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Summary of Federal Register notice "Minimal Risk Levels for Priority Substances and Guidance for Derivation" (61 Fed. Reg. 25873 - 25882) On May 23,1996, the Agency for Toxic Substances and Disease Registry (ATSDR) issued a Federal Register notice announcing ATSDR's internal guidance for deriving minimum risk levels (MRLs) for priority hazardous substances under the Comprehensive Environmental Response, Compensation, and Liability Act (CERCLA) Section 104. There is no due date for comments. 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. 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 also would 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. MRLs are screening levels used to identify contaminants and potential health effects that may be of concern at hazardous waste sites and releases. Inhalation MRLs are exposure concentrations expressed in units of parts per million for gases and volatile substances. Oral MRLs are MRLs are expressed as daily doses in units of milligrams per kilogram per day. MRLs for the inhalation and oral routes are derived for acute (1-14 days), itermediate (15-364) days, and chronic (365 days and longer) exposure durations. ATSDR does not establish MRLs for the dermal exposure route. MRLs are derived from No Observed Adverse Effect Levels (NOAELs), or, from "less serious" Lowest Observed Adverse Effect Levels (LOAELs). ATSDR defines an adverse health effect as a harmful or potentially harmful change in physiologic function, psychological state, or organ structure that may result in an observed deleterious health outcome. 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 judgment is required in this process and that, in some cases, there will be insufficient data to decide whether 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 freestanding NOAELs) for a given duration. The notice also describes ATSDR's method for computing inhalation MRLs. It discusses inter-species extrapolation, LOAEL to NOAEL extrapolation, extrapolation across durations, modifying factors, and intra-human variations. ATSDR states that its current approach for MRL derivation is similar to methods used by EPA to derive Reference Doses (RfDs) and Reference Concentrations (RfCs) for chronic exposures. The MRLs for Vinyl Chloride can be found in the table on page 25881. BFG 00050 Fedml Register / Vol. 61, No. 101 / Thursday. May 23. 1996 / Notices 25873 resolution, end uf on proper showing that there are genuine issues of material fact that cannot be resolved on the basis of sworn statements, affidavits, depositions, or other documents or that the nature of the matter in issue is such that an oral hearing and crossexamination are necessary for the development of an adequate record. It is further ordered. That Haewoo Air & Shipping Co., Ltd. d/b/a Haewoo Snipping Co.. Ltd. is designated Respondent in this proceeding; It is further ordered. That the Commission's Bureau of Enforcement is designated a party to this proceeding; It is further ordered. That notice of this Order be published in the Federal Register, and a copy be served on parties of record; It is further ordered. That other persons having an interest in participating in this proceeding may file petitions for leave to intervene in accordance with Rule 72 of the Commission's Rules of Practice and Procedure. 46 CFR 502.72: It is further ordered, That all further notices, orders, and/or decisions issued by or on behalf of the Commission in this proceeding, including notice of the time and place of bearing or prebearing conference, shall be served on parties of record; It is further ordered. That all documents submitted by any party of record in this proceeding shall be directed to the Secretary, Federal Maritime Commission, Washington, D C. 20573, and comply with Subpart H of the Commission's Rules of Practice and Procedure, 46 CFR 502.111--119, and shall be served on parties of record; and It is further ordered. That in accordance with Rule 61 of the Commission's Rules of Practice and Procedure, 46 CFR 502.61, the initial decision of the Administrative Law Judge shall be issued by January 20, 1997, and the final decision of the Commission shall be issued by May 20, 1997. By the Commission. Joseph C Polking, Secretary. (FR Doc. 96-13056 Filed 5-22-06; 8:45 am] mum coos sns-01-ei GENERAL ACCOUNTING OFFICE Federal Accounting Blende*da Advisory Board; Meeting AQENCY: General Accounting Office. ACTION: Notice of Meeting. SUMMARY: Pursuant to section 10(a)(2) of the Federal Advisory Committee Act (Pub. L. No. 92-463), as amended, notice is hereby given that the Federal Accounting Standards Advisory Board will meet on Thursday. May 30.1996, from 9 a.m. to 4 p.m. in room 7C13 of the General Accounting Office. 