Federal Register / Vol. 61, No. 125 / Thursday, June 27, 1996 / Notices 33511

ACTION: Extension of Comment Period.

SUMMARY: The Department of Health and

Human Services (HHS) is providing

notice of an extension of the time

deadline for submission of written

comments.

DATES: Written comments on the scope

and intent of the Commission’s

objectives must be received by 5:00 p.m.

E.D.T. on August 30, 1996.

ADDRESSES: Kenneth D. Fisher, Ph.D.,

Executive Director, Commission on

Dietary Supplement Labels, Office of

Disease Prevention and Health

Promotion, Room 738G, Hubert H.

Humphrey Building, 200 Independence

Ave., SW., Washington, DC 20201.

FOR FURTHER INFORMATION CONTACT:

Kenneth D. Fisher, Ph.D., (202) 690–

7102.

SUPPLEMENTARY INFORMATION: Public

Law 103–417, Section 12, authorized

the establishment of a Commission on

Dietary Supplement Labels whose seven

members have been appointed by the

President. The appointments to the

Commission by the President and the

establishment of the Commission by the

Secretary of Health and Human Services

reflect the commitment of the President

and the Secretary to the development of

a sound and consistent regulatory policy

on labeling of dietary supplements.

The Commission is charged with

conducting a study and providing

recommendations for regulation of label

claims and statements for dietary

supplements, including the use of

supplemental literature in connection

with their sale and, in addition,

procedures for evaluation of label

claims. The Commission is expected to

evaluate how best to provide truthful,

scientifically valid, and non-misleading

information to consumers in order that

they may make informed health care

choices for themselves and their

families. The Commission’s study report

may include recommendations on

legislation, if appropriate and necessary.

Notices announcing meetings of the

Commission on Dietary Supplement

Labels were published on February 1,

1996 (61 FR 3714), February 1, 1996 (61

FR 3714), February 23, 1996 (61 FR

7005), March 29, 1996 (61 FR 14102),

April 4, 1996 (61 FR 15076), and May

16, 1996 (61 FR 24798). Each notice also

indicated that written comments on the

tasks of the Commission were due on

June 30, 1996. This notice is to provide

an extension of the deadline for

receiving comments.

Dated: June 13, 1996.

Claude Earl Fox,

Deputy Assistant Secretary for Health

(Disease Prevention and Health Promotion).

[FR Doc. 96–16405 Filed 6–26–96; 8:45 am]

BILLING CODE 4160–17–M

Agency for Toxic Substances and

Disease Registry

[ATSDR–110]

Minimal Risk Levels for Priority

Substances and Guidance for

Derivation; Republication

Editorial Note: The document set forth

below was originally published at 61 FR

25873, May 23, 1996, and is reprinted

because of typesetting errors.

AGENCY: Agency for Toxic Substances

and Disease Registry (ATSDR),

Department of Health and Human

Services (HHS).

ACTION: Notice.

SUMMARY: The Comprehensive

Environmental Response,

Compensation, and Liability Act

(CERCLA) (42 U.S.C. 9604 et seq.), as

amended by the Superfund

Amendments and Reauthorization Act

(SARA) (Pub. L. 99–499), requires that

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) (42 U.S.C.

9604(i)(2)); prepare toxicological

profiles for each substance included on

the priority list of hazardous substances,

and to ascertain in the toxicological

profiles, significant human exposure

levels (SHELs) for hazardous substances

in the environment, and the associated

acute, subacute, and chronic health

effects (42 U.S.C. 9604(i)(3)); and assure

the initiation of a research program to

fill identified data needs associated with

the substances (42 U.S.C. 9604(i)(5)).

The ATSDR Minimal Risk Levels

(MRLs) were developed in response to

the mandate for SHELs and to provide

screening levels for health assessors and

other responders to identify

contaminants and potential health

effects that may be of concern at

hazardous waste sites and releases.

This notice announces the internal

guidance for derivation of MRLs for

priority hazardous substances by

ATSDR. The guidance represents the

agency’s current approach to deriving

MRLs and reflects the most current

scientific assessment. Comments from

the public on the process of deriving

MRLs are welcome. The MRLs for a

particular substance are published in

the toxicological profile for that

substance. A listing of the current

published MRLs is provided at the end

of the notice.

ADDRESSES: Comments on this notice

should bear the docket control number

ATSDR–110 and should be submitted

to: Division of Toxicology, Agency for

Toxic Substances and Disease Registry,

Mailstop E–29, 1600 Clifton Road, NE.,

Atlanta, Georgia 30333.

FOR FURTHER INFORMATION CONTACT: Dr.

Selene Chou, Division of Toxicology,

Agency for Toxic Substances and

Disease Registry, 1600 Clifton Road,

NE., Mailstop E–29, Atlanta, Georgia

30333, telephone (404)639–6308 or FAX

(404)639–6315.

SUPPLEMENTARY INFORMATION: CERCLA

requires that ATSDR prepare

toxicological profiles for priority

hazardous substances, and to ascertain

significant human exposure levels for

these substances in the environment,

and the associated acute, subacute, and

chronic health effects (42 U.S.C.

9604(i)(3)). Minimal Risk Levels (MRLs)

were developed as an initial response to

the mandate. Following discussions

with scientists within the HHS and the

EPA, ATSDR chose to adopt a practice

similar to that of the EPA’s Reference

Dose (RfD) and Reference Concentration

(RfC) for deriving substance-specific

levels. 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. These substance- specific

estimates, which are intended to serve

as screening levels, are used by ATSDR

health assessors and other responders to

identify contaminants and potential

health effects that may be of concern at

hazardous waste sites and releases. It is

important to note that MRLs are not

intended to define clean-up or action

levels for ATSDR or other Agencies.

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, MRLs are derived when

ATSDR determines that reliable and

sufficient data exist to identify the target

organ(s) of effect, or the most sensitive

health effect(s) for a specific exposure

duration for a given route of exposure to

the substance. MRLs are based on

noncancer health effects only and are

not based on a consideration of cancer

effects. Inhalation MRLs are exposure

concentrations expressed in units of

parts per million (ppm) for gases and

volatiles, or milligrams per cubic meter
33512 Federal Register / Vol. 61, No. 125 / Thursday, June 27, 1996 / Notices

(mg/m3) for particles. Oral MRLs are

expressed as daily human doses in units

of milligrams per kilogram per day (mg/

kg/day).

ATSDR uses the no-observed-adverseeffect-level/uncertainty factor approach

to derive MRLs for hazardous

substances. The MRLs are set below

levels that, based on current

information, might cause adverse health

effects in the people most sensitive to

such substance-induced effects (Barnes

and Dourson 1988; EPA 1990). MRLs are

derived for acute (1–14 days),

intermediate (15–364 days), and chronic

(365 days and longer) exposure

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 substanceinduced end point considered to be of

relevance to humans. ATSDR does not

use serious health effects (such as

irreparable damage to the liver or

kidneys, or birth defects) 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 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 or other hazardous substance

exposures that are not expected to cause

adverse health effects. Most MRLs

contain some degree of uncertainty

because of the lack of precise

toxicological information on the people

who might be most sensitive (e.g.,

infants, elderly, and nutritionally or

immunologically compromised) to the

effects of hazardous substances. ATSDR

uses a conservative (i.e., protective)

approach to address these uncertainties,

consistent with the public health

principle of prevention. Although

human data are preferred, MRLs often

must be based on results of animal

studies because relevant human studies

are lacking. In the absence of evidence

to the contrary, ATSDR assumes that

humans are more sensitive than animals

to the effects of hazardous substances,

and that certain persons may be

particularly sensitive. Thus, the

resulting MRL may be as much as a

hundredfold below levels shown to be

nontoxic in laboratory animals.

Proposed MRLs undergo a rigorous

review process. They are reviewed by

the Health Effects/MRL Workgroup

within the Division of Toxicology; an

expert panel of peer reviewers; the

agency wide MRL Workgroup, with

participation from other federal

agencies, including EPA; and are

submitted for public comment through

the toxicological profile public

comment period. Each MRL is subject to

change as new information becomes

available concomitant with updating the

toxicological profile of the substance.

MRLs in the most recent toxicological

profiles supersede previously published

levels. A listing of the current published

MRLs is provided at the end of this

notice.

