Page 1 of 28 July 1, 2004 MEMORANDUM SUBJECT: Transmittal of Minutes of the FIFRA Scientific Advisory Panel Meeting Held May 4 6, 2004: A Consultation On Dermal Sensitization Issues For Exposures To Pesticides TO: James J. Jones, Director Office of Pesticide Programs FROM: Paul I. Lewis, Designated Federal Official FIFRA Scientific Advisory Panel Office of Science Coordination and Policy THRU: Larry C. Dorsey, Executive Secretary FIFRA Scientific Advisory Panel Office of Science Coordination and Policy Joseph J. Merenda, Jr., Director Office of Science Coordination and Policy Please find attached the minutes of the FIFRA Scientific Advisory Panel open meeting held in Arlington, Virginia from May 4 6, 2004. These meeting minutes address a set of scientific issues being considered by the Environmental Protection Agency regarding a consultation on dermal sensitization issues for exposures to pesticides.

Attachment Page 2 of 28 cc:

Susan Hazen Adam Sharp Anne Lindsay Janet Andersen Debbie Edwards Steven Bradbury William Diamond Arnold Layne Tina Levine Lois Rossi Frank Sanders Margaret Stasikowski William Jordan Douglas Parsons Dayton Eckerson David Deegan Vanessa Vu ( SAB) Jack Housenger Timothy McMahon Jonathan Chen Barbara Hostage David Cooper Elizabeth Hofmann Michele Burgess OPP Docket Attachment Page 3 of 28 FIFRA Scientific Advisory Panel Members Dr. Steven Heeringa Dr. Stuart Handwerger Dr. Gary Isom Dr. Mary Anna Thrall Dr. Paul Bailey Dr. Gary Burleson Dr. Ih Chu Dr. Iain Foulds Dr. A. Wallace Hayes Dr. Abigail Jacobs Dr. Jean Meade Dr. Torkil Menne Dr. Nancy Monteiro Riviere Dr. Richard Pleus Dr. Paul David Siegel Page 4 of 28 SAP Report No. 2004 02 MEETING MINUTES FIFRA Scientific Advisory Panel Meeting, May 4 6, 2004 held at the Holiday Inn Rosslyn Hotel at Key Bridge Hotel Arlington, Virginia A Set of Scientific Issues Being Considered by the Environmental Protection Agency Regarding:

Consultation on Dermal Sensitization Issues for Exposures to Pesticides Page 5 of 28 NOTICE These meeting minutes have been written as part of the activities of the Federal Insecticide, Fungicide, and Rodenticide Act ( FIFRA), Scientific Advisory Panel ( SAP). These minutes have not been reviewed for approval by the United States Environmental Protection Agency ( Agency) and, hence, their contents do not necessarily represent the views and policies of the Agency, nor of other agencies in the Executive Branch of the Federal government, nor does mention of trade names or commercial products constitute a recommendation for use.

The FIFRA SAP was established under the provisions of FIFRA, as amended by the Food Quality Protection Act ( FQPA) of 1996, to provide advice, information, and recommendations to the Agency Administrator on pesticides and pesticide related issues regarding the impact of regulatory actions on health and the environment. The Panel serves as the primary scientific peer review mechanism of the EPA, Office of Pesticide Programs ( OPP) and is structured to provide balanced expert assessment of pesticide and pesticide related matters facing the Agency. Food Quality Protection Act Science Review Board members serve the FIFRA SAP on an ad hoc basis to assist in reviews conducted by the FIFRA SAP. Further information about FIFRA SAP meeting minutes and activities can be obtained from its website at http:// www. epa. gov/ scipoly/ sap/ or the OPP Docket at ( 703) 305 5805. Interested persons are invited to contact Paul Lewis, Designated Federal Official, via e mail at lewis. paul@ epa. gov. Page 6 of 28 SAP Report No. 2004 02 MEETING MINUTES: FIFRA Scientific Advisory Panel Meeting, May 4 6, 2004, held at the Holiday Inn Rosslyn Hotel at Key Bridge Hotel Arlington, Virginia A Set of Scientific Issues Being Considered by the Environmental Protection Agency Regarding:

Consultation on Dermal Sensitization Issues for Exposures to Pesticides Mr. Paul Lewis Steven Heeringa, Ph. D. Designated Federal Official FIFRA SAP Session Chair FIFRA Scientific Advisory Panel FIFRA Scientific Advisory Panel Date: July 1, 2004 Date: July 1, 2004 Page 7 of 28 Federal Insecticide, Fungicide, and Rodenticide Act Scientific Advisory Panel Meeting May 4 6, 2004 Consultation on Dermal Sensitization Issues for Exposures to Pesticides PARTICIPANTS FIFRA SAP Session Chair Steven Heeringa, Ph. D., Research Scientist & Director for Statistical Design, Institute for Social Research, University of Michigan, Ann Arbor, MI FIFRA Scientific Advisory Panel Members Stuart Handwerger, M. D., Director, Division of Endocrinology, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, OH Gary E. Isom, Ph. D., Professor of Toxicology, Purdue University, School of Pharmacy & Pharmacal Sciences, West Lafayette, IN Mary Anna Thrall, D. V. M., Professor, Microbiology, Immunology & Pathology, Colorado State University, College of Veterinary Medicine and Biomedical Sciences, Fort Collins, CO FQPA Science Review Board Members Paul Bailey, Ph. D., Senior Scientific Associate, Toxicology and Environmental Sciences Division, Intermediates and Synthetics Section, ExxonMobil Biomedical Sciences, Inc., Annandale, NJ Gary Burleson, Ph. D., President, BRT Burleson Research Technologies, Inc., Raleigh, NC Ih Chu, Ph. D., Head, Systemic Toxicology and Pharmacokinetics, Environmental Science Bureau, Health Canada, Ottawa, ON, Canada Iain Foulds, F. R. C. P., F. F. O. M. Senior Lecturer in Occupational and Environmental Dermatology,. The Birmingham Skin Centre, Sandwell and West Birmingham NHS Trust, United Kingdom A. Wallace Hayes, PhD., DABT, FATS, FIBiol, FACFE, ERT, Visiting Scientist, Department of Environmental Health, Harvard School of Public Health, Harvard University, Boston, MA Abigail Jacobs, Ph. D., Associate Director for Pharmacology and Toxicology, Offices of Drug Evaluation 4 and 5, CDER, FDA, Rockville, MD Jean Meade, D. V. M., Ph. D., Toxicologist, Office of the Director, NIOSH, Morgantown, WV Page 8 of 28 Torkil Menne, M. D., Chair, Department of Dermatology, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark Nancy Monteiro Riviere, Ph. D., Professor of Investigative Dermatology and Toxicology, Center for Chemical Toxicology Research and Pharmacokinetics, North Carolina State University, Raleigh, NC Richard Pleus, Ph. D., Director and Toxicologist, Intertox, Seattle, WA; Adjunct Associate Professor of Pharmacology University of Nebraska Medical Center; Faculty member of the Center for Environmental Toxicology, University of Nebraska Paul Siegel, Ph. D., M. S. P. H., Team Leader Bioorganic Chemistry/ Director Scientist, Analytical Services Branch, Health Effects Laboratory Division, NIOSH, Morgantown, WV PUBLIC COMMENTERS Oral statements were made by:

Michele Burgess, Ph. D., United States Environmental Protection Agency, Office of Solid Waste and Emergency Response Mr. James Aidala, The Acta Group, L. L. C., representing Forest Products Research Laboratory Howard Maibach, MD., University of California at San Francisco, representing Forest Products Research Laboratory Susan Hunter Youngren, Ph. D., The Acta Group, L. L. C. representing Forest Products Research Laboratory Mr. Dennis J. Morgan, representing Forest Products Research Laboratory Paul A. Cooper, Ph. D., University of Toronto, representing Osmose, Inc.

Mr. John Horton, representing Osmose, Inc.

Ms. Deborah Proctor, Exponent, Inc., representing Tierra Solutions, Inc.

Joel Barnhart, Ph. D., representing Elementis Chromium Mr. Warren Stickle, representing the Chemical Producers and Distributors Association Jane Vergenes, Ph. D., International Specialty Products, representing the ACC Biocides Panel Mr. Richard Wiles, representing the Environmental Working Group Page 9 of 28 Written statements were received from:

The ACTA Group, LLC Beyond Pesticides and The Healthy Building Network Joel Barnhart, Ph. D., Elementis Chromium, LLP Michele Burgess, Ph. D., United States Environmental Protection Agency, Office of Solid Waste and Emergency Response Forest Products Research Laboratory Dr. Peter Griem, Clariant GmbH INTRODUCTION The Federal Insecticide, Fungicide, and Rodenticide Act ( FIFRA), Scientific Advisory Panel ( SAP) has completed its review of the set of scientific issues being considered by the Agency pertaining to its review of dermal sensitization issues for exposures to pesticides. Advance notice of the meeting was published in the Federal Register on April 16, 2004. The review was conducted in an open Panel meeting held in Arlington, Virginia, from May 4 6, 2004. The meeting was chaired by Steven Heeringa, Ph. D. Mr. Paul Lewis served as the Designated Federal Official. Mr. Joseph J. Merenda, Jr. ( Director, Office of Science Coordination and Policy,. EPA) and Mr. Jim Jones ( Director, Office of Pesticide Programs, EPA) provided opening remarks at the meeting. Timothy McMahon, Ph. D. ( Office of Pesticide Programs, EPA) discussed the proposed hazard identification methodology for assessment of dermal sensitization risk, and Jonathan Chen, Ph. D. ( Office of Pesticide Programs, EPA) reviewed the proposed hazard identification methodology for assessment of dermal sensitization risk   a case study of Cr( VI) in wood preservatives. In preparing these meeting minutes, the Panel carefully considered all information provided and presented by the Agency presenters, as well as information presented by public commenters. This document addresses the information provided and presented within the structure of the charge by the Agency. Page 10 of 28 CHARGE Dermal sensitization, also known as allergic contact dermatitis ( ACD) is typically characterized by two phases, termed induction and elicitation. In the induction phase, the allergen is transported to regional draining lymph nodes where clonal expansion of allergenspecific T lymphocytes results. The elicitation phase results from a subsequent exposure to the allergen, in which the allergen specific T lymphocytes provoke a cutaneous immune response. Although several approaches have been proposed to assess threshold concentrations for induction and elicitation of ACD and risk determination for these concentrations, there is no established scientific approach within the Agency to do a quantitative risk assessment associated with ACD.

