for

humans exposed exclusively to chlorophenols were located. Available occupational data indicate that chemicals

involved in the production of phenoxy-based herbicides, and/or the end-use products themselves, may be

associated with the development of cancers of the hematopoietic and lymphatic systems (Eriksson et al. 1981;

Hardell et al. 1981). Positive results for carcinogenicity do not show a consistent trend across

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2. HEALTH EFFECTS

worker groups and cannot be specifically associated with a single contaminant or group of contaminants

(including trichlorophenols). No epidemiological evidence of adverse health effects associated with drinking

chlorophenol-contaminated water was located.

Most of the available animal data, which include several recent, well-conducted studies, have involved the oral

route of administration. After acute exposure, the higher chlorophenols, in particular, have effects on basal

metabolism that are typical of uncouplers of mitochondrial oxidative phosphorylation. Experimental results

suggest that the acute toxicity of tetrachlorophenols is the greatest, followed by the monochlorophenols and then

the trichlorophenols, with the dichlorophenols being the least toxic isomers (Borzelleca et al. 1985a). The

adverse effects sometimes reported after repeated exposures do not indicate a well-defined toxic syndrome.

Intermediate to high chlorophenol doses have been associated with marginal effects on the immune,

lymphoreticular, reproductive, and developmental systems, and a range of effects on the liver. Further research

to help define the experimental conditions and mechanisms associated with these noncarcinogenic findings, and

how they may relate to chlorophenol-exposed humans, is required. 2,4,6-TCP is an animal carcinogen that has

produced leukemia in rats and hepatocellular carcinoma and adenomas in mice (NCI 1979). Furthermore, other

chlorophenols have tumor promoting capabilities.

2.11.2 Identification of Data Needs

Acute-Duration Exposure. Information from animal studies indicates that most chlorophenols produce lethality

in experimental animals following a single-dose oral exposure of 89-5,000 mg/kg (Ahlborg and Larsson 1978;

Borzelleca et al. 1985a; Kobayashi et al. 1972; NTP 1989; Vernot et al. 1977). The limited inhalation and

dermal data tend to corroborate these findings (Carreon et al. 1980a; Duchosal and Biedermann 1991). The most

characteristic clinical sign after lethal or high sublethal doses of monochlorophenols is convulsions (Borzelleca

et al. 1985a, 1985b). Physiological changes associated with the uncoupling of oxidative phosphorylation

increase with the increasing degree of chlorination (Cascorbi and Ahlers 1989; Farquharson et al. 1958; Izushi et

al. 1988; Mitsuda et al. 1963; Narasimhan et al. 1992; Shannon et al. 1991; Stockdale and Selwyn 1971).

Following acute oral exposure, the order of toxicity as indicated by LD50s was tetrachlorophenols >

monochlorophenols > dichlorophenols > trichlorophenols (Borzelleca et al. 1985a; Deichmann and Mergard

1948). Maternal toxicity, but not fetal toxicity, was observed in rats treated by gavage with 2,4-DCP at 100

mg/kg/day on gestation days 6-15 (Rodwell et al. 1989). No maternal or fetal effects were observed at 25

mg/kg/day. The lowest acute oral LOAEL for the chlorophenols that was identified was 2.58 mg/kg/day for

electron microscopic changes in hepatocytes
CHLOROPHENOLS 124

2. HEALTH EFFECTS

(foamy cytoplasm, clustering of mitochondria, and endoplasmic reticulum) that were not observed at

1.28 mg/kg/day (Phornchirasilp et al. 1989a). Based on the NOAEL of 1.28 mg/kg/day for liver effects

following 4-CP exposure, an acute-duration oral MRL of 0.01 mg/kg/day was calculated for the

chlorophenols. Data are insufficient and are needed for the derivation of an acute inhalation MRL for the

chlorophenols. Additional experiments to assess dose-response relationships are needed because of reporting

deficiencies and methodological differences to obtain data for an inhalation MRL. These data are needed to

assess risk to workers exposed during accidental releases. The report of a worker who died after splattering pure

2,4-DCP on portions of his right arm and leg while disposing industrial wastes (Kintz et al. 1992) demonstrates

the toxicity of chlorophenols via dermal exposure. More comprehensive dermal toxicity studies analyzing both

acute toxicity incidence and localized effects are also needed. Finally, additional studies examining the liver

effects following oral exposure to chlorophenols other than 4-CP are needed to confirm that the MRL based on

4-CP exposure is truly protective of liver effects following exposure to these other compounds.

Intermediate-Duration Exposure. Occupational studies have typically involved individuals exposed to

chlorophenols for intermediate- or chronic-duration periods. The results of these studies are described under the

section Chronic-Duration Exposure and Cancer. Intermediate-duration oral administration of chlorophenols to

experimental animals generally produces no effects or marginal effects on systemic, immunological,

reproductive, and developmental end points (Bercz et al. 1990; Borzelleca et al. 1985a; Carlson 1978; Exon and

Koller 1982, 1983, 1985; Hattula et al. 1981). Immunological effects (a decrease in delayed type

hypersensitivity) appears to be the most sensitive target of 2,4-DCP toxicity (Exon and Koller 1985; Exon et al.

1984), and an intermediate oral MRL (0.003 mg/kg/day) based on a NOAEL for immunological effects has been

derived for the chlorophenols. Data are insufficient and are needed for the derivation of an intermediate-duration

exposure. The liver is the organ most consistently affected by the chlorophenols. Effects noted include enzyme

induction (Phornchirasilp et al. 1989a), increased liver weight (Bercz et al. 1990; Exon and Koller 1985),

hypertrophy (American Biogenics 1988), and centrilobular degeneration and focal necrosis (Hattula et al. 1981;

McCollister et al. 1961). Data on intermediate-duration dermal exposure of chlorophenols in humans or animals

are not available and are needed.

Additional studies examining the immunological effects following oral exposure to chlorophenols other than

2,4-DCP are needed to confirm that the intermediate-duration MRL based on 2,4-DCP exposure is truly

protective of liver effects following exposure to the other compounds. Mechanistic and toxicokinetic studies

may provide useful information about the rate of formation and time course of potential intermediates
CHLOROPHENOLS 125

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associated with chlorophenol-induced hepatotoxicity. Further development of dose-response relationships, with

respect to biomarkers of hepatic injury, is needed. These data may provide information about both mechanism of

action and potential adverse effects expected at the exposure concentrations associated with NPL sites.

Additional experiments to assess dose-response relationship are needed to obtain an intermediate inhalation

MRL. Studies focusing on organ function, in addition to histopathological analysis, would be particularly

important. Because the higher chlorinated compounds, in particular, contain toxic impurities (particularly

dioxins and dibenzofurans), the impurities of each test compound should be minimized since the effects of the

contaminants could override the effects from the substance tested. Studies specifically designed to examine the

interaction of dioxins and dibenzofurans with chlorophenols should also be completed.

Chronic-Duration Exposure and Cancer. Dermal or inhalation exposure to the chlorophenols used in phenoxy

herbicide production may be associated with cancer induction (Eriksson et al. 1981, 1990; Hardell et al. 1981;

Hoar et al. 1986). Most investigators, however, have found only weak trends or no evidence of an association

(Coggon et al. 1991; Kogevinas et al. 1992; Lynge 1985; Pearce et al. 1988; Smith et al. 1984; Woods et al.

1987). Many of the latter studies included a multinational cohort analysis of workers involved in similar

production processes. Current experimental methodology is not sufficiently sensitive to determine those

exposure factors, if any, that may be associated with the expression of cancer. Other investigators have observed

a possible association between chlorophenol exposure in production workers and the onset of hepatic

abnormalities, including porphyria (Bleiberg et al. 1964; Calvert et al. 1992). These results suggest the

possibility of biomonitoring individuals living near hazardous waste sites for serological evidence of hepatic

dysfunction. No data were located regarding the chronic effects of oral chlorophenol exposure in humans.

Available chronic studies with rats and mice, and evidence of clastogenicity, have indicated that 2,4,6-TCP

may produce carcinogenicity in animal models through mechanisms other than direct gene mutation

(Armstrong et al. 1993; Jansson and Jansson 1992; NCI 1979). Limited experimental data on mouse skin and

orally exposed rats suggest that 2-CP and 2,4-DCP may have tumor promoting capabilities, but are not

complete carcinogens (Boutwell and Bosch 1959; Exon and Koller 1985). Additional animal studies designed

to determine the conditions under which chlorophenols induce cancer, including supporting evidence for a

clastogenic or epigenetic role, are needed. Because of significant information gaps, data are not sufficient to

determine a chronic-duration MRL for chlorophenols by either the oral or inhalation route of exposure. Such

data should be obtained so that chronic-duration MRLs for chlorophenols can be calculated.
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Genotoxicity. There are no human studies on the genotoxicity of the eight chlorophenols. In general,

chlorophenols have been negative for mutagenicity in most prokaryotic assays (George et al. 1992; Haworth et al.

1983; Lawlor et al. 1979; Rapson et al 1980; Seuferer et al. 1979; Zeiger et al. 1988). Further mutagenicity studies

in these test systems are not needed. Neither 2-CP nor 2,4-DCP induced an increased incidence of SCEs in mouse

testicular or bone marrow cells (Borzelleca et al. 1985a). In other eukaryotic tests, 2,4,6-TCP has been associated

with structural chromosomal aberrations in both somatic and germ cells (Armstrong et al. 1993; Jansson and

Jansson 1992). Evidence of mutational activity in both in vivo (Fahrig et al. 1978) and in vitro (Fahrig et al. 1978;

Hattula and Knuutinen 1985; McGregor et al. 1988) assays is also available for 2,4,6-TCP. The implications of

these findings for cancer induction needs further research, including the use of both mammalian cell cultures and

additional in vivo clastogencity assays in mammals.

Reproductive Toxicity. No occupational or epidemiological studies of potential reproductive effects in exposed

individuals are available. Only one animal study comprehensively addresses the reproductive effects of

chlorophenols. Blackburn et al. (1986) did not find reproductive effects in male or female rats exposed to 2,4,6-

TCP by gavage at doses that caused other systemic effects (e.g., decreased body weight gain). There is limited

evidence that 2-CP, 2,4-DCP, and 2,4,6-TCP may reduce litter sizes when administered to rats in drinking water

(Exon and Koller 1985). This effect was significant only at p≤0.1 and was observed at doses that caused other

effects (e.g., increased liver weights, decreased delayed-type hypersensitivity). An increase in early embryo loss is

suggested by a teratology study of 2,3,4,6-TeCP (RTI 1987). However, the rats were dosed on gestation days 6-15

and not earlier in gestation; thus, further studies regarding the effect of 2,3,4,6- TeCP on pre- and early

implantation are needed. No data are available on the reproductive toxicity of chlorophenols after inhalation or

dermal exposure in humans or animals.

Developmental Toxicity. Pregnant women may be exposed to chlorophenols occupationally, through the drinking

water, or by living near a hazardous waste site. No data are currently available to assess the potential effects of

postimplantation exposure on the developing offspring of these women. Results from animal studies showed minor

effects occurring at doses that are maternally toxic (Blackburn et al. 1986; Exon and Koller 1985; Rodwell et al.

1989; RTI 1987; Schwetz et al. 1974). Frank teratogenic effects have not been observed following exposure of

animals during organogenesis. No data are available on the developmental toxicity of chlorophenols after

inhalation or dermal exposure in humans or animals.

Mechanistic studies indicated that cultured hepatocytes ameliorated the adverse developmental effects

associated with in vitro 4-CP exposure (Oglesby et al. 1992). This finding is apparently attributable to
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2. HEALTH EFFECTS

increased rates of detoxification in the hepatocyte cell cultures. In addition, results from mammalian embryo

assay indicate that monochlorophenols are not potent developmental toxicants or teratogens (Mayura et al.

1991). In vivo studies involving exposure around the implantation period may help corroborate these in vitro

data. Studies on developmental effects of postnatal exposure will also be useful.

Immunotoxicity. No experimental data involving the immunotoxic effects of human exposure to

chlorophenols are available. Oral studies in rats suggest that a low dose of 2,4-DCP (3 mg/kg/day) is

associated with a decreased delayed-type hypersensitivity response and an increased humoral immune

response with decreased thymus weights following intermediate exposure (Exon et al. 1984). Both erythroid and

myeloid elements of the bone marrow are depleted after oral administration with 500 mg/kg/day of 2,4-DCP for

13 weeks in rats (NTP 1989). Oral administration of other chlorophenols has been associated with elevated

spleen weights but not with significant effects on humoral or cell-mediated components (Borzelleca et al. 1985a;

Exon and Koller 1983, 1985). The implications of these findings for individuals exposed near NPL hazardous

waste sites can only be fully assessed with in vivo functional tests of immunocompetence, graft rejection, or

immunosurveillance in appropriate animals. Additional animal studies are also needed to provide dose-response

and/or threshold information. No data are available on the immunotoxicity of chlorophenols after inhalation

exposure in animals. Single dermal exposure of 50 mL of 2,4,5-TCP on one shaved flank of mice indicated

2,4,5-TCP can be a skin sensitizer (Kimber and Weisberger 1991). More data on immunotoxicity of

chlorophenols by all the routes of exposure are needed.

Neurotoxicity. Within 20 minutes of being accidentally splashed with 2,4-DCP on his right arm and leg, a

worker experienced seizures, collapsed, and died shortly thereafter (Kintz et al. 1992). At single oral doses >300

mg/kg monochlorophenols and dichlorophenols, chlorophenols can produce a variety of neurological effects,

including tremors, myoclonic convulsions, a hunched posture, dyspnea, collapse, and coma (Borzelleca et al.

1985a, 1985b; Duchosal and Biedermann 1991; Kobayashi et al. 1972; Phornchirasilp et al. 1989b; Spencer and

Williams 1950; Wil Research Laboratories 1982). Convulsions are common after high-dose (intraperitoneal

dose of 99 mg/kg) 2-CP administration and apparently are less frequent with increasing halogen substitution on

the phenol ring (Angel and Rogers 1972). Other investigators have not observed either clinical or

histopathological signs of neurological dysfunction after intermediate-duration exposure to doses up to 1,300

mg/kg/day of 2,4-DCP, trichlorophenols, or tetrachlorophenols (Bercz et al. 1990; NCI 1979; NTP 1989). Acute

administration of monochlorophenols has reportedly been associated with hyperactivity and decreased brain

weight (Borzelleca et al. 1985a). However, the investigators provided no detailed results, and the conclusions

remain questionable. As acute high-dose exposures resulting from
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2. HEALTH EFFECTS

accidents are possible, further studies regarding the dose-response relationship of neurotoxic effects following

exposure to chlorophenols are needed. The need is greatest for studies on neurotoxicity following dermal

exposure.

Epidemiological and Human Dosimetry Studies. As indicated above, accurate human dosimetry

studies may not be possible because environmental and occupational chlorophenols typically exist only in

association with other chlorinated organics. Consequently, it would be difficult to ascribe any observed health

effect to a single chemical or a single group of isomers. Additional studies in workers, such as sawmill

employees, that are exposed specifically to chlorophenols are needed. Careful monitoring of chlorophenol air

concentrations and skin exposure combined with kinetic measures of urinary output for specific isomers may

provide important correlative data for human dosimetry.

Biomarkers of Exposure and Effect

Exposure. Currently, no specific biomarkers for chlorophenols are known. The presence of chlorophenols or

their metabolites in urine is not necessarily diagnostic for chlorophenol exposure because these compounds are

also detectable in urine after exposure to other pesticides (Hill et al. 1989; Karapally et al. 1973; Shafik et al.

1973) and hexachlorocyclohexanes (Engst et al. 1976; Koransky et al. 1975). Well-designed animal metabolism

studies involving the kinetics of urinary chlorophenol conjugate excretion after exposure to a battery of

chlorinated organics are needed to provide data regarding the usefulness of urinary measures as biomarkers of

exposure for individuals living near hazardous waste sites.

Effect. No carcinogenic or noncarcinogenic effect in exposed humans has been associated with a specific

chlorophenol or a group of chlorophenols. With the possible exceptions of convulsions following

monochlorophenol exposure (Angel and Rogers 1972; Borzelleca et al. 1985a, 1985b; Farquharson et al. 1958),

clearly defined end points of toxicity in animals are not known. Furthermore, these end points that are associated

with chlorophenol exposure are not specific to chlorophenols. When in direct contact with skin and eyes, the

chlorophenols demonstrate varying degrees of corrosiveness (Bioassay Systems 1982; Rhodia 1978; Younger

Labs 1975). Other effects of chlorophenols, including effects on the immune system (Exon et al. 1984) and

reproduction (Exon and Koller 1985), are also not specific to chlorophenols.
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2. HEALTH EFFECTS

Further studies designed to identify specific biomarkers of effects of chlorophenols would facilitate medical

surveillance of exposed populations leading to early detection of potentially adverse health effects and possible

treatment.