441 G St.. NW., Washington. DC. The purpose of the meeting is to discuss and review the (1) Accounting for Natural Resources document. (2) JFMIP Cost Accounting Systems and Reporting project. (3) Invitation for Views: Accounting for the cost of Capital document, and (4) Rule 203 of the AJCPA's Code of Ethics. Any interested person may attend the meeting as an observer. Board discussions and reviews are open to the public. FOR FURTHER INFORMATION CONTACT: Ronald S. Young, Executive Staff Director, 750 First St.. NE., Room 1001, Washington, DC 20002, or call (202) 512-7350. Authority: Federal Advisory Committee Act Pub L. No. 92-463. section 10(a)(2), 86 Stat 770, 774 (1972) (current version at 5 U.S.C app. section 10(a)(2) (1966); 41 CFR 101-6.1015(1990). Dated: May 20.1996. IFR Doc 96-13040 Filed 5-22-96; 8.43 ami mum eooc taia-et-e DEPARTMENT OF HEALTH ANO HUMAN SERVICES HmMi Cara Financing Administration [HCFA317] Agancy Information Coiectton ActtvWaa. Submlaalon lor OMB Review; Commant Raquaat In compliance with the requirement of section 3506(c)(2)(A) of the Paperwork Reduction Act of 1995, the Health and Cara Financing Administration (HGFA), Department of Health and Human Services, has submitted to the Office of Management and Budget (OMB) the following proposals far the collection of information. Interested persona are invited to send comments regarding this burden estimate or any other aspect of this collection of information, including any of the following subjects: (1) The necessity and utility of the propoeed information collection for the proper performance of the agency's functions; (2) the accuracy of the estimated burden; (3) ways to enhance the quality, utility, and clarity of the information to be collected; and (4) the use of automated collection techniques or other forms of information technology to minimize the information collection burden. 1. Type of Request: Reinstatement, without change, of a previously approved collection for which approval has expired; Title of Information Collection: State Medicaid Eligibility Quality Control Sampling Plan: Form No.: HCFA-317: Use: The State MEQC sampling plan is necessary for HCFA to monitor the States' operation of the MEQC system. The sampling plan includes all data involved in the States' sample selection process--population sizes and sample frame lists, sample sizes, sample selection procedures, and claims collection procedures; Frequency: Annually: Affected Pu6/jc: State, local, or tribal government; Number of Respondents: 55; Total Annual Responses: 110; Total Annual Hours: 2,640. To request copies of the proposed paperwork collection referenced above. E-mail your request, including your address, to PaperworkGbc2a.gov, or call the Reports Clearance Office on (410) 76^1326. Written comments and recommendations for the propoeed information collections should be sent within 60 days of this notice directly to the HCFA Paperwork Clearance Officer designated at the following address: OMB Human Resources and Housing Branch, Attention: Allison Eydt. New Executive Office Building, Room 10235, Washington. D.C 20503. Dated: May 16.1996. rathlean 9. Lanes, Director. Management Planning and AnaJytis Staff, Office ofFinancialand Human Resources, Health Care Financing Administration. (FR Dee. 96-12962 Filed 5-22-96; 6:45 am] mum eooa isa-aa-e Agency lor Toxic Subefncee and Dloiooo Reglitty [AT9DR-110I MMmal Rftafc Levels for Priority Bubetenoeo end Guidance for Derivation AtMNCY: Agency for Toxic Substances and Disease Registry (ATSDR), Department of Health and Human Services (HHS). ACTION: Notice. IUMMART: The Comprehensive Environmental Response, Compensation, and Liability Act (CERCLA) (42 U.S.C 9604 et aeq.), as amended by the Superfund Amendments and Reauthorization Act (SARA) (Pub. L. 99-499), requires that BFG 00051 25874 Fdera] Register / Vol. 61, No. 101 / Thursday. May 23. 1996 / Notices ATSDR develop jointiy with the U.S. "nvironmental Protection Agency ;PA), in order of priority, a list of iiazardous substances most commonly found at facilities on the CERCLA National Priorities List (NPL) (42 U.S.C. 9604(i)(2)l; 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(0(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 cientiflc assessment. Comments from te 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, ME.. 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, subecute, and chronic health effects (42 U.S.C 9604{i)(3)), Minimal Risk Levels (MRLs) vere developed as an initial response to die mandate. Following discussions with scientists within toe HHS and toe EPA, ATSDR chose to adopt a practice similar to that of the EPA's Reference Dose (TlfD) 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 toe development of toxicological profiles, MRLs are derived when ATSDR determines that reliable and sufficient data exist to identify toe target organ(s) of effect, or the most sensitive health effect(i) 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 (mg/m3) for particles. Oral MRLs are expressed as daily human doses in units of milligrams per kilogram per day (mg/ kg/dayk ATSDR uses the no-observed-adverse effect-level/uncertainty factor approach to derive MRLs for hazardous substances. The MRLs are set below levels that, based on current information, might cause advene health effects in the people most sensitive to such substance-induced effects (Barnes and Dourson 1988; EPA 1990k MRLs are derived for acute (1-14 days), intermediate (15-384 days), and chronic (368 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 