Categories Used to Derive MRLs

The following health effect end points

can be used to derive MRLs:

Systemic

Respiratory

Cardiovascular

Gastrointestinal

Hematological

Musculoskeletal

Hepatic

Renal

Endocrine

Dermal

Ocular

Metabolic

Body weight change

Other systemic effects

Immunological and Lymphoreticular

Neurological

Reproductive

Developmental

To provide a better analysis of the

toxic potential of the profiled substance,

the same effect can be considered under

more than one system category; for

example, behavioral effects in the

offspring can be either neurological or

developmental. However, only one

system category per exposure route and

duration should be chosen as the basis

for deriving the MRL. If two different

effects within two different systems

would result in the same MRL value, the

MRL should be derived from the one

that is best supported by data from all

exposure routes and durations.

Classification of End Points as NOAELs,

Less Serious LOAELs or Serious

LOAELs

MRLs are derived from no-observedadverse-effect levels (NOAELs). In the

absence of NOAELs, MRLs can be

derived from less serious lowestobserved-adverse-effect levels

(LOAELs). MRLs are not derived from

serious LOAELs. In its 1986–1988

Biennial Report Volume II, ATSDR

defines an adverse health effect as a

harmful or potentially harmful change

in the physiologic function, psychologic

state, or organ structure that may result

in an observed deleterious health

outcome. Adverse health effects may be

manifested in pathophysiologic changes

in target organs, psychologic effects, or

overt disease. This definition is

interpreted to indicate that any effect

that enhances the susceptibility of an

organism to the deleterious effects of

other chemical, physical,

microbiological, or environmental

influences should be considered

adverse.

ATSDR acknowledges that a

considerable amount of judgement is

required in this process and that, in

some cases, there will be insufficient

data to decide whether or not an effect

will lead to significant dysfunction.

ATSDR generally will not derive an

MRL if no adverse health effect has been

reported in the published peer reviewed

literature in any target organ (e.g., all

free standing NOAELs) for a given

duration. However, data from other

durations and routes of exposure may

lend support for selecting an

appropriate end point to derive an MRL.

Deciding whether an end point is a

NOAEL or a LOAEL depends in part

upon the toxicity that occurs at other

doses in the studies evaluated, and in

part upon knowledge regarding the

mechanism of toxicity of the substance.

The distinction between less serious

and serious LOAEL is intended to help

the users of the toxicological profiles see

at what levels of exposure ‘‘major’’

effects begin to appear, and whether the

less serious effects occur at

approximately the same levels as

serious effects or at substantially lower

levels of exposure. In general, a dose

that evokes failure in a biological system

and can lead to morbidity or mortality

(e.g., acute respiratory distress or death)

is referred to as a serious LOAEL. A

more specific classification scheme is as

follows.

No Adverse Effects

• Weight loss or decrease in body

weight gain of less than 10%.

• Changes in organ weight of

nontarget organ tissues not associated

with abnormal morphologic or

biochemical changes.

• Increased mortality over controls

that is not statistically significant (p >

0.05).

• Some adaptive responses.

Less Serious Adverse Effects

• Reversible cellular alterations at the

ultrastructural level (e.g., dilated

endoplasmic reticulum) and at the lightmicroscopy level (e.g., cloudy swelling,

fatty change).

• Necrosis (dependent upon location,

distribution, reversibility or the degree

of associated dysfunction), metaplasia,

or atrophy with no apparent decrement

of organ function.
Federal Register / Vol. 61, No. 125 / Thursday, June 27, 1996 / Notices 33513

• Serum chemistry changes, e.g.,

moderate elevations of serum aspartate

aminotransferase (SGOT), serum alanine

aminotransferase (SGPT).

• Weight loss or decrease in body

weight gain of 10%–19%.

• Some adaptive responses.

Serious Effects

• Death

• Clinical effects of significant organ

impairment (e.g., convulsions, icterus,

cyanosis).

• Morphologic changes in organ

tissues that potentially could result in

severe dysfunction (e.g., marked

necrosis of hepatocytes or renal

tubules).

• Weight loss or decrease in body

weight gain of 20% or greater.

• Serum chemistry changes (e.g.,

major elevations of SGOT, SGPT)

• Major metabolic effects (e.g.,

ketosis, acidosis, alkalosis).

• Cancer effects.

Additional guidance on the

assessment of end-point-specific health

effects is available upon request.

The Adequacy of Database for

Derivation of an MRL

It is difficult to provide strict rules

governing this determination. Each

profiled substance presents its own

unique situation. The following key

points should be considered:

• Good quality human data are

generally preferred over animal data.

• Only one MRL is derived per

exposure period (acute, intermediate, or

chronic) for each route of exposure.

• The MRL is generally based on the

highest NOAEL (that does not exceed a

LOAEL) or the lowest LOAEL for the

most sensitive end point for that route

and exposure period.

• Although not a preferred end point

for MRL derivation, decreased body

weight gain can be used when the

decrease is greater than 10% and when

the study provides some indication that

weight loss is due to a systemic effect

of toxicant and not reduced food and/

or water intake.

• It is preferable to derive MRLs using

data for each exposure duration.

However, when this is not possible

because of limitations of the database

for a given duration, an MRL derived for

one duration may sometimes be

applicable to MRL(s) for other

duration(s) of the same route based on

consideration of the overall database.

Selection of Most Sensitive Effect

• The MRLs are based on the concept

that a threshold level of exposure exists

below which no noncancer health effect

is likely to occur, and, therefore, an

exposure level protective against the

most sensitive effect would also be

protective against all other effects. The

most sensitive effect is the first adverse

effect that occurs or is expected to occur

in humans as dose increases. However,

information on the mechanisms of

action should be considered when

assessing the significance of the effects.

Where the target organ of effect is not

clearly identified, an MRL is usually not

derived. However, the lack of

quantitative data for a particular system

category does not preclude derivation of

an MRL if other evidence, such as

information from human case studies,

toxicokinetics, and other exposure

routes, indicates that this system would

not be expected to be most sensitive to

the substance for the exposure route and

duration of concern.

Toxicokinetics data enter into

consideration when comparing

information across species, routes, and

durations for determination of the most

sensitive effect. Comparison of the

metabolism of the compound exhibiting

the toxic effect in animals with its

metabolism in humans may affect the

choice of the most sensitive end point.

Toxicokinetic differences among species

and for various chemical forms of the

compound may help to explain an

apparent inconsistency among studies.

Differences across routes of exposure

can also be explained by different rates

of absorption, metabolism (both

detoxication and activation), and

excretion.

Selection of a Representative, Quality

Study for MRL Derivation

ATSDR emphasizes its preference for

using data from humans whenever such

data are reliable and appropriate for

MRL derivation. However, human

studies must be of sufficient duration

and contain an adequate number of

documented exposed individuals to be

useful in risk assessment. In the absence

of adequate human studies, animal

studies are used. The author(s) of the

study must provide enough information

on the oral dose or inhalation exposure

concentration administered to the

treated animals to allow for estimation

of an equivalent human oral dose or

inhalation exposure. For both oral and

inhalation studies, the data presented in

the study should at least include the air,

water, or food concentration, the

duration of exposure, the frequency of

exposure (i.e., per day and per week),

the age of the animals, and evidence

that the food and water consumption

rates were not abnormal (e.g., from

weight gain data) for an animal of

similar age.

Background documents on general

factors that ATSDR considers in

evaluating the quality of a study are

available upon request. Other general

principles that have been accepted in

practice when evaluating studies

include:

• Considerations to the exposure

scenario more likely to occur in

environmental exposures. For example,

drinking water or feeding studies are

preferred over gavage oil studies for oral

exposures.

• Determination whether the study

data show a dose-response consistent

with other studies.

The following effects are not used for

MRL derivation:

• Increased incidence of mortality.

• Serious LOAELs.

• Health effects that occur in test

species as a result of mechanisms, or

metabolic processes that are not found

in humans (e.g., α2μ-globulin

nephropathy in male rats).

• Spontaneously occurring disorders

that are species and gender related (e.g.,

chronic progressive nephropathy in

male rats).

• Effects of unknown biological

significance, based on mechanism of

action, that do not affect known target

organs.

• Cancer effects.