Absorption, Distribution, Metabolism, and Excretion. Studies in sawmill workers indicate that

trichlorophenol and tetrachlorophenol are well absorbed during occupational exposure (Fenske et al. 1987;

Pekari et al. 1991). The dermal route had a greater absorption potential than the inhalation route. The

investigators determined that elimination half-lives were directly proportional to the degree of chlorination for

the tri-, tetra-, and pentachlorophenols. Concentrations of 2,4-DCP were measured in the blood, urine, bile, and

stomach contents of a worker who collapsed (within 20 minutes) and died shortly after being splashed with pure

2,4-DCP on his right arm and leg (Kintz et al. 1992). Attempts to attain additional data in humans are limited by

ethical considerations and by the fact that measurements of chlorophenol levels in the blood and urine of

manufacturing workers may not be specific for chlorophenol exposure.

The limited amount of data available from animal oral studies indicates that these chemicals are rapidly

absorbed, conjugated to polar metabolites in the liver and kidney, and excreted in the urine (Bahig et al. 1981;

Bray et al. 1952a, 1952b; Korte et al. 1978; Spencer and Williams 1950). Absorption also occurs after in vivo

(Carreon et al. 1980a, 1980b; Hencke and Lockwood 1978) and in vitro (Hughes et al. 1993; Huq et al. 1986)

dermal application. Rate constants for in vivo preparations were not located. Tissue burden is apparently shortlived, with plasma elimination half-lives of approximately 10 minutes after intravenous 2,4-DCP administration

(Somani and Khalique 1982), and peak tissue concentrations occurring approximately 30 minutes after

intraperitoneal 2,4,6-TCP dosing (Pekari et al. 1986). Plasma protein binding is significant after administration

of the higher chlorophenols; in humans, the extent of binding increases with the increasing degree of

chlorination (Pekari et al. 1991).

Studies concerning the inhalation absorption and oral absorption of chlorophenols from different media (e.g.,

water, soil) and the effect of ionization on dermal absorption are needed for estimating exposure at a hazardous

waste site.

More systematic information about absorption and elimination kinetics are needed. Furthermore, time series

studies using radiolabelled chlorophenols would help identify residence times in individual organs, which may

provide insight into potential target organs in human populations.
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2. HEALTH EFFECTS

Semiquinones and quinones may be potentially toxic but short-lived metabolites after oral exposure (Juhl et al.

1991; Phornchirasilp et al. 1989b). The extent and type of Phase II detoxification reactions is apparently speciesand isomer-related (Bahig et al. 1981; Bray et al. 1952a, 1952b; Pekari et al. 1986; Somani and Khalique 1982;

Spencer and Williams 1950). Broad-based experimentation to determine dose-effect relationships for hepatic

adaptive and toxic effects are needed. Part of this experimentation may involve estimation of the rate constants

for the formation of both potentially toxic intermediates and Phase II conjugates. Metabolic studies for

determining rate differences in conjugate formation between oral, inhalation, and dermal exposure may also

suggest route-specific differences in the expression of toxicity.

Comparative Toxicokinetics. Toxicokinetic studies with chlorophenols have been conducted in humans, mice,

rats, rabbits, and dogs (Azouz et al. 1953; Bray et al. 1952a, 1952b; Exon and Koller 1982; Fenske et al. 1987;

Hattula et al. 1981; Phomchirasilp et al. 1989a; Somani and Khalique 1982; Spencer and Williams 1950). The

results of these studies provide a limited profile of toxicokinetics information after oral exposure. These results

do not adequately characterize the metabolic rate differences between the various isomers. More comprehensive

toxicokinetic studies using radiolabelled isomers administered at several dose levels in two rodent species and

one or more nonrodents are needed. These data may be supplemented by hepatic and renal biopsy data and

urinary metabolite analysis obtained in exposed individuals.

Methods for Reducing Toxic Effects. The P-448 inducer 3-MC, and possibly other PAHs, apparently

increase the Phase 11 conjugation rates of phenolic substrates (Jansen et al. 1992; Wishart 1978a, 1978b). This

observation implies that certain chemicals may decrease the body burden of chlorophenols by accelerating the

elimination process. Despite this capability, PAH-induced P-448 metabolism may actually increase the extent of

hepatic injury through the formation of metabolites capable of undergoing covalent binding (Arrhenius et al.

1977). Research into the development of therapeutic agents that accelerate chlorophenol elimination through

Phase II detoxification reactions, but that do not produce bioreactive metabolites (such as semiquinones), may

be advisable.

Children’s Susceptibility No data are available on the health effects of chlorophenols on exposed

children. Since the metabolic enzymes for detoxification may have age dependent expression, there is a need for

such data.
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2. HEALTH EFFECTS

There is inadequate experimental evidence to evaluate whether pharmacokinetics of chlorophenols are

different in children. There are also limited data to show whether chlorophenols are stored in maternal

tissues. There are no direct data on whether chlorophenols cross the placenta or accumulate in breast milk.

There is no experimental evidence to evaluate whether metabolism of chlorophenols or their mechanism of

action is different in children. However, in humans, activity of UDP-glucuronosyltransferase (responsible for

glucuronide conjugates) does not reach adult levels until about 6-8 months of age, although the development of

this activity is isoform specific. Activity of sulfotransferases (responsible for sulfate conjugates) seems to

develop earlier, although again, it is isoform specific. The activity of some sulfotransferase isoforms may be

greater than that of adults during infancy and early childhood (Leeder and Kearns 1997). It will be helpful to

have data on the metabolism and mechanism of action of chlorophenols in children to determine whether

children are more vulnerable than adults to the health effects from exposure to chlorophenols. There are no

biomarkers of exposure or effect that have been validated in children or adults exposed as children. There are no

data to determine whether there are any interactions with other chemicals that are unique to children or whether

interactions observed in adults occur in children.

Child health data needs relating to exposure are discussed in 5.8.1 Data Needs: Exposures of Children.

2.11.3 On-going Studies

Dr. Corwin Hansch of Pomona College in California is developing quantitative structure-activity

relationships for a variety of chlorinated organics, including the monochlorophenols. The principal end point of

concern is teratogenicity in mice and rats. This work is currently being prepared for publication.

No other information regarding on-going research on the health effects of chlorophenols in humans or

animals were located.

CHLOROPHENOLS 133

3. CHEMICAL AND PHYSICAL INFORMATION

3.1 CHEMICAL IDENTITY

Information regarding the chemical identity of the chlorophenols is located in Table 3-l.

3.2 PHYSICAL AND CHEMICAL PROPERTIES

Information regarding the physical and chemical properties of the chlorophenols is located in Table 3-2. Except

for 2-CP, which is a liquid at room temperature, all the chlorophenols discussed in this profile are solids at room

temperature.





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4. PRODUCTION, IMPORT, USE, AND DISPOSAL

4.1 PRODUCTlON

Table 4-1 lists the facilities in each state that manufacture or process chlorophenol, the intended use, and the range

of maximum amounts of chlorophenol that are stored on site. There are currently 4 facilities that produce or

process chlorophenols in the United States The data listed in Table 4-1 are derived from the Toxics Release

Inventory (TR196 1998). Only certain types of facilities were required to report. Therefore, this is not an

exhaustive list.

The chlorinated phenols are manufactured by chlorination of phenol, or for the higher chlorinated phenols, the

chlorination of lower chlorinated phenols at high temperatures (WHO 1989). The manufacture of the

tetrachlorinated phenols requires a catalyst (e.g., iodine, ferric chloride). 2,4,5-TCP, 2,3,4,5-TeCP, and 2,3,5,6-

TeCP have also been produced by the alkaline hydrolysis of hexachlorobenzene (WHO 1989). Both processes of

chlorophenol production result in the formation of impurities. The impurities include polychlorinated dibenzo-pdioxins (PCDDs), polychlorinated dibenzofurans (PCDFs), polychlorinated phenoxyphenols, polychlorinated

diphenyl ethers, polychlorinated benzenes, and polychlorinated biphenyls. Because the higher chlorinated phenols

are produced at higher temperature, the contamination of the higher chlorinated phenols is greater than that of the

lower chlorinated phenols (WHO 1989).

Recent data about the production of the chlorinated phenols are very limited. The Toxics Release

Inventory has grouped all chlorophenols together for 1996 data. The BASF Corp. in Beaumont, Texas is the largest

manufacture or processor of chlorophenols with 100,000-999,000 pounds on site (TR1996 1998). 2,3,4,6-TeCP is

not produced commercially in the United States (HSDB 1998). Pentachlorophenol, which generally contains about

4% tetrachlorophenols and 0.1% trichlorophenols (Kalliokoski and Kauppinen 1990), is also not produced in the

United States (TR1996 1998). Additional data concerning the production of the chlorinated phenols were not

available.

4.2 IMPORT/EXPORT

Recent data concerning the import/export of chlorophenols were not available. The latest year for which HSDB

(1998) has United States import data on a given chlorophenol is listed below.

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4. PRODUCTION, IMPORT/EXPORT, USE, AND DISPOSAL

2-CP 1983 33,300 kg

4-CP 1975 33,900 kg

2,4-DCP 1977 500 kg

2,4,5-TCP 1981 216,000 kg

2,4,6-TCP 1980 250 kg

4.3 USE

All the chlorophenols have been used as biocides. The monochlorophenols have been used as antiseptics (HSDB

1998), although in this role they have largely been replaced by other chemicals (WHO 1989). Specifically, 4-CP

has been used as a disinfectant for home, hospital, and farm uses (WHO 1989) and as an antiseptic in root canal

treatment (Gurney and Lantenschlager 1982). 2,4-DCP has been used for mothproofing and as a miticide (WHO

1989), while the higher chlorophenols have been used as germicides, algicides, and fungicides.

The principal use of the monochlorophenols has been as intermediates for the production of higher

chlorinated phenols (WHO 1989). The largest uses for 2,4-DCP and 2,4,5-TCP have also been used as an

intermediate, especially in the production of the herbicides 2,4-dichlorophenoxyacetic acid (2,4-D) and 2,4,5-

trichlorophenoxyacetic acid (2,4,5-T) (WHO 1989). In the United States, 2,4-D is still in use, while 2,4,5-T was

taken off the market in 1985. 2,4,6-TCP has been used as an intermediate in the production of higher chlorinated

phenols especially 2,3,4,6-TeCP and pentachlorophenol (WHO 1989).

2,4,6-TCP and the tetrachlorophenols have also been used directly as wood preservatives (HSDB 1998). In this

role, the tetrachlorophenols are generally used as a mixture and are applied to lumber in an aqueous solution

(WHO 1989). Commercial pentachlorophenol, which is more frequently used as a wood preservative, also

contains about 4% tetrachlorophenols and 0.1% trichlorophenols (Kalliokoski and Kauppinen 1990). North

America and Scandinavia are the main regions of the world where chlorophenols have been used as wood

preservatives. The use of these compounds has been banned in Sweden since 1978, and production was banned

in Finland in 1984 (Kalliokoski and Kauppinen 1990).
CHLOROPHENOLS 142

4. PRODUCTION, IMPORT/EXPORT, USE, AND DISPOSAL

4.4 DISPOSAL

Chlorophenols are listed as toxic substances under Section 313 of the Emergency Planning and Community

Right to Know Act (EPCRA) under Title III of the Super-fund Amendments and Reauthorization Act (SARA)

(EPA 1995). Disposal of wastes containing chlorophenols is controlled by a number of federal regulations (see

Chapter 7).

The recommended method of disposing of large amounts of higher chlorinated phenols is incineration,

preferably after mixing with another combustible fuel (HSDB 1998). Necessary precautions include the

assurance of complete combustion in order to prevent the formation of toxic phosgene gas and the use of an acid

scrubber to remove any halo-acids produced upon combustion (Sittig 1985).
CHLOROPHENOLS 143

5. POTENTIAL FOR HUMAN EXPOSURE

5.1 OVERVIEW

One or more of the eight chlorophenols discussed in the profile has been identified in at least 171 of the 1,467

hazardous waste sites that have been proposed for inclusion on the EPA National Priorities List (NPL) (HazDat

1998). However, the number of sites evaluated for chlorophenols is not known. The frequency of these sites can

be seen in Figure 5-l.

The majority of known environmental releases of chlorophenols were to surface water (Scow et al. 1982). The

principal point source of water pollution by chlorophenols is industrial waste discharge; another point discharge

is the leaching of chlorophenols from landfills. Chlorophenols enter the atmosphere through volatilization, with

mono- and dichlorophenols being the most volatile. The primary nonpoint source pollution of chlorophenols

comes from the application of pesticides that are made from chlorophenols and the chlorination of waste water

containing phenol.

Once released to the environment, chlorophenols are subject to a series of physical, chemical, and biological

transformations. Sorption, volatilization, degradation, and leaching are the primary processes governing their

fate and transport. The pH in water and in soil and sediment is a major factor affecting the fate and transport of

chlorophenols in these media, since the degree to which the compounds ionize increases with increasing pH. In

addition, physiochemical properties of chlorophenols such as water solubility, Henry’s law constant, organic

carbon sorption coefficient, volatilization rate, and photolysis rate determine transport processes. Important

environmental parameters influencing these processes include organic matter content and clay content in soil,

sediment, and water, as chlorophenols are in general preferentially adsorbed to these soil constituents. In

general, as the number of chlorine molecules increase, there is a reduction in vapor pressure,

an increase in boiling point, and a reduction in water solubility of the chlorophenols (Solomon et al. 1994).

Therefore, increasing chlorination increases the tendency of these compounds to partition into sediments and

lipids and to bioconcentrate. Chlorophenols are subject to abiotic and biotic degradation and transformations.

However, compounds containing chlorine in the meta positions show greater resistance to microbial attack.

The general population may be exposed to chlorophenols through ingestion of chlorinated drinking water and

food contaminated with the compounds and inhalation of contaminated air. Exposure to 4-CP could also occur

through its use as a root canal packing. Populations with potentially unusually high exposure to

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5. POTENTIAL FOR HUMAN EXPOSURE

chlorophenols generally include employees of facilities that manufacture or use chlorophenols and their

derivatives and those who live in the vicinity of chlorophenol-containing waste disposal sites and waste

incinerators.

5.2 RELEASES TO THE ENVIRONMENT

5.2.1 Air

According to the Toxic Chemical Release Inventory, in 1996, releases of chlorophenols to the air from three

large processing facilities were 2148 kg (4,775 pounds) (TRI96 1998). Table 5-l lists amounts released from

these facilities. The TRI data should be used with caution because only certain types of facilities are required to

report. This is not an exhaustive list.

Both monochlorophenols and 2,4-DCP are volatile, and volatilization may be the major dispersal mechanism of

these chemicals into the atmosphere. Trichlorophenols and tetrachlorophenols are slightly volatile. However,

only a small fraction (approximately 5%) of chlorophenols (based on 2-CP, 2,4-DCP, and 2,4,6- TCP) are

emitted to the atmosphere (Scow et al. 1982). These releases are primarily in vapor form and are principally

associated with chlorophenol production and its use in the manufacture of end-use products (Scow et al. 1982).

Releases of chlorophenols to the atmosphere may also occur through the incineration of chlorinated wastes. 2,4-

DCP has been detected in atmospheric emissions from the combustion of municipal solid waste, hazardous

waste, coal, wood, and 2,4-DCP-based herbicides (Gomez et al. 1988; Junk et al. 1986; Oberg et al. 1989;

Paasivirta et al. 1985). Trichlorophenols have been detected in flue gas condensates and fly ash from municipal

incinerators (Viau et al. 1984). Di-, tri- and tetrachlorophenols have also been detected in fly ash from wood, oil,

and coal-fired power plants at concentrations in the ng/g level (Paasivirta et al. 1985).

Chlorophenols have been detected in air samples collected at 2 of the 1,467 current or former NPL hazardous

waste sites (HazDat 1998).

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5. POTENTIAL FOR HUMAN EXPOSURE

5.2.2 Water

According to the Toxic Chemical Release Inventory, in 1996, releases of chlorophenols to the water from three

large processing facilities were 6 kg (13 pounds) (TR196 1998). There were no releases of chlorophenols into

publicly owned treatment works (POTWs) in 1996 (TR196 1998). Table 5-l lists amounts released from these

facilities. The TRI data should be used with caution because only certain types of facilities are required to

report. This is not an exhaustive list.

