Six-Year Review

Chemical 

Contaminants

Health Effects 

Technical Support 

Document
 Printed on Recycled Paper

Office of Water

Office of Science and Technology

EPA 822-R-03-008

June 2003
ii

EPA 822-R-03-008

Six-Year Review

Chemical Contaminants 

Health Effects

Technical Support Document

June 2003

United States Environmental Protection Agency

Office of Water

Office of Science and Technology

Health and Ecological Criteria Division

1200 Pennsylvania Avenue, NW (4304 T)

Washington, D.C. 20460
iii
iv

CONTENTS

Abbreviations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . v

1. INTRODUCTION ..........................................................1

2. MAXIMUM CONTAMINANT LEVEL GOAL ...................................1

2.1. Reference Dose ......................................................1

2.2. Assessment of Carcinogenicity ..........................................2

3. IDENTIFYING CANDIDATES FOR POSSIBLE REGULATORY REVISION .........3

4. NOMINATION OF CHEMICALS FOR NEW RISK ASSESSMENT . . . . . . . . . . . . . . . . . 4

4.1. Priority Chemicals of Potential Reproductive/Developmental Concern ...........5

4.2. Other Nominations for New Risk Assessment ..............................7

5. SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9

Table 1. Cancer classification systems used by EPA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10

Table 2. Chemicals considered under the first Six-Year Review cycle . . . . . . . . . . . . . . . . . . . 11

Table 3. Assessment by IRIS, OPP, ATSDR, and NAS of chemicals considered under the first

Six-Year Review cycle . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18

Table 4. Evaluation of the literature search for reproductive and developmental toxicity . . . . . 23

Table 5. Overall review of chemicals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25

REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30
v

Abbreviations 

ATSDR Agency for Toxic Substances and Disease Registry

BMD Benchmark dose

bw Body weight

CCRIS Chemical Carcinogenesis Research Information System 

DART Developmental and Reproductive Toxicology

DEHA Di(2-ethylhexyl)adipate

EC European Commission

EPA U.S. Environmental Protection Agency

FQPA Food Quality Protection Act 

HSDB Hazardous Substances Data Bank

I Daily drinking water intake

IARC International Agency for Research on Cancer

IRIS Integrated Risk Information System

kg Kilogram

LOAEL Lowest-observed-adverse-effect level

MCL Maximum contaminant level

MCLG Maximum contaminant level goal

MF Modifying factor

MFL Million fibers per liter

mg Milligram

MRL Minimal risk level

NA Not available

NAS National Academy of Sciences

NDWAC National Drinking Water Advisory Council

NIEHS National Institute of Environmental Health Sciences

NOAEL No-observed-adverse-effect level

NPDWR National Primary Drinking Water Regulation 

NTP National Toxicology Program

OPP Office of Pesticide Programs

OST Office of Science and Technology

OW Office of Water

RfD Reference dose

RSC Relative source contribution

SDWA Safe Drinking Water Act 

TT Treatment technology

UF Uncertainty factor

UL Tolerable upper intake level

WHO World Health Organization
1

1. INTRODUCTION

The Environmental Protection Agency (EPA) has developed a Protocol for the Review of

Existing National Primary Drinking Water Regulations (USEPA, 2003a) based on

recommendations of the National Drinking Water Advisory Council (NDWAC, 2000), through

consultations with stakeholders representing a wide variety of interest groups, and internal

Agency deliberations. The Protocol outlines the approach to be used to review and identify

national primary drinking water regulations (NPDWRs) that warrant revision to maintain, or

provide for greater, public health protection. The key elements of the review process are health

effects, analytical and treatment technology, other regulatory revisions (e.g., monitoring and

reporting requirements), occurrence and exposure analysis and, as appropriate, economic

considerations.

The purpose of the health effects component of the review process is to identify, within the

limitations of the Agency’s available resources, new health risk assessments that indicate

possible change to the maximum contaminant level goal (MCLG) and, perhaps, to the maximum

contaminant level (MCL). 

A total of 68 regulated chemical contaminants are being considered during this first SixYear Review cycle. These are inorganic and organic contaminants regulated prior to the Safe

Drinking Water Act (SDWA) 1996 Amendments, except arsenic, radionuclides, disinfectant

residuals, and disinfection by-products, which are being or have already been reviewed in

separate actions. 

2. MAXIMUM CONTAMINANT LEVEL GOAL

Because the identification of contaminants for potential revision based on health effects is

dependent on whether or not the MCLG could change, a brief explanation of the derivation of

the MCLG is warranted. The MCLG is the maximum level of a contaminant in drinking water at

which no known or anticipated adverse health effects occur, allowing for an adequate margin of

safety. MCLGs are non-enforceable health goals. EPA establishes the MCL based on the

MCLG. The MCL is the maximum permissible level of a contaminant in water that is delivered

to any user of a public water system. Prior to the 1996 Amendments to the SDWA, the MCL

was set as close to the MCLG as was feasible. The 1996 Amendments to the SDWA permit

consideration of costs and benefits in establishing an MCL. MCLs are enforceable standards.

2.1. Reference Dose 

For chemicals exhibiting a threshold for toxic effects, EPA establishes the MCLG on the

basis of an oral reference dose (RfD). A change in the RfD could lead to a change in the MCLG

and thus in the MCL. The RfD is an estimate (with uncertainty spanning perhaps an order of

magnitude) of a daily oral exposure to the human population (including sensitive subgroups) that

is likely to be without an appreciable risk of deleterious noncancer effects during a lifetime. The

RfD is derived as follows:
2

RfD (mg/kg/day) = NOAEL or LOAEL or BMD

 UF × MF

where:

NOAEL = no-observed-adverse-effect level (mg/kg/day)

LOAEL = lowest-observed-adverse-effect level (mg/kg/day)

BMD = benchmark dose (mg/kg/day)

UF = uncertainty factor

MF = modifying factor

The UF is used to account for the extrapolation uncertainties (e.g., interindividual variation,

interspecies differences, duration of exposure, use of a LOAEL in place of a NOAEL), and

database adequacy. The MF is used as a judgment factor to account for the confidence in the

critical study (or studies) used in the derivation of the RfD (USEPA, 2000). 

The MCLG is then derived from the RfD as follows:

MCLG (mg/liter) = RfD × bw × RSC

 I

where:

bw = body weight (70 kg for adults, 10 kg for children, 4 kg for infants);

RSC = relative source contribution, the fraction of the RfD allocated to drinking

water (to take into account exposure from other sources);

I = daily drinking water intake (2 liters for adults, 1 liter for children, 0.64 liter

for infants). 

EPA generally assumes that the relative source contribution from drinking water is 20

percent of the RfD, unless other exposure data for the chemical are available. This allows 80

percent of the total exposure to come from sources other than drinking water, such as exposure

from food, inhalation, or dermal contact. The RSC is one factor that will determine whether or

not a change in the RfD will lead to a change in the MCLG.

It has also been the Agency policy to apply an additional safety factor to the RfD for

chemicals with limited evidence of carcinogenicity (Section 2.2). This practice is another factor

that must be evaluated to determine the impact of a change in RfD on the MCLG.