nas not yet identified a method suitable for this route of exposure. MRLs are generally bated on the most sensitive substance* induced 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) ss s basis for establishing MRLs. Exposure to 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 immunoiogicaliy 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 ofien must be based on results of animal studies because relevant human studies are lacking. In the absents of evidence to toe 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; toe agency wide MRL Workgroup, with participation from other federal agencies, including EPA; and are submitted for public comment through toe 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 and of this notice. Categories Used to Derive MRLs The following health effect and 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 BFG 00052 Federal Register / Vol. 61, No. 101 / Thursday, May 23, 1996 / Notices 25875 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 iowestobserved-advers effect levels (LOAELs). MRLs are not derived horn serious LOAELs. In its 1986--1988 Biennial Report Volume 11, 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 bean 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 ia 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 affects 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 ultrastructurai 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. Serum chemistry changes, e.g., moderate elevations of serum aspartate aminotransferase (SGOT), serum alanine aminotransferase (SGPT). Weight lose or deoeese 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 mult In severe dysfunction (e.g., marked necrosis of hepetocytes 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 affects. 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 baaed on the concept that a threshold level of exposure exists below which no noncencer health effect is likely to occur, end. 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, end other exposure routes, indicates that this system would not be expected to be most sensitive to the substance fix the exposure route and duration of concern. Toxicokinetics data enter into consideration when comparing information across species, routes, and durations for determination of the moat 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. BFG 00053 25876 Federal Register / Vol. 61, No. 101 / Thursday, May 23. 1996 / Notices Differences across routes of exposure i-*Ti )*> be explained by different rates )f absorption, meuboliam (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 imilar 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., a2u*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 ef Inhalation MUs 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/60G/8--90/066A, August 1990). Standard reference values should be obtained from EPA (1966): "Recommendations for and Documentation of Biological Values for Use in Risk Assessment" (EPA 600-6-- 87/006. February, 1966). 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 extrarespiratary affects (e.g., using die regional deposited does ratio and uptake from the entire respiratory system). 2. Adjusting From Intermittent to Continuous Doting ATSDR defines an MRL as "an estimate of the daily human exposure to a hazardous substance that la likely to be without appreciable risk of advene noncancer health affects 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 exposureperiod, 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 fectors 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 mimela were dosed for 6 hours e day for 5 days e week, the estimated "adjusted doee" becomes: Adjusted does * Intermittent dose x (6 hours/24 hours) x (5 days/7 days) intermediate and chronic duration inhalation studies are usually doeeadjusted for day and week exposures: acute duration inhalation studies can be duration adjusted from intermittent exposures to 24 hour* 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 x (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, doee 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 dotes are cosvaried to equivalent concentrations or doses of the parent substance by multiplying by the molecular weight ratio of parent to salt. Computation of Oral MXLs 1. Converting From Concentration to Dose For feeding studies, the equation for the conversion from food concentrations is: (ppm in food) x (ffkg body weight) mg/kg/dag The food consumption factor (f) is kg of food consumed per day. Unless the food consumption rate end body weights ere available, standard reference values should be obtained from H*A (1986). Far drinking water studies, the equation for conversion from water concentrations is: (ppm in water) x (C/kg body weight) mg/kg/day The water consumption rate (C) is liters of water *< per day. Unless C end body weights are provided in the study, standard reference values should be obtained from EPA (1968) or EPA (1966), as appropriate. BFG 00054 Federal Register / Vol. 61. No. 101 / Thursday, May 23, 1996 / Notices 25877 2. Converting From Intermittent to Doily 