Computation of Inhalation MRLs

1. Extrapolating From Animals to

Humans

When animal data is used in the

absence of adequate quantitative human

data, exposure concentrations should be

converted to human equivalent

concentrations by using dosimetry

adjustment in accordance with EPA

(1990), ‘‘Interim Methods for

Development of Inhalation Reference

Doses’’ (EPA/600/8–90/066A, August

1990). Standard reference values should

be obtained from EPA (1988):

‘‘Recommendations for and

Documentation of Biological Values for

Use in Risk Assessment’’ (EPA 600–6–

87/008, February, 1988).

For inhalation exposures to gases or

vapors, it may be necessary to convert

to human equivalent exposures for

respiratory effects (e.g., using the

regional gas dose ratio for the targeted

region of the respiratory tract) or extrarespiratory effects (e.g., using the blood

to air partition coefficient ratio).

For inhalation exposure to particles, it

may also be necessary to convert to

human equivalent exposures for

respiratory effects (e.g., using the

regional deposited dose ratio for the

targeted region of the respiratory tract),

or extrarespiratory effects (e.g., using the
33514 Federal Register / Vol. 61, No. 125 / Thursday, June 27, 1996 / Notices

regional deposited dose ratio and uptake

from the entire respiratory system).

2. Adjusting From Intermittent to

Continuous Dosing

ATSDR defines an MRL as ‘‘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’’. The ideal study

would involve continuous dosing over

the course of the study. If a study did

not involve continuous dosing over the

entire exposure period, an adjustment is

usually made. The ‘‘intermittent

exposure dose’’ (either the NOAEL or

LOAEL of the critical effect selected to

be used for MRL derivation) is

multiplied by correction factors to

adjust for full day and week exposures.

For example, in intermediate (longer

than 14 days) or chronic (longer than

364 days) studies in which the

experimental animals were dosed for 6

hours a day for 5 days a week, the

estimated ‘‘adjusted dose’’ becomes:

Adjusted dose = Intermittent dose × (6

hours/24 hours) × (5 days/7 days)

Intermediate and chronic duration

inhalation studies are usually doseadjusted for day and week exposures;

acute duration inhalation studies can be

duration adjusted from intermittent

exposures to 24 hours continuous

exposure, but are not adjusted to 1

week. For example, acute studies in

which animals were exposed for 6

hours/day for 3 days can be adjusted as

follows:

Adjusted dose = Intermittent dose × (6

hours/24 hours)

However, making duration

adjustments may not be appropriate in

every instance. The toxicokinetics and

mechanism of action should be

examined to the fullest extent possible

before a determination is made to adjust

for intermittent exposures. The

following are some factors to consider in

adjusting for dose and duration.

• When the critical effects are mainly

dependent on the exposure

concentrations and the substance being

tested is rapidly metabolized and/or

excreted, dose adjustment is

inappropriate.

• If the effects being examined are

mainly duration dependent (e.g., longer

periods of exposure increase the

severity of the effects being studied) and

metabolism/excretion is moderate to

slow, or the study identifies a

cumulative effect, duration adjustment

may be appropriate.

3. Converting From Salt to Parent

Substance

Salt concentrations or doses are

converted to equivalent concentrations

or doses of the parent substance by

multiplying by the molecular weight

ratio of parent to salt.

Computation of Oral MRLs

1. Converting From Concentration to

Dose

For feeding studies, the equation for

the conversion from food concentrations

is:

(ppm in food) × (f/kg body weight) =

mg/kg/day

The food consumption factor (f) is kg

of food consumed per day. Unless the

food consumption rate and body

weights are available, standard reference

values should be obtained from EPA

(1988).

For drinking water studies, the

equation for conversion from water

concentrations is:

(ppm in water) × (C/kg body weight) =

mg/kg/day

The water consumption rate (C) is

liters of water consumed per day.

Unless C and body weights are provided

in the study, standard reference values

should be obtained from EPA (1988) or

EPA (1986), as appropriate.

2. Converting From Intermittent to Daily

Dosing

By definition an MRL is ‘‘an estimate

of the daily human exposure to a

hazardous substance that is likely to be

without an appreciable risk of adverse

noncancer health effects over a specified

duration of exposure’’. If the principal

study did not involve daily dosing over

the entire exposure period, an

adjustment is usually made. The

‘‘intermittent dose’’ is multiplied by the

fraction of the study days over which

the test animals were actively dosed.

Acute oral studies are not adjusted to 1

week; intermediate and chronic oral

studies are usually dose-adjusted to full

week exposures. For example, for

animals orally dosed weekly 5 days a

week, the estimated ‘‘continuous dose’’

becomes:

adjusted dose = intermittent dose × (5

days/7 days)

Uncertainty factors and modifying

factor

When sufficient human data are not

available to allow an accurate

assessment of noncancer health risks,

ATSDR may extrapolate from available

information using uncertainty factors

(UFs) to account for different areas of

uncertainty in the database to derive

MRLs. In addition, a modifying factor

(MF) may be applied to reflect

additional scientific judgement on the

database.

MRLs are derived from human

equivalent no-observed-adverse-effect

levels and are calculated as follows:

MRL = (NOAEL) HEC / (UF × MF)

When an appropriate NOAEL does

not exist, the lowest LOAEL should be

used and a UF is applied for the use of

a LOAEL. Additional uncertainty factors

for human variability to protect

sensitive subpopulations, for

interspecies extrapolation when animal

studies are used for derivation of MRLs,

and for extrapolation across exposure

durations are also used.

The default value for each individual

UF is 10; if complete certainty in data

exists, a value of one can be used; and

an intermediate value is three. By

multiplying these individual

uncertainty factors, a combined UF is

obtained.

The use of UFs and MFs should be

based on scientific judgement on a caseby-case basis. General guidelines are as

follows:

Intrahuman variation

An UF of 10 is generally used to

account for intrahuman variation.

However, a UF of 3 or 1 may be applied

when a large epidemiologic study or a

study of the sensitive population was

used.

Interspecies Extrapolation

In the absence of adequate human

data, animal data are used; a UF of 10

is generally used to account for

extrapolation from animals to humans.

However, a UF of 3 or 1 may also be

used when comparative toxicological

data indicate that similar effects are

expected in humans at comparable

exposure levels. For inhalation MRLs,

when dosimetry adjustment is made for

converting animal exposure levels to

human equivalent concentrations, a UF

of 3 is generally applied to account for

any remaining uncertainty (Jarabek and

Segal 1994).

LOAEL to NOAEL Extrapolation

MRLs are derived from NOAELs. In

the absence of a NOAEL, the lowest

LOAEL that causes less serious adverse

health effects is used, and a UF of 10 is

generally applied. When the less serious

LOAEL approaches the threshold level,

that is, only minimal effects are

observed representing an early

indication of toxicity, the effect level is

considered to be a minimal LOAEL, and

a UF of 3 may be used.
Federal Register / Vol. 61, No. 125 / Thursday, June 27, 1996 / Notices 33515

Extrapolation Across Durations

It is preferable to derive MRLs using

data for each exposure duration.

However, when the database supports

extrapolation across acute, intermediate,

or chronic exposure durations, a UF

may be applied based on scientific

judgement. For example, the chronic

inhalation MRL for chlordane was

derived from the intermediate

inhalation MRL with an additional UF

of 10 to account for across duration

extrapolation; the chronic inhalation

MRL was supported by the limited data

on chronic exposure as well as the data

on oral exposure.

Modifying Factor (MF)

An MF greater than zero and up to 10

may be applied to reflect additional

concerns about the database not covered

by the UFs. The default value for MF is

1. An example is the use of an MF of

3 to account for the incomplete database

in deriving the chronic oral MRL for

4,4′-methylenebis(2-chloroaniline).

Another possible consideration is that if

a test substance is known to

bioaccumulate, some studies may

overestimate the dose needed to cause

effects. In such cases, a modifying factor

may be applied.

EPA RfDs and ATSDR MRLs

The current approach for MRL

derivation by ATSDR is similar to the

methods used by EPA to derive

Reference Doses (RfDs) and Reference

Concentrations (RfCs) for chronic

exposures. The following table shows

the difference in methodology used by

ATSDR and EPA in deriving MRLs and

RfDs/RfCs respectively.

As with RfD methodology, in deriving

MRLs, ATSDR uses UFs and MFs to

account for extrapolation from animals

to humans, from LOAEL to NOAEL, for

intraspecies variation, for across

duration extrapolation, and for

professional judgement on the database.