2.2. Assessment of Carcinogenicity

For drinking water contaminants regulated prior to the 1996 SDWA, OW followed a threecategory regulatory cancer classification system (Categories I, II, or III). These categories

specify decisions as to degree of concern for an agent’s carcinogenic potential as a contaminant

of drinking water, and define to some extent the approach to risk management that is taken for

establishing MCLGs. Categories I, II, and III are designations not defined in guidelines but that

reflect Office of Water (OW) policy.

EPA also used the six alphanumeric categories (A, B1, B2, C, D, E) of the 1986 cancer

guidelines (USEPA, 1986) in establishing the MCLG. The six-group classification system is

often equated to the three-category system in the NPDWR Federal Register announcements.

Table 1 describes the three categories and, with few exceptions (e.g., beryllium), their usual
3

equivalent alphanumeric classification. If a chemical is a known or probable human carcinogen

(Category I, generally Group A or B), the MCLG is generally set at zero because it is assumed,

in the absence of other data, that there is no known threshold for carcinogenicity. If a chemical

falls in Group C, a RfD approach along with an additional safety factor is used in deriving the

MCLG. The methodology used for establishing MCLGs for chemicals with varying degrees of

evidence of carcinogenicity is briefly described in Table 1.

Recent Agency assessments also use the 1996 Proposed Guidelines for Carcinogen Risk

Assessment (USEPA, 1996) or the draft revised Guidelines for Carcinogen Risk Assessment

(USEPA, 1999). The proposed and revised Guidelines use standard descriptors as part of the

hazard narrative to express the weight of evidence for carcinogenic hazard potential. These

hazard descriptors are given in the text whenever appropriate.

3. IDENTIFYING CANDIDATES FOR POSSIBLE REGULATORY REVISION 

EPA will identify regulated chemical contaminants for which there have been changes in

the RfD and/or in cancer risk assessment from oral exposure. Such changes could result in a

change in the MCLG and MCL. Chemicals thus identified are potential candidates for

regulatory revision.

Health risk assessments completed under the following programs will be examined:

• EPA Integrated Risk Information System (IRIS)

• EPA Office of Pesticide Programs (OPP)

• National Academy of Sciences (NAS)

• Agency for Toxic Substances and Disease Registry (ATSDR)

Table 2 lists the 68 chemicals included in the Six-Year Review process, the RfDs and

cancer groups on which the MCLGs are based, those established by IRIS and OPP, and

assessment dates. The uses of certain pesticides are currently "banned" or "severely restricted."

These pesticides are indicated as "canceled" under OPP columns. Updated risk assessments of 

canceled pesticides are usually done by EPA’s offices other than OPP. IRIS dates are difficult to

determine with any precision because of numerous sequential revisions described in the

“Revision History” for each substance. Dates of IRIS assessments are approximate and refer to

the most recent year when significant revisions were made to the RfD or cancer assessment. Risk

assessments conducted by IRIS and OPP can be found at www.epa.gov/iris/index.html and

www.epa.gov/pesticides/reregistration/status.htm, respectively.

IRIS and OPP do not use the three-category approach for cancer hazard characterization,

but use the 1986 Guidelines for carcinogen risk assessment and, recently, the 1996 and 1999

proposed cancer Guidelines (USEPA, 1986; USEPA, 1996; USEPA, 1999). For easy

comparison, Categories I, II, and III on which the MCLGs are based have been replaced by the

equivalent cancer groups of the 1986 cancer guidelines (Table 1). If the oral and inhalation

cancer groups differ, the cancer groups given in Table 2 are those for oral exposure. Whenever

appropriate, the cancer hazard descriptors of the 1996 or 1999 proposed cancer Guidelines are

also given in Table 2.
4

As indicated in Table 2, NAS established in 1997 a tolerable upper intake level (UL) for

fluoride of 10 mg/day for children older than eight years and for adults, based on protection

against skeletal fluorosis (NAS, 1997). The 1997 NAS evaluation of fluoride does not have an

impact on the MCLG. In addition, recent assessments of copper and selenium by NAS (NAS,

2000a; NAS, 2000b) do not have an impact on the MCLGs for these two chemicals.

ATSDR establishes oral minimal risk levels (MRLs) for non-neoplastic endpoints for acute,

intermediate, and chronic exposure durations. MRLs for oral chronic exposure are similar to

EPA’s RfDs. The chronic MRL for cadmium of 1999 is the only one among the chemicals under

consideration that is more recent than and different from the RfD established in 1991. As such,

cadmium would qualify for possible revision. However, a new IRIS assessment of cadmium is

due in 2003 or 2004 (Table 3). Further review and revision of cadmium is therefore not

appropriate until completion of the Agency’s ongoing assessment. In summary, ATSDR

completed assessments do not have an impact on the selection of chemicals for potential revision

during this first Six-Year Review cycle.

Nine chemicals given in bold in Table 2 potentially qualify for revision, because of

different RfD and/or cancer assessments postdating the MCLG. These are alachlor, beryllium,

chromium, 1,1-dichloroethylene, diquat, glyphosate, lindane, oxamyl and picloram. However, as

of December 31, 2002, updated assessments for alachlor (IRIS), diquat (OPP), and glyphosate

(IRIS) are expected in 2003 or 2004 (Table 3). In addition, the National Toxicology Program

has initiated subchronic and chronic toxicity studies for hexavalent chromium (NTP, 2002).

Therefore, further review and assessment of these four chemicals is not appropriate until

completion of the Agency’s ongoing assessments, and NTP studies. The remaining five

chemicals are potential candidates for revision and are listed below together with the latest

assessment date.

Beryllium (IRIS 1998)

1,1-Dichloroethylene (IRIS 2002)

Lindane (OPP 2002)

Oxamyl (OPP 2000)

Picloram (OPP 1998)

This tentative identification of chemicals potentially qualifying for revision was conducted

independently of other considerations (e.g., analytical and treatment technology, occurrence

data), which may influence the final selection of contaminants to be revised.

For some chemicals with an MCLG of zero (chlordane, vinyl chloride), a change in RfD

postdating the regulation occurred in 1998 or later without a change in cancer group. These

chemicals do not potentially qualify for revision because, following Agency policy, the MCLG

for these chemicals will remain at zero, irrespective of any change in RfD.

4. NOMINATION OF CHEMICALS FOR NEW RISK ASSESSMENT

In order to identify chemicals for which current risk assessments need updating, the Office

of Science and Technology conducted a full toxicological literature search, including

developmental and reproductive toxicity, for a number of chemicals with current risk 

assessments conducted prior to 1997. The toxicological literature search included at a minimum

the following databases: TOXLINE, MEDLINE, Developmental and Reproductive Toxicology

(DART), Chemical Carcinogenesis Research Information System (CCRIS), NTP, and Hazardous
1 Critical effect is defined as the biologically significant adverse effect expected to occur at the lowest dose.

5

Substances Data Bank (HSDB). In addition, recent risk assessments conducted by several

national and international institutions were also examined for toxicological information. These

organizations/institutions included the World Health Organization (WHO), the International

Agency for Research on Cancer (IARC), the European Commission, Health Canada, California

Environmental Protection Agency, ATSDR, NAS and NIEHS. 