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 x (S 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) hbc / (UF x 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 la 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. Extrapolation Across Durations It is preferable to derive MRLs using data for each exposure duration. However, when the database supports extrapolation acrosa 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 waa supported by the limited data on chronic exposure as wall 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 far 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'-msthylenebis(2-chloroaniliiioL Another possible consideration is that if s test substance is known to bloaccumulate. scene studies may overestimate lha does needed to cause effects. In such cases, a modifying factor may be applied. EPA RfDs and ATSDR MRU 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 Eteoeuraduration. Route of exposuro. UFs used: Human varttbtty. tntenpecm ex trapola tion. LOAEL to NOAEL Extrapolotion across duration. mcompM) Acute intermedtals Chronic Oral............. Inhahtion Yea.............. Yas.............. Yea________ Yaa___ ____ No------------- Chronic. Oral. tnhaleton. Yaa. Yas. Yas. Yas. Yas. Across route ss- trapote* lion. MF ............. No ________ Yaa____ _ Yas. Yas. MRLs for Essential Trace Elements Since many nutritionally essentia! elements have been found to be BFG 00055 25878 Federal Register / Vol. 61. No. 101 / Thursday, May 23. 1996 / Notices common contaminants at some toxic <iste sites, consideration was given to ,th 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 (RiD): Description and Use in Health Risk Assessments. Regulatory Toxicology and Pharmacology 0:471-406. 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. 11994). 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. Osin V. Broome, Deputy Administrator, Agency for Toxic Substances and Disease Registry. ATSDR Minimal Risk Levels (MRLS) For Hazardous Substances (March 1996) Substance name ACENAPHTHENE ......... ACETONE...................... ~ROLEIN ..................... ACRYLONITRILE....... . ALDRIN .......................... AMMONIA ..................... ANTHRACENE ............. ARSENIC ....................... BENZENE ...................... BIS (2-CHLORO-ETHYL) ETHER. BIS (CHLORO-ETHYL) ETHER. BORON .......................... 8ROMODICHLOROME- THANE. BROMOFORM ............... BROMOMETHANE ....... CA0MIUM ...................... CARBON DISULFIDE .... CARBON TETRA CHLORIDE. CHLORDANE CAS No. Route 000063-32-9 000067-64-1 000107-02-6 000107-13-1 000309-00-2 007664-41-7 000120-12-7 007440-38-2 000071-43-2 000111-44-4 ORAL............. INHALATION . INHALATION . INHALATION . ORAL.... -...... INHALATION . INHALATION . ORAL............. INHALATION . ORAL.... ........ ORAL_______ ORAL.... ........ ORAL______ _ ORAI________ INHALATION _ INHALATION - ORAL_______ ORAL_______ ORAL----------INHALATION . INHALATION . 000642-88-1 INHALATION . 007440-42-6 ORAL 000075-27-4 ORAL 000076-26-2 000074-63-9 007440-43-9 000076-15-0 000066-23-6 ORAL.. ORAL.. ORAL ,, INHALATION INHALATION INHALATION ORAL INHALATION . ORAL_______ INHALATION . ORAL_______ INHALATION 000067-74-9 INHALATION ORAL ORAL______ INHALATION INHALATION ORAL______ Duration INTERMEDIATE . ACUTE________ INTERMEDIATE . CHRONIC ______ INTERMEDIATE . ACUTE_______ INTERMEDIATE . CHRONIC______ ACUTE________ ACUTE________ INTERMEDIATE . CHRONIC______ ACUTE .. CHRONIC ACUTE CHRONIC INTERMEDIATE ~ INTERMEDIATE CHRONIC_______ ACUTE_________ INTERMEDIATE-. INTERMEDIATE-. INTERMEDIATE ~ ACUTE CHRONIC ACUTE CHRONIC ACUTE INTERMEDIATE CHRONIC_____ INTERMEDIATE CHRONIC_____ CHRONIC_____ CHRONIC_____ ACUTE_______ ACUTE_______ INTERMEDIATE ACUTE_______ INTERMEDIATE INTERMEDIATE CHRONIC_____ ACUTE_______ Value 0.6 mgftgfday ........ 26 ppm _________ 13 ppm ....--_____ 13 ppm _________ 2 mg/fcgttay......... . 0.00006 ppm ____ 0.000009 ppm___ 0.0006 mg/hQWy.. 0.1 ppm ................. 0.1 mgftgfday____ 0.01 mgffcgfday ___ 0.04 mgfVg/day ...... 0.002 mgfcQ/day.... 0.00003 mgfegftMy 0.5 ppm------------0.3 ppm------------0.3 mpfcg/day-----10 rntyktyday____ 0.003 mgfcQ/day .... 0.06 ppm .............. 0.Q2 ppm________ Factors End point 300 9 100 100 100 100 1000 100 10 100 1000 100 1000 1000 IX 10 IX IX 3 3X 10X Hepatic. Neurotogmai. Neuroiopcaf. Neurotogeal. HematotogeaL Ocular. Respiratory. Hematotogcal. NeurotogcaJ. Developmental. Reproductive. Hematological. Developmental. Hepatic. Respiratory. Respiratory. Other. Hepatic. DermaL imrmeioiogieaL Body Weight 0.0003 ppm_____ IX naepratnry. 0.01 mQftQWy .-- 0.04 mgrtcpMay___ 10X Developmental. 1X0 0.02 tngHtgtty 0.6 mgftpMay-----02 mtykgto*! 0.06 ppm --__ --. 0.06 ppm-----------0.006 ppm_______ 0.000 mgAgfdiy 0.0002 mg/m3____ 0.007 mgAgfOty 0.3 ppm------------0.01 &2 ppm 10X IX IX IX IX IX IX 10 3 X ax 3X RenalflJrtnary Nwotogieai. Hepatic. Neurologicel. MeuroloHical. Heurologrel. OealmHaitinel RenatfUrinary. RenaflUnnary. Neuroigicat. 