In addition, EPA uses a UF for an

incomplete database (EPA 1990)

whereas ATSDR incorporates scientific

judgement, including an incomplete

database in the MF. However, ATSDR

does not extrapolate across route of

exposure at this time. It is recognized

that the EPA derives RfDs as part of its

regulatory decision-making process.

Extrapolation across route of exposure

(most commonly using data from

inhalation studies to estimate levels by

the oral route) is sometimes used to

develop an RfD where there is

inadequate route-specific information.

Because MRLs may be based on more

recent data and are derived using a

slightly different methodology, or

because MRLs are derived as a result of

different scientific judgement, MRLs

and RfDs (or RfCs) for the same

substance are not necessarily of the

same value.

MRL RfD/RfC

Exposure duration.Acute Chronic.

Intermediate

Chronic

Route of exposure.Oral .............. Oral.

Inhalation Inhalation.

UFs used:

Human variability.Yes ............... Yes.

Interspecies extrapolation.Yes ............... Yes.

LOAEL to

NOAEL.

Yes ............... Yes.

Extrapolation

across

duration.

Yes ............... Yes.

Incomplete

database.

No ................ Yes.

Across

route extrapolation.

No ................ Yes.

MF ................ Yes ............... Yes.

MRLs for Essential Trace Elements

Since many nutritionally essential

elements have been found to be

common contaminants at some toxic

waste sites, consideration was given to

both essentiality and toxicity when

deriving MRLs for these substances.

Special reference was given to

background levels and levels that have

been published as Recommended

Dietary Allowances (RDA) or Estimated

Safe and Adequate Daily Dietary Intakes

(ESADDIs) by the Food and Nutrition

Board of the National Research Council.

MRLs should not be in conflict with the

corresponding RDAs and should be

protective for all age groups.

MRLs vs. Ambient Levels

Since MRLs serve as screening tools

for health assessors, it is important to

compare MRLs with ambient levels

reported in environmental monitoring

studies. When MRLs are lower than

ambient levels, the relevance of the

MRLs is in question, and special

consideration is warranted.

Future Approaches

ATSDR is considering the application

of physiologically based

pharmacokinetic (PBPK) modeling to

enhance understanding of dose and

across-route extrapolations. In addition,

ATSDR is evaluating the utility of

Benchmark Dose modelling, to obtain

low-incidence response exposure levels

calculated from mathematically fitted

dose-response curves, as an adjunct to

the current NOAEL/LOAEL approach in

deriving MRLs.

References

Barnes DG and Dourson M (1988). Reference

Dose (RfD): Description and Use in Health

Risk Assessments. Regulatory Toxicology

and Pharmacology 8:471–486.

EPA (1986). Research and Development:

Reference Values for Risk Assessment.

(ECAO–CIN–477 September 1986).

EPA (1988). Recommendations for and

Documentation of Biological Values for

Use in Risk Assessment. (EPA 600–6–87/

008 February 1988).

EPA (1990). Interim Methods for

Development of Inhalation Reference

Concentrations. (EPA/600/8–90/066A

August 1990).

Jarabek AM and Segal SA. (1994). Noncancer

Toxicity of Inhaled Air Pollutants:

Available Approaches for Risk Assessment

and Risk Management. In: Patrick DR, ed.

Toxic Air Pollution Handbook. New York:

Van Nostrand Reinhold, pp. 529–541.

Dated: May 17, 1996.

Claire V. Broome,

Deputy Administrator, Agency for Toxic

Substances and Disease Registry.

ATSDR MINIMAL RISK LEVELS (MRLS) FOR HAZARDOUS SUBSTANCES

[March 1996]

Substance name CAS No. Route Duration Value Factors End point

ACENAPHTHENE .......... 000083–32–9 ORAL ......................... INTERMEDIATE ........ 0.6 mg/kg/day ............ 300 Hepatic.

ACETONE ...................... 000067–64–1 INHALATION ............. ACUTE ...................... 26 ppm ...................... 9 Neurological.

INHALATION ............. INTERMEDIATE ........ 13 ppm ...................... 100 Neurological.

INHALATION ............. CHRONIC .................. 13 ppm ...................... 100 Neurological.

ORAL ......................... INTERMEDIATE ........ 2 mg/kg/day ............... 100 Hematological.

ACROLEIN ..................... 000107–02–8 INHALATION ............. ACUTE ...................... 0.00005 ppm ............. 100 Ocular.

INHALATION ............. INTERMEDIATE ........ 0.000009 ppm ........... 1000 Respiratory.
33516 Federal Register / Vol. 61, No. 125 / Thursday, June 27, 1996 / Notices

ATSDR MINIMAL RISK LEVELS (MRLS) FOR HAZARDOUS SUBSTANCES—Continued

[March 1996]

Substance name CAS No. Route Duration Value Factors End point

ORAL ......................... CHRONIC .................. 0.0005 mg/kg/day ...... 100 Hematological.

ACRYLONITRILE ........... 000107–13–1 INHALATION ............. ACUTE ...................... 0.1 ppm ..................... 10 Neurological.

ORAL ......................... ACUTE ...................... 0.1 mg/kg/day ............ 100 Developmental.

ORAL ......................... INTERMEDIATE ........ 0.01 mg/kg/day .......... 1000 Reproductive.

ORAL ......................... CHRONIC .................. 0.04 mg/kg/day .......... 100 Hematological.

ALDRIN .......................... 000309–00–2 ORAL ......................... ACUTE ...................... 0.002 mg/kg/day ........ 1000 Developmental.

ORAL ......................... CHRONIC .................. 0.00003 mg/kg/day .... 1000 Hepatic.

AMMONIA ...................... 007664–41–7 INHALATION ............. ACUTE ...................... 0.5 ppm ..................... 100 Respiratory.

INHALATION ............. CHRONIC .................. 0.3 ppm ..................... 10 Respiratory.

ORAL ......................... INTERMEDIATE ........ 0.3 mg/kg/day ............ 100 Other.

ANTHRACENE .............. 000120–12–7 ORAL ......................... INTERMEDIATE ........ 10 mg/kg/day ............. 100 Hepatic.

ARSENIC ....................... 007440–38–2 ORAL ......................... CHRONIC .................. 0.0003 mg/kg/day ...... 3 Dermal.

BENZENE ...................... 000071–43–2 INHALATION ............. ACUTE ...................... 0.05 ppm ................... 300 Immunological.

BIS (2-CHLORO-ETHYL)

ETHER.

000111–44–4 INHALATION ............. INTERMEDIATE ........ 0.02 ppm ................... 1000 Body Weight.

BIS (CHLOROMETHYL)

ETHER.

000542–88–1 INHALATION ............. INTERMEDIATE ........ 0.0003 ppm ............... 100 Respiratory.

BORON .......................... 007440–42–8 ORAL ......................... INTERMEDIATE ........ 0.01 mg/kg/day .......... 1000 Developmental.

BROMODICHLOROMETHANE.000075–27–4 ORAL ......................... ACUTE ...................... 0.04 mg/kg/day .......... 1000 Hepatic.

ORAL ......................... CHRONIC .................. 0.02 mg/kg/day .......... 1000 Renal/Urinary

BROMOFORM ............... 000075–25–2 ORAL ......................... ACUTE ...................... 0.6 mg/kg/day ............ 100 Neurological.

ORAL ......................... CHRONIC .................. 0.2 mg/kg/day ............ 100 Hepatic.

BROMOMETHANE ........ 000074–83–9 INHALATION ............. ACUTE ...................... 0.05 ppm ................... 100 Neurological.

INHALATION ............. INTERMEDIATE ........ 0.05 ppm ................... 100 Neurological.

INHALATION ............. CHRONIC .................. 0.005 ppm ................. 100 Neurological.

ORAL ......................... INTERMEDIATE ........ 0.003 mg/kg/day ........ 100 Gastrointestinal.

CADMIUM ...................... 007440–43–9 INHALATION ............. CHRONIC .................. 0.0002 mg/m3 ............ 10 Renal/Urinary.

ORAL ......................... CHRONIC .................. 0.0007 mg/kg/day ...... 3 Renal/Urinary.

CARBON DISULFIDE .... 000075–15–0 INHALATION ............. CHRONIC .................. 0.3 ppm ..................... 30 Neurological.

