Source: https://www.law.cornell.edu/cfr/text/40/part-132/appendix-C?qt-cfr_tabs=1
Timestamp: 2015-04-25 09:42:15
Document Index: 571190593

Matched Legal Cases: ['art 132', 'art 132', 'art 132', 'art 132', 'art 132', 'art 132', 'art 132', 'art 132', 'art 132', 'art 132']

40 CFR Part 132, Appendix C to Part 132 - Great Lakes Water Quality Initiative Methodologies for Development of Human Health Criteria and Values | LII / Legal Information Institute
CFR › Title 40 › Chapter I › Subchapter D › Part 132 › Appendix C 40 CFR Part 132, Appendix C to Part 132 - Great Lakes Water Quality Initiative Methodologies for Development of Human Health Criteria and Values
Pt. 132, App. C
Appendix C to Part 132—Great Lakes Water Quality Initiative Methodologies for Development of Human Health Criteria and Values
“Possible human carcinogens” are chemicals with limited evidence of carcinogenicity in animals in the absence of human data. Limited animal evidence is defined as data which suggests a carcinogenic effect but are limited because: (a) The studies involve a single species, strain, or experiment and do not meet criteria for sufficient evidence (see preceding paragraph); or (b) the experiments are restricted by inadequate dosage levels, inadequate duration of exposure to the agent, inadequate period of follow-up, poor survival, too few animals, or inadequate reporting; or (c) the studies indicate an increase in the incidence of benign tumors only. More specifically, this group can include a wide variety of evidence, e.g., (a) a malignant tumor response in a single well-conducted experiment that does not meet conditions for sufficient evidence, (b) tumor response of marginal statistical significance in studies having inadequate design or reporting, (c) benign but not malignant tumors with an agent showing no response in a variety of short-term tests for mutagenicity, and (d) response of marginal statistical significance in a tissue known to have a high or variable background rate.
1. Tier I: Weight of evidence of potential human carcinogenic effects sufficient to derive a Tier I HCC shall generally include human carcinogens, probable human carcinogens and can include, on a case-by-case basis, possible human carcinogens if studies have been well-conducted albeit based on limited evidence, when compared to studies used in classifying human and probable human carcinogens. The decision to use data on a possible human carcinogen for deriving Tier I criteria shall be a case-by-case determination. In determining whether to derive a Tier I HCC, additional evidence that shall be considered includes but is not limited to available information on mode of action, such as mutagenicity/genotoxicity (determinations of whether the chemical interacts directly with DNA), structure activity, and metabolism.
2. Tier II: Weight of evidence of possible human carcinogenic effects sufficient to derive a Tier II human cancer value shall include those possible human carcinogens for which there are at a minimum, data sufficient for quantitative risk assessment, but for which data are inadequate for Tier I criterion development due to a tumor response of marginal statistical significance or inability to derive a strong dose-response relationship. In determining whether to derive Tier II human cancer values, additional evidence that shall be considered includes but is not limited to available information on mode of action such as mutagenicity/genotoxicity (determinations of whether the chemical interacts directly with DNA), structure activity and metabolism. As with the use of data on possible human carcinogens in developing Tier I criteria, the decision to use data on possible human carcinogens to derive Tier II values shall be made on a case-by-case basis.
B. Noncarcinogens. All available toxicity data shall be evaluated considering the full range of possible health effects of a chemical, i.e., acute/subacute, chronic/subchronic and reproductive/developmental effects, in order to best describe the dose-response relationship of the chemical, and to calculate human noncancer criteria and values which will protect against the most sensitive endpoint(s) of toxicity. Although it is desirable to have an extensive database which considers a wide range of possible adverse effects, this type of data exists for a very limited number of chemicals. For many others, there is a range in quality and quantity of data available. To assure minimum reliability of criteria and values, it is necessary to establish a minimum database with which to develop Tier I criteria or Tier II values. The following represent the minimum data sets necessary for this procedure.
1. Tier I: The minimum data set sufficient to derive a Tier I human HNC shall include at least one well-conducted epidemiologic study or animal study. A well-conducted epidemiologic study for a Tier I HNC must quantify exposure level(s) and demonstrate positive association between exposure to a chemical and adverse effect(s) in humans. A well-conducted study in animals must demonstrate a dose response relationship involving one or more critical effect(s) biologically relevant to humans. (For example, study results from an animal whose pharmacokinetics and toxicokinetics match those of a human would be considered most biologically relevant.) Ideally, the duration of a study should span multiple generations of exposed test species or at least a major portion of the lifespan of one generation. This type of data is currently very limited. By the use of uncertainty adjustments, shorter term studies (such as 90-day subchronic studies) with evaluation of more limited effect(s) may be used to extrapolate to longer exposures or to account for a variety of adverse effects. For Tier I criteria developed pursuant to this procedure, such a limited study must be conducted for at least 90 days in rodents or 10 percent of the lifespan of other appropriate test species and demonstrate a no observable adverse effect level (NOAEL). Chronic studies of one year or longer in rodents or 50 percent of the lifespan or greater in other appropriate test species that demonstrate a lowest observable adverse effect level (LOAEL) may be sufficient for use in Tier I criterion derivation if the effects observed at the LOAEL were relatively mild and reversible as compared to effects at higher doses. This does not preclude the use of a LOAEL from a study (of chronic duration) with only one or two doses if the effects observed appear minimal when compared to effect levels observed at higher doses in other studies.