There are several accepted methods for hazard identification of dermal sensitization, including the Buehler occluded patch test, the guinea pig maximization test, and the murine local lymph node assay ( LLNA). The guinea pig maximization test as well as the Buehler test, while providing reliable information on skin sensitization, are best suited for hazard identification. Several proposals have been published regarding quantitative determination of sensitization induction and elicitation thresholds.

ISSUE 1: Quantitative Risk Assessment for the Induction Phase of ACD The Mouse Local Lymph Node Assay ( LLNA) is a test method for assessing the allergic contact dermatitis ( skin sensitization) potential of chemicals, specifically the induction phase of sensitization. Using the incorporation of radiolabeled thymidine or iododeoxyuridine into DNA, the LLNA measures lymphocyte proliferation in the draining lymph nodes of mice topically exposed to the test article. The stimulation index ( ratio of lymphocyte proliferation in treated mice compared to controls) is used as the indicator of potential sensitization. In 1998, following review by the FIFRA SAP, the LLNA was incorporated as a screening test in OPPTS Test Guideline 870.2600 Skin Sensitization. In 1999, the Interagency Coordinating Committee on the Validation of Alternative Methods ( ICCVAM) Immunotoxicity Working Group ( IWG) endorsed the LLNA as an acceptable alternative to currently accepted guinea pig test methods for hazard identification of chemicals with potential to produce contact hypersensitivity. Following additional studies to validate the method, the LLNA was endorsed by the SAP in December 2001 as a full stand alone assay. The OPPTS guideline 870.2600 ( Skin Sensitization) has been revised to include the LLNA as a stand alone assay for appropriate applications. The OPPTS guideline has also been harmonized with OECD's Guideline 429 for LLNA, which was adopted in April 2002. Although the LLNA has not been validated for determination of sensitization potency, approaches for determination of quantitative assessment of sensitization induction thresholds have been proposed in the scientific literature ( Gerberick 2000, 2001; Griem et al., 2003).

Gerberick ( 2000, 2001) proposed a methodology for determination of a ' sensitization reference dose' for sensitizers in consumer products. The lower boundary of the potency category for a sensitizing chemical is used as the starting point, with application of uncertainty factors for interindividual variability, product matrix effects, and use pattern. This approach was applied to the fragrance component cinnamic aldehyde and the preservative methylchloroisothiazolinone/ methylisothiazolinone for which both LLNA and human Page 11 of 28 sensitization potency were available ( Griem et al., 2003).

Griem et al ( 2003) proposed a quantitative approach in which identification of known human sensitizing chemicals used both an EC3 value ( defined as the concentration of a sensitizer required to generate a threefold stimulation of proliferation in draining lymph nodes) from an LLNA test and a NOAEL or LOAEL from human repeat insult patch tests ( HRIPT) or human maximization tests ( HMT). The reported concentrations were converted into specific and molar area doses. Comparison of the area doses of the LLNA and human test results indicated that sensitization thresholds were similar in mice and humans despite the fact that the area doses for different chemicals ranged over several orders of magnitude ( Griem et al., 2003). It was concluded from this analysis that the LLNA EC3 value is a useful measure of sensitizing potency in humans, and that the EC3 value can be used as a surrogate value for the human NOAEL that can be used as a starting point in quantitative risk assessment.

Uncertainty factors to account for interspecies variation, intraspecies variation, product matrix effects, and conditions of exposure ( including repeated exposures) have been proposed for use in conduct of dermal risk assessments. Griem et al. ( 2003) have discussed the application and magnitude of all of these uncertainty factors with respect to establishment of safe area doses for both induction and elicitation, while Felter et al ( 2003) have proposed the use of only the intraspecies variation factor, product matrix factor, and exposure conditions factor for determination of safe area doses for induction. The interspecies uncertainty factor is intended to account for differences in response between tests in animals and results in humans, although it has been reported ( Griem et al, 2003) that sensitizing area doses are very similar between murine and human data, thus supporting a potentially reduced uncertainty factor for this area. The intraspecies uncertainty factor is used to account for inherent variability in the human population based on age, sex, genetic makeup, or health status, and is generally agreed that a factor of 10 is appropriate for this uncertainty. An uncertainty factor may also be included for vehicle matrix effects, as the matrix in which an allergen is presented to the skin may have an influence on the potential for induction of ACD. Most experimental data are generated using simple vehicles, while actual exposures are usually to more complex formulations that may contain irritants or penetration enhancers. A factor of 10 may considered in such a case, while a reduced factor may be considered for mild formulations. Finally, an uncertainty factor may be applied to account for exposure variables that may influence the potential for induction of ACD, including the site of the body exposed, the integrity of the skin, and the potential for multiple exposures. Using the above approaches, a maximum uncertainty factor of 1000 or 3000 could be derived depending on the criteria used. By contrast, a minimum uncertainty factor of 10 could be derived if results from human studies are used.

Thresholds for induction of ACD can occur following a single exposure of sufficient magnitude, after contact with a large area of skin, or as a consequence of repeated skin applications ( Marzulli and Maibach). Griem et al. ( 2003) suggested a possible higher sensitizing potency of a chemical upon repeated exposures. This would make sense in the case of hexavalent chromium, as the significant irritancy of the chemical could lend itself to an increased sensitizing potency by allowing more chemical to penetrate the stratum corneum.

QUESTION 1: What are the strengths and weaknesses of the proposed quantitative approach for Page 12 of 28 determination of induction thresholds to dermal sensitizing chemicals? What other approaches does the Panel recommend EPA consider? Which uncertainty factors does the Panel feel are the most appropriate for application to quantitative methods of induction threshold determination? What factors should be included in the determination of the magnitude of each uncertainty factor?

ISSUE 2: Quantitative Risk Assessment for the Elicitation Phase of ACD Several proposals have been published regarding determination of elicitation thresholds in sensitized populations. The Minimum Elicitation Threshold ( MET) concept has been discussed in previous publications ( Nethercott et al., 1994; Zewdie, 1998; NJDEP, 1998; Basketter et al., 2003) specifically with respect to hexavalent chromium. The concept behind the MET is that there is an ' elicitation threshold' below which no sensitization reaction is expected; thus, the MET is analogous to an RfD ( Horowitz and Finley, 1994). The setting of an MET is usually performed as a result of tests in previously sensitized individuals; thus, the MET is considered protective of elicitation reactions. However, there has not been an extensive discussion of the criteria for employing this concept for purposes of risk assessment.

QUESTION 2:

What are the strengths and weaknesses of the proposed quantitative approaches for determination of elicitation thresholds to dermal sensitizing chemicals? What other approaches does the Panel recommend that EPA consider? Which uncertainty factors does the Panel feel are the most appropriate for application to quantitative methods of elicitation threshold determination? What factors should be included in the determination of the magnitude of each uncertainty factor?

ISSUE 3: Children Sensitivity Paustenbach et al. ( 1992) and Felter et al. ( 2002) have discussed the issue of whether children are more or less at risk for development of ACD. Paustenbach et al. addressed this issue specifically for hexavalent chromium, and this paper concluded that risk to children ages 3 to 8 is not likely to be greater than adults as there is no evidence that repeated exposures to hexavalent chromium places a person at greater risk of sensitization. Felter et al. suggested that infants and children may actually be at lower risk for development of ACD based on data gathered from dinitrochlorobenzene and pentadecylcatechol ( poison ivy allergen). However, it is also understood that young children may not have been exposed to different allergens as compared to adults. In addition, increased frequency of exposure in children may increase the chance of induction to different allergens.

QUESTION 3:

Does the Panel agree that the available scientific data suggest no significant difference in the relative sensitivity of children vs. adults to the induction and/ or elicitation of ACD? If so, please provide scientific justification for this position. If the Panel disagrees, please provide scientific justification, including supporting data and/ or uncertainties in the explanation. Page 13 of 28 ISSUE 4: Case Example  Cr( VI) in treated wood Data from murine LLNA tests as well as from human patch testing studies using hexavalent chromium are available in the scientific literature. Results of LLNA testing show EC3 values that indicate area doses that result in the induction of sensitization in the mouse, while the results of patch test studies in humans show area doses that result in elicitation of sensitization in already sensitized individuals. In the Agency's initial assessment seeking to assess dermal sensitization risk from hexavalent chromium, the lowest dose tested ( 0.018 ug/ cm2) from the human patch test study of Nethercott et al. ( 1994) was selected for determination of dermal risk from hexavalent chromium. A 10x uncertainty factor ( 3x for use of the lowest dose tested [ LOAEL] in this study, and 3x to account for the small size of the study population in the Nethercott study) was applied, resulting in a ' safe area' dose of 0.0018 ug/ cm2. Use of the test data of Basketter et al. ( 2001) and Hansen et. al ( 2003) also result in derivation of similar ' safe' area doses of 0.001 and 0.003 ug/ cm2 respectively. Use of the murine LLNA test data and application of an uncertainty factor of either 1000 or 3000 calculated ' safe' area doses of 0.01 or 0.003 ug/ cm2 respectively.

QUESTION 4: Please comment on the methods used for derivation of safe' area doses using the available LLNA data and the human patch test data, including the magnitude of the applied uncertainty factors, and include a scientific rationale in support of your position. Please comment on whether it is scientifically supportable to derive separate ` safe' area doses for protection against induction of dermal sensitization as well as elicitation in sensitized individuals by hexavalent chromium?