ORAL ......................... ACUTE ...................... 0.01 mg/kg/day .......... 300 Hepatic.

CARBON TETRACHLORIDE.000056–23–5 INHALATION ............. ACUTE ...................... 0.2 ppm ..................... 300 Hepatic.

INHALATION ............. INTERMEDIATE ........ 0.05 ppm ................... 100 Hepatic.

ORAL ......................... ACUTE ...................... 0.02 mg/kg/day .......... 300 Hepatic.

ORAL ......................... INTERMEDIATE ........ 0.007 mg/kg/day ........ 100 Hepatic.

CHLORDANE ................. 000057–74–9 INHALATION ............. INTERMEDIATE ........ 0.0002 mg/m3 ............ 100 Hepatic.

INHALATION ............. CHRONIC .................. 0.00002 mg/m3 .......... 1000 Hepatic.

ORAL ......................... ACUTE ...................... 0.001 mg/kg/day ........ 1000 Developmental.

ORAL ......................... INTERMEDIATE ........ 0.0006 mg/kg/day ...... 100 Hepatic.

ORAL ......................... CHRONIC .................. 0.0006 mg/kg/day ...... 100 Hepatic.

CHLORFENVINPHOS ... 000470–90–6 ORAL ......................... ACUTE ...................... 0.002 mg/kg/day ........ 1000 Neurological.

ORAL ......................... INTERMEDIATE ........ 0.002 mg/kg/day ........ 1000 Lymphoreticular.

ORAL ......................... CHRONIC .................. 0.0007 mg/kg/day ...... 1000 Neurological.

CHLOROBENZENE ....... 000108–90–7 ORAL ......................... INTERMEDIATE ........ 0.4 mg/kg/day ............ 100 Hepatic.

CHLORODIBROMOMETHANE.000124–48–1 ORAL ......................... ACUTE ...................... 0.04 mg/kg/day .......... 1000 Renal/Urinary.

ORAL ......................... CHRONIC .................. 0.03 mg/kg/day .......... 1000 Hepatic.

CHLOROETHANE ......... 000075–00–3 INHALATION ............. ACUTE ...................... 1300 ppm .................. 10 Neurological.

INHALATION ............. INTERMEDIATE ........ 76 ppm ...................... 100 Body Weight.

CHLOROFORM ............. 000067–66–3 INHALATION ............. ACUTE ...................... 1 ppm ........................ 30 Hepatic.

INHALATION ............. INTERMEDIATE ........ 0.05 ppm ................... 100 Hepatic.

INHALATION ............. CHRONIC .................. 0.02 ppm ................... 100 Hepatic

ORAL ......................... ACUTE ...................... 0.3 mg/kg/day ............ 100 Hepatic.

ORAL ......................... INTERMEDIATE ........ 0.1 mg/kg/day ............ 100 Hepatic.

ORAL ......................... CHRONIC .................. 0.01 mg/kg/day .......... 1000 Hepatic.

CHLOROMETHANE ...... 000074–87–3 INHALATION ............. ACUTE ...................... 0.5 ppm ..................... 100 Neurological.

INHALATION ............. INTERMEDIATE ........ 0.4 ppm ..................... 100 Body Weight.

INHALATION ............. CHRONIC .................. 0.4 ppm ..................... 100 Body Weight.

CHLORPYRIFOS ........... 002921–88–2 ORAL ......................... ACUTE ...................... 0.003 mg/kg/day ........ 10 Neurological.

ORAL ......................... INTERMEDIATE ........ 0.003 mg/kg/day ........ 10 Neurological.

CHROMIUM,

HEXAVALENT.

018540–29–9 INHALATION ............. INTERMEDIATE ........ 0.00002 mg/m3 .......... 10 Respiratory.

INHALATION ............. CHRONIC .................. 0.00002 mg/m3 .......... 10 Respiratory.

COBALT ......................... 007440–48–4 INHALATION ............. INTERMEDIATE ........ 0.00003 mg/m3 .......... 1000 Respiratory.

CRESOL, META- ........... 000108–39–4 ORAL ......................... ACUTE ...................... 0.05 mg/kg/day .......... 100 Respiratory.

CRESOL, ORTHO- ........ 000095–48–7 ORAL ......................... ACUTE ...................... 0.05 mg/kg/day .......... 100 Neurological.

CRESOL, PARA- ........... 000106–44–5 ORAL ......................... ACUTE ...................... 0.05 mg/kg/day .......... 100 Neurological.

CYANIDE ....................... 000057–12–5 ORAL ......................... INTERMEDIATE ........ 0.05 mg/kg/day .......... 100 Reproductive.
Federal Register / Vol. 61, No. 125 / Thursday, June 27, 1996 / Notices 33517

ATSDR MINIMAL RISK LEVELS (MRLS) FOR HAZARDOUS SUBSTANCES—Continued

[March 1996]

Substance name CAS No. Route Duration Value Factors End point

CYCLOTETRAMETHYLENE TETRANITRAMINE.002691–41–0 ORAL ......................... ACUTE ...................... 0.1 mg/kg/day ............ 1000 Neurological.

ORAL ......................... INTERMEDIATE ........ 0.05 mg/kg/day .......... 1000 Hepatic.

CYCLOTRIMETHY

LENETRINITRAMINE

(RDX).

000121–82–4 ORAL ......................... ACUTE ...................... 0.06 mg/kg/day .......... 100 Neurological.

ORAL ......................... INTERMEDIATE ........ 0.03 mg/kg/day .......... 300 Reproductive.

DDT, P,P′- ...................... 000050–29–3 ORAL ......................... ACUTE ...................... 0.0005 mg/kg/day ...... 1000 Developmental.

ORAL ......................... INTERMEDIATE ........ 0.0005 mg/kg/day ...... 100 Hepatic.

DI(2-ETHYLHEXYL)

PHTHALATE.

000117–81–7 ORAL ......................... ACUTE ...................... 1 mg/kg/day ............... 100 Reproductive.

ORAL ......................... INTERMEDIATE ........ 0.4 mg/kg/day ............ 100 Developmental.

DI-N-BUTYL PHTHALATE.000084–74–2 ORAL ......................... INTERMEDIATE ........ 0.6 mg/kg/day ............ 100 Developmental .

DI-N-OCTYL PHTHALATE.000117–84–0 ORAL ......................... ACUTE ...................... 2 mg/kg/day ............... 1000 Hepatic.

DIAZINON ...................... 000333–41–5 ORAL ......................... INTERMEDIATE ........ 0.0002 mg/kg/day ...... 1000 Developmental.

DICHLORVOS ............... 000062–73–7 INHALATION ............. ACUTE ...................... 0.002 ppm ................. 100 Neurological.

INHALATION ............. INTERMEDIATE ........ 0.0003 ppm ............... 100 Neurological.

INHALATION ............. CHRONIC .................. 0.00006 ppm ............. 100 Neurological.

ORAL ......................... ACUTE ...................... 0.004 mg/kg/day ........ 1000 Neurological.

ORAL ......................... INTERMEDIATE ........ 0.003 mg/kg/day ........ 10 Neurological.

DIELDRIN ...................... 000060–57–1 ORAL ......................... ACUTE ...................... 0.00007 mg/kg/day .... 1000 Immunological.

ORAL ......................... CHRONIC .................. 0.00005 mg/kg/day .... 100 Hepatic.

DIETHYL PHTHALATE 000084–66–2 ORAL ......................... ACUTE ...................... 7 mg/kg/day ............... 300 Reproductive.

ORAL ......................... INTERMEDIATE ........ 6 mg/kg/day ............... 300 Hepatic.

DISULFOTON ................ 000298–04–4 INHALATION ............. ACUTE ...................... 0.006 mg/m3 .............. 30 Neurological.

INHALATION ............. INTERMEDIATE ........ 2E–4 mg/m3 .............. 30 Neurological.

ORAL ......................... ACUTE ...................... 0.001 mg/kg/day ........ 100 Neurological.

ORAL ......................... INTERMEDIATE ........ 9E–5 mg/kg/day ........ 100 Developmental.

ORAL ......................... CHRONIC .................. 6E–5 mg/kg/day ........ 1000 Neurological.

ENDOSULFAN ............... 000115–29–7 ORAL ......................... INTERMEDIATE ........ 0.002 mg/kg/day ........ 100 Immunological.