0.06 ppm 0.02 mQftgfday_____ 0.007 mQfcgfttay-----0.0002 mgfm>______ 0.00002 mtym*------- 0.001 mgftcgfctay____ IX 3X IX IX 1000 10X nipCDu Hepatic. Heeatic. Development*. BFG 00056 Federal Register / Vol. 61, No. 101 / Thursday, May 23, 1996 / Notices 25879 ATSDR Minimal Risk levels (MRLS) For hazardous Substances--Continued (March 1996) Substance name CAS No. Route Duration Value actors End point CHLORFENVINPHOS CHLOROBENZENE .... CHLOROOIBROMOME THANE. CHLOROETHANE CHLOROFORM ... CHLOROMETHANE CHLORPYRIFOS......... CHROMIUM, HEXAVALENT. COBALT ........................ CRESOL, META- .......... CRESOL ORTHO- ....... CRESOL, PARA- .......... CYANIDE ...................... CYCLOTETRAMETHYL- ENE TETRANITRAMINE. CYCLOTRIMETHY LENETRINITRAMINE (RDX). OOT, P,P'- DU2-ETHYLHEXYL) PHTHALATE. DI-N-BUTYL PHTHAL ATE. DI-N-OCTYL PHTHAL ATE. DIAZINON ..... ............. DICHLORVOS ............ DIELDRIN .............. . DIETHYL PHTHALATE DISULFOTON ............ ENDOSULFAN............... ENDRIN ......................... EHTYL BENZENE ........ ETHYLENE GLYCOL .... ETHYLENE OXIDE.... . FLUORANTHENE ....... . FLUORENE.................... 000470-90-6 000108-90-7 000124-48-1 ORAL ORAL ORAL ORAL ORAL ORAL ORAL .... INTERMEDIATE .... CHRONIC......... .... ACUTE ............. .... INTERMEDIATE .... CHRONIC........ .... INTERMEDIATE .... ACUTE ............. 000075-00-3 000067-66-3 000074-67-3 002921-88-2 018840-29-9 ORAL.......... INHALATION INHALATION INHALATION INHALATION INHALATION ORAL.......... ORAL........... ORAL........... INHALATION INHALATION INHALATION ORAL.......... INHALATION INHALATION .... CHRONIC........ .... ACUTE ............. .... INTERMEDIATE .... ACUTE ............. .... INTERMEDIATE .... CHRONIC.......... .... ACUTE .............. .... INTERMEDIATE .... CHRONIC........ . .... ACUTE ............. .... INTERMEDIATE ....' CHRONIC .......... ... ACUTE ............. .... CHRONIC_____ ... INTERMEDIATE 007440-48-4 000108-39-4 000096-48-7 000106-44-6 000067-12-6 002691-41-0 INHALATION..... INHALATION ...... ORAL........... . ORAL................. ORAL_________ ORAL................. ORAL................. CHRONIC_____ INTERMEDIATE ACUTE_______ ACUTE ACUTE _______ INTERMEDIATE ACUTE_______ ... 0.0006 m^k^Oay ... 0.000 mfpVg/day . ... 0.002 mgfltg/tiay . ... 0.002 mgflqyoay . ... 0.002 mg/kgfday . ... 0.4 mgfeg/Oay.... ... 0.04 mg/k^day ... ... 0.03 mayday ... ... 1300 ppm .......... ... 76 ppm .............. - 1 ppm................. ... 0.05 ppm ........... ... 0.02 ppm ........... ... 0.3 m^t^day.... ... 0.1 mgfe^day.... ... 0.01 m^tgfday... ... 0.5 ppm........... . ... 0.4 ppm............. ... 0.4 ppm ........ ..... ... 0.003 m^k^day. ... 0.00002 mgfm* ... ... 0.00002 mgfm* 0.00002 mg/rvP ........ 0.00003 mgftn*____ 0.06 mgMVdey _ 0.06 mg/kglday-----0.X mgftcgfday --__ ax gnvfcgttey____ ai mgfcgldey _____ ORAL.... ........... 000121-82-4 ORAL_________ INTERMEDIATE ACUTE_______ 0.X mgHtQWy___ __ ax mgrttplday_____ * 000060-29-3 0X117-81-7 ORAL_____________ ORAL--------------------ORAL ORAL INTERMEDIATE____ ACUTE'____________ INTERMEDIATE____ ACUTE ____________ ax mgftgtfey -- 0.00X m^kgldey .. 0.00X mglk^dsy .. f mpftpldey_____ ORAL__________ 0X084-74-2 ORAL--------------- INTERMEDIATE____ 04 mgfcgftMy___ -- INTERMEDIATE____ 08 mgfegMey______ 0X117-64-0 ORAL ACUTE 000333-41-6 000062-73-7 000060-67-1 000084-66-2 000296-04-4 0X115-29-7 000072-20-6 0X100-41-4 0X107-21-1 000075-21-6 000206-44-0 000086-73-7 ORAL______________ INHALATION _______ INHALATION_______ INHALATION_______ ORAL ORAL_____ ______ ORAL ORAL______________ ORAL ORAL_____ _________ INHALATION_______ INHALATION ______ ORAL ORAL--------------------- ORAL ORAL_____________ ORAL--------------------ORAL ORAL INHALATION_______ ORAL_____________ INHALATION..... ...... ORAL__ ___________ ORAL_____________ INTERMEDIATE____ ACUTE____________ INTERMEDIATE____ CHRONIC__________ ACUTE INTERMEDIATE____ ACUTE CHRONIC__________ ACUTE____________ INTERMEDIATE____ ACUTE____________ INTERMEDIATE____ ACUTE____________ INTERMEDIATE____ CHROMC__________ INTERMEDIATE____ CHRONIC INTERMEDIATE____ CHRONIC__________ INTERMEDIATE____ CHRONIC INTERMEDIATE____ INTERMEDIATE____ INTERMEDIATE____ 0.0002 mgfkgMey___ 0.002 ppm____ _____ aaox ppm________ aooox ppm_______ 0.004 mpikgjasy____ 0.0X mgfrQMey____ 0.00007 mQftgAMy__ 0.000X mQftgttay__ 7 mgftgMsy .. ...... . 6 mpfegWy------ ----OOXm^nP 2E-4 mom* 0X1 mofkgMay-----9E-6 mgaoWey___ 6E-6 mgAmlday --... 0.0X mQfcgWay-----0.002 mgfcQMay____ 0X2 mgiltgiday____ a0003 mgftgMey___ 0Ad 3---p*pm -- .** 0X ppm ...------------- 0.4 mgdtQMsy 0.4 myfcpWy IX IX 1X0 1000 10X IX 10X Heoettc. Hepatic. Neurological. Lymphorencuiar. Neuroiogicai. Hepatic. Renal/Unnary. 10X Hepatic. 10 Neuroiogicai. IX Body Weight. 30 Hepatic. IX Hepatic. IX Hepatic IX Hepatic. IX Hepatic. 10X Hepatic. 100 Neuroiogicai. 100 Body Weight. IX Body Weight. 10 Neurological. 10 Respiratory. 10 Respiratory. 10 10X IX IX IX IX 10X Respiratory. Respiratory. Respiratory. Heurotogwal. NeuroiogcaJ. Reproductive. Neuroiogicai. 10X Hepatic. IX Neurological. 3X 10X IX IX Reproductive. Developmental. Hepatic. Reproductive. IX Developmental. IX Developmental 10X Hepatic. 