SUMMARY OF PANEL DISCUSSION AND RECOMMENDATIONS   The Panel did not endorse any particular method for risk assessment related to the identification of thresholds for induction by dermal sensitizing chemicals but acknowledged the importance of incorporating all relevant data into the weight of evidence.   Although the Panel sees promise in the use of the LLNA as a quantitative risk assessment tool, further development and validation of this application is necessary.   The Panel proposed the following uncertainty factors be considered for the induction phase: interspecies variation ( value of 1 10), intraspecies variation ( value of 1 10), matrix/ vehicle ( value of less than 1 to 10), and exposure ( value of less than 1 to 10).   Given that sensitization responses are based on dose/ surface area, the Panel concluded that both the Minimum Elicitation Threshold ( MET) and LLNA exposure methodologies are appropriate for collecting sensitization data.   The Panel identified four uncertainty factors ( UF) for application to quantitative methods of elicitation threshold determination: interspecies variation, intraspecies variation, exposure, and vehicle/ matrix.   The Panel agreed with the Agency that there is no evidence of a significant difference in the sensitivity of children versus adults to the induction/ or elicitation of ACD.   Based on current exposure levels of hexavalent chromium in the environment, sensitivity in children is very rare. Page 14 of 28   There are no data to suggest that allergic contact dermatitis occurs more frequently in children with atopic dermatitis compared to non atopic children.   Due to the availability of human data, there is no need at this stage to consider LLNA studies for the derivation of the ` safe' area dose ( mass per unit area) for chromate exposure.   The Panel identified the critical dose ( lowest observed adverse effect level) [ LOAEL] from the Nethercott et al. ( 1994) study should be 0.088ug/ cm2, which the Panel considered to still be a conservative safety level.   Applying a matrix/ vehicle ( value 0.1), interspecies variation ( value 1), intraspecies variation ( value 1), and exposure ( value 3 to 10) uncertainty factors, the S RfD calculated as specific to hexavalent chromium in treated wood ranged from 0.09 to 0.3 ug/ cm2 .   The Panel's estimate of an S RfD should be protective against elicitation and therefore would also be protective of induction.   Although the Panel calculated a S RfD for hexavalent chromium in ACC treated wood, the Panel stressed that the Agency consider all data as part of a weight of evidence approach.

Panel Response To Question 1 General Comments Before beginning to address the specific questions, the Panel offered some general comments relevant to the overall risk assessment process. Firstly, it was stated that there has been no established scientific approach within the Agency to conduct a quantitative risk assessment associated with allergic contact dermatitis ( ACD) ( Stern et al., 2003) and although several methods have been proposed and show promise, the Panel suggested that the weight of evidence approach remains appropriate at this time. The mechanisms of the induction and elicitation phases of ACD as well as the science underlying the proposed test methods will be discussed before evaluating the relevancy and validity of the proposed approaches. Each chemical has its own thresholds for induction and elicitation. For example, thresholds for Cr VI cannot be extrapolated to Cr III. Thresholds for induction of ACD can occur following a single dermal exposure of sufficient magnitude, after contact with the skin, or as a consequence of repeated skin applications ( Marzulli and Maibach 1975). Griem et al. ( 2003) suggested a possible higher potential for inducing sensitization to a chemical upon repeated exposures.

ACD is characterized by two phases. The first is the induction phase which requires exposure of a susceptible individual to an allergen in sufficient concentration and for a sufficient duration to activate specific immune mechanisms that result in the acquisition of sensitization. During the induction phase, the allergen must penetrate the stratum corneum layers and be taken up by epidermal Langerhans cells which then process and transport the allergen to regional draining lymph nodes. Presentation of allergen results in clonal expansion of allergen specific T lymphocytes and the generation of effector and memory T cells. The second phase is termed elicitation where re exposure to the allergen ( challenge) in a previously sensitized individual results in the elicitation of an inflammatory dermal response ( Stern et al., 1993). As with induction, the elicitation phase requires penetration of the allergen through the stratum corneum and presentation by antigen presenting cells. Page 15 of 28 It is important when evaluating data derived from both animal and human studies to consider elements of the experimental design. Most animal assays used in the evaluation of ACD were originally designed for hazard identification. Guinea pig assays have been used for decades to predict the potential of chemicals to induce ACD in humans. The most frequently used tests are the Guinea Pig Maximization Test ( GMT) and the Buehler test. These tests rely on the induction of sensitization in animals with the read out being the elicitation of a dermal inflammatory response following challenge. As the name would imply, the GMT provides for an exaggerated exposure regimen which includes intradermal injection of the allergen along with the use of an adjuvant and topical application under an occluded patch to maximize the potential to induce sensitization. In the Buhler test, animals undergo multiple exposures under an occluded patch. For the guinea pig assays, the end point is subjective and semi quantitative.

More recently, a murine assay, the Local Lymph Node Assay ( LLNA), has been developed which evaluates the induction/ sensitization phase of ACD and provides for a dose response evaluation. Animals in this assay receive three consecutive days of topical exposure to intact, non occluded skin. The read out is a quantitative measurement of 3H thymidine or I125  deoxyuridine incorporation into draining lymph node cells as an indication of cellular proliferation. The LLNA has undergone intra and inter laboratory validation and peer review sponsored by the ICCVAM ( NIH 1999). The results of the ICCVAM review supported an equivalent percent accuracy for the LLNA and guinea pig assays in predicting the sensitizing potential of chemicals (~ 73%).

The Panel cited the strengths of the LLNA as:

  It is mechanistically based, i. e. allergenic substances cause proliferation of lymphocytes;   It provides an objective and quantitative endpoint;   It permits the evaluation of ACD potential of chemicals that are too toxic to be tested in humans;   It has been sufficiently validated for a hazard assessment;   It reduces stress in animals due to the short duration of the assay, the open application of test material and the lack of the elicitation of the inflammatory response.

Deficiencies of the LLNA were described as:

  The irritant properties of the matrix or test substance may contribute to the local lymph node proliferation resulting in false positives for strong irritants;   The method has not been sufficiently evaluated using mixtures;   At the time of the ICCVAM review, its application had not yet been validated for metals or aqueous soluble materials ( however since that time investigators have shown a similar predictive accuracy of the LLNA for metals ( 85%) as compared to low molecular weight chemicals ( 88%) ( Basketter et al. 1999) and alternative vehicles for testing aqueous soluble materials have been investigated ( Ryan et al., 2002).

Like the guinea pig assays, human tests to evaluate sensitization potential require the induction of sensitization and subsequent evaluation of the elicitation response following Page 16 of 28 challenge. Exposure under an occluded patch is used for induction in the Human Maximization Test ( HMT) and the Human Repeated Insult Test ( HRIPT), while the Open Epicutaneous Test utilizes topical application to non occluded skin. The data from these tests are semi qualitative and based on subjective scoring using macroscopic observation ( i. e., + 1 to + 4). Although ethical issues may limit future human testing, the Panel felt strongly that when human data are available they should be given primary consideration.

Panel Conclusions/ Recommendations in Response to Question 1.

Proposed quantitative approaches The Panel did not endorse any particular method for risk assessment related to the identification of thresholds for induction by dermal sensitizing chemicals but acknowledged the importance of incorporating all relevant data into the weight of evidence. The Panel strongly agreed that given that the threshold for induction is considered to be higher than that required for elicitation ( Friedman 1990), that establishing a safe level below the threshold for elicitation would also be protective of induction. Therefore it was anticipated that risk assessment for the induction phase of sensitization would only be appropriate for chemicals where no data were available ( e. g. new chemicals). If risk assessment is based on induction only, exposure limits will be more conservative. If people are protected from induction, then elicitation should not be an issue ( Gerberick and Robinson 2000). While there is basis for this hypothesis, there may be unanticipated exposure scenarios that could lead to a sensitized subpopulation.

In 1999, ICCVAM recommended that with certain protocol modifications, the LLNA was sufficiently validated as a stand alone test for the identification of skin sensitizing chemicals with the exception of metals, mixtures, and the use of aqueous vehicles ( National Institutes of Health 1999) . Since that time several authors have proposed the use of the LLNA for risk assessment. The first step was the analysis of dose response data to calculate an EC3 value ( the concentration of chemical required to elicit a 3 fold increase in lymphocyte proliferation as compared to vehicle) as an estimation of the concentration of a chemical required to induce sensitization ( Kimber and Basketter 1997). EC3 values of chemicals were then used to establish relative potencies. Potency data generated using this method compared favorably with the corresponding human data ( Basketter et al. 2000; Gerberick et al. 2001).

More recent studies ( Gerberick and Robinson 2000; Gerberick et al. 2001; and Griem et al. 2003) have incorporated LLNA derived EC3 values into quantitative risk assessment protocols. Gerberick et al. ( 2000, 2001) proposed a methodology for determining the ` sensitization reference dose' for sensitizers in consumer products. The lower boundary of the potency category for a sensitizing chemical was used as the starting point, with the application of uncertainty factors for interindividual variability, product matrix effects, and use pattern. This approach was applied to the fragrance component cinnamic aldehyde and the preservative methyl chloroisothiazolinone/ methylisothiazolinone for which both LLNA and human sensitization potency were available ( Griem et al., 2003).

Griem et al. ( 2003) proposed a quantitative approach using both an EC3 value from the LLNA and a NOAEL or LOAEL from HRIPT or HMT. The reported concentrations were Page 17 of 28 converted into specific and molar area doses. The authors concluded from their analysis that the LLNA EC3 value was a useful measure of sensitizing potency in humans, and that the EC3 value can be used as a surrogate value for the human NOAEL and as a starting point in quantitative risk assessment.

Although the Panel sees promise in the use of the LLNA as a quantitative risk assessment tool, further development and validation of this application is necessary. Validation should include different classes of chemicals including metals. Academia, industry, and contract laboratories should participate in the validation process.