The majority (85%) of known environmental releases of three chlorophenols (2-CP, 2,4-DCP, and

2,4,6-TCP) were to surface water (Scow et al. 1982). The estimated 1977 water emissions of 2,4-DCP were

741,000 pounds from U.S. production facilities (Scow et al. 1982). Industrial waste discharge is a major point

source of water pollution by mono- and dichlorophenols (Krijgsheld and Van der Gen 1986). Monochlorophenol

concentrations of between 10-20 μg/L have been released in waste water produced during the manufacture of

specialty chemicals (Buikema et al. 1979; Hites et al. 1979), and 5.3 μg/L of 4-CP was detected in a bleaching

effluent released to surface water from a straw mill (Folke and Lindgaard-Jorgensen 1985). 2,4-DCP or 2,4,6-

TCP were also detected in effluents discharged from industries that manufacture iron and steel, electrical

components, photographic equipment/supplies, pharmaceuticals, and organic chemicals/plastics and from paper

pulp and paperboard mills (EPA 1981; Paasivirta et al. 1985). Oikari et al. (1985) reported that concentrations of

2,4,6-TCP and 2,3,4,6-TeCP were higher downstream from a pulp and paper mill than upstream from the

facility. Free chlorophenols were still present in water 11 km downstream from the mill. However, the release of

chlorophenols to water from pulp bleaching mills is being reduced as the use of elemental chlorine for bleaching

is being phased out in favor of the use of chlorine dioxide (Solomon et al. 1994). Compared to chlorine, chlorine

dioxide bleaching results in the production of fewer chlorophenols, and the chlorophenols that are produced

contain fewer chlorine molecules.

Other sources of discharge of chlorophenols into aquatic systems include sewage treatment plants and

drinking water treatment, which can result in the chlorination of phenol. In a study of 40 Canadian potable water

treatment facilities, 4-CP, 2,4-DCP, and 2,4,6-TCP are the three halogenated phenols found most frequently in

samples taken from chlorinated water supplies (Sithole and Williams 1986). The frequency of detection ranged

from 1 to 12 out of 40 samples. Mean values were <7 Νg/L and the maximum values <130 Νg/L. 2-CP has also

been detected in treated drinking water in the Netherlands (1 μg/L) (Buikema et al.
CHLOROPHENOLS 148

5. POTENTIAL FOR HUMAN EXPOSURE

1979). The maximum monochlorophenol concentrations measured in river water range from 2-6 μg/L

(Krijgsheld and van der Gen 1986).

2-CP has been detected in the leachate from a municipal landfill, while 2,4-DCP was found in the leachate from

an industrial landfill (Brown and Donnelly 1988). 2-CP was detected in the runoff from 1 of 15 cities, while

neither 2,4-DCP nor 2,4,6-TCP were detected in the runoff from 3 cities (Cole et al. 1984). Analysis of

groundwater taken from 479 waste disposal sites found that 2,4-DCP was detected at 19 sites, 2-CP at 14 sites,

and 2,4,5-TCP at 2 sites, while 2,3,4,6-TeCP was not detected at any of the sites (Plumb 1991).

The detection of 2,4,6-TCP in industrially unpolluted surface water in Sweden at concentrations up to

10 ng/L suggests that this compound can be formed by natural chlorination of humic substances (Grimvall et al.

1991). A laboratory investigation (Hodin et al. 1991) reported that the addition of chloroperoxidase from the

fungus Culduriomyces fumugo, hydrogen peroxide, and potassium chloride to bog water (pH adjusted to 3 with

100 mM phosphate) did result in the production of 2,4,6-TCP. Chloroperoxidase could also chlorinate added

phenol to form 2-CP and 4-CP. These results suggest that chloroperoxidase-mediated chlorination of natural

organic matter does contribute to the levels of chlorophenols (especially 2,4,6-TCP) that are found in surface

water.

Chlorophenols have been detected in groundwater and surface water collected at 98 and 25 of the

1,467 current or former NPL hazardous waste sites, respectively (HazDat 1998).

5.2.3 Soil

According to the Toxic Chemical Release Inventory, in 1996, there were no releases of chlorophenols to soil

(TRI96 1998); however, an estimated 5,246 kg (11,658 pounds) are disposed of in off site facilities. In addition,

about 51,099 kg (113,554 pounds) are disposed of by underground injection. Therefore, manufacturing and

processing industries are sources of release in soils surrounding the disposal sites. Table 5-l lists amounts

released from these facilities. The TRI data should be used with caution because only certain types of facilities

are required to report. This is not an exhaustive list.

Releases of chlorophenols to soils may occur through several processes such as disposal of manmade wastes

(e.g., landfills), atmospheric deposition, and accidental releases (e.g., spills) (Scow et al. 1982). Smith (1985)

has found that the herbicide 2,4-dichlorophenoxyacetic acid can be degraded to 2,4-DCP following
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5. POTENTIAL FOR HUMAN EXPOSURE

soil application. Unspecified trichloro- and tetrachlorophenols have been identified at sites cornposting yard

waste and municipal solid waste (Malloy et al. 1993). The investigators (Malloy et al. 1993) suggested that the

source was pentachlorophenol on treated wood in chipped form that had been added as a bulking agent. The use

of chlorophenols as a wood preservative (predominantly 2,3,4,6-TeCP) has also resulted in the contamination of

soil around sawmills where these compounds were used (Kitunen et al. 1985, 1987; Valo et al. 1984).

Chlorophenols have been detected in soil, sediment, and leachate collected at 65, 31, and 12 of the

1,467 current or former NPL hazardous waste sites, respectively (HazDat 1998).

5.3 ENVIRONMENTAL FATE

5.3.1 Transport and Partitioning

The environmental fate and transport of chlorophenols are controlled by their physical and chemical

properties and environmental conditions. As shown in Table 3-2, all chlorophenols are solids at room

temperature except 2-CP, which is a liquid. In general, as the number of chlorine molecules increase, there is a

reduction in vapor pressure, an increase in boiling point, and a reduction in water solubility (Solomon et al.

1994). Therefore, increasing chlorination increases the tendency of the chlorophenols to partition into sediments

and lipids and to bioconcentrate.

The higher vapor pressures of the monochlorophenols suggest that among the chlorophenols, these

compounds are most likely to be found in air. Specific data concerning monochlorophenols in air were not

identified. The vapor pressures of the chlorophenols suggest that the compounds will not partition from the

vapor phase to the particulate phase (Eisenreich et al. 1981). That 2,4-DCP and other chlorophenols do not

partition into the particulate phase is supported by the identification of 2,4-DCP, 2,4,5-TCP, 2,4,6-TCP, and

2,3,4,6-TeCP in rain but not on rain filters (Leuenberger et al. 1985). This study indicates that gas scavenging

rather than particle scavenging is the more important process for removing chlorophenols from the air

(Leuenberger et al. 1985). Estimated rain/air partition coefficients at 8°C are 2.2 x 104

 for 2,4-DCP and 1.8 x 104

for 2,4,5-TCP and 2,4,6-TCP combined (Leuenberger et al. 1985).

The rate of chemical evaporation from an aqueous solution largely depends on a chemicals vapor pressure and

water solubility (Henry’s law constant). Among the chlorophenols discussed in this profile, 2-CP has
CHLOROPHENOLS 150

5. POTENTIAL FOR HUMAN EXPOSURE

the highest vapor pressure and, therefore, is mostly likely to evaporate from water (Krijgsheld and Van der Gen

1986). In laboratory studies, evaporation half-lives of 2-CP and 4-CP from water 0.38 cm deep were 1.35-1.6 hours

and 12.8-17.4 hours, respectively (Chiou et al. 1980). Since the evaporation rate is inversely related to the depth of

water, extrapolation of these data indicates that-2-CP evaporation in water 1 meter deep would require

approximately 15 days. The amount of volatilization of 2-CP from fine sandy soil (0.087% organic carbon),

applied in spiked municipal waste water, was too small to be directly measured (Piwoni et al. 1986).

Volatilization of 2,4-DCP from water is expected to be slow and, therefore, not a major removal process from

surface waters. Using the Henry’s law constant, a half-life of 14.8 days was calculated for evaporation from a

model river 1 meter deep with a current of 1 meter/second and a wind velocity of 3 meters/second, neglecting

adsorption to sediment (Thomas 1982). The biological treatment of waste water containing 2,4-DCP has shown

that none of the chemical is removed by stripping (Stover and Kincannon 1983). Volatilization from near-surface

soil is also not expected to be a significant removal process.

The Henry’s law constants for 2,4,5-TCP (0.0039) and 2,4,6-TCP (0.0043) are similar to 2,4-DCP (0.0033).

Therefore, the volatilization of these trichlorophenols should be similar to that of 2,4-DCP. In 2-hour laboratory

studies, the volatilization rates of 2,4,6-TCP from water and three soil types were determined by Kilzer et al.

(1979). These rates, expressed as the percentage of applied compound per milliliter of water evaporated from

humus, loam, sand, and water, were 0.15,0.73, 1.05, and 1.4%, respectively, in the first hour after the addition of

50 ppb 2,4,6-TCP. Similar rates were reported during the second hour. In wind tunnel experiments, Sugiura et al.

(1984) estimated a half-life of 48 hours for loss of 2,4,6-TCP from water through volatilization. An estimated 58%

of 2,4,6-TCP in a nutrient solution in which tomatoes were grown was lost to the air (from photolysis and/or

volatilization) over a period of 30 days (Fragiadakis et al. 1981).

Experimental studies examining the volatilization of tetrachlorophenols were not located. Based on lower Henry’s

law constants and a greater potential to exist as the dissociated compound in the environment, tetrachlorophenols

would be less likely to volatilize from water and soil than the lower chlorinated chlorophenols .

In addition to vapor pressure and solubility, pKa and log Kow (octanol water partition coefficients) are other

important properties which determine the transport and partitioning of chemicals. The lower chlorophenols have

higher pKa values (7.42-8.49). Therefore, in natural waters these compounds will exist primarily as the
CHLOROPHENOLS 151

5. POTENTIAL FOR HUMAN EXPOSURE

undissociated compounds, and adsorption to sediments at a pH of not more than one unit greater than the pKa can

be predicted based on the organiccontent of the sediments and the octanol/water partition coefficient (Schellenberg

et al. 1984). In contrast, the pKa values of the tetrachlorophenols are lower (5.48-6.96) so that at ambient pH values

these compounds are present predominantly in the ionized form, and the adsorption to sediemtns will also be

dependant on the ionic strength of the wat (Schellenberg et al. 1984).

In general, a chemical will preferentially partition into organic matter if its log Kow is > 1 (Scow et al. 1982). Log

Kows for the chlorophenols are all > 2 (see Table 3-2); therefore, the chlorophenols will all tend to partition into

sediments. Despite this prediction, a modeling study completed by Yoshida et al. (1987) suggests that most of the

2,4,6-TCP released to surface waters would remain in the water rather than absorb to sediments. They estimated

that in a river receiving daily inputs of the compounds, 72% would be in the water and 28% in the sediment. In a

deep, otherwise unpolluted lake, 84% would be in the water and 16% in the sediment. Laboratory sorption

experiements with natural sediments containing up to 10% organic matter have been conducted using 2-CP and

2,4-DCP (Isaacson and Frink 1984). Sediment sorption capacity was extensive (up to 0.3 mmol/g), and up to 90%

of the adsorption was irreversible.

Chlorophenols are capable of binding to soil organic matter via covalent bond formation, resulting from

biologically or chemically catalyzed reactions. In a batch sorption experiment, the binding of 4-CP to soil requires

oxygen and soil bioactivity, indicating a biologically mediated oxidative coupling reaction. The addition of

hydrogen peroxide, which may be an oxygen source, caused a 4.4 fold increase in 4-CP binding (Bhandari et al.

1996).

As the number of chlorines on phenols increases, sorption of chlorophenols to organic material in soil increases.

For example, at two sawmills in Finland where chlorophenol wood preservative (primarily 2,3,4,6-TeCP) was

used, soil was contaminated to a depth of 80 to 100 cm to the same extent as at the surface (Valo et al. 1984). As

soil depth increased, the concentration of dichlorophenols increased. The investigators attributed this observation to

a greater transport of dichlorophenols through the soil and to the relatively increased degradation of the higher

chlorinated phenols. An experimental study that examined the movement of 2-CP and 2,4,5-TCP through two soil

types (organic carbon 2.1 mg C/g soil or 1.5 mg C/g soil) found that the relative velocity of the chlorophenol

through soil into water was 3.5-4 times greater for 2-CP compared to 2,4,5-TCP (Kjeldsen et al. 1990). The

chlorophenols moved slowest in the soil with the greatest organic carbon content.
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5. POTENTIAL FOR HUMAN EXPOSURE

Chlorophenol groundwater contamination will occur if sufficient quantities of the chemical are present to exceed

the sorption capacity of the vadose zone saturated soils (Scow et al. 1982). Contamination is most likely in soils

with low organic carbon content or high pH. Once in groundwater, sorption of chlorophenols by the solid

aquifer matrix may be estimated based on log Kow and organic carbon content, provided that the organic carbon

content exceeds 0.1% and the aquifer pH is not sufficiently high for significant dissociation to occur

(Schellenberg et al. 1984; Schwarzenbach and Westall 1985). In a natural gradient tracer test conducted within

an unconsolidated aquifer, sorption was not an important factor, compared to dispersion and degradation, in the

attenuation of 4-CP concentrations (Sutton and Barker 1985). The authors attributed this finding to the low

organic carbon content of the aquifer sand unit, which prevented significant hydrophobic sorption.

The bioaccumulation potential of 2-CP, 4-CP, 2,4-DCP, 2,4,5-TCP, 2,4,6-TCP, and 2,3,4,6-TeCP was

reviewed by Loehr and Krishnamoorthy (1988). Based on bioconcentration values and log octanol/water

partition coefficients, they concluded that all chlorophenols studied had the potential for accumulation in aquatic

organisms. Logs of bioconcentration factors ranged from 0.81-2.33 for 2-CP, 1.79-3.28 for 2,4,5-TCP, and 1.95-

2.3 for 2,3,4,6-TeCP. Values of bioconcentration factors for 4-CP, 2,4-DCP, and 2,4,6-TCP were predicted

mathematically (Veith et al. 1980).

Research on biomagnification of chemical residues within the aquatic food chain indicates that the potential for

residue accumulation by fish through food chains is relatively insignificant (<10%) for most compounds when

compared to the tissue residues resulting from the bioconcentration process (i.e., direct uptake from water)

(Barrows et al. 1980). These data suggest that only those chemicals that are relatively persistent in fish tissues

appear to have any potential for significant transfer through food chains (Barrows et al. 1980). A very short

tissue half-life of <l day was measured after bluegill sunfish exposure to 2-CP was terminated (Veith et al.

1980). Therefore, due to their relatively low bioconcentration factors (<1,000) and short biological half-lives

(<7 days), monochlorophenols will probably not biomagnify within aquatic food chains (Barrows et al. 1980).

Data regarding the biomagnification of the higher chlorophenols were not located.

Isensee and Jones (1971) studied the uptake of 2,4-DCP from solution and soil by oats and soybeans. The

compound was taken up by the plants, with the concentrations decreasing as the plants matured. At maturity,

2,4-DCP in oat seeds was below detection (<0.001 μg/g) and in soybeans was 0.003 μg/g. Data regarding the

uptake of other chlorophenols by plants were not located.
CHLOROPHENOLS 153

5. POTENTIAL FOR HUMAN EXPOSURE

The bioaccumulation of 2,3,4,6-TeCP was examined in earthworms (Lumbricus rubellus and Aporrectodea

caliginosa tuberculata) at a sawmill that had been closed 28 years before sampling (Haimi et al. 1992). At a

distance of 5 meters from the dipping basin, 2,3,4,6-TeCP concentrations were 430 and 1,980 μg/g fat in

Lumbricuss and Aporrectodea, respectively, while soil concentrations were 336 μg/g dry soil. The difference

between the two species was attributed to greater ingestion of contaminated soil by Aporrectodea. Additional

data regarding bioaccumulation of chlorophenols in terrestrial organisms was not identified. It is not known

whether 2,3,4,6-TeCP biomagnifies up the terrestrial food chain. Based on physical properties (i.e., greatest log

octanol water partition coefficient), the tetrachlorophenols, rather than lower chlorinated phenols, would have

the greatest potential to biomagnify.

5.3.2 Transformation and Degradation

5.3.2.1 Air

Limited data on the environmental transformations of atmospheric chlorophenols are available. Although

chlorophenols absorb primarily in deep ultraviolet, some absorption in the solar visible spectrum is possible

because of the overlap between this spectrum and the ultraviolet spectrum (Bunce and Nakai 1989). Bunce and

Nakai (1989) found that photolysis and hydroxyl (OH) radical attack were complementary processes for 4 of the

chlorophenols. As indicated below, a greater percentage of 2-CP and 4-CP were degraded by hydroxyl attack

compared to photolysis, while with increasing chlorination, photolytic degradation increased and hydroxyl

attack decreased. Tetrachlorophenols were not tested in this study.