4.1. Priority Chemicals of Potential Reproductive/Developmental Concern

With the passage of the 1996 SDWA Amendments and FQPA of 1996, a concerted effort

was made by EPA to take into account reproductive and developmental effects, and effects of

chemicals on sensitive subpopulations. However, contaminants under consideration in this first

Six-Year Review cycle were regulated in 1992 or earlier and might not have received adequate

scrutiny for reproductive and developmental effects. Accordingly, a literature search was

conducted by EPA’s Office of Science and Technology (OST) to identify contaminants for

which developmental and/or reproductive effects might now appear to be the critical effects1

.

Contaminants thus identified will be nominated as high priority for new Agency assessments.

New assessments by IRIS or OPP are ongoing for several chemicals included in this first

Six-Year Review cycle. Any reproductive or developmental effects of these chemicals will be

taken fully into consideration as part of these new assessments. Therefore, a literature search for

reproductive/developmental effects was not considered useful for the 31 chemicals listed below

with ongoing IRIS (USEPA, 2002; USEPA, 2003b) or OPP assessments, as of December 31,

2002. Expected completion years of these assessments are indicated below. If, upon completion

of these new assessments, it is determined that there is a potential impact on the MCLG, the

chemicals in question will be considered candidates for possible revision in the next Six-Year

Review cycle, unless a compelling reason exists to accelerate the review of that NPDWR. 
6

Acrylamide (IRIS, 2003/2004)

Alachlor (IRIS, 2003/2004)

Antimony (IRIS, 2003/2004)

Asbestos (IRIS, 2005)

Atrazine (OPP, 2003) *

Benzo[a]pyrene (IRIS, 2003/2004)

Cadmium (IRIS, 2003/2004)

Carbofuran (OPP, 2003/2004)

Carbon tetrachloride (IRIS, 2003/2004)

Copper (IRIS, 2003/2004)

2,4-D (OPP, 2004)

Di(2-ethylhexyl)phthalate (IRIS, 2003/2004)

1,2-Dichlorobenzene (IRIS, 2003/2004)

1,4-Dichlorobenzene (IRIS, 2003/2004)

1,2-Dichloroethane (IRIS, 2003/2004)

Diquat (OPP, 2003)

Endothall (OPP, 2003/2004)

Ethylbenzene (IRIS, 2003/2004)

Ethylene dibromide (IRIS, 2003/2004)

Glyphosate (IRIS, 2003/2004)

Methoxychlor (OPP, 2003)

Pentachlorophenol (IRIS, 2003/2004)

Polychlorinated biphenyls (IRIS, 2003/2004)

Simazine (OPP, 2003/2004)

Styrene (IRIS, 2003/2004)

2,3,7,8-TCDD (IRIS, 2003/2004)

Tetrachloroethylene (IRIS, 2003/2004)

Toluene (IRIS, 2003/2004)

1,1,1-Trichloroethane (IRIS, 2003/2004)

Trichloroethylene (IRIS, 2003/2004)

Xylenes (IRIS, 2003/2004)

* Amended OPP Interim Reregistration Eligibility Decision (IRED) scheduled for release October 2003

Twelve chemicals are not under review by IRIS or OPP but have an MCLG of zero. These

are listed below, together with the year of the most recent Agency cancer assessments (see also

Table 2). 

Benzene (00)

Chlordane (98)

1,2-Dibromo-3-chloropropane (91)

Dichloromethane (92)

1,2-Dichloropropane (91)

Epichlorohydrin (92)

Heptachlor (92)

Heptachlor epoxide (92)

Hexachlorobenzene (92)

Lead (91)

Toxaphene (91)

Vinyl chloride (00)

For these chemicals, an MCLG of zero will remain at zero, irrespective of new information

on reproductive or developmental effects, unless new information indicates that the

dose-response relationship for tumorigenesis is nonlinear. EPA reviewed recent IRIS, ATSDR

and IARC carcinogenicity assessments for these 12 chemicals to determine whether these

assessments may now indicate a mode of action that implies nonlinearity of the dose-response, in

which case an MCLG of zero would no longer be appropriate and might be based instead on

threshold effects such as reproductive or developmental effects. EPA did not find any data to

support such a nonlinear mode of action (IARC, 1999; IARC, 2001; ATSDR, 1999). Therefore,

revision of the MCLG of zero for these 12 chemicals is not appropriate at this time. 

Information on potential reproductive and developmental effects for chemicals with

MCLGs of zero may have an impact on risk management strategies, such as monitoring

frequency, to control peak occurrence. This aspect of the assessment will be considered during

subsequent Six-Year Review cycles, in conjunction with available occurrence data, to determine

whether changes in risk management strategies might provide for better public health protection.

For chemicals with nonzero MCLGs, evaluation of the literature search for reproductive

and developmental effects was not considered necessary if new Agency assessments were

finalized in 1997 or later. These assessments are recent enough to have considered reproductive

and developmental toxicity as a part of the evaluation. Agency assessments finalized in 1997 or

later are available for nine chemicals. These are barium (1998), beryllium (1998), chromium
7

(1998), 1,1-dichloroethylene (2002), hexachlorocyclopentadiene (2001), lindane (2002),

inorganic mercury (1997), oxamyl (2000), and picloram (1998). 

The literature search for reproductive and developmental effects for the remaining 16

chemicals listed in Table 4 was evaluated. For various reasons briefly described in Table 4,

RfDs for three chemicals—cyanide, di(2-ethylhexyl)adipate, thallium—could be affected by new

information on developmental and/or reproductive toxicity. The small number of chemicals thus

identified is not surprising, as EPA’s selection of contaminants for new IRIS or OPP assessment

is biased toward chemicals for which there is an indication that reproductive or developmental

effects may be of concern. In conclusion, three chemicals are high priority and, at the request of

OST, new IRIS risk assessments have been initiated for these chemicals. The new risk

assessments are expected to be completed in the 2005 time frame for cyanide, 2003/2004 for

di(2-ethylhexyl)adipate, and 2005 for thallium (USEPA, 2003b).

4.2. Other Nominations for New Risk Assessment

As described above, the literature search for reproductive and developmental effects for 16

chemicals was evaluated. Three of these chemicals were identified as of potential reproductive

or developmental concern, and IRIS risk assessments were initiated in 2002. It was considered

desirable to determine, through a literature search for all other toxicological endpoints, if new

health effects information had become available for any of the remaining 13 chemicals, in which

case the chemical would be nominated for a new assessment.

Of the 13 chemicals under consideration, NAS conducted a recent assessment of selenium

and no new information was identified which may have an impact on the current MCLG (NAS,

2000b). Therefore, selenium was eliminated from further consideration and a toxicological

literature search was conducted by OST for the remaining 12 chemicals. These are: 

Dalapon

cis-1,2-Dichloroethylene

trans-1,2-Dichloroethylene

Dinoseb

Endrin

Fluoride 

Monochlorobenzene

Nitrate

Nitrite

2,4,5-TP (Silvex)

1,2,4-Trichlorobenzene

1,1,2-Trichloroethane

There is new information on the effects of fluoride on bone and on the contribution of

various sources to total fluoride exposure (dental health products, water, food, beverages)

(WHO, 2002). At the request of EPA, NAS has agreed to review the toxicological data on

fluoride for all toxicological endpoints, including effects on bone. NAS will also examine the

data on relative fluoride exposure from drinking water compared to fluoride exposure from the

diet and fluoride-containing dental products. It is anticipated that the NAS review will be

completed in 2004. 