10X IX IX IX 10X 10 10X IX 3X 3X X 30 IX IX 10X IX IX IX IX IX IX IX ax 3X Developmental. Meurologcal. Neurabpea. Naurological. Neurological. Naurological. Immunotogal. Hepebc. naproxctNe. rupcDC. Naurological. Neuroto^eal. Neurological. Developmental. Neurological. Immunological. rUpCDC Neurological. Naurological. Developmental. Renel/Unnary. RenaVUrinary. Hepatic. Hepeoc BFG 00Q57 25880 Federal Register / Vo]. 61. No. 101 / Thursday. May 23. 1996 / Notices ATSDR Minimal Risk Levels (MRLs) For Hazardous Substances--Continued [March 19961 Substance name NE. HEXACHLOROBUTADIENE. HEXACHLOROCYCLOHEXANE. BETA-. HEXACHLOROCYCLOHEXANE. GAMMA-. HEXACHLOROETHANE ISOPHORONE .............. IP_d .IPT PI IPI IP_7 IPT PI IFI KFPDNF t^concPKiP M XYI FNF MANGANESE ........... . MERCURY, INORGANIC * -^RCURY, METALLIC HOXYCHLOR ........ METHYL PARATHION METHYL-T-BUTYL ETHER. METHYLENE CHLORIDE. METHYLMERCURIC CHLORIDE. MIREX ............................ N-NITROSODI-N-PRO- PYLAMINE. NAPHTHALENE ............. NICKEL .......................... P-XYLENE ..................... P ENTACHLOROPHEN- OL. PHENOL ........................ POLYBROMINATEO BIPHENYLS. POLYCHLORINATED BIPHENYLS. PROPYLENE GLYCOL 'NITRATE SELENIUM ..................... SODIUM FLUORIDE .... STYRENE ..................... CAS No. Route Duration Value Factors End point 068476-30-2 INHALATION ............ acute ..................... 0.02 mg/m1 ............... 000118-74-1 ORAL acute ..................... 0.006 rngkfyday....... 1000 Neurological. 300 Developmental. ORAL......................... INTERMEDIATE....... 0.0003 mg/kg/day..... ORAL......................... CHRONIC................. 0.00002 m^kg/day .... 000087-68-3 ORAL......................... INTERMEDIATE .!..... 0.0002 m^kg/day..... 300 Reproductive. 1000 Developmental. 1000 Renal/Unnary. 000319-85-7 ORAL......................... INTERMEDIATE....... 0.0003 mgfcg/day..... 300 Hepatic. 000058-89-9 ORAL......................... ACUTE ...................... 0.01 m0k$y<fay......... 300 Neurologea/. 000067-72-1 000078-69-1 050815-00--4 HZ0600-22-T 000143-60-0 008008-20-6 000108-38-3 007439-96-6 HZ0900-19-T 007439-97-6 000072-43-6 000298-00-0 001634 04 4 ORAL......................... INHAI ATION INHALATION ............ OfiAl ............ ORA1 .............. INUAI ATir*l ORAL.... .....-............. ORAL........... ............. INHALATION INHALATION ORAL......................... ORAL......... -............. nRAi INHALATION ORAL............ ............. INHALATION........ .. ORAL______ _____ _ near INHALATION _____ ... INHALATION_______ ORAL__ ___________ ORAL_____________ ORAI_______________ INHALATION INTERMEDIATE____ ACUTE..................... INTERMEDIATE........ ACUTE ...................... INTERMEDIATE....... INTERMEDIATE___ _ INTERMEDIATE ....... CHRONIC ................. INTERMEDIATE CHRONIC ACUTE _____ _______ INTERMEDIATE____ CHRONIC INTERMEDIATE____ INTERMEDIATE____ CHROMC___ ______ ACUTE____________ INTERMEDIATE ACUTE______ __ _ CHRONC_________ ACUTE____________ INTERMEDIATE____ CHRONIC_________ ACUTE____________ 0.00004 m^kg'day .... 0.5 ppm..................... 0.09 ppm ....... _......... 0.1 mgkg/day............ 0.01 mgfegttay......... 0.0002 ppm ............... 3 mgfcg/day............... 02 mgflqyday............ 9 mg/m*_______ _____ 0.3 mg/m>_____ ____ 0.01 mgAcg/day_____ 0.0006 mQ/kg/Oay___ 0.0006 mg/kg/day..... 0.01 mglm* 0.6 mgfcg/day .....-- 0.0003 mg/m1______ 0.007 mgifcg/dty..... 0.002 mgfeg/day____ 0.00002 mgfm3 0.000014 mgfm* 0.02 mgftgMay_____ 0.02 mgAtg/day......... 0.0003 mg/kgMey..... 2 ppm........................ 300 too 100 100 100 1000 100 1000 300 300 100 100 100 1000 1000 100 100 100 too 100 1000 1000 100 100 Immunological. Neuroiogcai. Respiratory. Hepatic. Hepatic. Hepatic. Other. Hepatic Hepatic. Hepatic. Neurologcal. Renal/Unnary. Renal/Urinary. Hepatic. Hepatic. Neurological. Renal/Urinary. Renal/Unnary. Developmental. Neurological. naproductwe. naproductNa. Neurological. Meuoriogical. 000075-09-2 INHALATION_______ INHALATION_______ ORAL_____ .... ORAI INHALATION_______ INTERMEDIATE____ CHROteC___J_____ ACUTE____________ IMTERMEpfATE .... .. ACUTE____ _ 0.7 ppm..... .............. 0.7 ppm....................4 0.4 mgfe^day............ OJmgAgflday 0.4 ppm ..................... 100 Neurological. 100 Renal/Unnary. 100 Neurological. 300 Hepatic 100 Neurological. INHALATION. INTERMEDIATE____ 0.03 ppm__________ ORAL- __________ chronk:_________ 0.06 mgfcg/dey 000115-09-3 ORAL......................... ACUTE____________ 0.00012 mg/kg/day .... 1000 Hepatic 100 nipiQC* 10 Developmental. ORAL_____________ 002385-85-6 nRAi 000621-64-7 noai INTERMEDIATE CHRONIC acirns 0.00012 mgfeg/day .... 0.0008 mg/kg/dty___ 0.096 mgfleg/fey....... 10 Developmental. 100 Hepatic 100 Hepatic 000091-20-3 007440-02-0 000106-84-3 000087-86-6 INHALATION _______ ORAL ORAL. ___________ INHALATION..... ....... ORAI________ __ ___ ORAL_____________ CHRONIC_________ AOIfTP INTERMEDIATE____ INTERMEDIATE____ ACUTE ____________ ACUTE____________ 0.002 ppm ---------- ---0.06 mg/kg/day......... 0.02 tngfcgttay_____ 0.00004 mg/m*_____ 1 mg/fcg/day________ 0.006 mg/kg/day --... 1000 1000 300 100 100 1000 NMmOQH. Neuroiogcai. Hepatic neepkaiory Neurologicel. Developmental. ORAL INTERMEDIATE____ 0.001 mgergMay__ 000108-96-2 ORAL.. ________ __ ATJITF 0.6 mgfegday____ _ 067774-32-7 ORAL . ACUTE____________ 021 mgfcg/day____ - 1000 Hepatic 100 Developmental. 