Photolytic degradation Hydroxyl Radical Attack

Chlorophenol (% per hour) (% per hour)

2-CP 0.024 41

4-CP 0.022 41

2,4-DCP 0.11 11

2,4,5-TCP 2.3 8

5.3.2.2 Water

Both direct photolysis and the reaction of chlorophenols with hydroxyl radicals and singlet oxygen produced by

ultraviolet radiation may be important processes of chlorophenol degradation near the water surface. Photolysis

of monochlorophenols in water results in dechlorination, with the position of the chlorine on the ring strongly

influencing the transformation (Boule 1982). In the molecular form, 2-chlorophenol is
CHLOROPHENOLS 154

5. POTENTIAL FOR HUMAN EXPOSURE

converted into pyrocatechol. However, in the anionic form, it is reduced in a cyclopentadienic acid and

dimerizes. For 3-chlorophenol, the photochemical product is resorcinol regardless of the pH. For 4-chlorophenol,

hydroquinone is formed along with polyphenolic oligomers (Boule 1982). The photolysis rates of 2-CP in natural

waters depends on pH, season, and dissolved organic material (Kawaguchi 1992a, 1992b). In all cases the

reaction rate is first order. Based on empirical data, these investigators proposed that direct photolysis of 2-CP

may only occur in natural waters at pH between 7 and 9. Indirect photolysis in lake waters was only significant

in summer months; in sea waters, indirect photolysis has a more significant role in the spring and fall.

Kawaguchi et al. (1992a, 1992b) also found that the dissolved organic matter in pond water does not contribute

to indirect photolysis as significantly as a humic acid solution.

The photocatalytic degradation process with titanium dioxide particles has been shown to be feasible for

achieving a high degree of removal of 2-chlorophenol in water (Ku et al. 1996), with almost complete

disappearance in only a few hours of illumination time. However, the demineralization of reaction intermediates

requires a longer time, and was found to be more effective for acidic solutions. Increasing the light intensity

would significantly increase the decomposition rate of 2-chlorophenol at pH 3, but not pH 11. The higher

removals at acidic conditions may be due to the increased amounts of undissociated 2-chlorophenol species

adsorbed on the TiO2 surface; the TiO2 acting as a catalyst in the photochemical degradation.

The reaction of hydroxyl radicals with monochloro- and dichlorophenols was studied by Kochany and Bolton

(1991) using spin trapping with electron paramagnetic resonance detection of spin adducts. The reaction rate of

4-CP (3.2/1010 M-1s

-1) and 2,4-DCP (3.8/1010 M-1s-1) with hydroxyl radicals was greater than the reaction rate of

2-CP (1.92/1010 M-1s

-1). The observation that chlorophenols with meta-substitution have even slower reaction

rates (1.04/1010 M-1s

-1for 3-CP, 0.9/1010 M-1s-1 for 3,5-DCP) indicates that for the monochloro- and

dichlorophenols, the location of chlorine rather than the number of chlorines is more important in determining

the reaction rate. Higher chlorinated phenols were not examined in this study. Chlorophenols may also be

removed via reaction with photochemically produced singlet oxygen in natural waters. The estimated half-life for

the reaction of 2,4-DCP at pH 7 and 2,4,6-TCP with singlet oxygen at pH 5.5 under midday sun (assuming a

singlet oxygen concentration of 4x10-14) using experimentally determined rate constants is 62 hours (Scully and

Hoigne 1987). The rate of reaction of singlet oxygen with 2,4-DCP and 2,4,6-TCP increased significantly as the

solution pH was raised from 5.5 to 9 (Scully and Hoigne 1987). This observation is consistent with a study by

Tratnyek and Hoigne (1991) who found that the reaction of phenolate ions with singlet oxygen was about one

order of magnitude greater than the reaction of the undissociated chlorophenol. The compounds examined in this
CHLOROPHENOLS 155

5. POTENTIAL FOR HUMAN EXPOSURE

study were 2-CP, 4-CP, 2,4-DCP, and 2,4,6-TCP. Although tetrachlorophenols are most likely to exist as ions in

natural waters, it is not known whether the ions react more readily with singlet oxygen than do the undissociated

tetrachlorophenol compounds.

Hwang et al. (1986) studied the photolysis and microbial degradation of 4-CP, 2,4-DCP, and 2,4,5-TCP in both

estuarine and distilled water. Photolysis was the primary transformation process for 2,4-DCP and 2,4,5-TCP, with

the rate of photolysis decreased in the order 2,4,5-TCP, 2,4-DCP, and 4-CP. The rate of photolysis of 2,4-DCP was

greater in estuarine compared to distilled water, suggesting a photosensitized reaction, The type of water had no

effect on the photolysis of 4-CP and 2,4,5-TCP. Unlike the polychlorinated phenols, microbial degradation was the

primary transformation process for 4-CP (Hwang et al. 1986).

There are numerous studies regarding the microbial degradation of chlorophenols in water and sediments

(Abrahamsson and Klick 1991; Aly and Faust 1964; Banerjee et al. 1984; Genther et al. 1989; Hwang et al.

1986; Vaishnav and Korthals 1988), as well as numerous studies concerning the degradation of these

compounds by sludge (Armenante et al. 1992; Battersby and Wilson 1989; Boyd and Shelton 1984; Liu and

Pacepavicius 1990; Tabak et al. 1981). Although as a group chlorophenols are poorly biodegradable and

persistent in the environment, several studies have shown that aerobic degradation of chlorophenol congeners

is possible (Steiert et al. 1988; Armenante et al. 1992). The aerobic degradation of chlorphenols by

microorganisms requires the participation of the enzyme’s oxygenases to incorporate atmospheric oxygen into

their substrates. For fission of the benzene nucleus, the ring is usually first dihydroxylated by an oxygenase

such that two hydroxyl groups are situated either ortho or para to one another on the ring (Steiert and

Crawford 1985). Subsequent ring fission occurs through another oxygenase-catalyzed reaction involving the

insertion of dioxygen into the aromatic nucleus. The crucial step in the biodegradation of chlorophenols is the

removal of the chlorine substituents. For the catabolism of the lesser substituted phenols (mono- and

dichlorophenols), dioxygenase from chlorophenol-degrading bacteria usually opens the dihydroxylated

aromatic ring before dechlorination takes place (Steiert and Crawford 1985). With more highly substituted

phenols, some of the chlorosubstituents must be removed before ring cleavage since the halogen atoms

deactivate the aromatic nucleus to electrophilic attack by dioxygenases.

It has been reported that 4-CP can be partially or completely degraded by several aerobic bacteria such as

Pseudomonas sp. B13 (Knackmuss 1978) and Azobactirium sp. GPl (Wieser 1997). The catabolic

degradation routes for mono- or dichlorophenols are known to be meta- and modified ortho-pathways (Bae

et al. 1996). In these pathways, 4-CP is hydroxylated to 4-chlorocatechol which then undergoes intradiol
CHLOROPHENOLS 156

5. POTENTIAL FOR HUMAN EXPOSURE

cleavage before the chloro-substituent is removed. In addition, 4-CP degradation by Azobactirium

ureufaciens CPR706 was reported via a pathway in which the chloro-substituent of 4-CP was replaced

with an incoming hydroxyl group to form hydroquinone (Bae et al. 1996). After 4-CP degradation was

completed, the accumulated hydroquinone disappeared from the medium via ring fission forming the 4-

hydroxymuconic semialdehyde intermediate. The general observation of these studies is that

compounds with a chlorine in the meta- and/or para- position are the most resistant to degradation

(Abrahamsson and Klick 1991). In addition, if the bacteria have not been cultured in the presence of a

chlorophenol, they require an adaption period before the compounds can be degraded. For example,

degradation of 2,4-DCP was observed in natural water collected from a river following lag times of 2.5

and 8.3 days for 2 separate collections (Banerjee et al. 1984). The rates of degradation of 4-CP, 2,4-CP,

and 2,3,4,5-TeCP in river water were 6.5 x 10-6, 2.3x10-6, and 1.4x10-7 moles/hour, respectively

(Banerjee et al. 1984). A study by Liu and Pacepavicius (1990) indicates that the position, rather than

the number of chlorine atoms, is more important in determining the biodegradation of chlorophenols.

The biodegradation of chlorophenols was studied in both aerobic and anaerobic systems using a

pentachlorophenol-degrading bacterial culture. The results, shown in Table 5-2, indicate lag time to

degradation, and half-life tended to be shorter for compounds with a chlorine in the 4 position and

longer for compounds with a chlorine at the 5 position. Anaerobic degradation of the chlorophenols

required a longer lag time and the half-lives were longer.

Reductive dehalogenation of chlorinated aromatic compounds whereby chlorines are being replaced by

hydrogens occurs extensively under anaerobic conditions (Steiert and Crawford 1985). Anaerobic

dehalogenation of 2-chlorophenol, a common intermediate of polychlorophenol degradation, by mixed

cultures was reported (Theme1 et al. 1996). Acetate was found to be the major end product, with phenol and

benzoate as intermediate products, but CO, was not found to be an end product.

A study of anaerobic degradation of chlorophenols in waste water in an upflow anaerobic sludge blanket reactor

indicated that the higher chlorophenols were converted to lower chlorinated compounds via reductive

dechlorination reactions (Woods et al. 1989). The rate of these reactions was dependent on the position of the

chlorine; chlorines adjacent to the hydroxyl group were preferentially removed, and meta chlorines were removed

following acclimation, with no evidence for the removal of para chlorines. Woods et al. (1989) also found no

evidence for the dechlorination of monochlorophenols in this system.

4-chlorophenol was demonstrated to be quickly removed from formulated waste water catalyzed by

horseradish peroxidase (Zhang et al. 1997) to form radicals or quinones, which might be subsequently

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5. POTENTIAL FOR HUMAN EXPOSURE

polymerized to form less soluble large molecules and precipitated from aqueous phase. The flocculant might

increase the removal percentage of the pollutant through enhancing the sedimentation of the reaction products The

optimum pH for the removal efficiency of chlorophenol was 9.0. The analytical method would, thus, have to

quantify both salt and acid forms of the chlorophenol.

5.3.2.3 Sediment and Soil

Chlorophenol isomers undergo biodegradation in soils under aerobic conditions. Aerobic microorganisms that can

degrade chlorophenols have been isolated from soil bacterial cultures. Pseudomonas picketti DTP0602, which used

2,4,6-TCP as the sole source of carbon and energy, was isolated from mixed cultures of soil bacterial populations

that had been acclimatized to 2,4,6-TCP (Kiyohara et al. 1992). This bacterial species dechlorinates the chlorine

atom at position 4 of various CPs to yield their corresponding hydroquinones and may involve oxygenation. Two

different enzyme systems for hydroxylation at the ortho and para positions of the phenol ring may be present in

this bacterial species. The para-hydroxylation system, which may use a monooxygnease, possibly involves the

dechlorination of a 4-position chlorine atom of CPs. 2,4,6-Trichlorophenol-4-monooxygenase, a dehalogenating

enzyme, was also isolated from TCP-degrading soil bacterium Azotobacter sp., strain GPl (Wieser et al. 1997).

NADH, flavin adenine dinucleotide, and O2 are required as cofactors. 2,6-dichlorohydroquinone and Cl-

 ions were

identified as reaction products. TCP was the best substrate for this enzyme. However, the majority of other

chlorophenols converted by the enzyme bear a chloro substituent in the 4-position. 2,6-dichlorophenol, also

accepted as a substrate, was hydroxylated in the 4-position to 2,6-dichlorohydroquinone in a nondehalogenating

reaction. It was also reported that the addition to the culture medium of a vitamin solution containing biotin, folk

acid, pyridoxine hydrochloride, riboflavin, thiamine hydrochloride, niacin, pantothenic acid, cyanocobalamin, paminobenzoic acid, and thioctic acid can increase the aerobic degradation and dechlorination of 2-CP and 4-CP by

Pseudomonas picketti strain LDl culture by 1l-16% (Kafkewitz et al. 1996).

The extent and rate of biodegradation depend on numerous factors, including soil pH, organic carbon content,

biomass, and the chlorophenol isomer and its concentration. In neutral clay-loam soil at 20°C under aerobic

conditions, 2-CP was degraded the fastest (Baker and Mayfield 1980). Decomposition rates were as follows: 100%

of the 2-CP in 1.5 days, 95% of the 2,4,6-TCP in 3 days, 83% of the 4-CP in 20 days, 81% of the 2,4-DCP in 40

days, and 72 and 31% of the 2,4,5-TCP and 2,3,4,5-TeCP, respectively, in 160 days (Baker and Mayfield 1980).

Dasappa and Loehr (1991) examined the loss of 2-CP, 4-CP, 2,4 DCP, and 2,4,6-TCP from a laboratory soil

microcosm. The loss from soil and the water soluble fraction were examined at two
CHLOROPHENOLS 159

5. POTENTIAL FOR HUMAN EXPOSURE

concentrations for each compound. The loss of chlorophenols from the water soluble fraction was about 1.5 times

greater than the loss from soil, and chemical loss was slower at higher initial concentrations. Mineralization of

2,4,5-TCP in soil not previously exposed to chloroorganics has been reported (Matus et al. 1996). The observation

of 2,3,4,6-TeCP in soil (157-338 μg/g dry soil) at a sawmill 28 years after it closed provides evidence that this

compound can persist in soil. Soil concentrations of 2,3,4,6-TeCP when the mill was closed were not stated. In

general, degradation or complete mineralization to carbon dioxide (CO2) is greater in soils with low organic carbon

content (Kjeldsen et al. 1990), slightly alkaline pH (Balfanz and Rehm 1991), increased temperatures (Baker and

Mayfield 1980; Baker et al. 1980; Balfanz and Rehm 1991), and increased inoculum concentrations (Balfanz and

Rehm 1991).

Microbial degradation of chlorophenols in soil under anaerobic conditions has not been observed consistently. For

2-CP, 4-CP, 2,4-DCP, 2,4,5-TCP, 2,4,6-TCP, and 2,3,4,5-TeCP, no statistically significant differences in

degradation rates between nonsterile and sterile clay loam soils occurred when both soil samples were incubated

under anaerobic conditions (Baker and Mayfield 1980).

In a study of the degradation of halogenated phenols in anoxic marine sediments, the main degradation

pathway was progressive dehalogenation with ortho > para > meta. Sediments which had been exposed to effluent

water from a paper and pulp mill showed a higher dehalogenation potential (Abrahamsson and Klick 1991).

Another study demonstrated that anaerobic degradation of chlorophenols with an estuarine sediment

inoculum was coupled to sulfate reduction, which was the electron sink. The relative rates of degradation

were 4-chlorophenol > 3 chlorophenol > 2 chlorophenol, 2,4-dichlorophenol (Haggblom and Young 1990).

5.4 LEVELS MONITORED OR ESTIMATED IN THE ENVIRONMENT

5.4.1 Air

During seven rain events in Portland, Oregon, in 1984, 2,4-DCP was detected in the air in all seven events

at an average concentration of 1.5 ng/m3

 (0.23 ppt), combined 2,4,5-TCP and 2,4,6-TCP were detected in

6/7 events at an average concentration of 0.15 ng/m3

 (0.02 ppt), and 2,3,4,6-TeCP was detected in 5/7

events at an average concentration of 0.27 ng/m3

 (0.03 ppt) (Leuenberger et al. 1985). Average

concentrations in rain for the seven events were 5.9, 1.1, 1.4, and 20 ng/m3

 (0.89. 0.14,0.17, and 2.1 ppt) for
CHLOROPHENOLS 160

5. POTENTIAL FOR HUMAN EXPOSURE

2,4-DCP, 2,4,5-TCP, 2,4,6-TCP, and 2,3,4,6-TeCP, which were detected in 7/7, 4/7, 5/7, and 7/7 of the events

respectively. Additional data regarding ambient levels of chlorophenols in indoor or outdoor air were not

identified. However, data on 2-CP levels after the accidental derailment and rupture of a train tanker are

available. On the day of the accident, air concentrations ranging from 0.02 to 0.7 mg/m3

 (0.04 to 0.19 ppm) were

detected in the immediate vicinity of the spill (Scow et al. 1982). Eighteen days after the spill, air levels were <2

μg/m3

 (<0.5 ppb). No additional data are available regarding air emissions following accidental releases.