No new information was found for any of the remaining chemicals that could have an

impact on the MCLG. Accordingly, and for the time being, these contaminants will not be

nominated for new IRIS assessments. 

Because of considerable stakeholder interest in nitrate and nitrite, a more detailed rationale

for not considering these two chemicals as potential candidates for new IRIS assessments is

provided here. At the request of EPA, NAS evaluated the 1991 MCLGs and MCLs for nitrate

and nitrite. NAS evaluated the epidemiological and toxicological studies available for these
8

chemicals and concluded that EPA’s current MCLGs and MCLs for nitrate and nitrite are

adequate to protect human health. NAS also concluded that exposure to nitrate/nitrite

concentrations found in drinking water in the United States is unlikely to contribute to human

cancer risk (NAS, 1995). In 1997, California established Public Health Goals for nitrate and

nitrite in drinking water identical to EPA’s MCLGs and concluded that recent epidemiological

studies do not support an association between nitrate and nitrite exposure from drinking water

and increased cancer rates in humans (Cal/EPA, 1997). More recently, the World Health

Organization (WHO) evaluated nitrate and nitrite and established the same "guideline values" for

these two chemicals as EPA’s MCLGs, to protect against methemoglobinemia in bottle-fed

infants below three months of age, the most susceptible segment of the population. WHO also

concluded that there is no evidence for an association between nitrite and nitrate exposure in

humans and the risk of cancer (WHO, 1998).

A number of studies on nitrate and nitrite have become available since WHO’s assessment

of 1998. Some of these studies that could possibly have an impact on the MCLGs are discussed

here. In an epidemiological study in Iowa, Weyer et al. (2001) found a positive relationship

between nitrate levels in drinking water and risk of bladder and ovarian cancers, and an inverse

relationship for cancer of the uterine corpus and rectum. The authors recognized that additional

studies were needed before confirming these trends. Several limitations of the study were also

pointed out by the authors, including lack of information on individual water consumption and

poor characterization of the magnitude of exposure to nitrate, relatively small sample size for

bladder cancer, lack of information on occurrence of bladder infections, lack of information on

concomitant exposure to other contaminants in drinking water, including disinfection byproducts. No clear and consistent associations were found between increasing nitrate in drinking

water and non-Hodgkin’s lymphoma, leukemia, or cancers of the colon, breast, lung, pancreas,

or kidney (Weyer et al., 2001). Other epidemiological studies of nitrate and/or nitrite and nonHodgkin’s lymphoma (Ward et al., 1996), gastric, esophageal or brain cancer (Van Loon et al.,

1998, Barrett et al., 1998) are also inconclusive. Several epidemiological studies of maternal

ingestion of nitrate in drinking water failed to confirm an association between nitrate exposure

and developmental effects in offspring (e.g., Croen et al., 1997).

There are differing views on the role of nitrate/nitrite versus gastrointestinal infections as

the cause of infant methemoglobinemia (Avery, 1999; Knobeloch et al., 2000). It is recognized

that bottle-fed infants have a high probability of developing gastrointestinal infections because of

their low gastric acidity. It is also recognized that gastrointestinal infections and low acidity

enhance the conversion of nitrate to nitrite and methemoglobin formation in infants. This is an

additional reason for considering these infants as a high-risk group for developing

methemoglobinemia from exposure to nitrate/nitrite (WHO, 1998).

NTP carried out toxicology and carcinogenesis studies of sodium nitrite (NTP, 2001).

There was no evidence of carcinogenic activity of sodium nitrite in male or female rats, nor in

male mice. There was equivocal evidence of carcinogenic activity in female mice based on a

positive trend in the incidences of squamous cell papilloma or carcinoma (combined) of the

forestomach. Given these conclusions, a change in the cancer assessment of nitrite is not

warranted at this time. 

The outcome of the review of nitrate and nitrite indicates that the basis of the current

MCLGs for these two chemicals remain appropriate and, therefore, nitrate and nitrite are not

nominated for new IRIS assessments at this time.
9

5. SUMMARY 

Five chemicals have been identified as potentially qualifying for revision on the basis of

new IRIS or OPP health assessments that could impact the MCLG. These are beryllium, 1,1-

dichloroethylene, lindane, oxamyl, and picloram. This tentative identification of chemicals

potentially qualifying for revision was conducted independently of other considerations (e.g.,

analytical and treatment technology, occurrence data), which may influence the final selection of

contaminants to be revised.

Three chemicals - cyanide, di(2-ethylhexyl)adipate and thallium - are high priority for

reevaluation because of reproductive and/or developmental concerns. New IRIS risk

assessments of these chemicals have been initiated. The new risk assessments are expected to be

completed in the 2004/2005 time frame for cyanide, 2003/2004 for di(2-ethylhexyl)adipate, and

2004/2005 for thallium (USEPA, 2003b).

New data have become available regarding the effect of fluoride on bone, and the

contribution of various sources to total fluoride exposure (WHO, 2002). At the request of EPA,

NAS has initiated a review of the toxicological data on fluoride, including effect on bone, as well

as the relative contribution of various sources to the overall exposure to fluoride. 

Hexavalent chromium is under study by the National Toxicology Program (NTP, 2002).

Once the subchronic and chronic studies are completed, the Agency will evaluate the

toxicological data with regard to their impact on the present MCLG. 

Table 5 summarizes the review process applied to each of the 68 chemicals under

consideration.
10

Table 1. Cancer classification systems used by EPA (USEPA, 1986; USEPA, 1989; USEPA,

1992)

Three-category approach for

establishing MCLGs

Corresponding five-group classification

system of 1986 cancer guidelines

MCLG generally set at zero 

Category I:

Known or probable human

carcinogens: Strong evidence of

carcinogenicity

Sufficient human or animal evidence of

carcinogenicity.

Generally Group A or B:

A: Human carcinogen

Sufficient evidence from epidemiological studies

to support a causal association. 

B: Probable human carcinogen

B1: Limited evidence of carcinogenicity from

epidemiological studies.

B2: Inadequate evidence or no data from

epidemiological studies; sufficient evidence from

animal studies.

MCLG based on the RfD with an additional safety factor of up to 10 to account for

possible carcinogenicity, or is based on excess cancer risk range of 10-5 to 10-6

Category II:

Limited evidence of carcinogenicity

Some limited but insufficient evidence of

carcinogenicity from animal data.

Generally Group C:

Possible human carcinogen

Limited evidence of carcinogenicity in animals in

the absence of human data.

MCLG established using the RfD approach

Category III:

Inadequate or no evidence of

carcinogenicity in animals

Group D or Group E:

D: Not classifiable as to human

carcinogenicity

Inadequate human and animal evidence of

carcinogenicity, or no data available.

E: Evidence of non-carcinogenicity for 

humans

No evidence of carcinogenicity in two different

animal species, or in both epidemiological and

animal studies.
1 Under the 1996 proposed cancer guidelines, alachlor is characterized as likely to be carcinogenic to

humans at high doses, but not likely at low doses.

2

 Asbestos: Group C based on limited evidence of carcinogenicity by the oral route; Group A by inhalation

exposure (USEPA, 1989).