Uncertainty Factors Uncertainty factors to account for interspecies variation, intraspecies variation, product matrix effects, and conditions of exposure ( including repeated exposures) have been proposed for the conduct of dermal risk assessments. Griem et al. ( 2003) discussed the application and magnitude of all of these uncertainty factors with respect to establishment of safe area doses for both induction and elicitation, while Felter et al. ( 2003) discussed the use of only the intraspecies variation factor, product matrix factor, and exposure conditions factor for determination of safe area doses for induction. Uncertainty factors are generally assigned a value between 1 and 10. The interspecies uncertainty factor is intended to account for differences in response between tests in animals and results in humans. The intraspecies uncertainty factor is used to account for inherent variability in the human population based on age, sex, genetic makeup, or health status, and is generally agreed that a factor of 10 is appropriate for this uncertainty. An uncertainty factor may also be included for vehicle matrix effects, as the matrix in which an allergen is presented to the skin may have an influence on the potential for induction of ACD. Most experimental data are generated using simple vehicles, while actual exposures are usually to more complex formulations that may contain irritants or penetration enhancers. An uncertainty factor may be applied to account for exposure variables that may influence the potential for induction of ACD, including the site of the body exposed, the integrity of the skin, and the potential for multiple exposures. Using the above approaches, a maximum uncertainty factor of 1000 or 3000 could be derived depending on the criteria used. By contrast, a minimum uncertainty factor of less than 1 could be derived if proper human studies are conducted and used.

The Panel proposed the following uncertainty factors be considered for the induction phase: interspecies variation, intraspecies variation, matrix/ vehicle, and exposure as described below. Uncertainty factors must be assigned on a case by case basis dependent in part on the experimental design from which the data were generated and the use of the chemical and product matrix.

Intraspecies variation  the Panel recommended a value for intraspecies variation of 1 10. The values depend on the experimental design of the study in question including factors such as the sample size, age, gender and ethnic composition of the sample population.

Interspecies variation  the Panel recommended values from 1 to 10. The values depend on the experimental design of the study in question. Rodent skin is much more permeable than Page 18 of 28 human skin for most compounds, potentially allowing enhanced penetration of the chemical and greater bioavailability ( Tregear et al. 1975; Bartek et al. 1972). In addition, Griem et al. ( 2003) reported that sensitizing area doses are similar between murine and human data, thus suggesting a potentially reduced uncertainty factor for this area. Thus, this could result in an interspecies variation closer to 1.

Matrix/ vehicle  this uncertainty factor is dependent upon the matrix used during testing as well as the anticipated matrix during use. Exposures during testing may have been exaggerated as compared to normal use. For example, exposure during patch testing may have been occluded for 48 hours. Additionally, DMSO, an irritant and skin penetration enhancer, is frequently used in the LLNA. Conversely, if mixtures were tested where the matrix included agents which may interfere with dermal penetration of the test article such as barrier creams or agents that may interfere with physiological responses such as vasoconstrictors or anti inflammatory agents, an uncertainty factor of greater than 1 would be expected. Therefore once the matrix used during testing and the anticipated matrix of exposure have been considered, the matrix/ vehicle value assigned may range from less than 1 ( e. g., DMSO) to 10 ( e. g., dexamethasone).

Exposure  there is a need to consider the total dose when establishing an uncertainty factor for exposure. This may be dependent on the body site where exposure occurs as dermal penetration has been shown to vary between anatomical locations. The potential for repeat exposure and exposure to damaged skin must also be taken into consideration. Thus, the Panel recommended values from less than 1 to 10.

Panel Response To Question 2 Given that sensitization responses are based on dose/ surface area, the Panel concluded that both the Minimum Elicitation Threshold ( MET) and LLNA exposure methodologies are appropriate for collecting sensitization data ( however, the LLNA does not measure elicitation). The use of the MET approach eliminates the need to extrapolate from animal data to humans. Variability with using this approach relates to the reliability of the patch test data ( i. e. variability in defining threshold, the concentration of the patch test material, vehicle used, proper occlusion, consistency between readers, irritant responses, skin condition at patch site, patch time and the sample size). The issue related to sample size could be addressed by using 95% confidence limits. The 10% MET may not be an acceptable approach for new chemicals, however, since a sensitized population would not be available for testing, and ethical issues may prohibit the use of the HRIPT.

Although the LLNA method shows promise and data are being accumulated related to the use of the assay in risk assessment, the Panel does not feel that the method's suitability is yet adequately demonstrated. Validated methods for estimating elicitation thresholds do not currently exist. The Panel encourages the Agency to support research in methods development for use in risk assessment.

The Panel identified four uncertainty factors ( UF) for application to quantitative methods of elicitation threshold determination: interspecies variation, intraspecies variation, Page 19 of 28 vehicle/ matrix and exposure. For all uncertainty factors, determination of the magnitude should be assessed on a case by case basis. When animal models are used, it will be necessary to assign interspecies uncertainty factors. For mouse models, this UF should be on the low end of the 1 10 scale. Sensitization is based on dose per surface area and not on a mg/ kg basis as with other toxicological effects and data have demonstrated a similarity in doses required to sensitize humans and mice ( Gerberick et al. 2001). Additionally, dermal penetration is an important factor in the initiation of sensitization and, as stated previously, mouse skin is more permeable than human.

Intraspecies factors will be dependent on whether animal or human data are used for evaluation. When the extrapolation is from animal data to human, in addition to the interspecies factor, an intraspecies factor of 10 is generally used to account for differences in age, gender, ethnic background, genetic polymorphisms and skin condition. When human data are used, intraspecies uncertainty factors should take into account the study design and quality of the data, bearing in mind that the study population may consist of a sensitive subpopulation. The uncertainty factor should be dependent upon the number of people patch tested in relation to the percentage of individuals sensitized and the quality of the patch test data. The quality of the patch test data will depend on the expertise of the readers and consistency within and between centers. The determination of the threshold for interpreting a positive patch test reaction is variable. Additionally, an individual's irritant threshold, genetic factors, polymorphisms related to dermal metabolism, skin condition, and ultraviolet exposure may all influence their reaction.

Exposure factors must take into account repeat exposures, dermal integrity, potential for occlusion and anatomical site of exposure. The vehicle/ matrix factors should take into account the matrix in which the chemical was tested as well as the vehicle/ matrix anticipated during environmental exposure. This should include factors such as the irritant nature of the matrix, the presence of penetration enhancers or retardants and the bioavailability of chemical from the matrix.

Panel Response To Question 3 Background and Panel Recommendations On Clinical Aspects of ACD in Children Compared to adults, ACD in children is rare. However this may be due to decreased exposure and not a difference in their immunologic response. The Panel agreed with the Agency that there is no evidence of a significant difference in the sensitivity of children versus adults to the induction/ or elicitation of ACD. The Panel recommended the Agency review the article on this subject by Hjorth ( 1981). Historically, most cases of ACD in children have been caused by nickel, cobalt, fragrance, rubber additives and occasionally potassium dichromate. Most clinical cases in children are acute contact dermatitis settling rapidly with withdrawal from the allergen. Chronic dermatitis in children as a result of allergic contact factors is the exception. In recent years p phenylenediamine has become a more frequent contact allergen in children as a result of temporary ` Henna' Tattoos. A single exposure to p phenylenediamine from Henna tattoos can induce sensitization within 10 days, resulting in severe reactions at the site of exposure ( Brancaccio et al 2002; Sidbury and Storrs 2000). The dermatitis experienced by children is equivalent to that experienced by adults. It involves any site exposed to an allergen and can Page 20 of 28 cause severe discomfort including itching, weeping, and pain. Significant morbidity can result.

Primary Sensitization In Children Like adults, children can be sensitized with only one exposure to an allergen. Pphenylenediamine is one such example. Epstein et al ( 1961) demonstrated positive reactions to pentadecyl catechol ( poison ivy) could be expressed in children of different age groups. This study suggested that not only can children be sensitized but that the rate of sensitization increases with increasing age. The rate of demonstrable sensitization rose from 30% in children under 1 year to 50% between 1 and 3 years. From ages 3 to 8 the rate rose further to 76%. However, the older children may have had increased environmental exposure to this common allergen with increasing age resulting in increased reaction rates. Thus, this study does not indicate that very young children are less likely to become sensitized.

Thimerosal reactions are common in young adults. Up to 15% of Swedish army recruits demonstrated this sensitivity ( Hansonn and Moller 1971). This sensitivity is acquired from vaccinations preserved with thimerosal given in the early years of life.

Population Based Patch Test Studies One cohort study has recently been performed by Mortz et al ( 2002). The study was designed to investigate both atopic disease and delayed type hypersensitivity. The cohort examined 1000 children aged 10 to 14 years old who were patch tested using the T. R. U. E test. 15.2% revealed patch test positive reactions. This figure was similar to that of an adult population ( Neilsen and Menne 1992). The most common positive allergens were nickel, fragrances and thimerosal.

A study by Wohrl et al. ( 2003) reported 2776 consecutive patch tests given to a variety of age ranges. In the under 10 year old age range, 62% gave positive reactions. In the over 70 year old age range, a lower figure of 34.9% gave positive reactions. The study suggested that children may be more easily sensitized. However, this study makes no allowance for the selection of patients for patch testing in the first instance. There is often reluctance to patch test small children because of the discomfort of the testing, the small skin area available for testing and the cause of the ACD which is usually detectable from patient history. The patch test tends to be used in children to support a suspicion of sensitivity when confirmation is required and therefore when a child is tested it is more likely to be positive. In adults with persistent dermatitis, patch testing is more likely to be conducted in the hope of identifying a relevant allergen. Hence the incidence of positive patch test reactions in adults can be expected to be considerably lower.