5.4.2 Water

Grimvall et al. (1991) measured 2,4,6-TCP in unpolluted surface waters in remote areas of southern Sweden and

in pulp bleaching plant recipient waters, Lake Vattern and the Baltic Sea. Concentrations up to 10 ng 2,4,6-

TCP/L were found in unpolluted waters, with concentrations of 2,4,6-TCP in Lake Vattern decreasing from 12

ng/L to 1 ng/L with increasing distance from the bleaching plant. 2,4,6-TCP concentrations in the Baltic Sea

were <l ng/L. This study suggests that 2,4,6-TCP can be formed by both industrial and natural chlorination of

humic substances, an observation that was confirmed in the laboratory (Haimi et al. 1992).

Analysis of chlorophenol concentrations downstream of paper mills along the Rainy River in Canada and

northern Minnesota did not identify 2-CP, 4-CP, 2,4,5-TCP, 2,3,5,6-TeCP, or 2,3,4,5-TeCP using methods with

detection limits as low as 50 ng/L (Merriman 1988). In water samples from northern Alberta, Canada, 2-CP was

not detected (detection limit 0.005 μg/L), while 2,4-DCP concentrations were <0.002-7.1 μg/L, and 2,4,6-TCP

concentrations were <0.002-17 μg/L (Morales et al. 1992). 2,4-DCP, 2,4,6-TCP, and 2,3,4,6-TeCP were

identified in water samples from at least one of the three sampling stations. A summary of STORET data of

priority pollutants in ambient water (Staples 1985) indicated that 2-CP was detected in 0.2% of 814 samples,

2,4-DCP was detected in 0.4% of 876 samples, and unspecified trichlorophenols were detected in 0.1% of 880

samples. Analysis of runoff from 15 United States cities for 2-CP, 2,4-DCP, and 2,4,6-TCP identified only 2-

CP, which was found in samples from only one city (Cole et al. 1984).

Chlorophenols are produced during the chlorination of organic material present in industrial and municipal

waste waters. Consequently, several investigators have detected these chemicals downstream of waste water

discharge points. Maximum surface water concentrations measured in 13 samples downstream from a

chlorinated waste water discharge in the Netherlands were (in μg/L) 0.6 for 2-CP, 2.1 for 4-CP, 0.33 for 2,4-

DCP, 0.32 for 2,4,5-TCP, 0.74 for 2,4,6-TCP, 0.02 for 2,3,4,5-TeCP, 0.2 for 2,3,4,6-TeCP, and 0.08 for
CHLOROPHENOLS 161

5. POTENTIAL FOR HUMAN EXPOSURE

2,3,5,6-TeCP (Wegman and van de Broek 1983). Maximum monochlorophenol concentrations of between 2 and 6

μg/L have been measured in European rivers (Krijgsheld and van der Gen 1986).

Chlorination of drinking water at treatment plants can result in detectable levels of chlorophenols if the

required precursors are available in the raw water (Krijgsheld and van der Gen 1986). In a study of Canadian

potable water treatment facilities conducted in the summer, maximum concentrations of 65, 127, 72, and

148 ng/L of 2-CP, 4-CP, 2,4-CP, and 2,4,6-TCP, respectively, were measured, while 2,3,4,5-TeCP was not

detected in the water (Sithole and Williams 1986).

5.4.3 Sediment and Soil

Chlorophenols have been detected in groundwater from waste disposal sites indicating that these compounds can

leach through soil (Plumb 1991). 2,4-DCP was detected most frequently, followed by 2,4,6-TCP, 2-CP, and 2,4,5-

TCP. 2,3,4,6-TeCP was not detected at any of the 479 sites. It was not reported how much of each chlorophenol

was disposed at each site, and soil concentrations at the sites were not reported. 2,4-DCP in the concentration range

of 3.2-79.7 μg/L, as well as other organic compounds, has been found in groundwater samples taken near an

abandoned creosote waste site in Conroe, Texas (Bedient et al. 1984). It is not clear whether soil samples were

analyzed for 2,4-DCP, although soil concentrations of other organic compounds were provided. Kitunen et al.

(1985) reported soil concentrations (in mg/kg wet weight) of 2.7- 47.4, 2, 4-DCP; 0.8-15.7, 2, 4, 5-TCP; 7.3-

1,258.3, 2, 4, 6-TCP; 231-1,776.4, 2, 3, 4,6-TeCP; and 0.9-2.2, 2, 3, 4, 5-TeCP in soil at an operating sawmill in

Finland where chlorophenols (predominantly 2,3,4,6-TeCP) were being used as a wood preservative. The highest

concentrations of chlorophenols were found at depths of 5-40 centimeters. Soil concentrations of 157-338 mg

2,3,4,6-TeCP/kg dry soil were found at a sawmill in Finland 28 years after it had closed, indicating that this

compound can persist for long periods (Haimi et al. 1992). Soil concentrations of 2,3,4,6-TeCP when the sawmill

was in operation were not reported, and soil concentrations of other chlorophenols discussed in this profile were

not measured.

A limited amount of data concerning chlorophenol sediment concentrations in areas of known surface water

contamination is available. 2-CP and 4-CP were not detected in sediments, while the maximum concentrations of

2,4-DCP, 2,4,5-TCP, 2,4,6-TCP, 2,3,4,5-TeCP, 2,3,4,6-TeCP, and 2,3,5,6-TeCP were 10, 15, 3.7, 9.8, 4.9, and 2.8

pg/kg, respectively (Wegman and van de Broek 1983). In the same study, none of the isomers appeared in sediment

samples collected from six locations in the vicinity of chemical and industrial waste water effluent discharge

points. These findings may be misleading because of the poor sensitivity
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5. POTENTIAL FOR HUMAN EXPOSURE

(detection limit of 10 μg/kg) of the gas chromatography/electron capture detector (GC/ECD) analytical

procedure. No 2-CP, 2,4-DCP, or 2,4,6-TCP was detected in sediment samples from northern Alberta, Canada,

where water concentrations of these chlorophenols were low or not detectable (Morales et al. 1992). The limits

of detection in sediments were 0.02 μg/g for 2-CP and 0.01 μg/g for 2,4-DCP and 2,4,6-TCP.

5.4.4 Other Environmental Media

The use of the chlorophenoxy herbicides may result in contamination with 2,4-DCP and 2,4,5-TCP. For

example, Cook et al. (1983) analyzed the free and acid hydrolyzable residues of 2,4-DCP in millet resulting

from treatment with 2,4-dichlorophenoxyacetic acid. The total residues of 2,4-DCP ranged from not detected

(<0.02 ppm detection limit) to 0.031 ppm for postemergence and preharvest treatment. Only 15-19% of the 2,4-

DCP residues were in the free unaltered form, while the remaining residues were conjugated to sugars and

amino acids and converted to the free form by acid hydrolysis.

Few data were found on the levels of chlorophenols in U.S. foods. Most of the data or estimates are for

concentrations in fish or shellfish. Based on the EPA (1980a) estimated bioaccumulation factor (BCF) of 150 in

the edible portion of fish and assuming ambient water concentration of 30 ppb, tissue concentrations of 4.5 mg

2,4,6-TCP/kg bodyweight in fish were estimated by Scow et al. (1982). The authors stated that the 30 ppb value

for water represents a maximum case exposure. 2-CP, 2,4-DCP, and 2,4,6-TCP were not detected in 22

composite samples of fish collected from harbors and tributaries of the Great Lakes (DeVault 1985). 4-CP, 2,4-

DCP, and 2,4,6-TCP were not detected (detection limit 0.02 mg/kg) in fish from 13 Lake Michigan tributaries

(Camanzo et al. 1987) or in fish from northern Alberta, Canada, (detection limit 0.01 μg/g) (Morales et al.

1992). Fish in the Fraser River estuary downstream from a lumber mill were found to contain chlorophenols

including 2,4,5-TCP, 2,4,6-TCP, 2,3,5,6-TeCP, 2,3,4,6-TeCP, and 2,3,4,5-TeCP (Carey et al. 1988). Among the

chlorophenols discussed in this profile, 2,3,4,6-TeCP was the most predominant compound, and the highest

concentrations (49 ng/g) were found in sculpin, which had concentrations of about 400 times the concentration

found in water in the estuary. Trichlorophenol (combined 2,4,5 and 2,4,6 isomers) concentrations of 29-629 ppb

(wet weight) were measured in fish livers collected from the Pacific Ocean 6 km northwest of the discharge

zone for the Los Angeles County waste water treatment plant by Gossett et al. (1983). Concentrations in edible

tissues were not measured.

In addition to environmental contamination of food, another potential source for chlorophenol contamination of

food is migration from packaging materials. Shang-Zhi and Stanley (1983) reported levels of
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5. POTENTIAL FOR HUMAN EXPOSURE

0.1-0.68 ppm 2,4,6-TCP and 0.14-0.55 ppm 2,3,4,6-TeCP in cardboard food containers. Analysis for other

chlorophenols was not completed. Shang-Zhi and Stanley (1983) indicated that the source of chlorophenol

contamination was polyvinyl acetate and starch adhesives used in carton manufacture.

5.5 GENERAL POPULATION AND OCCUPATIONAL EXPOSURE

Oral exposure to chlorophenol-contaminated food and water is the main route of exposure to the general

population Water contaminated through chlorination is most likely to contain lower chlorinated phenols, while

higher chlorinated phenols are more likely to be found in fish. Exposure to 2,4-DCP through contaminated food

may result from the production of 2,4-DCP via degradation/metabolism of 2,4-dichlorophenoxy-based

herbicides applied to food crops (Scow et al. 1982; WHO 1989). Although food monitoring data are lacking,

exposure to 2,4-DCP through the ingestion of food is expected to be relatively minor. Estimates of total

chlorophenol intake reviewed by WHO (1989) ranged from 2.2 μg/person/day assuming contaminated water

and fish were the main sources of exposure, to about 10-40 μg/person/day assuming indoor rooms were treated

with a chlorophenol preservative.

The identification of chlorophenols in urine and fat of persons not occupationally exposed to chlorophenols

confirms general population exposure to these compounds. Analysis of urine from 197 children living near a

herbicide manufacturing plant in Arkansas for 2,4-DCP, 2,4,5-TCP, and 2,4,6-TCP, identified these compounds

in 27,54, and 11% of the samples, respectively (Hill et al. 1989). The 95th percentile concentrations (in ppb)

were 7 for 2,4-DCP, 7 for 2,4,5-TCP, and 4 for 2,4,6-TCP. In the National Health and Nutrition Examination

Survey (NHANES II), 2,4,5-TCP was detected (detection limit 5 ppb) in 3.4% of about 6,000 urine samples

taken from a representative sample of nonoccupationally exposed persons from 64 communities in the United

States during 1976-1980 (Kutz et al. 1992; Murphy et al. 1983). The maximum concentration detected was 56

ppb (Kutz et al. 1992). The investigators warn that because of the considerable variability among the recovery

rates over time and between laboratories, the level for 2,4,5-TCP may be underestimated. The average fat

concentrations of combined 2,3,4,6-TeCP and 2,3,5,6-TeCP and of 2,3,4,5-TeCP in autopsy specimens were 22

and 6 ng/g respectively in Kingston, Ontario, which is near the Great Lakes, relative to 7 ng/g for 2,3,4,6-TeCP,

2,3,5,6-TeCP, and 2,3,4,5-TeCP in tissue from persons living in Ottawa (Williams et al. 1984). 2,3,4,6-TeCP

was detected in 29/46 adipose samples from persons in Finland not occupationally exposed to chlorophenols,

while 2,4,6-TCP was detected in only one adipose sample (Mussalo-Rauhamaa et al. 1989). The concentration

of 2,3,4,6-TeCP in adipose tissue ranged from
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5. POTENTIAL FOR HUMAN EXPOSURE

<0.00l (the detection limit) to 0.031 μg/g. 2,3,4,6,-TeCP was also found in 2/13 liver samples, while

2,4,6-TCP was not detected (0.001 μg/g detection limit) in any liver samples.

Occupational exposure to chlorophenol isomers may occur during chemical production and during subsequent

use as intermediates in the synthesis of higher chlorinated phenols, phenolic resins, dyes, and drugs (Exon et al.

1984; Krijgsheld and Van der Gen 1986). Exposures result from inhalation and/or dermal contact and are most

likely associated with process, storage, or fugitive emissions at chemical manufacturing plants. NOES (1990)

estimates that 2,796 workers, principally clinical laboratory technicians at hospitals, are potentially exposed to

4-CP. Chemists comprise the majority of the 975 workers potentially exposed to 2-CP and the 852 workers

potentially exposed to 2,4,6-TCP, while janitors; engineers; and furnace, kiln, and oven operators are among the

895 workers potentially exposed to 2,4,5-TCP (NOES 1990). No estimates of the number of workers exposed to

the other chlorophenols discussed in this profile were available.

Occupational exposure to chlorophenols may also occur during the incineration of wastes containing

chlorinated chemicals (Angerer et al. 1992a, 1993) and through indirect exposure following worker inhalation

and subsequent metabolism of chlorobenzene (Kusters and Lauwerys 1990; Yoshida et al. 1986). In a study of

53 municipal waste incinerator workers’ urine, concentrations of 2,4-CP and 2,4,5-TCP were small but

significantly (p,0.05; nonparametric U-test of Wilcoxon, Mann, and Whitney) greater than the urinary

concentrations of these chlorophenols in 248 persons with no known occupational exposure to organic

chemicals (Angerer et al. 1992a, 1993). However, 4-CP and combined 2,3,4,6-TeCP and 2,3,5,6-TeCP urine

concentrations were small but significantly higher in the control group, which included 88 people from urban

communities, than in the incinerator workers. The investigators suggested that the higher 4-CP urine

concentrations in the urban population were a result of atmospheric exposure to chlorobenzene, but they did not

have an explanation for the higher tetrachlorophenol concentrations (Angerer et al. 1992a). Median and 95

percentile concentrations (μg/g creatinine) of chlorophenols in the urine from the two populations are shown

below.

Waste Incineration (n=53) Controls (n=248)

 Median 95% Median 95%

4-CP 1.2 3.8 1.7 6.6

2,4-DCP/2,5-DCP 10.5 86.6 3.9 46.4

2,4,5-TCP 1.2 3.2 0.8 4.0

2,4,6-TCP 0.9 2.3 0.6 3.7

2,3,4,6-TeCP/2,3,5,6-TeCP 0.3 1.5 1.2 25.6
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5. POTENTIAL FOR HUMAN EXPOSURE

An industrial hygiene investigation of workers exposed to chlorophenols at a sawmill indicated that dermal

exposure was the most important route (Lindroos et al. 1987). The workers were exposed to a wood preservative

that contained 80% 2,3,4,6-TeCP, 10-20% 2,4,6-TCP, and 5% pentachlorophenol. Median urinary

concentrations of total chlorophenols were 7.8 μmol/L in workers with the skin as the main route of exposure,

1.4 μmol/L in workers with combined inhalation and skin exposure, and 0.9 μmol/L in workers with inhalation

as the principal route of exposure.

As with the general population, occupational exposure to chlorophenols can also occur following accidents that

result in the release of these chemicals to the environment, such as the previously discussed train derailment. On

the day of the accident, 2-CP air concentrations of 0.02-0.7 mg/m3

 (0.004-0.19 ppm) were detected in the

immediate vicinity (Scow et al. 1982). Eighteen days after the spill, air concentrations were reduced to

<2 μg/m3 (<0.5 ppb). Urine levels in the clean-up workers were 1.98 mg/L approximately 2 months following

the spill; however, the pathways, duration, and time of exposure were not recorded, so that the exposure levels

cannot be estimated (Scow et al. 1982).

Potential exposure to chlorophenols tends to be limited because of the pronounced odor and taste imparted by

the presence of these substances. For example, the odor of 2,4-DCP can be detected in water at 0.35 μg/L (Hoak

1957), and 2,4-DCP can be tasted in water at 8 pg/L (Burttschell et al. 1959). Odor thresholds as low as 0.3-9 15

μg/L in water have also been reported for chlorophenols (Hoak 1957). Although chlorophenols have low odor

thresholds in water, 2-CP, 4-CP, 2,4-DCP, and 2,4,6-TCP have been noted to affect the flavor of fish at

concentrations of about 2 to 43 times lower than the odor thresholds for these compounds in water (Persson

1984). Data for the other chlorophenols discussed in this profile were not available.

5.6 EXPOSURES OF CHILDREN

This section focuses on exposures from conception to maturity at 18 years in humans and briefly considers

potential pre-conception exposure to germ cells. Differences from adults in susceptibility to hazardous

substances are discussed in 2.6 Children’s Susceptibility.

Children are not small adults. A child’s exposure may differ from an adult’s exposure in many ways.