100 Endocrine. 001338-38-3 ORAL____ __ ______ CHROMC__________ 0.00002 mg/kg/day .... 300 ImrmaiologicaL 006423-43-4 INHALATION _______ ACUTE------------------ 0.003 ppm __ 10 Neurological. 007782-49-2 007681-49-4 000100-42-6 INHALATION_______ IMMAI ATlftN ORAL_____________ ORAL INHALATION_______ ORAL..................-.... INTERMEDIATE____ CHRONIC CHRONIC CHRONW_______ . CHRONIC_________ INTERMEDIATE____ 0.00004 ppm____-- 0.00004 ppm _ . .. 0.002 mgfcgWy____ 1000 1000 10 0.08 ppm . ... ------02 mgftg/day............ IX 10X BFG Hemetmnjicai HematotogicaL Dermal. Neurological. Hepatic 00058 Federal Register / VoL 61, No. 101 / Thursday, May 23, 1996 / Notices 25681 ATSDR Minimal Risk Levels (MRLs) For Hazardous Substances--Continued (Man* 19961 Substance name CAS No. Route Duration Value Factors End porn TETRACHLOROETHYLEI IE 000127-16-4 tetrachloroeth- YLENE. TITANIUM TETRACHLORIDE. 007550-45-0 0001108-68-3 001330-20-7 TRICHLOROETHYLENE 008001-35-2 000079-01-6 VINYL ACETATE .......... VINYL, CHLORIDE ....... 007440-62-2 000108-06-4 000075-01-4 ZINC............................... 1,1,1TRICHLOROETHANE. 1.1.22-TETRACHLORO-ETHANE. 007440-66-6 000071-66-6 000079-34-6 i i 9-TRi-rm ORrw ETHANE. 1.1-OI-CHLOROETHENE. 1. I*DI-METHYL-HYDRAZINE. 1.2.3-TRI-CHLORO PROPANE. t e2-DI*BROMO-3CHLORO-PRO-PANE. 1 2-ni-THI nRO-FTHANE. 000079-00-6 000075-36-4 000067-14-7 000096-16-4 000096-12-8 000107-06-2 i nnrv ETHENE. CIS*. 1 P-fil-CHt ORfL ETHENE. TRANS-. 000156-60-2 000166-60-6 1,2-DI-CHLORO-PROPANE. 000078-67-6 ... ...... .... .... 1 ^-OHMETHYL-HYORA- 000640-73-6 ZINE. INHALATION............ IMMAf ATION nRAi INHALATION ............ INHALATION ............ INMAI ATION DRAt ......... ORAL......................... INMAI ATION INHALATION............ NHAI ATIO^J ORAL......................... ORAI ............... ORAL .................. ikimai ATinu INHAI ATION .......... HRAf ORAL......................... INHALATION............ ORAL..................-..... INHALATION..... ....... INHALATION_______ inhalation_______ ORAL_____________ ORAI_____________ ORAL......................... INHALATION..... -..... INHALATION.... ........ INHALATION ........... INMAI ATinM ORAI____________ __ ORAL_____________ ORAL...... ............. ORAI............... ............ ORAL_____________ INHALATION_______ ORAL_____________ INHALATION_______ INHALATION . ___ INHALATION.. ORAL______________ INHALATION_______ ORAL_____________ INMAI ATION INMAI ATION ORAL . .. .- .. ooai ........... ORAL______ _______ INMA| >TV>I INHALATION ORAL______________ INHALATION_______ INHALATION_______ ORAL .... ORAI_______________ ORAI____________ __ ORAL_____________ ACUTE ..................... CHRONIC................. ACUTE ..................... CHRONIC................. ACUTE ..................... CHRONIC................. acute ...................... INTERMEDIATE....... ACUTE ..................... INTERMEDIATE....... CHRONIC................. INTERMEDIATE....... ACUTE ..................... INTFRMFOIATF ACUTE ...................... INTERMEDIATE....... ACUTE ............. ....... INTERMEDIATE____ acute.................. INTERMEDIATE____ INTERMEDIATE____ ACUTE ____________ INTERMEDIATE____ CHRONIC__ _______ INTERMEDIATE____ CHRONIC_________ ACUTE ____ ______ _ INTERMEDIATE____ ACUTE ____ _______ INTERMEDIATE____ ACUTE ____________ INTERMEDIATE____ CHRONIC___ ______ ATIITF INTERMEDIATE____ INTERMEDIATE _ CHRONIC_________ INTERMEDIATE____ CHRONIC_________ ACUTE____________ INTERMEDIATE____ INTERMEDIATE____ INTERMEDIATE____ ACUTE------------------ OMPONir INTERMEDIATE ____ An nr INTERMEDIATE____ ACUTE .. INTERMEDIATE____ INTERMEDIATE____ ACUTE INTERMEDIATE____ An rTF INTERMEDIATE____ CHRONIC_________ INTERMEDIATE 0.2 ppm .................... 10 Neurctfogcai. 0.04 PPM ................. 0.001 m<ym3............. 3 ppm ....................... 0.02 mg/kg/day......... 0.7 ppm .................... 0.2 mg/kg/day........... 0.006 m0k<^day....... 0.001 mgkg/day ........ 0.002"m^kg'day....... p pnn? 0.003 mgfcg/dey....... 0.01 ppm.................. IX5ppm ~-------..._---0.03 ppm . 0.00002 mgJkg/dey .... 0.3 mgftQ/dey ____ 1X3 mgfcgtfey ........... 2 ppm............ ........... 0.7 ppm ...... ........... 1 ppm ------------------- 0.3 mjykgMay--------- 0.3 mokQ/dey______ 0.04 mQWday_____ 04)2 ppm --------------- 0.009 mgikg/day-----0.000009 ppm______ 0.000009 ppm ______ 0.0003 ppm------------ 0.03 mgftg/dby-------0.0002 ppm 0.002 mgfcQWy------ 02mg6agMey--------- Q3mQfcQmy -- <19 mn CL2ppm___________ 02 mgfcQ/dqr. 04)6 ppm--------------- 0.007 ppm_________ 0,1 mgfkQttlay ............ 007 mokgWey_____ 009 mgkQ/day-------00003 mg/kg/day___ 100 1000 90 Respiratory. 30 30 300 300 Neurological. IX 300 Development. IX 1000 Renat/Unnary. 10X Hepatic. IX Hepatic. 30 300 IX IX Development. IX IX Renat/Unnary. IX Respiratory. IX Development 300 1 UwA10X Hepebc. 3 1 lemetoiogiceL 3 HematoiogceL IX NeureiogKal. IX Neurological. 10 Neuroto^cal. 300 Mnoetir IX Hepatic. 3X Body Weight 3X Body Weight IX Neuroloflal. IX n* *i-p--v-iCi IX nipoc. 10X 10X mn* *oppC- u-Qcc*. 10X Hepebc. IX neapeMoi'y. IX rKpucIX n^roductHe. 