Children's Exposure To Hexavalent Chromium And ACD Based on current exposure levels of hexavalent chromium in the environment, sensitivity in children is very rare. Children around the world have for years been exposed to chromate in treated woods ( CCA and ACC) and there are no reports in the literature of either sensitization occurring from this exposure or the elicitation of dermatitis in a sensitized child. Panel members Page 21 of 28 had collectively more than 50 years of patch testing experience, yet could not recall a single case of sensitization to hexavalent chromium being attributable to treated wood exposure either in children or in adults. Nor could they recall a single case of elicitation of ACD in hexavalent chromium sensitized children. One case was reported of an adult who had been previously sensitized to hexavalent chromium in the construction industry. This patient subsequently returned to work at a wood treatment plant, directly handled freshly treated wet wood and subsequently developed an elicitation reaction from this exposure. This resulted in removal of the patient from the source.

There are no data to suggest that allergic contact dermatitis occurs more frequently in children with atopic dermatitis compared to non atopic children. Some studies actually suggest that the incidence of delayed type hypersensitivity is reduced in atopic children ( Agner and Menne 2001). Therefore, children with active atopic skin disease should not be at any increased risk of ACD from hexavalent chromium in treated woods. This conclusion also applies when exposure might be expected to occur on actively inflamed skin.

Panel Response To Question 4 Introduction ACD to hexavalent chromium may sometimes be very severe, with a major impact on the quality of life for some sensitized individuals. ACD can be a reversible condition if exposure is removed. In chromate dermatitis, the condition can persist when exposure is apparently removed ( Wall 1980; Freeman 2000). As stated previously, there is no published literature to suggest that there is any primary sensitization or elicitation of ACD as a result of chromate exposure from treated woods.

LLNA Data There were five studies cited by the Agency on the use of the LLNA and induction of chromate sensitivity ( Griem 2003). However, as noted previously by the Panel, the LLNA has not been formally evaluated for use in risk assessment and issues still remain regarding the use of the LLNA in assessing metals. There are a number of well designed human studies in chromate sensitized individuals. Thus, due to the availability of human data, there is no need at this stage to consider LLNA studies for the derivation of the ` safe' area dose ( mass per unit area) for chromate exposure.

Exposure Scenario for Chrome VI Case Study A major concern in conducting a risk assessment on hexavalent chromium in treated wood is the paucity of exposure data. The Panel suggested that if exposure scenarios are to be considered, the following situations be considered:   Wood treated with ACC ( aged versus newly treated wood).   Contact of treated wood used in the construction of structural components of outdoor play sets.   Wood used in home patios, porches, decks, docks, etc. Page 22 of 28   Woods treated with deck cleaners and bleaches.

Chromate Human Threshold Studies The critical human chromate study conducted by Nethercott et al. ( 1994) was an elicitation study of an identified chromate sensitized population. This therefore represents a specialized subpopulation of the general population. Although there are no methods available to predict which individuals have a particular propensity for developing ACD to chromate, Nethercott et al. ( 1994) identified their subpopulation from a group of 6000 patients who had been patch tested. Of this group, 102 were re patch tested to hexavalent chromate and 54 were confirmed to be chromate sensitive. This is therefore a significantly large population of sensitized individuals. The study had a good experimental design with several rounds of testing to not only reconfirm sensitivity but also to establish a dose response relationship for elicitation. The hexavalent chromium sensitized subpopulation was identified using the T. R. U. E. test, a sensitive patch test system for metals. The Nethercott et al. ( 1994) study was conducted under occlusion and can be considered to be conservative.

The Panel also reviewed other chromium studies. The Hansen et al. ( 2002; 2003) study was supportive but not large enough to be considered by itself as there was a smaller subpopulation of 17 hexavalent chromium sensitized individuals compared to the Nethercott et al. ( 1994) study. The study by Fowler et al. ( 1999) did not have a good experimental design and therefore cannot be considered as a critical study. Other studies cited were reviewed ( e. g. Hansen et al. 2002) and these are also supportive but have larger thresholds for elicitation of reactions. If designed for risk assessment purposes, a more appropriate study should have been undertaken over a period of at least four weeks, performed as an Open Test with repeated daily exposures.

The Critical Dose ( LOAEL)

The Panel identified the critical dose ( lowest observed adverse effect level) [ LOAEL] from the Nethercott et al. ( 1994) study should be 0.088ug/ cm2, which the Panel considered to still be a conservative safety level. This dose was in contrast to the 0.018ug/ cm2 suggested by the Agency. At 0.088ug/ cm2 reactions occurred in 4 out of 54 subjects tested, representing about 10% of the hexavalent chromium sensitized subpopulation and equivalent to a MET 10.

Uncertainty Factors Considerations Areas of uncertainty are considered when extrapolating the result of the critical dose to conditions relevant to the human exposure of interest. In this case, the Panel assessed human exposure to wood treated with hexavalent chromium. As presented previously by the Panel, the areas of uncertainty that have been identified for dermal risk assessment are: ( 1) interspecies variation; ( 2) intraspecies variation; ( 3) vehicle or product matrix effects; and ( 4) exposure considerations ( i. e., area of the body exposed, repeated exposures). For each of these four areas, a range of values less than 1 to as high as 10 were chosen. A summary of the values chosen for each UF is presented in Table 1. Page 23 of 28 Given that the Nethercott et al. study ( 1994) was conducted in humans and there was no need for an UF for interspecies variation, a value of 1 was assigned. As the subjects in Nethercott et al. ( 1994) were sensitized to hexavalent chromium, these individuals represent a subpopulation of the normal population, which would have a reaction to hexavalent chromium. This subpopulation is more sensitive to induction and subsequent elicitation to hexavalent chromium. Thus for intraspecies UF, a value of 1 was chosen as a conservative estimate.

Another major area for data extrapolation involves the matrix in which the chemical is present and how the individual was exposed ( Felter et al. 2002). The product matrix may affect the permeability of the skin such that there may be an enhancement or inhibition of the chemical penetration into the skin. This includes such things as irritants, penetration enhancers or inhibitors etc. The subjects in the Nethercott et al. ( 1994) study were tested to hexavalent chromium in occluded patches for a continuous 48 hour period. Patch testing with occlusion is designed to maximize penetration of the test substance. Thus for the matrix UF, a value of 0.1 was chosen to account for the more artificial situation in the Nethercott et al. ( 1994) study relative to actual exposures to wood treated with hexavalent chromium. A value of less than 1 was considered appropriate where the test matrix is likely to induce enhanced penetration and or augment the induction/ elicitation process relative to the matrix of environmental concern. As the Panel has presented in response to this and previous questions, uncertainty factors range from 1 to 10 ( Dourson et al. 1996). The Panel is cognizant their selection of an uncertainty factor less than 1 deviates from traditional uncertainty factor analyses. However, based on the conditions presented by the Panel, the Panel believed that an uncertainty factor less than 1 was appropriate for the matrix effect.

The Nethercott et al. ( 1994) exposure assessment provides for an estimate of the dermal exposure to the test substance in units of ug/ cm2. Such factors as site of body exposed, effect of occlusion, dermal integrity and certain environmental conditions were included in the Panel's determination of an exposure UF. The real world exposure to hexavalent chromium would consist of short term repeated dermal exposures. Typically, most potential dermal exposures would be prevented by barriers people would have as a part of their normal life, such as clothing, shoes, and towels. However, it is likely that hands and feet can come into short term and repeated contact to treated wood. On decks with built in furniture, people would have dermal exposure on the legs ( e. g. back of the thighs and calves) if they are wearing short pants. Furthermore the exposure to hexavalent chromium could be enhanced from routine cleaning of decking with alkaline based deck cleaning products. The Panel's determination of an exposure UF accounts for the differences between conditions in the Nethercott et al. ( 1994) study and those conditions likely to be encountered for ACC hexavalent chromium treated wood products. Thus, for the exposure UF a value ranging from 3 to 10 was chosen to account for real world repeated exposures that would occur to wood treated with hexavalent chromium. Page 24 of 28 Table 1. Summary of Uncertainty Factors Condition Uncertainty Factor Matrix/ vehicle 0.1 Interspecies variation 1 Intraspecies variation 1 Exposure 3 to 10 Estimated S RfD S RfD is a conservative estimate, with associated uncertainty, of a dermal exposure ( in units of ug/ cm2 ) that would not be expected to result in the induction of sensitization in the general population, including more responsive subpopulations ( Felter et al 2003). The minimum elicitation threshold ( MET 10%) is the concentration that would elicit an allergenic reaction in 10% of a sensitized population. As described previously, the Panel selected a MET 10 of 0.088 ug/ cm2 from the Nethercott et al. ( 1994) study for use in calculating a S RfD. Applying the uncertainty factors presented in Table 1 ( uncertainty factors ranged from 0.3 to 1), the S RfD calculated as specific to hexavalent chromium in treated wood ranged from 0.09 to 0.3 ug/ cm2 . This calculation is presented in Figure 1.

Figure 1. Calculation of S RfD 0.088 ug/ cm2 = 0.3 to 0.09 ug/ cm2 (. 1) ( 1) ( 3 to 10) [. 3 to 1]

The Panel's estimate of an S RfD should be protective against elicitation and therefore would also be protective of induction, as thresholds for induction are generally higher than those for elicitation ( Kimber et al., 2003). Although the Panel calculated a S RfD for hexavalent chromium in ACC treated wood, the Panel stressed that the Agency consider all data as part of a weight of evidence approach.

Panel Consideration Of Relationship Of Environmental Media And The Acceptable Area Dermal Dose During the public comments section of this FIFRA SAP meeting, the EPA, Office of Solid Waste and Emergency Response, presented comments on the relationship of environmental media ( e. g. soil, wood or water) and acceptable area dermal dose. While the Panel was not explicitly charged with responding to the issues presented by EPA OSWER, they decided that such issues require consideration by the FIFRA SAP. EPA OSWER's questions to the Panel and the Panel's response are presented below.