Children drink more fluids, eat more food, and breathe more air per kilogram of body weight, and have a larger

skin surface in proportion to their body volume. A child’s diet often differs from that of adults. The developing

human’s source of nutrition changes with age: from placental nourishment to breast milk or
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5. POTENTIAL FOR HUMAN EXPOSURE

formula to the diet of older children who eat more of certain types of foods than adults. A child’s behavior and

lifestyle also influence exposure. Children crawl on the floor; they put things in their mouths; they may ingest

inappropriate things such as dirt or paint chips; they spend more time outdoors. Children also are closer to the

ground, and they do not have the judgement of adults in avoiding hazards (NRC 1993).

In a study that analyzed urine samples from 197 children living near a herbicide manufacturing plant in

Arkansas for 2,4-DCP, 2,4,5-TCP, and 2,4,6-TCP, these compounds were identified in 27,54, and 11% of the

samples, respectively (Hill et al. 1989). The 95th percentile concentrations (in ppb) were 7 for 2,4-DCP, 7 for

2,4,5-TCP, and 4 for 2,4,6-TCP. No measurements have been made of chlorophenols or their metabolite levels

in aminiotic fluid, meconium, cord blood, or neonatal blood that indicate prenatal exposure; nor have

measurements been made of chlorophenols or metabolite levels in breast milk. However, because of their

relative rapid metabolism and excretion in the urine, chlorophenols are not expected to accumulate in maternal

tissues.

There are no known unique exposure pathways for children to chlorophenols. However, 4-CP has been used at

home as disinfectant, and 2,4-DCP has been used for mothproofing and as a miticide (WHO 1989), while the

higher chlorophenols have been used as germicides, algicides, and fungicides. Thus, children may be exposed

via accidental ingestion. Because children like to play outdoors and put fingers in their mouths, they may also be

exposed via incidental ingestion and dermal contact of contaminated soil. The most likely way that children can

be exposed is via drinking water that has beetrdisinfected with chlorine. Exposure to 2,4-DCP through

contaminated food may result from the production of 2,4-DCP via degradation of the herbicide 2,4-

dichlorophenoxyacetic acid applied to food crops or via ingestion of fish contaminated with TeCP. However,

dietary exposure is expected to be minor as chlorophenols generally do not accumulate in animal tissues.

No studies have been found that examine the exposure of children from parents’ work clothes, skin, hair, tools,

or other objects removed from the workplace. Chlorophenols have been used as biocides. 2,4,6-TCP and the

tetrachlorophenols have also been used as wood preservatives. No known information is available at this time

concerning exposure from application of wood preservatives, herbicides, and other consumer products and this

exposure is unlikely to be significant.
CHLOROPHENOLS 167

5. POTENTIAL FOR HUMAN EXPOSURE

5.7 POPULATIONS WITH POTENTIALLY HIGH EXPOSURES

In comparison to members of the general population, workers in certain occupational groups have much greater

potential for exposure to high concentrations of chlorophenols (Scow et al. 1982). While quantitative data are

not available, workers involved in the production of either chlorophenols or chemicals synthesized from

chlorophenols are potentially the most heavily exposed (WHO 1989). Exposure may occur through both

inhalation and dermal absorption. Workers in plants that use chlorobenzene are also likely to be heavily exposed

to monochlorophenols via the metabolism of inhaled chlorobenzene to monochlorophenols (Kusters and

Lauwerys 1990; Ogata et al. 1991; Yoshida et al. 1986). However, most of the inhaled chlorobenzene was

metabolized to 4-chlorocatechol rather than chlorophenols, as the average exposed worker excreted three times

more 4-chlorocatechol than chlorophenols in the urine (Kustus and Lauwerys 1990; Yoshida et al. 1986) Thus,

exposure via metabolism of chlorobenzene is not an important route of exposure.

Workers at sawmills where the higher chlorinated phenols are used as wood preservatives have the highest

potential for being exposed to tetrachlorophenols (WHO 1989). The observation of higher urinary

concentrations of mixed tetrachlorophenols during hot humid weather when use of protective clothing was

minimal (geometric means 196.7 ppm hot humid weather; 98.5 ppm cooler weather) suggests that dermal

exposure is an important route of tetrachlorophenol exposure in these workers (Kleinman et al. 1986). The

higher volatility of tetrachlorophenols in warmer weather may have also contributed to the higher urinary

concentrations of mixed tetrachlorophenols found when the weather was hot. Higher general population

exposure may occur through dermal or oral contact with contaminated soils and/or groundwater in the vicinity

of disposal or accident sites and through dermal or oral contact with surface waters into which chlorinated

effluents have been discharged (Scow et al. 1982). In addition, inhalation and metabolism of chlorobenzene

found in urban air can result in higher exposure to monochlorophenols (Angerer et al. 1992b, 1993).

5.8 ADEQUACY OF THE DATABASE

Section 104(i)(5) of CERCLA, as amended, directs the Administrator of ATSDR (in consultation with the

Administrator of EPA and agencies and programs of the Public Health Service) to assess whether adequate

information on the health effects of the chlorophenols are available. Where adequate information is not

available, ATSDR, in conjunction with the NTP, is required to assure the initiation of a program of research
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5. POTENTIAL FOR HUMAN EXPOSURE

designed to determine the health effects (and techniques for developing methods to determine such health

effects) of the chlorophenols.

The following categories of possible data needs have been identified by a joint team of scientists from

ATSDR, NTP, and EPA. They are defined as substance-specific informational needs that if met would

reduce the uncertainties of human health assessment. This definition should not be interpreted to mean that all

data needs discussed in this section must be filled. In the future, the identified data needs will be evaluated and

prioritized, and a substance-specific research agenda will be proposed.

5.8.1 Identification of Data Needs

Physical and Chemical Properties. The physical and chemical properties of chlorophenols have been

well studied, and reliable values for key parameters for most chlorophenols are available for use in

environmental fate and transport models (see Table 3-2). Therefore, further studies of the physical and

chemical properties of chlorophenols are not essential at the present time.

Production, Import/Export, Use, Release, and Disposal. According to the Emergency Planning and

Community Right-to-Know Act of 1986,42 U.S.C. Section 11023, industries are required to submit chemical

release and off-site transfer information to the EPA. The Toxics Release Inventory (TRI), which contains this

information for 1996, became available in May of 1998. This database will be updated yearly and should

provide a list of industrial production facilities and emissions.

Chlorophenols have a variety of different uses (HSDB 1998). 2,4-DCP is used as an intermediate in the

production of herbicides and the manufacture of compounds used in mothproofing, antiseptics, and seed

disinfectants. It is also used to produce miticides and wood preservatives. 4-CP is used as an intermediate in the

production of acaricides, rodenticides, and dyes; it is used most commonly as a local antiseptic for dental

procedures. 2-CP is used in the production of higher chlorinated phenols, dyestuffs, preservatives, and as a

disinfectant/bacteriocide/germicide. It is also used for extracting sulfur and nitrogen compounds from coal.

2,4,5-TCP is used as a fungicide/bactericide; an intermediate in the manufacture of herbicides, hide and leather

processing; and in swimming pool and sick-room related surfaces. 2,3,4,6-TeCP is used as a fungicide,

pesticide, a slimicide for paper mills, and a preservative. 2,3,4,5-TeCP and 2,3,5,6-TeCP are used primarily as

fungicides (HSDB 1998). Chlorophenols are potentially hazardous chemicals and are subject to a variety of

regulations (see Chapter 7).
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5. POTENTIAL FOR HUMAN EXPOSURE

Data regarding the production methods for the chlorophenols are available; however, data regarding current

production and import/export of the chlorophenols are extremely limited (HSDB 1994; Krijgsheld and van de

Gen 1986; TR192 1994). No TRI data are currently available (domestic production or environmental release) for

the monochlorophenols, 2,4-DCP, or the tetrachlorophenols. General disposal information for chlorophenols is

adequately described in the literature. At low concentrations in aqueous media, microbial degradation followed

by adsorption on activated charcoal is the common disposal method (WHO 1989).

Environmental Fate. The behavior of chlorophenols in solid and aqueous media depends on numerous

physicochemical variables. These chemicals are partitioned to and transported in the air, soil, and water. The pH

of soil and water is a major factor controlling their partitioning among the media, their mobility, and their

ultimate fate in the environment. These processes are well characterized.

Atmospheric chlorophenols, primarily associated with production processes, are apparently removed by free

radical oxidation, photolysis, and both wet and dry deposition (Bunce and Nakai 1989; Scow et al. 1982). More

specific data regarding atmospheric dispersion and photochemical reaction rates are needed for occupational

settings. Volatilization of the higher chlorinated phenols from water and soil is expected to be a slow process,

but there were no experimental data located in the available literature. Experimental data are available pertaining

to many of the transformations of chlorophenols in the environment including biodegradation in water, soil, and

sediment and photodegradation in water. Confirmation of the estimated slow rate of volatilization in addition to

data regarding the overall half-lives for chlorophenols in air are needed to estimate potential inhalation exposure

near hazardous waste sites that contain chlorophenols. Data regarding the overall half-life in water and soil are

needed to estimate potential oral and dermal exposure to chlorophenols.

Bioavailability from Environmental Media. The observation of systemic effects following

inhalation, oral, and dermal exposure indicates that the chlorophenols are readily absorbed (see Chapter 2 for

more details). Systematic studies of the bioavailability of the chlorophenols from different media have not been

completed. Because the compounds are relatively lipophilic and become adsorbed to soil and sediments, a study

of the bioavailability of these compounds from soil relative to water following oral exposure are needed.
CHLOROPHENOLS 170

5. POTENTIAL FOR HUMAN EXPOSURE

Food Chain Bioaccumulation. Chlorophenols bioconcentrate in aquatic (fish) organisms to a limited

extent, with the greatest bioaccumulation (up to 400) observed for the tetrachlorophenols (Carey et al.

1988). The extent of bioconcentration is limited by relatively rapid metabolism and excretion (Veith et al. 1980).

Additional data on the bioaccumulation of chlorophenols within both aquatic and terrestrial

organisms are needed.

Exposure Levels in Environmental Media. Reliable monitoring data for the levels of chlorophenols

in contaminated media at hazardous waste sites are needed so that the information obtained on levels of

chlorophenols in the environment can be used in combination with the known body burden of

chlorophenols to assess the potential risk of adverse health effects in populations living in the vicinity of

hazardous waste sites. Few data are available concerning the levels of chlorophenols in ambient air or near

known sources of atmospheric pollution. Limited monitoring data on chlorophenol levels in surface water are

available. Additional monitoring for current data for better characterization of the ambient chlorophenol

concentrations in air, surface water, groundwater, soils, and sediment are needed. These data are particularly

needed in the vicinity of industrial and municipal chlorinated wastewater discharge points and hazardous waste

sites, where individuals may be exposed by oral and/or dermal contact, such that estimates of human intake can

be made.

Exposure Levels in Humans. This information is necessary for assessing the need to conduct health

studies on these populations. Limited data regarding chlorophenol levels in urine in humans and adipose tissue

are currently available. Toxicokinetic data on occupationally and environmentally exposed humans are needed

to determine whether there are biomarkers of exposure. Because chlorophenols are metabolites of other

chemicals, measurement of these compounds in biological samples (e.g., blood, urine) can provide an estimate

of internal dose but may not provide information about the dose of chlorophenols to which individuals were

exposed.

This information is necessary for assessing the need to conduct health studies on these populations.

Exposures of Children No exposure and body burden studies have been conducted on children;

therefore, it is not known whether children are different from adults in their weight-adjusted intake of

chlorophenols, or if unique exposure pathways for children exist. There is also no monitoring of

chlorophenol levels in food (crops, fish), nor in environmental media, following application of herbicides and

wood preservatives. Children whose parents work in manufacturing facilities that produce or use
CHLOROPHENOLS 171

5. POTENTIAL FOR HUMAN EXPOSURE

chlorophenols may also potentially be exposed to chlorophenols via parents’ work clothes, skin, hair, tools, or

other objects removed from the workplace; however, no studies exist on this means of exposure. A take home

exposure study may be warranted if such occupational exposure settings are identified. Measurement of

chlorophenols and their metabolites in breast milk will also help to determine whether children may be exposed

via milk ingestion.

There are no known specific means to decrease exposure, but since children may be more susceptible to

chlorophenols, it may be helpful to evaluate methods to do so.

Exposure Registries. No exposure registries for chlorophenols were located. These substances are not

currently compounds for which a subregistry has been established in the National Exposure Registry. These

substances will be considered in the future when chemical selection is made for subregistries to be established.

The information that is amassed in the National Exposure Registry facilitates the epidemiological research

needed to assess adverse health outcomes that may be related to exposure to these substances.

The development of an exposure registry would provide valuable data on exposure levels and frequency. In

addition to providing information on exposure levels and duration, a registry would be useful in identifying

sources of exposure such as hazardous waste sites and manufacturing and use facilities. Knowledge about

exposure levels and sources would be valuable in developing strategies to control unnecessary sources and these

exposures. The ability to correlate sources and exposure levels with health effects would be useful in identifying

disease conditions that may result from exposure to the chlorophenols.

5.8.2 On-going Studies

As part of the Third National Health and Nutrition Evaluation Survey (NHANES III), the Environmental Health

Laboratory Sciences Division of the National Center for Environmental Health, Centers for Disease Control,

will be analyzing human urine samples for 2,4-DCP, 2,4,5TCP, 2,4,6-TCP, and other phenolic compounds.

These data will give an indication of the frequency of occurrence and background levels of these compounds in

the general population. The measurement of these compounds is being used as a marker of pesticide exposure,

rather than just an indication of chlorophenol exposure.

CHLOROPHENOLS 173

6. ANALYTICAL METHODS

The purpose of this chapter is to describe the analytical methods that are available for detecting, and/or

measuring, and/or monitoring chlorophenols, their metabolites, and other biomarkers of exposure and effect to

these isomers. The intent is not to provide an exhaustive list of analytical methods. Rather, the intention is to

identify well-established methods that are used as the standard methods of analysis. Many of the analytical

methods used for environmental samples are the methods approved by federal agencies and organizations such

as EPA and the National Institute for Occupational Safety and Health (NIOSH). Other methods presented in this

chapter are those that are approved by groups such as the Association of Official Analytical Chemists (AOAC)

and the American Public Health Association (APHA). Additionally, analytical methods may be included that

modify previously used methods to obtain lower detection limits, and/or to improve accuracy and precision.

The principal methods used to analyze chlorophenols are gas chromatography with various detectors

including flame ionization, electron capture and selected ion monitoring mass spectrometry, and high pressure

liquid chromatography. Chlorophenols are highly polar with relatively low vapor pressures, which makes them

difficult to measure directly using gas chromatography. To prevent adsorption problems and to improve peak

shapes, chlorophenols are usually converted to less polar derivatives before analysis (Hajslova et al. 1988).

6.1 BIOLOGICAL MATERIALS

Methods for analysis of biological materials are summarized in Table 6-1. All methods require that the

sample be extracted with an organic solvent. If the extraction of urine is completed under acid conditions,

conjugates will be hydrolyzed so that total amounts (free + conjugates) of the various chlorophenols can be

measured (Hargesheimer and Coutts 1983). Removal of other organic compounds, using XAD-4 resin (Edgerton

et al. 1980; Wright et al. 1981) or a florisil column (Stein and Narang 1984), can improve the detection of

chlorophenols. Techniques that require less chromatographic separation are the tandem mass spectrometry

(MS/MS) methods described by Yost et al. (1984). These methods, especially the triple-stage quadrupole

method, were suggested for rapid screening of a large number of samples. Yost et al. (1984) estimated that to

analyze 25 samples by the more standard high-resolution gas chromatography/mass spectrometry method would

require 186 hours, while the same number of samples could be analyzed in 27 hours by the triple-stage

quadrupole tandem mass spectrometry method.



CHLOROPHENOLS 177

6. ANALYTICAL METHODS

Edgerton (1981) studied the stability of 2,4,6-TCP and 2,3,5,6-TeCP in human urine and found that the

compounds were stable for up to 40 days if frozen at -4°C. A loss of these compounds occurred if the

specimens were thawed and refrozen.

6.2 ENVIRONMENTAL SAMPLES

Methods for analysis of environmental samples are summarized in Table 6-2. All methods require extraction of

chlorophenols with an organic solvent, and most methods derivatize the chlorophenols before analysis. Samples

for chlorophenol determination should be collected into amber glass containers and stored in the refrigerator

(APHA 1992). It is also recommended that samples be extracted within 7 days of collection and analyzed within

40 days of extraction. Using gas chromatography with an electron capture detector, Hajslova et al. (1988)

compared detection limits and percentage of recovery for 2,4-DCP, 2,4,5-TCP, 2,4,6-TCP, and 2,3,5,6-TeCP

extracted from water with or without derivatization (acetates, methyl, and pentafluorobenzyl derivatives). All

three types of derivatization lowered sample detection limits and increased the percentage of recovery for the triand tetrachlorophenols. The detection limit of 2,4-DCP was lowered from 5 to 0.03 mg/L only following

derivatization with pentafluorobenzyl bromine, although derivatization decreased recovery from 104 to 85%.