10X Raproductive. IX wiHwowpcii 3X llpietlr ax Ranel/Uflnary. tx IX llametnlngiral. 10X lip in 10X Hepebc. IX Hepebc. 10X neepiriinry. 10X 10X 10X 10X 10X flMpirmry. Naurologral. I mwmmgirN Hepebc. Hepebc. BFG 00059 23882 Federal Register / Vol. 61, No. 101 / Thursday. May 23, 1996 / Notices ATSDR Minimal Risk Levels (MRLs) For Hazardous Substances--Continued [Marc* 19961 substance name 1 3-Di-CHLORO PROPENE. 1.3-DI-NITRO-BENZENE 1,4-Ol-CHLORO-SENZENE. l-METHYLNAPHTHALENE. 2,3,4,7,8-PENTACHLORO-OI-BENZOFURAN. 2,3.7.8-TETR. ACHLORO-DIBENZOP-DIOXIN. 2.4.6-TRI-CHLOROPHENOL. 2.4,6-TRI-NfTROTOLUENE. 2,4-D1-NITRO-PHENOL 2,4-DI-NITRO-TOLUENE 2, NITRO-TOLUENE 4. TTHYL-ENE-6IS ^HLOROANILINE). 4.6-Ol-NlTROOCRE- SOL. CAS NO. Route Duration value Factors End point 000542-75-6 INHALATION ............ INTERMEDIATE....... 0.003 ppm ................ 100 Respiratory. 000099-65-0 000106--45-7 INHALATION ............ ORAI ORAL......................... INHALATION ............ CHRONIC :................. ACUTE ............... ...... INTERMEDIATE....... INTERMEDIATE.... 0.002 ppm ................ 0.008 mgflcgSday....... 0.0006 mtykg/day..... 0.2 ppm .................... 100 100 1000 100 Respiratory. Hematological. Hepatic. ORAL......................... INTERMEDIATE....... 0.1 mg/kgttay........... 000090-12-0 ORAL......................... CHRONIC................. 0.07 mgikgttay......... 100 Hepatic. 1000 Respiratory. 057117-31-4 ORAL -....................... ACUTE .... -............... 0.000001 mgrtt^dey 3000 immunological. ORAL......................... INTPRMPniATF R*V* 001746-01-6 ORAL..................... ACUTE ------------------ 0.0000001 mg/kg/day 3000 Hepatic. 1000 Hepatic ORAL......................... ORAL......................... 000088-06-2 ORAL......................... intermediate....... CHRONIC............. INTERMEDIATE____ 0.000000001 mg/kg' day. 0.000000001 mg/ty day. 0.04 mpfcpWay .......... 000118-96-7 ORAL........... ............. INTERMEDIATE____ 0.0006 mgftgfttoy___ 000061-28-6 000121-14-2 000606-20-2 000101-14-4 ORAL...................... ORAL___________ ..... ORAL______________ ORAL______________ ORAL______________ ORAL___________ __ ACUTE ____________ ACUTE .--............... INTERMEDIATE____ VnnUVvIV INTERMEDIATE____ CHRONIC_________ 0.01 mgfcgKay_____ 0.06 mgftgdey 0.06 mghgMay 0.002 mghpfttoy___0.04 mgfcgMay _ 0.003 mgftgMey ........ 000534-52-1 ORAL______________ ACUTE ------------------ 0.004 mgfcgWay------ ORAL--------- ------- INTERMEDIATE____ 0.004 mgAcgftfcy____ 1000 Reproductive. 1000 Reproductive. 100 Reproductive. 1000 Hepatic. 100 1000 too 100 100 3000 Body Weight I lemerologirst Reproducers. Hematological Maumtoggal. Hepatic. 100 Neurological. 100 Naurological. IFR Doc. 96-12991 Filed 5-22-96; 6:45 am) BICUMO COM 41S3-JO-# Food and Drug Administration Advisory Committee; Science Board to the Food and Drug Administration; Formation of a Subcommittee agency: Food and Drug Administration, HHS. action: Notice. summary: The Food and Drug Administration (FDA) is announcing the formation of a subcommittee of the Science Board to the Food and Drug Administration (Science Board). This subcommittee has been established to address issues related to science and research in FDA. The subcommittee's preliminary recommendations will be predated to the FDA Science Board for fu' biic discussion at a future Sc .e Board meeting. FOR FURTHER INFORMATION CONTACT: Susan A. Homire, Office of Science (HF-33). Food and Drug Administration, 5600 Fishers Lane. RockviUe, MD 20657, 301-827-3340. SUPW MWTARY TORMATION. The Food and Drug Administration (FDA) is announcing the formation of a subcommittee to the Science Board to the Food end Drug Administration. This subcommittee has been established to eddrees issues related to science end research in FDA. The subcommittee will meet several times over the next 6 to 9 months to develop preliminary wminTMiiilitiiiM for the Science Board on a process for review of research programs within FDA. During this period there will be opportunities for public comment; these opportunities will be announced In the Federal at least 15 days prior to each scheduled public meeting. The subcommittee's preliminary recommendations will be presented to the Science Board for full public discussion at e future Science Board meeting. This notice is issued under the Federal Advisory Committee Act of October 6,1972 (Pub. L. 92-463 (5 U.S.C app. 2)). Dated: May 16.1996. Michael A. Friedaaa, DeputyCommissionerfor Operations. (PR Doc. 96-12677 Filed 5-22-96; 8:45 am| gn^w. ograpnn^aaliHwI aoletoag|aica|iiBrmnumAmMn Trials; Procedure to Monitor CNnlcsl rvoio rnMMs; morning or neview Committee and Request for Submlaaions toner: Food and Drug Administration, HHS. action: Notice. SUMMARY: The Food and Drug Administration (FDA) is announcing a meeting of the clinical hold review committee, which reviews the clinical hold orders that the Center for Biologies Evaluation and Re--arch (CBER) has placed on certain investigational biological product trials. FDA is inviting any interested biological product company to use this confidential mechanism to submit to the committee for its review the name and number of BFG 00060