2. Tier II: When the minimum data for deriving Tier I criteria are not available to meet the Tier I data requirements, a more limited database may be considered for deriving Tier II values. As with Tier I criteria, all available data shall be considered and ideally should address a range of adverse health effects with exposure over a substantial portion of the lifespan (or multiple generations) of the test species. When such data are lacking it may be necessary to rely on less extensive data in order to establish a Tier II value. With the use of appropriate uncertainty factors to account for a less extensive database, the minimum data sufficient to derive a Tier II value shall include a NOAEL from at least one well-conducted short-term repeated dose study. This study shall be of at least 28 days duration, in animals demonstrating a dose-response, and involving effects biologically relevant to humans. Data from studies of longer duration (greater than 28 days) and LOAELs from such studies (greater than 28 days) may be more appropriate in some cases for derivation of Tier II values. Use of a LOAEL should be based on consideration of the following information: severity of effect, quality of the study and duration of the study.
C. Bioaccumulation factors (BAFs).
1. Tier I for Carcinogens and Noncarcinogens: To be considered a Tier I cancer or noncancer human health criterion, along with satisfying the minimum toxicity data requirements of sections II.A.1 and II.B.1 of this appendix, a chemical must have the following minimum bioaccumulation data. For all organic chemicals either: (a) a field-measured BAF; (b) a BAF derived using the BSAF methodology; or (c) a chemical with a BAF less than 125 regardless of how the BAF was derived. For all inorganic chemicals, including organometals such as mercury, either: (a) a field-measured BAF or (b) a laboratory-measured BCF.
2. Tier II for Carcinogens and Noncarcinogens: A chemical is considered a Tier II cancer or noncancer human health value if it does not meet either the minimum toxicity data requirements of sections II.A.1 and II.B.1 of this appendix or the minimum bioaccumulation data requirements of section II.C.1 of this appendix.
III. Principles for Development of Tier I Criteria or Tier II Values
RAD=risk associated dose in milligrams of toxicant per kilogram body weight per day (mg/kg/day).
0.00001 (1×10−5)=incremental risk of developing cancer equal to one in 100,000.
q1*=slope factor (mg/kg/day)−1.
HCV=Human Cancer Value in milligrams per liter (mg/L).
RAD=Risk associated dose in milligrams toxicant per kilogram body weight per day (mg/kg/day) that is associated with a lifetime incremental cancer risk equal to one in 100,000.
BW=weight of an average human (BW=70 kg).
WCd=per capita water consumption (both drinking and incidental exposure) for surface waters classified as public water supplies=two liters/day.
WCr=per capita incidental daily water ingestion for surface waters not used as human drinking water sources=0.01 liters/day.
FCTL3=mean consumption of trophic level 3 of regionally caught freshwater fish=0.0036 kg/day.
FCTL4=mean consumption of trophic level 4 of regionally caught freshwater fish=0.0114 kg/day.
TL3=bioaccumulation factor for trophic level 3 fish, as derived using the BAF methodology in appendix B to part 132.
TL4=bioaccumulation factor for trophic level 4 fish, as derived using the BAF methodology in appendix B to part 132.
HNV=Human noncancer value in milligrams per liter (mg/L).
ADE=Acceptable daily exposure in milligrams toxicant per kilogram body weight per day (mg/kg/day).
RSC=Relative source contribution factor of 0.8. An RSC derived from actual exposure data may be developed using the methodology outlined by the 1980 National Guidelines (see 45 FR 79354).
FCTL3=mean consumption of trophic level 3 fish by regional sport fishers of regionally caught freshwater fish=0.0036 kg/day.
FCTL4=mean consumption of trophic level 4 fish by regional sport fishers of regionally caught freshwater fish=0.0114 kg/day.
TL3=human health bioaccumulation factor for edible portion of trophic level 3 fish, as derived using the BAF methodology in appendix B to part 132.
TL4=human health bioaccumulation factor for edible portion of trophic level 4 fish, as derived using the BAF methodology in appendix B to part 132.