The APHA approved method for analyzing phenols including 2-CP, 2,4-DCP, and 2,4,6-TCP uses gas

chromatography and a flame ionization detector (APHA 1992). If there are interfering substances in the sample,

APHA (1992) recommends derivitization of the sample with pentafluorobenzyl bromide, followed by clean-up

through a silica gel column. Gas chromatography with an electron capture detector is then used to analyze the

derivatized chlorophenols.

6.3 ADEQUACY OF THE DATABASE

Section 104(I)(5) of CERCLA, as amended, directs the Administrator of ATSDR (in consultation with the

Administrator of EPA and agencies and programs of the Public Health Service) to assess whether adequate

information on the health effects of the chlorophenols is available. Where adequate information is not available,

ATSDR, in conjunction with the NTP, is required to assure the initiation of a program of research designed to

determine the health effects (and techniques for developing methods to determine such health effects) of the

chlorophenols.





CHLOROPHENOLS 183

6. ANALYTICAL METHODS

The following categories of possible data needs have been identified by a joint team of scientists from

ATSDR, NTP, and EPA. They are defined as substance-specific informational needs that if met would

reduce the uncertainties of human health assessment. This definition should not be interpreted to mean that all

data needs discussed in this section must be filled. In the future, the identified data needs will be evaluated and

prioritized, and a substance-specific research agenda will be proposed.

6.3.1 Identification of Data Needs

Methods for Determining Biomarkers of Exposure and Effect

Exposure. Analytical methods are available to determine levels of chlorophenols in urine (Angerer et al. 1981;

Hargesheimer and Coutts 1983; Kusters and Lauwerys 1990; Van Roosmalan et al. 1980; Wright et al. 1981)

and other biological samples, including blood and tissue (Morales et al. 1992; Stein and Narang 1984).

Chlorophenols, especially the lower chlorinated compounds, are metabolites of a number of other compounds

including pesticides. Therefore, the value of urinary chlorophenols as a measure of exposure to chlorophenols,

per se, at hazardous waste sites, where exposure to many compounds can occur, is not clear. Further research on

the relationship between low-level exposure and levels of chlorophenols in biological media would be helpful in

assessing the risks and health effects of chronic low-level exposure.

Effect. There are no specific markers of the biological effects of chlorophenols. Acute exposure to

monochlorophenols results in myelonic convulsions (Angel and Rogers 1972; Borzelleca et al. 1985a, 1985b;

Farquharson et al. 1958), and exposure to chlorophenols also results in effects on the immune system (Exon et

al. 1984) and on reproduction (Exon and Koller 1985). Further studies are needed to relate levels of

chlorophenols in biological media to observed effects. One would doubt that these biological effects (myelonic

convulsions) are specific enough to be a food biomarker of effect.

Methods for Determining Parent Compounds and Degradation Products in Environmental

Media. Although there is limited information available about determining levels of chlorophenols in air

(Kauppinen and Lindroos 1985), the relatively low vapor pressure of these compounds suggests that, under

environmental conditions, exposure through air would be minimal. Sufficient information is available

concerning the measurement of the chlorophenols in water (Abrahamsson and Xie 1983; Alarcon et al. 1987;

APHA 1992; Bengtsson 1985; Hajslova et al. 1988; Realini 1981; Woodrow et al. 1986; Zigler and Phillips
CHLOROPHENOLS 184

6. ANALYTICAL METHODS

1967), soil (Buisson et al. 1984; Narang et al. 1983) and sediment (the media of concern for human exposure)

(Xie 1983).

Current analytical methods are sensitive enough to measure background levels in environmental media. The

precision, accuracy, reliability, and specificity of these methods are sufficiently documented

.

6.3.2 On-going Studies

No on-going studies regarding the development analytical methods for the chlorophenols were identified.
CHLOROPHENOLS 185

7. REGULATIONS AND ADVISORIES

The international, national, and state regulations and guidelines regarding chlorophenols in air, water, and other

media are summarized in Table 7-l. Occupational standards (OSHA) or guidelines (ACGIH) have not been set

for any of the eight chlorophenols discussed in this profile.

The chlorophenols as a group have been classified as an IARC group 2B carcinogen (IARC 1987). This

classification is based on limited evidence of carcinogenicity in humans exposed during the production of

chlorophenoxy herbicides and sufficient animal evidence of carcinogenicity for 2,4,6-TCP. The evidence of

carcinogenicity in aimals for 2,4,5-TCP was considered inadequate.

At relatively low concentrations, chlorophenols give water an unpleasant medicinal taste (EPA 1980a).

Based on taste thresholds, the EPA has developed ambient water quality criteria. A comparison of the

ambient water quality criteria with the health based RfD indicates that a water concentration resulting in the RfD

would be well above the taste threshold. For example, drinking two liters of water in a day

containing the ambient water quality criteria concentration of 2,4-DCP would result in a dose of 0.009

μg/kg/day relative to the RfD of 3 μg/kg/day.

An acute-duration oral MRL of 0.01 mg/kg/day has been derived for the chlorophenols based on a NOAEL for

liver effects in rats identified in the study of 4-CP by Phornchirasilp et al. (1989b). An intermediateduration oral

MRL of 0.003 mg/kg/day has been derived for the chlorophenols based on a NOAEL for immunological effects

observed in rats following treatment with 2,4-DCP (Exon and Koller 1985; Exon et al. 1984). These MRLs are

derived from the chlorophenol with the lowest duration-specific LOAEL and, therefore, should protect against

effects following exposure to all chlorophenols as well as exposure to mixtures of chlorophenols, if effects of

multiple chlorophenols are additive.

Rather than derive a single RfD for all the chlorophenols, the EPA has derived RfDs for individual

compounds for which data were available. The oral RfD for 2-CP is 0.005 mg/kg/day based on a decrease

(p<0.1) in litter size observed at 50 but not 5 mg/kg/day (Exon and Koller 1982, 1985). The oral RfDs for 2,4-

DCP and 2,4,5-TCP are 0.003 mg/kg/day and 0.1 mg/kg/day, respectively (IRIS 1998). These values are based

on the same studies and NOAELs as described for the MRLs.




CHLORPHENOLS 190

7. REGULATIONS AND ADVISORIES

2,4,6-TCP has been categorized as a group B2 carcinogen (probably human carcinogen) based on leukemias in

male rats and hepatocellular adenomas or carcinomas in male mice (NCI 1979), and no RfD has been derived

(IRIS 1998). An RfD of 0.03 mg/kg/day has been derived for 2,3,4,6-TeCP based on increased liver weights and

hypertrophy observed in rats treated by gavage at 100 but not 25 mg/kg/day (American Biogenics 1988).
CHLOROPHENOLS 191

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*Veith GD, Macek KJ, Petrocelli SR, et al. 1980. An evaluation of using partition coefficients and water

solubility to estimate bioconcentration factors for organic chemicals in fish. Aquatic Toxicology ASTM

STP707. Eaton JG, Parrish RP, Hendricks AC, eds., Amer Sot Test Mater 116-129.

*Vernot EH, MacEwen JD, Haun CC, et al. 1977. Acute toxicity and skin corrosion data for some organic and

inorganic compounds and aqueous solutions. Toxicol Appl Pharmacol 42:417-423.

*Viau AC, Studak SM, Karasek FW. 1984. Comparative analysis of hazardous compounds on fly-ash from

municipal waste incineration by gas chromatography/mass spectrometry. Can J Chem 62:2140-2145.

Videla LA, Troncoso P, Arisi ACM, et al. 1997. Dose-dependent effects of acute lindane treatment on

Kupffer cell function assessed in the isolated perfused rat liver. Xenobiotica 27(7):747-757.

*Vieira I, Sonnier M, Cresteil T. 1996. Developmental expression of CYP2El in the human liver:

Hypermethylation control of gene expression during the neonatal period. Eur J Biochem 238:476-483.

Waliszewski SM, Pardio VT, Waliszewski KN, et al. 1996. Detection of some organochlorine pesticides in

cow’s milk. Food Additives and Contaminants 13(2):23l-235.

*Wegman RC, van den Broek HH. 1983. Chlorophenols in river sediment in the Netherlands. Water Res

17:227-230.

*Weinbach EC, Garbus J. 1965. The interaction of uncoupling phenols with mitochondria and with

mitochondrial protein. 3 Biol Chem 240(4):181l-1819.

*West JR, Smith HW, Chasis H. 1948. Glomerular filtration rate, effective renal blood flow, and maximal

tubular excretory capacity in infancy. J Ped 32a:10-18.

*WHO. 1989. Environmental Health Criteria 93. Chlorophenols other than pentachlorophenol. World Health

Organization, Geneva, Switzerland

*Widdowson EM, Dickerson JWT. 1964. Chemical composition of the body. In: Comar CL, Bronner F, eds.

Mineral metabolism: An advanced treatise, volume II, The elements part A. New York, NY: Academic Press.
CHLOROPHENOLS 216

8. REFERENCES

Wiegel J. 1996. Characterization of selected bacteria and enzymes involved in the sequential anaerobic

degradation of 2,4-dichlorophenol. Dept. of Microbiology, Georgia Univ.

*Wieser M, Wagner B, Eberspacher J, et al. 1997. Purification and characterization of 2,4,6-trichlorophenol-4-

monooxygenase, a dehalogenating enzyme form Azotobacter sp. Strain GPl . J Bacterial 179(1):202-208.

*Wil Research Laboratories, Inc. 1982. Acute oral toxicity study in Fischer 344 female rats with

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[peer reviewed].

*Williams DT, Lebel GL, Junkins E. 1984. A comparison of organochlorine residues in human adipose tissue

autopsy samples from 2 Ontario (Canada) municipalities. J Toxicol Environ Health 13(1):19-30.

*Wishart GJ. 1978a. Demonstration of functional heterogeneity of hepatic uridine diphosphate

glucuronosyltransferase activities after administration of 3-methylcholanthrene and phenobarbital to rats.

Biochem J 174(2):671-672.

*Wishart GJ. 1978b. Functional heterogeneity of UDP-glucuronosyltransferase as indicated by its differential

development and inducibility by glucocorticoids: Demonstration of two groups within the enzyme’s activity

towards twelve substrates. Biochem J 174(2):485-489.

*Woodrow JE, Majewski MS, Seioer JN. 1986. Accumulative sampling of trace pesticides and other organics in

surface water using XAD4 resin. J Environ Sci Health, Part B 21(2):143-164.

*Woods JS, Polissar L, Severson RK, et al. 1987. Soft tissue sarcoma and non-Hodgkin’s lymphoma in

relation to phenoxyherbicide and chlorinated phenol exposure in western Washington, DC. J Nat1 Cancer Inst

78:899-910.

*Woods SL, Ferguson JF, Benjamin MM. 1989. Characterization of chlorophenol and chloromethoxybenzene

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*Wright LH, Edgerton TR, Arbes SJ, Jr, et al. 1981. The determination of underivatized chlorophenols in human

urine by combined high performance liquid chromatography mass spectrometry and selected ion monitoring.

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vinylidene chloride polymer. Environmental Science and Technology 22:646-650.

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*Yoshida M, Sunaga M, Hara I. 1986. Urinary metabolite levels in workers exposed to chlorobenzene.

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CHLOROPHENOLS 217

8. REFERENCES

*Yost RA, Fetterolf DD, Hass JR. 1984. Comparison of mass spectrometric methods for trace level screening of

hexachlorobenzene and trichlorophenol in human blood serum and urine. Anal Chem 56:2223-2228.

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diuresis. Clin Toxicol 12(1):41-48.

*Younger Laboratories. 1975. Toxicologic evaluation of ortho-chlorophenol. Final Report. Submitted to EPA by

Monsanto. TSCA 8ECP, Microfiche No. OTS053483 1.

*Younger Laboratories. 1976. Toxicologic investigation of: 2,4-dichlorophenol-93% (final report).

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*Zeiger E, Anderson B, Haworth S, et al. 1988. Salmonella mutagenicity tests. IV. Results from the testing of

300 Chemicals. Environ Mol Mutagen 1l(supp1. 12):1-158.

*Ziegler EE, Edwards BB, Jensen RL, et al. 1978. Absorption and retention of lead by infants. Pediatr Res

12:29-34.

*Zhang Y, Yang DJ, Fang CR. 1997. Monitoring of organochlorine pesticide residues-the GEMS/ food

program in China. Biomed Environ Sci 10:102- 106.

Zhou JL, Fileman TW, Evans S. 1996. Seasonal distribution of dissolved pesticides and polynuclear aromatic

hydrocarbons in the humber estuary and humber coastal zone. Marine Pollution Bulletin 32(8/9):599-608.

*Zigler MG, Phillips WF. 1967. Thin-layer chromatographic method for estimation of chlorophenols.

Environ Sci Technol 1:65-67.

CHLOROPHENOLS 219

9. GLOSSARY

Acute Exposure -- Exposure to a chemical for a duration of 14 days or less, as specified in the Toxicological

Profiles.

Adsorption Coeffkient (Koc) -- The ratio of the amount of a chemical adsorbed per unit weight of organic

carbon in the soil or sediment to the concentration of the chemical in solution at equilibrium.

Adsorption Ratio (Kd) -- The amount of a chemical adsorbed by a sediment or soil (i.e., the solid phase)

divided by the amount of chemical in the solution phase, which is in equilibrium with the solid phase, at a fixed

solid/solution ratio. It is generally expressed in micrograms of chemical sorbed per gram of soil or sediment.

Bioconcentration Factor (BCF) -- The quotient of the concentration of a chemical in aquatic organisms at a

specific time or during a discrete time period of exposure divided by the concentration in the surrounding water

at the same time or during the same period.

Cancer Effect Level (CEL) -- The lowest dose of chemical in a study, or group of studies, that produces

significant increases in the incidence of cancer (or tumors) between the exposed population and its appropriate

control.

Carcinogen -- A chemical capable of inducing cancer.

Ceiling Value -- A concentration of a substance that should not be exceeded, even instantaneously.

Chronic Exposure -- Exposure to a chemical for 365 days or more, as specified in the Toxicological

Profiles.

Developmental Toxicity -- The occurrence of adverse effects on the developing organism that may result from

exposure to a chemical prior to conception (either parent), during prenatal development, or postnatally to the

time of sexual maturation. Adverse developmental effects may be detected at any point in the life span of the

organism.

Embryotoxicity and Fetotoxicity -- Any toxic effect on the conceptus as a result of prenatal exposure to a

chemical; the distinguishing feature between the two terms is the stage of development during which the insult

occurred. The terms, as used here, include malformations and variations, altered growth, and in utero death.

EPA Health Advisory -- An estimate of acceptable drinking water levels for a chemical substance based on

health effects information. A health advisory is not a legally enforceable federal standard, but serves as technical

guidance to assist federal, state, and local officials.

Immediately Dangerous to Life or Health (IDLH) -- The maximum environmental concentration of a

contaminant from which one could escape within 30 min without any escape-impairing symptoms or

irreversible health effects.
CHLOROPHENOLS 220

9. GLOSSARY

Intermediate Exposure -- Exposure to a chemical for a duration of 15-364 days, as specified in the

Toxicological Profiles.

Immunologic Toxicity -- The occurrence of adverse effects on the immune system that may result from

exposure to environmental agents such as chemicals.

In vitro -- Isolated from the living organism and artificially maintained, as in a test tube.

In vivo -- Occurring within the living organism.

Lethal Concentration(Lo) ( LCLO) -- The lowest concentration of a chemical in air which has been reported to

have caused death in humans or animals.

Lethal Concentration(50) (LC50) -- A calculated concentration of a chemical in air to which exposure for a

specific length of time is expected to cause death in 50% of a defined experimental animal population.

Lethal Dose(LO) (LDLO) -- The lowest dose of a chemical introduced by a route other than inhalation that is

expected to have caused death in humans or animals.

Lethal Dose(50) (LD50) -- The dose of a chemical which has been calculated to cause death in 50% of a

defined experimental animal population.

Lethal Time(50) (LT50) -- A calculated period of time within which a specific concentration of a chemical is

expected to cause death in 50% of a defined experimental animal population.

Lowest-Observed-Adverse-Effect Level (LOAEL) -- The lowest dose of chemical in a study, or group of

studies, that produces statistically or biologically significant increases in frequency or severity of adverse effects

between the exposed population and its appropriate control.

Malformations -- Permanent structural changes that may adversely affect survival, development, or function.

Minimal Risk Level -- An estimate of daily human exposure to a dose of a chemical that is likely to be without

an appreciable risk of adverse noncancerous effects over a specified duration of exposure.