ORAL ......................... CHRONIC .................. 0.002 mg/kg/day ........ 100 Hepatic.

ENDRIN ......................... 000072–20–8 ORAL ......................... INTERMEDIATE ........ 0.002 mg/kg/day ........ 100 Neurological.

ORAL ......................... CHRONIC .................. 0.0003 mg/kg/day ...... 100 Neurological.

EHTYL BENZENE ......... 000100–41–4 INHALATION ............. INTERMEDIATE ........ 0.3 ppm ..................... 100 Developmental.

ETHYLENE GLYCOL .... 000107–21–1 ORAL ......................... CHRONIC .................. 2 mg/kg/day ............... 100 Renal/Urinary.

ETHYLENE OXIDE ........ 000075–21–8 INHALATION ............. INTERMEDIATE ........ 0.09 ppm ................... 100 Renal/Urinary.

FLUORANTHENE .......... 000206–44–0 ORAL ......................... INTERMEDIATE ........ 0.4 mg/kg/day ............ 300 Hepatic.

FLUORENE .................... 000086–73–7 ORAL ......................... INTERMEDIATE ........ 0.4 mg/kg/day ............ 300 Hepatic.

FUEL OIL NO. 2 ............ 068476–30–2 INHALATION ............. ACUTE ...................... 0.02 mg/m3 ................ 1000 Neurological.

HEXACHLOROBENZENE.000118–74–1 ORAL ......................... ACUTE ...................... 0.008 mg/kg/day ........ 300 Developmental.

ORAL ......................... INTERMEDIATE ........ 0.0003 mg/kg/day ...... 300 Reproductive.

ORAL ......................... CHRONIC .................. 0.00002 mg/kg/day .... 1000 Developmental.

HEXACHLOROBUTADIENE.000087–68–3 ORAL ......................... INTERMEDIATE ........ 0.0002 mg/kg/day ...... 1000 Renal/Urinary.

HEXACHLOROCYCLOHEXANE, BETA-.000319–85–7 ORAL ......................... INTERMEDIATE ........ 0.0003 mg/kg/day ...... 300 Hepatic.

HEXACHLOROCYCLOHEXANE, GAMMA-.000058–89–9 ORAL ......................... ACUTE ...................... 0.01 mg/kg/day .......... 300 Neurological.

ORAL ......................... INTERMEDIATE ........ 0.00004 mg/kg/day .... 300 Immunological.

HEXACHLOROETHANE 000067–72–1 INHALATION ............. ACUTE ...................... 0.5 ppm ..................... 100 Neurological.

INHALATION ............. INTERMEDIATE ........ 0.09 ppm ................... 100 Respiratory.

ORAL ......................... ACUTE ...................... 1 mg/kg/day ............... 100 Hepatic.

ORAL ......................... INTERMEDIATE ........ 0.01 mg/kg/day .......... 100 Hepatic.

HYDRAZINE .................. 000302–01–2 INHALATION ............. INTERMEDIATE ........ 0.0002 ppm ............... 1000 Hepatic.

ISOPHORONE ............... 000078–59–1 ORAL ......................... INTERMEDIATE ........ 3 mg/kg/day ............... 100 Other.

ORAL ......................... CHRONIC .................. 0.2 mg/kg/day ............ 1000 Hepatic.

JP–4 JET FUEL ............. 050815–00–4 INHALATION ............. INTERMEDIATE ........ 9 mg/m3 ..................... 300 Hepatic.

JP–7 JET FUEL ............. HZ0600–22–T INHALATION ............. CHRONIC .................. 0.3 mg/m3 .................. 300 Hepatic.

KEPONE ........................ 000143–50–0 ORAL ......................... ACUTE ...................... 0.01 mg/kg/day .......... 100 Neurological.

ORAL ......................... INTERMEDIATE ........ 0.0005 mg/kg/day ...... 100 Renal/Urinary.

ORAL ......................... CHRONIC .................. 0.0005 mg/kg/day ...... 100 Renal/Urinary.

KEROSENE ................... 008008–20–6 INHALATION ............. INTERMEDIATE ........ 0.01 mg/m3 ................ 1000 Hepatic.

M–XYLENE .................... 000108–38–3 ORAL ......................... INTERMEDIATE ........ 0.6 mg/kg/day ............ 1000 Hepatic.

MANGANESE ................ 007439–96–5 INHALATION ............. CHRONIC .................. 0.0003 mg/m3 ............ 100 Neurological.

MERCURY, INORGANIC HZ0900–19–T ORAL ......................... ACUTE ...................... 0.007 mg/kg/day ........ 100 Renal/Urinary.

ORAL ......................... INTERMEDIATE ........ 0.002 mg/kg/day ........ 100 Renal/Urinary.

MERCURY, METALLIC 007439–97–6 INHALATION ............. ACUTE ...................... 0.00002 mg/m3 .......... 100 Developmental.
33518 Federal Register / Vol. 61, No. 125 / Thursday, June 27, 1996 / Notices

ATSDR MINIMAL RISK LEVELS (MRLS) FOR HAZARDOUS SUBSTANCES—Continued

[March 1996]

Substance name CAS No. Route Duration Value Factors End point

INHALATION ............. CHRONIC .................. 0.000014 mg/m3 ........ 100 Neurological.

METHOXYCHLOR ......... 000072–43–5 ORAL ......................... ACUTE ...................... 0.02 mg/kg/day .......... 1000 Reproductive.

ORAL ......................... INTERMEDIATE ........ 0.02 mg/kg/day .......... 1000 Reproductive.

METHYL PARATHION 000298–00–0 ORAL ......................... CHRONIC .................. 0.0003 mg/kg/day ...... 100 Neurological.

METHYL-T-BUTYL

ETHER.

001634–04–4 INHALATION ............. ACUTE ...................... 2 ppm ........................ 100 Neuorlogical.

INHALATION ............. INTERMEDIATE ........ 0.7 ppm ..................... 100 Neurological.

INHALATION ............. CHRONIC .................. 0.7 ppm ..................... 100 Renal/Urinary.

ORAL ......................... ACUTE ...................... 0.4 mg/kg/day ............ 100 Neurological.

ORAL ......................... INTERMEDIATE ........ 0.3 mg/kg/day ............ 300 Hepatic.

METHYLENE CHLORIDE.000075–09–2 INHALATION ............. ACUTE ...................... 0.4 ppm ..................... 100 Neurological.

INHALATION ............. INTERMEDIATE ........ 0.03 ppm ................... 1000 Hepatic.

ORAL ......................... CHRONIC .................. 0.06 mg/kg/day .......... 100 Hepatic.

METHYLMERCURIC

CHLORIDE.

000115–09–3 ORAL ......................... ACUTE ...................... 0.00012 mg/kg/day .... 10 Developmental.

ORAL ......................... INTERMEDIATE ........ 0.00012 mg/kg/day .... 10 Developmental.

MIREX ............................ 002385–85–5 ORAL ......................... CHRONIC .................. 0.0008 mg/kg/day ...... 100 Hepatic.

N-NITROSODI-N-PROPYLAMINE.000621–64–7 ORAL ......................... ACUTE ...................... 0.095 mg/kg/day ........ 100 Hepatic.

NAPHTHALENE ............. 000091–20–3 INHALATION ............. CHRONIC .................. 0.002 ppm ................. 1000 Respiratory.

ORAL ......................... ACUTE ...................... 0.05 mg/kg/day .......... 1000 Neurological.

ORAL ......................... INTERMEDIATE ........ 0.02 mg/kg/day .......... 300 Hepatic.

NICKEL .......................... 007440–02–0 INHALATION ............. INTERMEDIATE ........ 0.00004 mg/m3 .......... 100 Respiratory

P-XYLENE ..................... 000106–42–3 ORAL ......................... ACUTE ...................... 1 mg/kg/day ............... 100 Neurological.

PENTACHLOROPHENOL.000087–86–5 ORAL ......................... ACUTE ...................... 0.005 mg/kg/day ........ 1000 Developmental.

ORAL ......................... INTERMEDIATE ........ 0.001 mg/kg/day ........ 1000 Hepatic.

PHENOL ........................ 000108–95–2 ORAL ......................... ACUTE ...................... 0.6 mg/kg/day ............ 100 Developmental.

POLYBROMINATED

BIPHENYLS.