3

 Asbestos: Limited animal evidence for carcinogenicity via ingestion, and epidemiologic data in this regard

are inadequate. Group A by inhalation exposure.

4 Under the 1996 proposed cancer guidelines, barium is characterized as not likely to be carcinogenic to

humans following oral exposure.

5

 Under the 1996 proposed cancer guidelines, benzene is characterized as a known human carcinogen for all

routes of exposure. 

11

Table 2. Chemicals considered under the first Six-Year Review cycle

(New RfD and/or cancer assessment have become available for nine chemicals given in bold). 

 Regulation (month/year) IRIS (year) OPP (month/year)

Chemical MCLG

mg/L

MCL

mg/L

RfD

mg/kg/d

Cancer 

group

RfD

mg/kg/d

Cancer

group

RfD 

mg/kg/d

Cancer

group 

1. Acrylamide 0

(1/91)

TT 0.0002 B2 0.0002

(91)

B2

(91)

2. Alachlor 0

(1/91)

0.002 0.01 B2 0.01

(93)

NA 0.01

(9/98)

— 1

(9/98) 

3. Antimony 0.006

(7/92)

0.006 0.0004 D 0.0004

(91)

NA

4. Asbestos (fibers > 10

:m in length)

7 MFL

(1/91)

7 MFL — C 2 NA — 3

(88)

5. Atrazine 0.003

(1/91)

0.003

(1/91)

0.005 C 0.035

(93)

NA

6. Barium 2

(7/91)

2 0.07 D 0.07

(98)

D4

(98)

7. Benzene 0

(7/87)

0.005 — A 0.004 A 5

(00)

8. Benzo[a]pyrene 0

(7/92)

0.0002 — B2 NA B2 

(92)
Table 2 (continued)

 Regulation (month/year) IRIS (year) OPP (month/year)

Chemical MCLG

mg/L

MCL

mg/L

RfD

mg/kg/d

Cancer 

group

RfD

mg/kg/d

Cancer

group

RfD 

mg/kg/d

Cancer

group 

6 EPA classified beryllium in Group B2, probable human carcinogen, based on clear evidence of its

carcinogenicity via inhalation or injection in several animal species. However, EPA also placed beryllium in

drinking water Category II for regulation (limited evidence of carcinogenicity considering the weight of evidence for

carcinogenicity via ingestion, potency, exposure, and pharmacokinetics). The MCLG was derived using the RfD and

applying an additional safety factor of 10 for possible carcinogenic potential. 

7

 B1 based on inhalation exposure. Under the 1996 proposed cancer guidelines, inhaled beryllium is

characterized as a likely carcinogen in humans, and the human carcinogenic potential of ingested beryllium cannot

be determined.

8 Carcinogenicity studies of cadmium administered orally to animals have shown no evidence of

carcinogenic response. B1 based on inhalation exposure. 

9 Under the 1996 proposed cancer guidelines, chlordane is characterized as a likely human carcinogen by

all routes of exposure.

10 Under the 1996 proposed cancer guidelines, the oral carcinogenicity of Cr VI cannot be determined.

11 Under the 1996 proposed cancer guidelines, there are inadequate data to determine the potential

carcinogenicity of Cr III.

12

9. Beryllium 0.004

(7/92)

0.004 0.005 B2 6 0.002

(98)

B1 7

(98)

10. Cadmium 0.005

(1/91)

0.005 0.0005 D 0.0005 

(91)

— 8

(91)

11. Carbofuran 0.04

(1/91)

0.04 0.005 E 0.005

(87)

NA

12. Carbon tetrachloride 0

(7/87)

0.005 0.0007 B2 0.0007

(91)

B2 

(91)

13. Chlordane 0

(1/91)

0.002 0.00006 B2 0.0005

(98)

B2 9

(98)

Canceled

14. Chromium

 (total)

 Cr (VI)

 Cr (III)

0.1

(1/91)

0.1 0.005 D

0.003

(98)

1.5

(98)

D 10

(98)

D 11

(98)
Table 2 (continued)

 Regulation (month/year) IRIS (year) OPP (month/year)

Chemical MCLG

mg/L

MCL

mg/L

RfD

mg/kg/d

Cancer 

group

RfD

mg/kg/d

Cancer

group

RfD 

mg/kg/d

Cancer

group 

12 NAS (2000a) considered that the MCLG for copper was appropriate. Copper action level: 1.3 mg/L.

13 Under the draft revised guidelines for carcinogen risk assessment (USEPA, 1999), the data for 1,1-DCE

are inadequate for an assessment of human carcinogenic potential by the oral route. 

13

15. Copper 1.3 12

(6/91)

TT 12 — D NA D

(88)

16. Cyanide 0.2

(7/92)

0.2 0.02 D 0.02

(87)

D

17. 2,4-D (2,4-Dichloro

phenoxyacetic acid)

0.07

(1/91)

0.07 0.01 D 0.01

(87)

NA D

(7/96)

18. Dalapon (2,2-di

chloropropionic acid)

0.2

(7/92)

0.2 0.03 D 0.03

(88)

NA Canceled

19. Di(2-ethylhexyl) 

adipate

0.4

(7/92)

0.4 0.6 C 0.6

(92)

C

(92)

20. Di(2-ethylhexyl) 

phthalate

0

(7/92)

0.006 0.02 B2 0.02 

(88)

B2

(88)

21. 1,2-Dibromo-3-

chloropropane (DBCP)

0

(1/91)

0.0002 — B2 NA

(91)

NA Canceled

22. Dichlorobenzene o-

(1,2-Dichlorobenzene)

0.6

(1/91)

0.6 0.09 D 0.09

(90)

D 

(90)

Canceled

23. Dichlorobenzene p-

(1,4-Dichlorobenzene)

0.075

(7/87)

0.075 0.1 C NA 

(94)

NA 

24. Dichloroethane(1,2-)

(Ethylene dichloride)

0

(7/87)

0.005 — B2 NA B2

(91)

Canceled 

25. Dichloroethylene 

(1,1-)

0.007

(7/87)

0.007 0.009 C 0.046

(02)

C13

(02)

26. Dichloroethylene 

(cis-1,2-)

0.07

(1/91)

0.07 0.01 D NA D

(90)

27. Dichloroethylene 

(trans-1,2-)

0.1

(1/91)

0.1 0.02 D 0.02

(88)

NA

28. Dichloromethane 

(methylene chloride)

0

(7/92)

0.005 0.06 B2 0.06

(91)

B2

(91)

Canceled

29. Dichloropropane 

(1,2-)

0

(1/91)

0.005 — B2 NA

(91)

NA
Table 2 (continued)

 Regulation (month/year) IRIS (year) OPP (month/year)

Chemical MCLG

mg/L

MCL

mg/L

RfD

mg/kg/d

Cancer 

group

RfD

mg/kg/d

Cancer

group

RfD 

mg/kg/d

Cancer

group 

14 NAS (1997) established a tolerable upper intake level (UL) for fluoride of 10 mg/day for children older

than 8 years and for adults, based on protection against skeletal fluorosis. The 1997 NAS evaluation of fluoride does

not affect the MCLG. 