EPA OSWER Questions ( 1) Does the Panel agree that environmental matrix variables will influence the acceptable area dermal dose to induce/ elicit contact dermal sensitization in an individual when exposed to a Page 25 of 28 chemical incorporated in an environmental media?

( 2) Please describe how media specific characteristics have or do not have a substantial impact on determining an environmental acceptable dermal dose for a chemical incorporated in soil, wood, and water matrices.

Panel Response The FIFRA SAP agreed that matrix ( wood, soil, water) variables can influence the amount of compound available for penetration through the stratum corneum bilipid layers to have an effect. Thus, the use of uncertainty factors are applied to account for this variation. For example, wet cement is different from cement powder. Aqueous solutions can hydrate the stratum corneum, thereby increasing the rate of penetration of a compound through the skin. The pH of the matrix can also influence the penetration of a compound and change the charge of a compound. Fixation of a compound in an environmental medium can lower the bioavailability of that compound.

Media specific characteristics can play an important role in assessing the bioavailability of a compound. The physical/ chemical characteristics, including potential for the matrix to cause dermal irritation, may contribute to or decrease a compound's ability to cause dermal induction/ elicitation. Metal speciation of the compound in the matrix is also important, for example Cr ( VI) is more toxic than Cr ( III) and therefore poses a greater hazard. It is not important how much of a chemical is in the matrix but how much is leached out of it and available for exposure. All of these factors can influence how much material/ compound would be available to have an effect. Page 26 of 28 REFERENCES Agner T and T Menné. Individual predisposition to irritant and allergic contact dermatitis 173 187. In: Textbook of Contact Dermatitis. Eds. RJG Rycroft, T Menné, PJ Frosch, J P Lepoittevin. Third Edition. Springer Verlag Berlin Heidelberg 2001.

Bartek MJ, La Budde JA, Maibach HI: Skin permeability in vivo: comparison in rat, rabbit, pig and man. J Invest. Dermatol. 58, 114 123,1972.

Basketter, DA, L Blai, CA Ryan RJ Dearman, I Kimber, GF Gerberick, et al. 2000. Use of the local node assay for the estimation of relative contact allergy potency. Contact Dermatitis 42: 344 348.

Basketter DA, Lea LJ, Cooper KJ, Ryan CA, Gerberick GF, Dearman RF, Kimber I. 1999. Identification of metal allergens in the local lymph node assay. Am J Contact Dermat. Dec. 10( 4): 207 12.

Brancaccio RR, Brown LH, Chanh YT, Fogelman JP, Mafong EA, Cohen DE. Identification and quantification of para phenylenediamine in a temporary black henna tattoo. Am J Contact Derm. 2002. March 13( 1): 15 18.

Dourson, ML, SP Felterr and D. Robinson. 1996. Evolution of science based uncertainty factors in noncancer risk assessment. Regulatory Toxicology and Pharmacology 24: 108 120.

Epstein WI, Sullivan FJ, Ferguson EH. A histamine analogue that does not cause itching. Arch Dermatol. 1961. Aug. 84: 290 2.

Felter SP, Ryan CA, Basketter DA, Gilmour NJ, Gerberick GF. Application of the risk assessment paradigm to the induction of allergic contact dermatitis. Regul Toxicol Pharmacol. 2003 Feb. 37( 1): 1 10.

Felter SP, Robinson MK, Basketter DA, Gerberick GF. A review of the scientific basis for uncertainty factors for use in quantitative risk assessment for the induction of allergic contact dermatitis. Contact Dermatitis. 2002. 47( 5): 257 266.

Fowler JF Jr. Systemic contact dermatitis caused by oral chromium picolinate. Cutis. 2000 Feb. 65( 2): 116.

Freeman S. Shoe dermatitis. Contact Dermatitis. 1997 May 36( 5): 247 51.

Friedmann PS. The immunology of allergic contact dermatitis: the DNCB story. Adv Dermatol. 1990. 5: 175 95.

Gerberick, GF, MK Robinson, CA Ryan, RJ Dearman, I Kimber, DA Basketter, et al. 2001. Contact allergy potency: correlation of human and local lymph node assay data. Am J Contact Page 27 of 28 Dermatitis 12: 156 161.

Gerberick, GF, MK Robinson, SP Felter, IR White and DA Basketter. 2001. Understanding fragrance allergy using an exposure based risk assessment approach. Contact Dermatitis 45: 333 340.

Gerberick GF and MK Robinson. 2000. A skin sensitization risk assessment approach for evaluation of new ingredients and products. Am J Contact Dermatitis 11( 2): 65 73.

Griem, P, C Goebel and H Scheffler. 2003. Proposal for a risk assessment methodology for skin sensitization based on sensitization potency data. Regulatory Toxicology and Pharmacology 38: 269 290.

Hansonn H and Moller H Intacutaneous test reactions to tuberculin containing Merthiolate as a preservative. Scan J of Inf Diseases 1971. 3: 169.

Hjorth N 1981 Contact Dermatitis in children . Acta dermatovener ( Stockholm) Suppl: 36 39 Kimber I, Basketter DA, Butler M, Gamer A, Garrigue JL, Gerberick GF, Newsome C, Steiling W, Vohr HW. Classification of contact allergens according to potency: proposals. Food Chem Toxicol. 2003 Dec. 41( 12): 1799 809.

Kimber I and DA Basketter. 1997. Contact sensitization: a new approach to risk assessment. Hum Ecol Risk Assess 3: 385 395. Basketter DA, LJ Lea, A Dickens, D Briggs, I Pate, RJ Dearman, et al. 1999. A comparison of statistical approaches to the derivation of EC3 values from local lymph node assay dose responses. J. Appl. Toxicol 19: 261 266.

Marzulli , FN and Maibach HI. 1975. Relevance of animal models: the hexachlorophene story. In Animal Models in Dermatology ( Maibach HI, Ed. pp. 156 167. Churchill Livingstone, Edinburgh.).

Monteiro Riviere NA: The Integument. In The Biology of the Domestic Pig, ( Eds. W G Pond and HJ Mersmann), Cornell University Press, Ithaca, NY. Chapt. 14, 625 652, 2001.

Mortz CG, Lauridsen JM, Bindslev Jensen C, Andersen KE. 2002. Contact allergy and allergic contact dermatitis in adolescence prevalence measures and associations. The Odense Adolescence Cohort Study on Atopic Diseases and Dermatitis ( TOACS). Acta Derm Ven 82: 352 358.

National Institutes of Health. ( NICEATM. NIH Publication No: 99 449, 1999). The Murine Local Lymph Node Assay: A test method for assessing the allergic contact dermatitis potential of chemicals/ compounds: Results of an independent peer review evaluation coordinated by the interagency coordinating committee on the validation of alternative methods ( ICCVAM) and the National Toxicology Program for the Evaluation of Alternative Toxicological Methods. Page 28 of 28 Nethercott J et al., ( 1994) A Study of Chromium Induced Allergic Contact Dermatitis with 54 Volunteers: Implications for Environmental Risk Assessment, Occup. Environ. Med. 1994. 51: 371 380.

Nielsen NH and Menne T. Allergic contact sensitization in an unselected Danish population. The Glostrup Allergy Study, Denmark. Acta Derm Venereol. 1992 Nov. 72( 6): 456 60. [ Note: Erratum in: Acta Derm Venereol ( Stockh) 1993 Oct. 73( 5): 397]

Ryan, CA, LW Cruse, RA Skinner, RJ Dearman, I Kimber, and GF Gerberick. 2002. Examination of a vehicle for use with water soluble materials in the murine local lymph node assay. Food Chem Toxicol 40( 11): 1719 1725.

Sidbury and Storrs FJ. Prurigic eruption at the site of a temporary tattoo. American Journal of Contact Dermatitis 2000: 11: 182 183.

Stern AH, RE Bagdon, RE Hazen, and FN Marzulli. 1993. Risk assessment of the allergic dermatitis potential of environmental exposure to hexavalent chromium. J. Toxicology Environmental Health 40: 613 641.

Tregear, RT. Molecular movement, the permeability of skin. In Physical Functions of Skin, pp. 1 52, Academic Press, NY. 1966.

Wall LM and Gebauer KA. 1991. A follow up study of occupational skin disease in Western Australia. Contact Dermatitis 24: 241 243.

Wohrl S, Hemmer W, Focke M, Gotz M, Jarisch R. 2003. Pediatr Dermatol. Patch testing in children, adults, and the elderly: influence of age and sex on sensitization patterns. Mar Apr. 20( 2): 119 23.


August                                                   VPP Stakeholder Meeting                     Day-After Report
On August 28, 2017, the second Stakeholder Meeting took place immediately prior to the Voluntary Protection Programs Participants Association (VPPPA) National Conference, in New Orleans, Louisiana. A total of 29 attendees preregistered and approximately 60 people attended. This was the second Stakeholder Meeting on the recalibration of OSHA's Voluntary Protection Programs (VPP) so that it continues to represent safety and health excellence, leverages partner resources, further recognizes the successes of long-term participants, and supports smart program growth.
Doug Kalinowski, Director of the Directorate of Cooperative and State Programs (DCSP), welcomed the attendees, highlighted the objective of these gatherings, and provided a summary of what OSHA had learned from the first Stakeholder Meeting. While attendees actively shared ideas with OSHA during the first Stakeholder event on July 17 in Washington, DC, because of the proximity in time (and location) to the VPPPA conference, there was a greater diversity of attendees and a greater breadth of ideas proposed at this second event. OSHA posed four questions:
   * What changes can the Agency make to the VPP process and flow?
   * What changes should the Agency make to Corporate/Long term Participants?
   * What changes should the Agency make to the Special Government Employee (SGE) program?
   * What other ideas are there to enhance and improve VPP moving forward?
For this second Stakeholder event, DCSP requested that participants not repeat ideas that had been previously mentioned and instead focus on new recommendations. Common themes from participants included comments mirroring some areas already being considered by OSHA:
   * Looking at different levels of recognition. For example, Platinum statuses (with attendant additional expectations) for long-term participants with mature safety and health management systems who are committed to VPP safety culture.
   * Reconsidering the requirement that a Safety and Health professional has to be employed by the company for two years before he/she can apply to be an SGE.
   * Scheduling reapproval cycles for longer than three to five years - Process Safety Management (PSM) sites could go through reapprovals more frequently, while a smaller site would have fewer complex issues, so could wait longer for reapproval.
   * Reviewing the requirement that every VPP participant, as a part of their active engagement in the program, must designate at least one SGE.
Specific new recommendations included both procedural and policy changes (some recommendations include exact language from participants):
   * Exploring Changes to the Program to Facilitate Applications and Audits
         o Recommendation for OSHA to adopt the Modified Application Process (MAP) from Region VI. An SGE would go into an applicant site, do the evaluation and then hand over the paperwork to the OSHA audit team. This would shorten the audit time.
         o New applicants should have an SGE mentor who not only provides advice and support for the applicant, but may perform a pre-visit before the initial audit. OSHA should not have to go to the site if the applicant is not ready.
         o Do a follow-up survey six months after an audit to get some feedback.
         o Remove the requirement to get an Medical Access Order (MAO).