Mutagen -- A substance that causes mutations. A mutation is a change in the genetic material in a body cell.

Mutations can lead to birth defects, miscarriages, or cancer.

Neurotoxicity -- The occurrence of adverse effects on the nervous system following exposure to chemical.

No-Observed-Adverse-Effect Level (NOAEL) -- The dose of chemical at which there were no statistically or

biologically significant increases in frequency or severity of adverse effects seen between the exposed

population and its appropriate control. Effects may be produced at this dose, but they are not considered to be

adverse.

Octanol-Water Partition Coefficient (Kow) -- The equilibrium ratio of the concentrations of a chemical in noctanol and water, in dilute solution.
CHLOROPHENOLS 221

9. GLOSSARY

Permissible Exposure Limit (PEL) -- An allowable exposure level in workplace air averaged over an Shour

shift.

q1

*

 -- The upper-bound estimate of the low-dose slope of the dose-response curve as determined by the

multistage procedure. The q1* can be used to calculate an estimate of carcinogenic potency, the incremental

excess cancer risk per unit of exposure (usually μg/L for water, mg/kg/day for food, and μg/m3 for air).

Reference Dose (RfD) -- An estimate (with uncertainty spanning perhaps an order of magnitude) of the daily

exposure of the human population to a potential hazard that is likely to be without risk of deleterious effects

during a lifetime. The RfD is operationally derived from the NOAEL (from animal and human studies) by a

consistent application of uncertainty factors that reflect various types of data used to estimate RfDs and an

additional modifying factor, which is based on a professional judgment of the entire database on the chemical.

The RfDs are not applicable to nonthreshold effects such as cancer.

Reportable Quantity (RQ) -- The quantity of a hazardous substance that is considered reportable under

CERCLA. Reportable quantities are (1) 1 pound or greater or (2) for selected substances, an amount established

by regulation either under CERCLA or under Sect. 3 11 of the Clean Water Act. Quantities are measured over a

24-hour period.

Reproductive Toxicity -- The occurrence of adverse effects on the reproductive system that may result from

exposure to a chemical. The toxicity may be directed to the reproductive organs and/or the related endocrine

system. The manifestation of such toxicity may be noted as alterations in sexual behavior, fertility, pregnancy

outcomes, or modifications in other functions that are dependent on the integrity of this system.

Short-Term Exposure Limit (STEL) -- The maximum concentration to which workers can be exposed for up

to 15 min continually. No more than four excursions are allowed per day, and there must be at least 60 min

between exposure periods. The daily TLV-TWA may not be exceeded.

Target Organ Toxicity -- This term covers a broad range of adverse effects on target organs or

physiological systems (e.g., renal, cardiovascular) extending from those arising through a single limited

exposure to those assumed over a lifetime of exposure to a chemical.

Teratogen -- A chemical that causes structural defects that affect the development of an organism.

Threshold Limit Value (TLV) -- A concentration of a substance to which most workers can be exposed

without adverse effect. The TLV may be expressed as a TWA, as a STEL, or as a CL.

Time-Weighted Average (TWA) -- An allowable exposure concentration averaged over a normal S-hour

workday or 40-hour workweek.

Toxic Dose (TD50) -- A calculated dose of a chemical, introduced by a route other than inhalation, which is

expected to cause a specific toxic effect in 50% of a defined experimental animal population.

Uncertainty Factor (UF) -- A factor used in operationally deriving the RfD from experimental data. Ufs are

intended to account for (1) the variation in sensitivity among the members of the human population, (2) the

uncertainty in extrapolating animal data to the case of human, (3) the uncertainty in
CHLOROPHENOLS 222

9. GLOSSARY

extrapolating from data obtained in a study that is of less than lifetime exposure, and (4) the uncertainty in using

LOAEL data rather than NOAEL data. Usually each of these factors is set equal to 10.
CHLOROPHENOLS A-1

APPENDIX A

ATSDR MINIMAL RISK LEVELS AND WORKSHEETS

The Comprehensive Environmental Response, Compensation, and Liability Act (CERCLA) [42 U.S.C. 9601 et

seq.], as amended by the Super-fund Amendments and Reauthorization Act (SARA) [Pub. L. 99-4991, requires

that the Agency for Toxic Substances and Disease Registry (ATSDR) develop jointly with the U.S.

Environmental Protection Agency (EPA), in order of priority, a list of hazardous substances most commonly

found at facilities on the CERCLA National Priorities List (NPL); prepare toxicological profiles for each

substance included on the priority list of hazardous substances; and assure the initiation of a research program to

fill identified data needs associated with the substances.

The toxicological profiles include an examination, summary, and interpretation of available toxicological

information and epidemiologic evaluations of a hazardous substance. During the development of toxicological

profiles, Minimal Risk Levels (MRLs) are derived when reliable and sufficient data exist to identify the target

organ(s) of effect or the most sensitive health effect(s) for a specific duration for a given route of exposure. An

MRL is an estimate of the daily human exposure to a hazardous substance that is likely to be without

appreciable risk of adverse noncancer health effects over a specified duration of exposure. MRLs are based on

noncancer health effects only and are not based on a consideration of cancer effects. These substance-specific

estimates, which are intended to serve as screening levels, are used by ATSDR health assessors to identify

contaminants and potential health effects that may be of concern at hazardous waste sites. It is important to note

that MRLs are not intended to define clean-up or action levels.

MRLs are derived for hazardous substances using the no-observed-adverse-effect level/uncertainty factor

approach. They are below levels that might cause adverse health effects in the people most sensitive to such

chemical-induced effects. MRLs are derived for acute (1-14 days), intermediate (15-364 days), and chronic (365

days and longer) durations and for the oral and inhalation routes of exposure. Currently, MRLs for the dermal

route of exposure are not derived because ATSDR has not yet identified a method suitable for this route of

exposure. MRLs are generally based on the most sensitive chemical-induced end point considered to be of

relevance to humans. Serious health effects (such as irreparable damage to the liver or kidneys, or birth
CHLOROPHENOLS A-2

APPENDIX A

defects) are not used as a basis for establishing MRLs. Exposure to a level above the MRL does not mean that

adverse health effects will occur.

MRLs are intended only to serve as a screening tool to help public health professionals decide where to look

more closely. They may also be viewed as a mechanism to identify those hazardous waste sites that are not

expected to cause adverse health effects. Most MRLs contain a degree of uncertainty because of the lack of

precise toxicological information on the people who might be most sensitive (e.g., infants, elderly, nutritionally

or immunologically compromised) to the effects of hazardous substances. ATSDR uses a conservative (i.e.,

protective) approach to address this uncertainty consistent with the public health principle of prevention.

Although human data are preferred, MRLs often must be based on animal studies because relevant human

studies are lacking. In the absence of evidence to the contrary, ATSDR assumes that humans are more sensitive

to the effects of hazardous substance than animals and that certain persons may he particularly sensitive. Thus,

the resulting MRL may be as much as a hundredfold below levels that have been shown to be nontoxic in

laboratory animals.

Proposed MRLs undergo a rigorous review process: Health Effects/MRL Workgroup reviews within the

Division of Toxicology, expert panel peer reviews, and agencywide MRL Workgroup reviews, with

participation from other federal agencies and comments from the public. They are subject to change as new

information becomes available concomitant with updating the toxicological profiles. Thus, MRLs in the most

recent toxicological profiles supersede previously published levels. For additional information regarding MRLs,

please contact the Division of Toxicology, Agency for Toxic Substances and Disease Registry, 1600 Clifton

Road, Mailstop E-29, Atlanta, Georgia 30333.
CHLOROPHENOLS A-3

APPENDIX A

MINIMAL RISK LEVEL (MRL) WORKSHEET

Chemical Name: 4-Chlorophenol- Other chlorophenols - Mixture of chlorophenols

CAS Number: 106-48-9 (4-chlorophenol)

Date: July 1995

Profile Status: Draft 4, pre-public comments

Route: [ ] Inhalation [x] Oral

Duration: [X] Acute [ ] Intermediate [ ] Chronic

Graph Key: 14

Species: Rat

Minimal Risk Level: 0.01 [X] mg/kg/day [ ] ppm

Reference: Phornchirasilp et al. 1989b

Experimental design: (human study details or strain, number of animals per exposure/control groups, sex,

dose administration details):

Groups of 4-9 male Sprague-Dawley rats were treated by gavage with 4-CP in corn oil 2 times per day for 2

weeks at doses of 0, 0.32, 0.64, 1.28, 2.58, 5.2, 10.2, and 20.6 mg/kg/day. Liver effects were assessed by the

determination of liver weights; microsomal protein levels; cytochrome P-450 activity; and benzphetamine,

ethylmorphine, and aminopyrine n-demethylase activities. Electron microscopic examinations of hepatocytes

was also completed.

Effects noted in study and corresponding doses:

No significant alterations in relative liver weights were observed. A significant increase in microsomal

protein and cytochrome P-450 levels were observed in the 4-CP treated rats. The maximum increase (290%

of control) in cytochrome P-450 levels was observed in the 0.64 mg/kg group. Significant increases in the

activities of drug-metabolizing enzymes were also observed. Electron microscopic examination revealed

foamy cytoplasm and clustering of mitochondria and endoplasmic reticulum in the liver cells of rats exposed

to ≥2.58 mg/kg/day. Based on the electron microscopic changes, 2.58 mg/kg/day is considered a LOAEL,

and 1.28 mg/kg/day is considered a NOAEL.

Dose and end noint used for MRL derivation:

[x] NOAEL [ ] LOAEL

1.28 mg/kg/day lack of electron microscopic changes in hepatocytes

Uncertainty Factors used in MRL derivation:

[ ] 10 for use of a LOAEL

[x] 10 for extrapolation from animals to humans

[x] 10 for human variability
CHLOROPHENOLS A-4

APPENDIX A

Was a conversion used from nnm in food or water to a mg/body weight dose?

If so, explain: None

If an inhalation study in animals, list the conversion factors used in determining human equivalent dose:

Other additional studies or uertinent information which lend support? to this MRL:

There are no additional studies that examine liver effects following oral exposure to 4-CP, and studies

regarding liver effects of other chlorophenols use higher doses and do not examine hepatocytes with an

electron microscope. For example, decreases in microsomal NADPH-cytochrome c reductase activity and P-450

content were observed in rats treated with 2,4,5-TCP but not 2,4,6-TCP at 400 mg/kg/day for 14 days (Carlson

1978). Microscopic examinations were not completed.

Among the chlorophenols examined in the chlorophenol profile (2-CP, 2,4-DCP, 2,4,5-TCP, 2,4,6-TCP, 2,3,4,5-

TeCP, 2,3,4,6-TeCP, and 2,3,5,6-TeCP), the acute LOAEL for 4-CP was the lowest LOAEL identified.
CHLOROPHENOLS A-5

APPENDIX A

MINIMAL RISK LEVEL (MRL) WORKSHEET

Chemical Name: 2,4-Dichlorophenol- Other chlorophenols - Mixture of chlorophenols

CAS Number: 120-83-2 (2,4dichlorophenol)

Date: July 1995

Profile Status: Draft 4, pre-public comments

Route: [ ] Inhalation [x] Oral

Duration: [ ] Acute [x] Intermediate [ ] Chronic

Graph Key: 43

Species: Rat

Minimal Risk Level: 0.003 [x] mg/kg/day [ ] ppm

Reference: Exon et al. 1984; Exon and Koller 1985

Experimental design: (human study details or strain, number of animals per exposure/control groups, sex, dose

administration details):

Groups of 10 female Sprague-Dawley rats were exposed to 2,4-DCP (99% pure) in the drinking water at 0,3, 30,

or 300 ppm from weaning through breeding at 90 days, parturition, and weaning of pups. Ten randomly selected

offspring/groups were then continued on the same treatment regimen as the dams for an additional 10 weeks.

IRIS (1994) indicates that doses were calculated by the authors, but the doses are not presented in the papers. To

be consistent with IRIS, a 10% drinking water intake factor was used so that estimated 2,4- DCP intakes were

0,0.3,3, and 30 mg/kg/day, at 0,3,30, and 300 ppm, respectively.

Effects noted in study and corresnondine doses:

At 30 mg/kg/day, there was a trend for decreased litter sizes (0,9.8±1.3; 30,6.2 ±1.6). Exon and Koller (1985)

indicated that this effect was significant at p≤0.1, but Exon et al. (1984) does not indicate a significant

difference. At 30 mg/kg/day significant (p≤0.05) increases in spleen and liver weights were observed, with no

effects on body weight noted. Histological examinations of the liver, spleen, and thymus did not reveal any

effects. Examination of immune functions showed a significant (p<0.05) decrease in delayed type

hypersensitivity response to bovine serum albumin in Freund’s complete adjuvant at 3 and 30 mg/kg/day, with

no effect at 0.3 mg/kg/day. Antibody production (in response to keyhole limpet hemocyanin) was significantly

increased only at 3 mg/kg/day. No significant effects on phagocytic activity were noted.

Dose and end point used for MRL derivation:

[x] NOAEL [ ] LOAEL

A NOAEL of 0.3 mg/kg/day for a lack of effect on delayed type hypersensitivity was used as the basis of the

MRL.
CHLOROPHENOLS A-6

APPENDIX A

Uncertainty Factors used in MRL derivation:

[ ] 10 for use of a LOAEL

[X] 10 for extrapolation from animals to humans

[X] 10 for human variability

Was a conversion used from ppm in food or water to a mg/bodv weight dose? Yes.

If so, explain:

A 10% water intake as used in IRIS was used to convert from ppm in water to a mg/kg/day dose.

If an inhalation study in animals, list the conversion factors used in determining human equivalent dose:

Other additional studies or pertinent information which lend support to this MRL:

No other studies of 2,4-DCP examine functional immunological end points. LOAELs identified in other

intermediate-duration studies were 500 mg/kg/day, associated with bone marrow hyperplasia in rats fed

2,4-DCP in the diet for 13 weeks (NTP 1989), and 325 mg/kg/day for minimal hepatocellular necrosis in

mice fed 2,4-DCP in the diet for 13 weeks (NTP 1989). For chronic exposure, LOAELs of 250 and 820

for reduced body weight in rats and mice were identified (NTP 1989). Therefore, the LOAEL of 3

mg/kg/day for a decrease in delayed type hypersensitivity is the lowest LOAEL, and the MRL is based on

the highest NOAEL of 0.3 mg/kg/day. This LOAEL may also be lower than other studies because it is the

only study in which 2,4-DCP was administered in water. Unfortunately, there are no studies available to

indicate whether there are differences in the absorbed dose following treatment in food relative to water.

2,4-DCP was not carcinogenic in rats or mice (NTP 1989).

An intermediate-duration NOAEL of 0.3 mg/kg/day for increased liver weights at 3 mg/kg/day was also

identified by Exon and Koller (1985). Effect levels below the NOAEL of 0.3 mg/kg/day was not identified

in intermediate-duration studies of the other chlorophenols.
ALUMINUM B-1

APPENDIX B

USER'S GUIDE

Chapter 1

Public Health Statement

This chapter of the profile is a health effects summary written in non-technical language. Its intended

audience is the general public especially people living in the vicinity of a hazardous waste site or

chemical release. If the Public Health Statement were removed from the rest of the document, it would

still communicate to the lay public essential information about the chemical.

The major headings in the Public Health Statement are useful to find specific topics of concern. The

topics are written in a question and answer format. The answer to each question includes a sentence that

will direct the reader to chapters in the profile that will provide more information on the given topic.

Chapter 2

Tables and Figures for Levels of Significant Exposure (LSE)

Tables (2-1, 2-2, and 2-3) and figures (2-1 and 2-2) are used to summarize health effects and illustrate

graphically levels of exposure associated with those effects. These levels cover health effects observed

at increasing dose concentrations and durations, differences in response by species, minimal risk levels

(MRLs) to humans for noncancer end points, and EPA's estimated range associated with an upper- bound

individual lifetime cancer risk of 1 in 10,000 to 1 in 10,000,000. Use the LSE tables and figures for a

quick review of the health effects and to locate data for a specific exposure scenario. The LSE tables and

figures should always be used in conjunction with the text. All entries in these tables and figures

represent studies that provide reliable, quantitative estimates of No-Observed-Adverse- Effect Levels

(NOAELs), Lowest-Observed- Adverse-Effect Levels (LOAELs), or Cancer Effect Levels (CELs).

The legends presented below demonstrate the application of these tables and figures. Representative

examples of LSE Table 2-1 and Figure 2-1 are shown. The numbers in the left column of the legends

correspond to the numbers in the example table and figure.

LEGEND

See LSE Table 2-1

(1) Route of Exposure One of the first considerations when reviewing the toxicity of a substance using

these tables and figures should be the relevant and appropriate route of exposure. When sufficient data