15 This is the RfD calculated from the MCLG assuming 70kg body weight and intake of 2L/day. The

MCLG was developed from a lowest effect level for crippling skeletal fluorosis of 20 mg/day with continuous

exposures over a 20-year or longer period. The LOAEL was divided by an uncertainty factor of 2.5 and a drinking

water intake of 2L/day to obtain the MCLG. 

16 For objectionable dental fluorosis, a cosmetic effect. 

17 For crippling skeletal fluorosis in humans.

14

30. Dinoseb 0.007

(7/92)

0.007 0.001 D 0.001

(89)

D

(89)

Canceled

31. Diquat 0.02

(7/92)

0.02 0.0022 D 0.0022

(87)

NA 0.005

(3/95)

E

(3/95)

32. Endothall 0.1

(7/92)

0.1 0.02 D 0.02

(87)

NA

33. Endrin 0.002

(7/92)

0.002 0.0003 D 0.0003

(89)

D

(89)

Canceled

34. Epichlorohydrin 0

(1/91)

TT NA B2 NA B2

(92)

35. Ethylbenzene 0.7

(1/91)

0.7 0.1 D 0.1 

(91)

D

(91)

36. Ethylene dibromide 

(EDB; 1,2-Dibromoethane) 

0

(1/91)

0.00005 — B2 NA B2

(91)

Canceled

37. Fluoride 14 4.0

(11/85)

4.0

(4/86)

0.11 15 — 0.0616

0.1217

(87)

NA

38. Glyphosate 0.7

(7/92)

0.7 0.1 D 0.1

(89)

D

(89)

2

(9/93)

E

(9/93)

39. Heptachlor 0

(1/91)

0.0004 0.0005 B2 0.0005

(91)

B2

(91)

0.0005

(92)

B2

(92)

40. Heptachlor epoxide 0

(1/91)

0.0002 0.000013 B2 0.000013

(91)

B2

(91)

0.000013

(92)

B2

(92)
Table 2 (continued)

 Regulation (month/year) IRIS (year) OPP (month/year)

Chemical MCLG

mg/L

MCL

mg/L

RfD

mg/kg/d

Cancer 

group

RfD

mg/kg/d

Cancer

group

RfD 

mg/kg/d

Cancer

group 

18 RfD of HCCP based on the same toxicological study as that of the MCLG but using benchmark dose

modeling for the dose-response analysis. 

19 HCCP: E by inhalation exposure; the potential for carcinogenicity by the oral route is unknown.

20 Lead action level: 0.015 mg/L.

21 Lindane: An additional safety factor of three was applied to the RfD to take into account the evidence for

increased susceptibility of the young demonstrated in developmental neurotoxicity and reproductive toxicity studies

in rats, giving a population adjusted dose (PAD) of 0.0016 mg/kg/day.

22 Under the draft revised guidelines for carcinogen risk assessment (USEPA, 1999), the data for lindane

show suggestive evidence of carcinogenicity, but not sufficient to assess human carcinogenic potential.

23 Mercury Study Report to Congress assessment (USEPA, 1997): RfD for inorganic Hg of 0.0003

mg/kg/day retained. Under the 1996 proposed cancer guidelines, inorganic mercury is not likely to be a human

carcinogen at levels found in water.

24 RfDs for nitrate and nitrite, in mg N/kg/day, back-calculated from epidemiological studies on the basis of

0.64 L/day and a 4-kg infant. 

15

41. Hexachlorobenzene 0

(7/92)

0.001 0.0008 B2 0.0008

(91)

B2

(91)

Canceled

42. Hexachlorocyclopentadiene0.05

(7/92)

0.05 0.007 D 0.006 18

(01)

— 19

(01)

43. Lead 0

(6/91)

TT 20 — B2 NA B2

(88)

44. Lindane ((-hexachlorocyclohexane) 

0.0002

(1/91)

0.0002 0.0003 C 0.0003 

(88)

NA 0.0047 21

(7/02)

— 22

(7/02)

45. Mercury (Inorganic) 0.002

(1/91)

0.002 0.0003 D 0.0003 23

(97)

— 23

(97)

46. Methoxychlor 0.04

(1/91)

0.04 0.005 D 0.005

(90)

D

(90)

47. Monochlorobenzene

(Chlorobenzene)

0.1

(1/91)

0.1 0.02 D 0.02

(90)

D

(90)

48. Nitrate (as N) 10

(1/91)

10 1.6 24 D 1.6 24

(91)

NA
Table 2 (continued)

 Regulation (month/year) IRIS (year) OPP (month/year)

Chemical MCLG

mg/L

MCL

mg/L

RfD

mg/kg/d

Cancer 

group

RfD

mg/kg/d

Cancer

group

RfD 

mg/kg/d

Cancer

group 

25 RfD for nitrite, in mg N/kg/day, back-calculated from epidemiological studies on the basis of 1 L/day

and a 10-kg child. It is equivalent to a RfD of 0.16 mg/kg/day if 0.64 L/day and a 4-kg infant were used. 

26 NAS (2000b) tolerable upper intake level (UL) for selenium for adolescents and adults is 0.4 mg/day, a

value equivalent to the RfD of 0.005 mg/kg/day established in 1991. 

16

49. Nitrite (as N) 1

(1/91)

1 0.16 24 D 0.125

(87)

NA

Nitrate + Nitrite (as N) 10

(1/91)

10 — — — —

50. Oxamyl (Vydate) 0.2

(7/92)

0.2 0.025 E 0.025

(87)

NA 0.001

(10/00)

E

(10/00)

51. Pentachlorophenol 0

(1/91)

0.001 0.03 B2 0.03

(91)

B2 

(91)

52. Picloram 0.5

(7/92)

0.5 0.07 D 0.07

(87)

NA 0.2

(4/98)

E

(4/98)

53. Polychlorinated

biphenyls (Aroclors)

0

(1/91)

0.0005 — B2 2 - 7 x10-5

(96)

B2 

(96)

54. Selenium 26 0.05

(1/91)

0.05 0.005 D 0.005

(91)

D

(91)

55. Simazine 0.004

(7/92)

0.004 0.005 C 0.005

(93)

NA

56. Styrene 0.1

(1/91)

0.1 0.2 C 0.2 

(90)

NA 

57. 2,3,7,8-TCDD 

(Dioxin)

0

(7/92)

3x10-8 10-9 B2

58. Tetrachloroethylene

(“perc”)

0

(1/91)

0.005 0.01 B2 0.01 

(88)

NA Canceled

59. Thallium 0.0005

(7/92)

0.002 0.00007 D 0.00008 

(90)

D

(90)

Canceled 

60. Toluene 1

(1/91)

1 0.2 D 0.2

(90)

D

(90)

61. Toxaphene 0

(1/91)

0.003 NA B2 NA B2

(91)

Canceled
Table 2 (continued)

 Regulation (month/year) IRIS (year) OPP (month/year)

Chemical MCLG

mg/L

MCL

mg/L

RfD

mg/kg/d

Cancer 

group

RfD

mg/kg/d

Cancer

group

RfD 

mg/kg/d

Cancer

group 

27 Under the 1996 proposed cancer guidelines, vinyl chloride is a known human carcinogen by the

inhalation route of exposure, based on human epidemiological data, and by analogy the oral route because of

positive animal bioassay data as well as pharmacokinetic data allowing dose extrapolation across routes. 