   * Use of SGEs
         o Use an SGE-only team for short audits (smaller companies, non-complicated processes).
         o Create an SGE clearing house  - Is there a place for SGEs to share information with each other, maybe a newsletter or a web page?
         o Provide SGEs with a longer time before start of audit to put them in a schedule and clear with their companies.
         o Revise the frequency of reapprovals and use of SGEs. Combine annual self-evaluation with one OSHA person and the company's SGEs.

   * Technology and Communications
         o Recommendation for OSHA pilot using web-based system and sync with OIS for report and audit submissions. (Note: DCSP is updating our internal data base, and we are currently in update testing mode. We are also looking at Regional databases)
         o Create a process to share Best Practices and the knowledge gained.  How to sell VPP?  How do you market the program?
         o Mechanisms to share SGE information and Best Practices, like a newsletter.  Something that corporations can share up through their ranks.
   * Out-of-the-Box Ideas
         o The current trend is for risk-based programs.  OSHA needs to change the criteria and requirements to be more risk-based.  Maybe focus on the smaller companies for Safety and Health Management Systems (SHMS) and VPP.
         o Move to a business plan model so that VPP is incorporated into part of a business process.
         o Insurance companies should add a line item to their audit and underwriting to take into account that a site has VPP status.
As a part of the Stakeholder meeting, one participant shared their VPP story:
      Our company has been in VPP for 22 years. We have had these conversations with our CEOs. Why we should be in VPP for long term? VPP is a brand. We used it 22 years ago to drive a conversation around safety excellence. We went from Merit to Star...Our performance has improved and have sustained it to world class level. We want to give back - we have 15 SGEs, we help other companies and IOSHA, and the State Governor.  When you think about the bottom line...VPP pays off...Look at all of the models and certifications...our people like the integrity, transparency and the partnership.

In addition, the docket is still open for comments until October 20, 2017. After that, we anticipate working to synthesize all of the ideas and proposals to reflect the full scope of stakeholder input.


[Federal Register Volume 82, Number 246 (Tuesday, December 26, 2017)]
[Rules and Regulations]
[Pages 60859-60860]
[FR Doc No: 2017-27676]

-----------------------------------------------------------------------

DEPARTMENT OF TRANSPORTATION

Federal Aviation Administration

14 CFR Part 97

[Docket No. 31168; Amdt. No. 3777]

Standard Instrument Approach Procedures, and Takeoff Minimums and
Obstacle Departure Procedures; Miscellaneous Amendments

AGENCY: Federal Aviation Administration (FAA), DOT.

ACTION: Final rule.

-----------------------------------------------------------------------

SUMMARY: This rule establishes, amends, suspends, or removes Standard
Instrument Approach Procedures (SIAPs) and associated Takeoff Minimums
and Obstacle Departure Procedures (ODPs) for operations at certain
airports. These regulatory actions are needed because of the adoption
of new or revised criteria, or because of changes occurring in the
National Airspace System, such as the commissioning of new navigational
facilities, adding new obstacles, or changing air traffic requirements.
These changes are designed to provide safe and efficient use of the
navigable airspace and to promote safe flight operations under
instrument flight rules at the affected airports.

DATES: This rule is effective December 26, 2017. The compliance date
for each SIAP, associated Takeoff Minimums, and ODP is specified in the
amendatory provisions.
    The incorporation by reference of certain publications listed in
the regulations is approved by the Director of the Federal Register as
of December 26, 2017.

ADDRESSES: Availability of matters incorporated by reference in the
amendment is as follows:

For Examination

    1. U.S. Department of Transportation, Docket Ops-M30, 1200 New
Jersey Avenue SE, West Bldg., Ground Floor, Washington, DC 20590-0001.
    2. The FAA Air Traffic Organization Service Area in which the
affected airport is located;
    3. The office of Aeronautical Navigation Products, 6500 South
MacArthur Blvd., Oklahoma City, OK 73169 or,
    4. The National Archives and Records Administration (NARA). For
information on the availability of this material at NARA, call 202-741-
6030, or go to: http://www.archives.gov/federal_register/code_of_federal_regulations/ibr_locations.html.

Availability

    All SIAPs and Takeoff Minimums and ODPs are available online free
of charge. Visit the National Flight Data Center at nfdc.faa.gov to
register. Additionally, individual SIAP and Takeoff Minimums and ODP
copies may be obtained from the FAA Air Traffic Organization Service
Area in which the affected airport is located.

FOR FURTHER INFORMATION CONTACT: Thomas J. Nichols, Flight Procedure
Standards Branch (AFS-420), Flight Technologies and Programs Divisions,
Flight Standards Service, Federal Aviation Administration, Mike
Monroney Aeronautical Center, 6500 South MacArthur Blvd., Oklahoma
City, OK 73169 (Mail Address: P.O. Box 25082, Oklahoma City, OK 73125)
Telephone:<PHONE_NUMBER>.

SUPPLEMENTARY INFORMATION:
    This rule amends Title 14 of the Code of Federal Regulations, Part
97 (14 CFR part 97), by establishing, amending, suspending, or removes
SIAPS, Takeoff Minimums and/or ODPS. The complete regulatory
description of each SIAP and its associated Takeoff Minimums or ODP for
an identified airport is listed on FAA form documents which are
incorporated by reference in this amendment under 5 U.S.C. 552(a), 1
CFR part 51, and 14 CFR part 97.20. The applicable FAA forms are FAA
Forms 8260-3, 8260-4, 8260-5, 8260-15A, and 8260-15B when required by
an entry on 8260-15A.
    The large number of SIAPs, Takeoff Minimums and ODPs, their complex
nature, and the need for a special format make publication in the
Federal Register expensive and impractical. Further, airmen do not use
the regulatory text of the SIAPs, Takeoff Minimums or ODPs, but instead
refer to their graphic depiction on charts printed by publishers of
aeronautical materials. Thus, the advantages of incorporation by
reference are realized and publication of the complete description of
each SIAP, Takeoff Minimums and ODP listed on FAA form documents is
unnecessary. This amendment provides the affected CFR sections and
specifies the types of SIAPs, Takeoff Minimums and ODPs with their
applicable effective dates. This amendment also identifies the airport
and its location, the procedure, and the amendment number.

Availability and Summary of Material Incorporated by Reference

    The material incorporated by reference is publicly available as
listed in the ADDRESSES section.
    The material incorporated by reference describes SIAPS, Takeoff
Minimums and/or ODPS as identified in the amendatory language for part
97 of this final rule.

The Rule

    This amendment to 14 CFR part 97 is effective upon publication of
each separate SIAP, Takeoff Minimums and ODP as Amended in the
transmittal. Some SIAP and Takeoff Minimums and textual ODP amendments
may have been issued previously by the FAA in a Flight Data Center
(FDC) Notice to Airmen (NOTAM) as an emergency action of immediate
flight safety relating directly to published aeronautical charts.
    The circumstances that created the need for some SIAP and Takeoff
Minimums and ODP amendments may require making them effective in less
than 30 days. For the remaining SIAPs and Takeoff Minimums and ODPs, an
effective date at least 30 days after publication is provided.
    Further, the SIAPs and Takeoff Minimums and ODPs contained in this
amendment are based on the criteria contained in the U.S. Standard for
Terminal Instrument Procedures (TERPS). In developing these SIAPs and
Takeoff Minimums and ODPs, the TERPS criteria were applied to the
conditions existing or anticipated at the affected airports. Because of
the close and immediate relationship between these SIAPs, Takeoff
Minimums and ODPs, and safety in air commerce, I find that notice and
public procedure under 5 U.S.C. 553(b) are impracticable and contrary
to the public interest and, where applicable, under 5 U.S.C. 553(d),
good cause exists for making some SIAPs effective in less than 30 days.
    The FAA has determined that this regulation only involves an
established body of technical regulations for which frequent and
routine amendments are necessary to keep them operationally current.
It, therefore--(1) is not a ``significant regulatory action'' under
Executive Order 12866; (2) is not a ``significant rule'' under DOT
Regulatory Policies and Procedures (44 FR 11034; February 26,1979); and
(3) does not warrant preparation of a regulatory evaluation as the
anticipated impact is so minimal. For the same reason, the FAA
certifies that this amendment will not have a significant economic
impact on a substantial

number of small entities under the criteria of the Regulatory
Flexibility Act.

List of Subjects in 14 CFR Part 97

    Air traffic control, Airports, Incorporation by reference,
Navigation (air).

    Issued in Washington, DC, on December 1, 2017.
John S. Duncan,
Director, Flight Standards Service.