067774–32–7 ORAL ......................... ACUTE ...................... 0.01 mg/kg/day .......... 100 Endocrine.

POLYCHLORINATED

BIPHENYLS.

001336–36–3 ORAL ......................... CHRONIC .................. 0.00002 mg/kg/day .... 300 Immunological.

PROPYLENE GLYCOL

DINITRATE.

006423–43–4 INHALATION ............. ACUTE ...................... 0.003 ppm ................. 10 Neurological.

INHALATION ............. INTERMEDIATE ........ 0.00004 ppm ............. 1000 Hematological.

INHALATION ............. CHRONIC .................. 0.00004 ppm ............. 1000 Hematological.

SELENIUM ..................... 007782–49–2 ORAL ......................... CHRONIC .................. 0.002 mg/kg/day ........ 10 Dermal.

SODIUM FLUORIDE ..... 007681–49–4 ORAL ......................... CHRONIC .................. 0.05 mg/kg/day .......... 10 Musculoskeletal.

STYRENE ...................... 000100–42–5 INHALATION ............. CHRONIC .................. 0.06 ppm ................... 100 Neurological.

ORAL ......................... INTERMEDIATE ........ 0.2 mg/kg/day ............ 1000 Hepatic.

TETRACHLOROETHYLENE.000127–18–4 INHALATION ............. ACUTE ...................... 0.2 ppm ..................... 10 Neurological.

INHALATION ............. CHRONIC .................. 0.04 ppm ................... 100 Neurological.

ORAL ......................... ACUTE ...................... 0.05 mg/kg/day .......... 1000 Developmental.

TITANIUM TETRACHLORIDE.007550–45–0 INHALATION ............. CHRONIC .................. 0.001 mg/m3 .............. 90 Respiratory.

TOLUENE ...................... 000108–88–3 INHALATION ............. ACUTE ...................... 3 ppm ........................ 30 Neurological.

INHALATION ............. CHRONIC .................. 1 ppm ........................ 30 Neurological.

ORAL ......................... ACUTE ...................... 0.8 mg/kg/day ............ 300 Neurological.

ORAL ......................... INTERMEDIATE ........ 0.02 mg/kg/day .......... 300 Neurological.

TOTAL XYLENES .......... 001330–20–7 INHALATION ............. ACUTE ...................... 1 ppm ........................ 100 Neurological.

INHALATION ............. INTERMEDIATE ........ 0.7 ppm ..................... 300 Developmental.

INHALATION ............. CHRONIC .................. 0.1 ppm ..................... 100 Neurological.

ORAL ......................... INTERMEDIATE ........ 0.2 mg/kg/day ............ 1000 Renal/Urinary.

TOXAPHENE ................. 008001–35–2 ORAL ......................... ACUTE ...................... 0.005 mg/kg/day ........ 1000 Hepatic.

ORAL ......................... INTERMEDIATE ........ 0.001 mg/kg/day ........ 100 Hepatic.

TRICHLOROETHYLENE 000079–01–6 INHALATION ............. ACUTE ...................... 2 ppm ........................ 30 Neurological.

INHALATION ............. INTERMEDIATE ........ 0.1 ppm ..................... 300 Neurological.

ORAL ......................... ACUTE ...................... 0.5 mg/kg/day ............ 100 Developmental.

ORAL ......................... INTERMEDIATE ........ 0.002 mg/kg/day ........ 100 Developmental.

VANADIUM .................... 007440–62–2 INHALATION ............. ACUTE ...................... 0.0002 mg/m3 ............ 100 Respiratory.

ORAL ......................... INTERMEDIATE ........ 0.003 mg/kg/day ........ 100 Renal/Urinary.

VINYL ACETATE ........... 000108–05–4 INHALATION ............. INTERMEDIATE ........ 0.01 ppm ................... 100 Respiratory.

VINYL CHLORIDE ......... 000075–01–4 INHALATION ............. ACUTE ...................... 0.5ppm ...................... 100 Developmental.

INHALATION ............. INTERMEDIATE ........ 0.03 ppm ................... 300 Hepatic.

ORAL ......................... CHRONIC .................. 0.00002 mg/kg/day .... 1000 Hepatic.

ZINC ............................... 007440–66–6 ORAL ......................... INTERMEDIATE ........ 0.3 mg/kg/day ............ 3 Hematological.

ORAL ......................... CHRONIC .................. 0.3 mg/kg/day ............ 3 Hematological.

1,1,1-

TRICHLOROETHANE.

000071–55–6 INHALATION ............. ACUTE ...................... 2 ppm ........................ 100 Neurological.
Federal Register / Vol. 61, No. 125 / Thursday, June 27, 1996 / Notices 33519

ATSDR MINIMAL RISK LEVELS (MRLS) FOR HAZARDOUS SUBSTANCES—Continued

[March 1996]

Substance name CAS No. Route Duration Value Factors End point

INHALATION ............. INTERMEDIATE ........ 0.7 ppm ..................... 100 Neurological.

1,1,2,2-TETRACHLOROETHANE.000079–34–5 INHALATION ............. ACUTE ...................... 1 ppm ........................ 10 Neurological.

INHALATION ............. INTERMEDIATE ........ 0.4 ppm ..................... 300 Hepatic.

ORAL ......................... ACUTE ...................... 0.3 mg/kg/day ............ 100 Hepatic.

ORAL ......................... INTERMEDIATE ........ 0.3 mg/kg/day ............ 300 Body Weight.

ORAL ......................... CHRONIC .................. 0.3 mg/kg/day ............ 300 Body Weight.

1,1,2-TRICHLORO-ETHANE.000079–00–5 ORAL ......................... ACUTE ...................... 0.3 mg/kg/day ............ 100 Neurological.

ORAL ......................... INTERMEDIATE ........ 0.04 mg/kg/day .......... 100 Hepatic.

1,1-DICHLOROETHENE.000075–35–4 INHALATION ............. INTERMEDIATE ........ 0.02 ppm ................... 100 Hepatic.

ORAL ......................... CHRONIC .................. 0.009 mg/kg/day ........ 1000 Hepatic.

1,1-

DIMETHYLHYDRAZINE.

000057–14–7 INHALATION ............. INTERMEDIATE ........ 0.000009 ppm ........... 1000 Hepatic.

INHALATION ............. CHRONIC .................. 0.000009 ppm ........... 1000 Hepatic.

1,2,3-TRICHLORO-PROPANE.000096–18–4 INHALATION ............. ACUTE ...................... 0.0003 ppm ............... 100 Respiratory.

ORAL ......................... INTERMEDIATE ........ 0.06 mg/kg/day .......... 100 Hepatic.

1,2-DIBROMO-3-

CHLOROPROPANE.

000096–12–8 INHALATION ............. INTERMEDIATE ........ 0.0002 ppm ............... 100 Reproductive.

ORAL ......................... INTERMEDIATE ........ 0.002 mg/kg/day ........ 1000 Reproductive.

1,2-DICHLORO-ETHANE.000107–06–2 INHALATION ............. ACUTE ...................... 0.2 ppm ..................... 100 Immunological.

INHALATION ............. CHRONIC .................. 0.2 ppm ..................... 300 Hepatic.

ORAL ......................... INTERMEDIATE ........ 0.2 mg/kg/day ............ 300 Renal/Urinary.

1,2-DICHLOROETHENE, CIS-.000156–59–2 ORAL ......................... ACUTE ...................... 1 mg/kg/day ............... 100 Hematological.

ORAL ......................... INTERMEDIATE ........ 0.3 mg/kg/day ............ 100 Hematological.

1,2-DICHLOROETHENE, TRANS-.000156–60–5 INHALATION ............. ACUTE ...................... 0.2 ppm ..................... 1000 Hepatic.

INHALATION ............. INTERMEDIATE ........ 0.2 ppm ..................... 1000 Hepatic.

ORAL ......................... INTERMEDIATE ........ 0.2 mg/kg/day ............ 100 Hepatic.

1,2-DICHLORO-PROPANE.000078–87–5 INHALATION ............. ACUTE ...................... 0.05 ppm ................... 1000 Respiratory.

INHALATION ............. INTERMEDIATE ........ 0.007 ppm ................. 1000 Respiratory.

ORAL ......................... ACUTE ...................... 0.1 mg/kg/day ............ 1000 Neurological.