17

62. 2,4,5-TP (Silvex;

2,4,5-Trichlorophenoxy

propionic acid)

0.05

(1/91)

0.05 0.008 D 0.008

(88)

D

(88)

Canceled

63. Trichlorobenzene 

(1,2,4-)

0.07

(7/92)

0.07 0.01 D 0.01

(92)

D

(91)

64. Trichloroethane

(1,1,1-)

0.20

(7/87)

0.20 0.035 D NA

(91)

D

(90)

65. Trichloroethane

(1,1,2-)

0.003

(7/92)

0.005 0.004 C 0.004

(91)

C

(91)

Canceled

66. Trichloroethylene 0

(7/87)

0.005 — B2 NA

(89)

NA

(89)

Canceled

67. Vinyl chloride 0

(7/87)

0.002 — A 0.003

(00)

A 27

(00)

68. Xylenes (total) 10

(1/91)

10 2 D 2 

(88)

D 

(88)
1 Subchronic and chronic toxicological studies of Cr VI initiated by NTP.

18

Table 3. Assessment by IRIS, OPP, ATSDR, and NAS of chemicals considered under the first Six-Ye

Chemical, Year Regulated 90/91 92/93 94/95 96 97 98 99 00 01 

Acrylamide *91 IRIS 

Alachlor *91 IRIS OPP 

Antimony *92 IRIS ATSDR 

Asbestos *91 ATSDR 

Atrazine *91 IRIS 

Barium *91 ATSDR IRIS

Benzene *87 ATSDR IRIS

Benzo[a]pyrene *92 IRIS ATSDR 

Beryllium *92 IRIS 

Cadmium *91 IRIS ATSDR 

Carbofuran *91 

Carbon tetrachloride *87 IRIS ATSDR 

Chlordane *91 ATSDR IRIS

Chromium *91 IRIS ATSDR 

Copper ‘91 NAS Cyanide *92 ATSDR 
Table 3 (continued)

Chemical, Year Regulated 90/91 92/93 94/95 96 97 98 99 00 01 

19

2,4-D *91 

Dalapon *92

Di (2-ethylhexyl)adipate *92 IRIS 

Di (2-ethylhexyl)phthalate *92 

1,2-DBCP *91 IRIS ATSDR

1,2-Dichlorobenzene *91 IRIS 

1,4-Dichlorobenzene *87 IRIS ATSDR 1,2-Dichloroethane *87 IRIS ATSDR 

1,1-Dichloroethylene *87 ATSDR 

cis-1,2-Dichloroethylene *91 IRIS ATSDR

trans-1,2-Dichloroethylene *91 ATSDR

Dichloromethane *92 IRIS ATSDR 

1,2-Dichloropropane *91 IRIS

Dinoseb *92

Diquat *92 OPP 

Endothall *92 

Endrin *92 ATSDR

Epichlorohydrin *91 IRIS
Table 3 (continued)

Chemical, Year Regulated 90/91 92/93 94/95 96 97 98 99 00 01 

2 Mercury Study Report to Congress (USEPA, 1997).

20

Ethylbenzene *91 IRIS ATSDR 

Ethylene dibromide *91 IRIS ATSDR 

Fluoride *86 NAS NAS 

Glyphosate *92 OPP 

Heptachlor *91 IRIS OPP

ATSDR

Heptachlor epoxide *91 IRIS OPP

ATSDR

Hexachlorobenzene *92 IRIS 

Hexachlorocyclopentadiene

*92

ATSDR IRIS

Lead *91 ATSDR

Lindane *91 ATSDR 

Mercury *91 (Inorganic) IRIS EPA 2 ATSDR

Methoxychlor *91 IRIS 

Monochlorobenzene *91 IRIS

ATSDR 
Table 3 (continued)

Chemical, Year Regulated 90/91 92/93 94/95 96 97 98 99 00 01 

3 Joint IRIS/ Styrene Information and Research Council.

21

Nitrate *91 IRIS NAS

Nitrite *91 NAS

Oxamyl *92 OPP

Pentachlorophenol *91 IRIS ATSDR 

Picloram *92 OPP

PCBs *91 IRIS ATSDR 

Selenium *91 IRIS NAS 

Simazine *92 IRIS 

Styrene *91 IRIS ATSDR 

2,3,7,8-TCDD *92 ATSDR 

Tetrachloroethylene *91 ATSDR 

Thallium *92 IRIS ATSDR 

Toluene *91 IRIS ATSDR 

Toxaphene *91 IRIS ATSDR

2,4,5-TP *91 
Table 3 (continued)

Chemical, Year Regulated 90/91 92/93 94/95 96 97 98 99 00 01 

22

1,2,4-Trichlorobenzene *92 IRIS

1,1,1-Trichloroethane *87 IRIS ATSDR 

1,1,2-Trichloroethane *92 IRIS

Trichloroethylene *87 ATSDR 

Vinyl chloride *87 ATSDR IRIS

Xylenes *91 ATSDR 
1 NAS assessment of fluoride initiated

23

Table 4. Evaluation of the literature search for reproductive and developmental toxicity

(New IRIS assessments initiated for chemicals given in bold)

Chemical Comments

Cyanide Based on NTP (1993) 13-week study, ATSDR (1997) identified a NOAEL of 4.5

mg/kg/day for reproductive effects in male rats (decreases in epididymis and testis

weights and reduction in spermatid head size and count). The current 1992 NPDWR

RfD of 0.02 mg/kg/day is based on a NOAEL of 10.8 mg/kg/day in a 2-year study

for weight loss, thyroid effects and myelin degeneration in rats. New IRIS

assessment initiated.

Dalapon Literature search performed for the Six-Year Review did not identify any

information to support consideration of a revision to the RfD (and therefore the

MCLG).

Di(2-ethylhexyl)adipate Current RfD/MCLG of 1992 based on a developmental toxicity study in rats that

identified a NOAEL of 170 mg/kg/day. WHO (1996) and the European

Commission (EC 1999) considered the LOAEL to be 170 mg/kg/day and the

NOAEL to be the next lower dose of 28 mg/kg/day. Similarly, IARC (2000)

indicated effects at 170 mg/kg/day. New IRIS assessment initiated to reevaluate the

available developmental and reproductive studies, and to evaluate new studies that

have become available on the toxicity of DEHA and its metabolites.

cis-1,2-Dichloroethylene Literature search performed for the Six-Year Review did not identify any

information to support consideration of a revision to the RfD (and therefore the

MCLG). 

trans-1,2-

Dichloroethylene

Literature search performed for the Six-Year Review did not identify any

information to support consideration of a revision to the RfD (and therefore the

MCLG). 

Dinoseb Current RfD based on three-generation reproductive study in rats. Developmental

effects seen at higher doses than are reproductive effects. New information does not

support need to revise RfD/MCLG.

Endrin Reproductive and developmental effects occur at doses above those causing

hepatotoxicity, the critical effect. New information does not support need to revise

RfD/MCLG.

Fluoride 1 No new studies identified in the literature search indicating that fluoride adversely

affects reproductive or developmental endpoints. Epidemiological studies show no

evidence of an association between the consumption of fluoridated drinking water

by mothers and increased risk of spontaneous abortion or congenital malformation

(WHO, 2002).

Monochlorobenzene Literature search performed for the Six-Year Review did not identify any

information to support consideration of a revision to the RfD (and therefore the

MCLG). 
Table 4 (continued)

Chemical Comments

24

Nitrate Current RfD/MCLG established to protect infants, the most susceptible segment of

the population. Epidemiological studies of maternal nitrate exposure from drinking

water and developmental effects in offspring or spontaneous abortion are

inconclusive (Croen et al., 1997). Reproductive and developmental effects in

experimental animals are not the critical effects. Epidemiological studies of nitrate

in drinking water and cancer incidence, including non-Hodgkin’s lymphoma, a

childhood cancer, and bladder cancer are inconclusive (Weyer et al., 2001; Ward et

al., 1996). New information does not support need to revise RfD/MCLG.

Nitrite Current RfD/MCLG is protective of methemoglobinemia in infants, the most

susceptible segment of the population. Sodium nitrite was tested in mice by NIEHS

(Chapin et al., 1997) using the Reproductive Assessment by Continuous Breeding

protocol; reproductive effects are not the critical effects and did not occur at doses

as high as 425 mg nitrite/kg/day. New information does not support need to revise

RfD/MCLG.

Selenium NAS (2000b) assessment of Se confirms the current RfD of 1991 based on

epidemiological studies of selenosis in humans. Epidemiological studies of Se

deficiency and male infertility, pregnancy-induced hypertension and congenital

heart disease, are inconclusive (ATSDR, 1996). In experimental animals,

reproductive and developmental toxicity are not the critical effects (NTP, 1996).

New information does not support need to revise RfD/MCLG.

Thallium ATSDR (1992) identified LOAELs in rats for developmental effects (impairment of

learning ability) and reproductive effects (histological alteration of testis) of 0.08

and 0.7 mg/kg/day, respectively, compared to the NOAEL of 0.2 mg/kg/day, the

highest dose tested and the basis of the NPDWR. Also, the present NOAEL of 0.2

mg/kg/day is debatable: Cal/EPA (1999) considers the NOAEL to be the next lower

dose tested of 0.04 mg/kg/day for changes in blood chemistry, alopecia and

lacrimation in rats. Evaluation of developmental neurological effects of TI by the

oral route need to be assessed. New IRIS assessment initiated.

2,4,5-TP (Silvex) Current RfD protective of chronic liver effects would also protect against

fetotoxicity and teratogenicity. New information does not support need to revise

RfD/MCLG.

1,2,4-Trichlorobenzene Current RfD based on a multigeneration reproductive study in rats. New

information does not support need to revise RfD/MCLG.

1,1,2-Trichloroethane Literature search performed for the Six-Year Review did not identify any

information to support consideration of a revision to the RfD (and therefore the

MCLG).
1 Ongoing NTP subchronic and chronic toxicological studies for Cr VI (NTP, 2002).

25

Table 5. Overall review of chemicals

Chemical RfD/Cancer

group

changed

 Ongoing

IRIS or OPP

 assessment 

MCLG = 0 Recent ($97) 

EPA 

assessment

available 

Evaluate

Literature

search for

repro/develop

endpoints 

High priority,

nominate for

new IRIS

assessment

Evalu

Litera

search fo

tox endp

Acrylamide Yes No NoAlachlor Yes Yes No NoAntimony Yes No NoAsbestos Yes No NoAtrazine Yes No NoBarium Yes No NoBenzene Yes Yes No NoBenzo[a]pyrene Yes No NoBeryllium Yes Yes No NoCadmium Yes No NoCarbofuran Yes No NoCarbon tetrachloride Yes No NoChlordane Yes Yes No NoChromium Yes NTP 1 Yes No No

Copper Yes No No
Table 5 (continued)

Chemical RfD/Cancer

group

changed

 Ongoing

IRIS or OPP

 assessment 

MCLG = 0 Recent ($97) 

EPA 

assessment

available 

Evaluate

Literature

search for

repro/develop

endpoints 

High priority,

nominate for

new IRIS

assessment

Evalu

Litera

search fo

tox endp

26

Cyanide Yes Yes No2,4-D Yes No NoDalapon Yes No Yes Di(2-ethylhexyl) adipate Yes Yes NoDi(2-ethylhexyl)phthalate

Yes No No

1,2-DBCP Yes No No1,2-Dichlorobenzene Yes No No1,4-Dichlorobenzene Yes No No1,2-Dichloroethane Yes No No1,1-Dichloroethylene Yes Yes No NoDichloroethylene(cis-1,2-)

Yes No Yes 

Dichloroethylene (trans1,2-) Yes No Yes Dichloromethane Yes No No1,2-Dichloropropane Yes No No
Table 5 (continued)

Chemical RfD/Cancer

group

changed

 Ongoing

IRIS or OPP

 assessment 

MCLG = 0 Recent ($97) 

EPA 

assessment

available 

Evaluate

Literature

search for

repro/develop

endpoints 

High priority,

nominate for

new IRIS

assessment

Evalu

Litera

search fo

tox endp

27

Dinoseb Yes No Yes Diquat Yes Yes No NoEndothall Yes No NoEndrin Yes No Yes Epichlorohydrin Yes No NoEthylbenzene Yes No NoEthylene dibromide Yes No NoFluoride Yes No Yes Glyphosate Yes Yes No NoHeptachlor Yes No NoHeptachlor epoxide Yes No NoHexachlorobenzene Yes No NoHexachlorocyclopentadiene Yes No NoLead Yes No NoLindane Yes Yes No No
Table 5 (continued)

Chemical RfD/Cancer

group

changed

 Ongoing

IRIS or OPP

 assessment 

MCLG = 0 Recent ($97) 

EPA 

assessment

available 

Evaluate

Literature

search for

repro/develop

endpoints 

High priority,

nominate for

new IRIS

assessment

Evalu

Litera

search fo

tox endp

28

Mercury (inorganic) Yes No NoMethoxychlor Yes No NoMonochlorobenzene Yes No Yes Nitrate Yes No Yes Nitrite Yes No Yes Oxamyl Yes Yes No NoPentachlorophenol Yes No NoPicloram Yes Yes No NoPCBs Yes No NoSelenium Yes No No (NAS, Simazine Yes No NoStyrene Yes No No2,3,7,8-TCDD Yes No NoTetrachloroethylene Yes No NoThallium Yes Yes NoToluene Yes No No
Table 5 (continued)

Chemical RfD/Cancer

group

changed

 Ongoing

IRIS or OPP

 assessment 

MCLG = 0 Recent ($97) 

EPA 

assessment

available 

Evaluate

Literature

search for

repro/develop

endpoints 

High priority,

nominate for

new IRIS

assessment

Evalu

Litera

search fo

tox endp

29

Toxaphene Yes No No2,4,5-TP (Silvex) Yes No Yes Trichlorobenzene (1,2,4-) Yes No Yes Trichloroethane (1,1,1-) Yes No NoTrichloroethane (1,1,2-) Yes No Yes Trichloroethylene Yes No NoVinyl chloride Yes Yes No NoXylenes Yes No No
30

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EPA_822-R-03-008

Six-Year_Review_-_Chemical_Contaminants_

Health_Effects_Technical_Support_Document