ORAL ......................... INTERMEDIATE ........ 0.07 mg/kg/day .......... 1000 Hematological.

ORAL ......................... CHRONIC .................. 0.09 mg/kg/day .......... 1000 Hepatic.

1,2-DIMETHYL-HYDRAZINE.000540–73–8 ORAL ......................... INTERMEDIATE ........ 0.0008 mg/kg/day ...... 1000 Hepatic.

1,3-DICHLOROPROPENE.000542–75–6 INHALATION ............. INTERMEDIATE ........ 0.003 ppm ................. 100 Respiratory.

INHALATION ............. CHRONIC .................. 0.002 ppm ................. 100 Respiratory.

1,3-DINITRO-BENZENE 000099–65–0 ORAL ......................... ACUTE ...................... 0.008 mg/kg/day ........ 100 Reproductive.

ORAL ......................... INTERMEDIATE ........ 0.0005 mg/kg/day ...... 1000 Hematological.

1,4-DICHLORO-BENZENE.000106–46–7 INHALATION ............. INTERMEDIATE ........ 0.2 ppm ..................... 100 Hepatic.

ORAL ......................... INTERMEDIATE ........ 0.1 mg/kg/day ............ 100 Hepatic.

1-METHYLNAPHTHALENE.000090–12–0 ORAL ......................... CHRONIC .................. 0.07 mg/kg/day .......... 1000 Respiratory.

2,3,4,7,8-

PENTACHLORODIBENZO-FURAN.

057117–31–4 ORAL ......................... ACUTE ...................... 0.000001 mg/kg/day 3000 Immunological.

ORAL ......................... INTERMEDIATE ........ 0.00000003 mg/kg/

day.

3000 Hepatic.

2,3,7,8-

TETRACHLORODIBENZO-P-DIOXIN.

001746–01–6 ORAL ......................... ACUTE ...................... 0.0000001 mg/kg/day 1000 Hepatic.

ORAL ......................... INTERMEDIATE ........ 0.000000001 mg/kg/

day.

1000 Reproductive.

ORAL ......................... CHRONIC .................. 0.000000001 mg/kg/

day.

1000 Reproductive.

2,4,6-TRICHLORO-PHENOL.000088–06–2 ORAL ......................... INTERMEDIATE ........ 0.04 mg/kg/day .......... 100 Reproductive.

2,4,6-TRINITROTOLUENE.000118–96–7 ORAL ......................... INTERMEDIATE ........ 0.0005 mg/kg/day ...... 1000 Hepatic.

2,4-DINITROPHENOL ... 000051–28–5 ORAL ......................... ACUTE ...................... 0.01 mg/kg/day .......... 100 Body Weight.

2,4-DINITROTOLUENE 000121–14–2 ORAL ......................... ACUTE ...................... 0.06 mg/kg/day .......... 1000 Hematological.

ORAL ......................... INTERMEDIATE ........ 0.05 mg/kg/day .......... 100 Reproductive.
33520 Federal Register / Vol. 61, No. 125 / Thursday, June 27, 1996 / Notices

ATSDR MINIMAL RISK LEVELS (MRLS) FOR HAZARDOUS SUBSTANCES—Continued

[March 1996]

Substance name CAS No. Route Duration Value Factors End point

ORAL ......................... CHRONIC .................. 0.002 mg/kg/day ........ 100 Hematological.

2,6-DINITROTOLUENE 000606–20–2 ORAL ......................... INTERMEDIATE ........ 0.04 mg/kg/day .......... 100 Neurological.

4,4′-METHYLENE-BIS

(2-CHLOROANILINE).

000101–14–4 ORAL ......................... CHRONIC .................. 0.003 mg/kg/day ........ 3000 Hepatic.

4,6-DINITRO-O-CRESOL.000534–52–1 ORAL ......................... ACUTE ...................... 0.004 mg/kg/day ........ 100 Neurological.

ORAL ......................... INTERMEDIATE ........ 0.004 mg/kg/day ........ 100 Neurological.

[FR Doc. 96–12991 Filed 5–22–96; 8:45 am]

BILLING CODE 1505–01–D

Centers for Disease Control and

Prevention

[Announcement Number 662]

Applied Research in Emerging

Infections—Controlling the Spread of

Antimicrobial Resistance in

Community-Acquired Bacterial

Pathogens

Introduction

The Centers for Disease Control and

Prevention (CDC) is implementing a

program for competitive cooperative

agreement and/or research project grant

applications to support applied research

on emerging infections. CDC announces

the availability of fiscal year (FY) 1996

funds to provide assistance for a

program to conduct research on

controlling the spread of antimicrobial

resistance among community-acquired

bacterial pathogens.

The CDC is committed to achieving

the health promotion and disease

prevention objectives of Healthy People

2000, a national activity to reduce

morbidity and mortality and improve

the quality of life. This announcement

is related to the priority area of

Immunization and Infectious Diseases.

(For ordering a copy of Healthy People

2000, see the section Where To Obtain

Additional Information.)

Authority

This program is authorized under

sections 301(a) and 317(k)(2) [42 U.S.C.

241(a) and 247b(k)(2)] of the Public

Health Service Act, as amended.

Smoke-Free Workplace

CDC strongly encourages all grant

recipients to provide a smoke-free

workplace and to promote the nonuse of

all tobacco products, and Public Law

103–227, the Pro-Children Act of 1994,

prohibits smoking in certain facilities

that receive Federal funds in which

education, library, day care, health care,

and early childhood development

services are provided to children.

Eligible Applicants

Applications may be submitted by

public and private, nonprofit and forprofit organizations and governments

and their agencies. Thus, universities,

colleges, research institutions, hospitals,

other public and private organizations,

including State and local governments

or their bona fide agents, federally

recognized Indian tribal governments,

Indian tribes or Indian tribal

organizations, and small, minority- and/

or women-owned businesses are eligible

to apply.

Availability of Funds

Approximately $250,000 is available

in FY 1996 to fund one or two awards.

It is expected that the awards will begin

on or about September 30, 1996, and

will be made for a 12-month budget

period within a project period of up to

two years. Funding estimates may vary

and are subject to change. Continuation

awards within an approved project

period will be made on the basis of

satisfactory progress and availability of

funds.

Purpose

The purpose of the emerging

infections extramural research program

is to provide financial and technical

assistance for applied research projects

on emerging infections in the United

States. As a component of this emerging

infections extramural research program,

this announcement focuses on

controlling the spread of antimicrobial

resistance among community-acquired

bacterial respiratory pathogens.

Specifically, the purpose of this

announcement is to provide assistance

for the development and

implementation of a program to promote

judicious antimicrobial use in an

outpatient population, and the

evaluation of its impact on carriage or

infection with community-acquired

drug-resistant bacterial respiratory

pathogens. If successful, such a project

could serve as the scientific foundation

for national efforts to change antibiotic

use practices of physicians in order to

decrease the spread of resistance.

Program Requirements

In conducting activities to achieve the

purpose of this program, the recipient

shall be responsible for the activities

under A., below and CDC shall be

responsible for conducting activities

under B., below. In Recipient Activities

below, the study of drug resistant S.

pneumoniae, H. influenzae, or M.

catarrhalis in a pediatric population are

examples of an appropriate approach

and are provided for illustration

purposes. Applicants may propose

studies which focus on other

populations and/or pathogens which are

appropriate under the Purpose section

of this announcement.

A. Recipient Activities

1. Select study population. This may

include selection of non-overlapping

control and intervention groups of

patients for participation. One example

of an appropriate approach would be to

enroll children from two groups of day

care centers, from two small towns, or

from two communities within a large

metropolitan area. These groups of

children would constitute discrete

populations and be served by different

medical care providers. They would be

similar demographically, have similar

utilization of medical care, and

comparable baseline rates of carriage or

infection with resistant pathogens.

2. Collect and analyze baseline data.

For example, nasopharyngeal (NP)

carriage rates for drug-resistant

Streptococcus pneumoniae (DRSP) and/

or β-lactamase producing Haemophilus

influenzae or Moraxella catarrhalis

could be measured in the two groups of

children by separate NP swab surveys

conducted several months before and

immediately prior to the start of the

intervention phase. NP surveys for the

intervention and control groups would

be done concurrently. Laboratory

methods would include evaluating the

potential for carriage of multiple

populations of pneumococci, which