Adoption of the Amendment

    Accordingly, pursuant to the authority delegated to me, Title 14,
Code of Federal Regulations, Part 97 (14 CFR part 97) is amended by
establishing, amending, suspending, or removing Standard Instrument
Approach Procedures and/or Takeoff Minimums and Obstacle Departure
Procedures effective at 0901 UTC on the dates specified, as follows:

PART 97--STANDARD INSTRUMENT APPROACH PROCEDURES

0
1. The authority citation for part 97 continues to read as follows:

    Authority:  49 U.S.C. 106(f), 106(g), 40103, 40106, 40113,
40114, 40120, 44502, 44514, 44701, 44719, 44721-44722.

0
2. Part 97 is amended to read as follows:

Effective 4 January 2018

Sacramento, CA, Sacramento Intl, ILS OR LOC RWY 34L, Amdt 7F

Effective 1 February 2018

Anchorage, AK, Ted Stevens Anchorage Intl, ILS RWY 15, Amdt 6D
Anchorage, AK, Ted Stevens Anchorage Intl, RNAV (GPS) RWY 7L, Amdt
2D
Anchorage, AK, Ted Stevens Anchorage Intl, RNAV (GPS) RWY 15, Amdt
2D
Anchorage, AK, Ted Stevens Anchorage Intl, RNAV (GPS) Y RWY 7R, Amdt
4D
Anchorage, AK, Ted Stevens Anchorage Intl, RNAV (RNP) RWY 33, Orig-C
Anchorage, AK, Ted Stevens Anchorage Intl, RNAV (RNP) Z RWY 7R,
Orig-C
Klawock, AK, Klawock, KLAWOCK TWO, Graphic DP
Prattville, AL, Prattville--Grouby Field, RNAV (GPS) RWY 9, Amdt 2E
Helena/West Helena, AR, Thompson-Robbins, RNAV (GPS) RWY 17, Amdt 1
Helena/West Helena, AR, Thompson-Robbins, RNAV (GPS) RWY 35, Amdt 1
Helena/West Helena, AR, Thompson-Robbins, VOR RWY 35, Amdt 1
Merced, CA, Merced Rgnl/Macready Field, RNAV (GPS) RWY 12, Orig-B
Red Bluff, CA, Red Bluff Muni, RNAV (GPS) RWY 33, Orig-A
Pahokee, FL, Palm Beach Co Glades, RNAV (GPS) RWY 18, Amdt 1
Pahokee, FL, Palm Beach Co Glades, RNAV (GPS) RWY 36, Amdt 1
Pahokee, FL, Palm Beach Co Glades, Takeoff Minimums and Obstacle DP,
Amdt 2
Pahokee, FL, Palm Beach Co Glades, VOR/DME-A, Orig-A, SUSPENDED
Albany, GA, Southwest Georgia Rgnl, ILS OR LOC RWY 4, Amdt 13
Albany, GA, Southwest Georgia Rgnl, LOC BC RWY 22, Amdt 8A, CANCELED
Albany, GA, Southwest Georgia Rgnl, RNAV (GPS) RWY 4, Amdt 1C
Albany, GA, Southwest Georgia Rgnl, RNAV (GPS) RWY 16, Amdt 1B
Albany, GA, Southwest Georgia Rgnl, RNAV (GPS) RWY 22, Amdt 1B
Albany, GA, Southwest Georgia Rgnl, RNAV (GPS) RWY34, Amdt 2B
Albany, GA, Southwest Georgia Rgnl, Takeoff Minimums and Obstacle
DP, Orig-A
Albany, GA, Southwest Georgia Rgnl, VOR RWY 16, Amdt 27B
Independence, KS, Independence Muni, ILS OR LOC RWY 35, Amdt 2
Independence, KS, Independence Muni, RNAV (GPS) RWY 17, Amdt 2
Independence, KS, Independence Muni, RNAV (GPS) RWY 35, Amdt 1
Independence, KS, Independence Muni, VOR-A, Amdt 3
Pittsburg, KS, Atkinson Muni, RNAV (GPS) RWY 17, Amdt 3
Pittsburg, KS, Atkinson Muni, RNAV (GPS) RWY 22, Amdt 1C
Pittsburg, KS, Atkinson Muni, RNAV (GPS) RWY 35, Amdt 3
Pittsburg, KS, Atkinson Muni, Takeoff Minimums and Obstacle DP, Amdt
2
Topeka, KS, Philip Billard Muni, Takeoff Minimums and Obstacle DP,
Amdt 1A
Saginaw, MI, MBS Intl, ILS OR LOC RWY 5, Amdt 11
Saginaw, MI, MBS Intl, ILS OR LOC RWY 23, Amdt 5
Saginaw, MI, MBS Intl, RNAV (GPS) RWY 5, Amdt 2
Saginaw, MI, MBS Intl, RNAV (GPS) RWY 14, Amdt 2
Saginaw, MI, MBS Intl, RNAV (GPS) RWY 23, Amdt 2
Saginaw, MI, MBS Intl, RNAV (GPS) RWY 32, Amdt 2
Saginaw, MI, MBS Intl, VOR RWY 14, Amdt 14
Glencoe, MN, Glencoe Muni, RNAV (GPS) RWY 13, Orig-A
St Joseph, MO, Rosecrans Memorial, Takeoff Minimums and Obstacle DP,
Amdt 8
Lovelock, NV, Derby Field, RNAV (GPS) RWY 2, Amdt 1A
Prineville, OR, Prineville, RNAV (GPS) RWY 10, Amdt 2
Prineville, OR, Prineville, RNAV (GPS) RWY 28, Amdt 2
Norfolk, VA, Norfolk Intl, ILS OR LOC RWY 5, Amdt 26C
Norfolk, VA, Norfolk Intl, ILS OR LOC RWY 23, Amdt 8
Norfolk, VA, Norfolk Intl, RNAV (GPS) RWY 14, Amdt 1
Norfolk, VA, Norfolk Intl, RNAV (GPS) Z RWY 5, Amdt 2
Norfolk, VA, Norfolk Intl, RNAV (GPS) Z RWY 23, Amdt 2
Norfolk, VA, Norfolk Intl, RNAV (RNP) Y RWY 5, Amdt 1
Norfolk, VA, Norfolk Intl, RNAV (RNP) Y RWY 23, Amdt 1
Norfolk, VA, Norfolk Intl, VOR RWY 14, Amdt 3

    RESCINDED: On November 20, 2017 (82 FR 55047), the FAA published
an Amendment in Docket No. 31161, Amdt No. 3771 to Part 97 of the
Federal Aviation Regulations under section 97.37. The following
entry for Buckland, AK, and Billings, MT, effective December 7,
2017, are hereby rescinded in its entirety:

Buckland, AK, Buckland, Takeoff Minimums and Obstacle DP, Amdt 2
Billings, MT, Billings Logan Intl, Takeoff Minimums and Obstacle DP,
Amdt 7A

[FR Doc. 2017-27676 Filed 12-22-17; 8:45 am]
 BILLING CODE 4910-13-P


[Federal Register: August 4, 2009 (Volume 74, Number 148)]
[Notices]
[Page 38656-38657]
[DOCID:fr04au09-60]

-----------------------------------------------------------------------

DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. FDA-2008-N-0582]

Kim C. Hendrick: Debarment Order

AGENCY:  Food and Drug Administration, HHS.

ACTION:  Notice.

-----------------------------------------------------------------------

SUMMARY:  The Food and Drug Administration (FDA) is issuing an order
under the Federal Food, Drug, and Cosmetic Act (the act) permanently
debarring Kim C. Hendrick, M.D., from providing services in any
capacity to a person that has an approved or pending drug product
application. We base this order on a finding that Dr. Hendrick was
convicted of a felony under Federal law for conduct relating to the
development or approval, including the process for development or
approval, of a drug product, and for conduct otherwise relating to the
regulation of a drug product under the act. After being given notice of
the proposed permanent debarment and an opportunity to request a
hearing within the timeframe prescribed by regulation, Dr. Hendrick
failed to request a hearing. Dr. Hendrick's failure to request a
hearing constitutes a waiver of his right to a hearing concerning this
action.

DATES:  This order is effective August 4, 2009.

ADDRESSES:  Submit applications for special termination of debarment to
the Division of Dockets Management (HFA-305), Food and Drug
Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852.

FOR FURTHER INFORMATION CONTACT:  Robert Hummel, Sr., Division of
Compliance Policy (HFC-230), Office of Enforcement, Office of
Regulatory Affairs, Food and Drug Administration, 5600 Fishers Lane,
Rockville, MD 20857,<PHONE_NUMBER>.

SUPPLEMENTARY INFORMATION:

I. Background

    Section 306(a)(2)(A) of the act (21 U.S.C. 335a(a)(2)(A)) requires
debarment of an individual if FDA finds that the individual has been
convicted of a felony under Federal law for conduct relating to the
development or approval, including the process for development or
approval, of any drug product. Section 306(a)(2)(B) of the act requires
debarment of an individual if FDA finds that the individual has been
convicted of a felony under Federal law for conduct otherwise relating
to the regulation of any drug product under the act.
    On September 11, 2007, the U.S. District Court for the Eastern
District of Michigan accepted Dr. Hendrick's guilty plea and entered
judgment against him for one count of mail fraud, a federal felony
offense under 18 U.S.C. 1341. This offense was committed when Dr.
Hendrick was a licensed physician practicing medicine in the State of
Michigan. Dr. Hendrick agreed to participate in the clinical research
trial for Augmentin XR, including its use in the treatment of adults
with Acute Bacterial Sinusitis (ABS). As part of his participation in
the clinical study, he agreed to conduct the study in conformity with
the protocol established by GlaxoSmithKline and to comply with FDA
regulations. He also agreed to take X-rays, before and after treatment,
of persons he diagnosed with ABS, and to have an independent
radiologist analyze these and issue reports regarding the X-rays.
    Dr. Hendrick admitted that instead of having an independent
radiologist review the X-rays and issue reports, he allowed certain X-
rays to be sent in batch form, which was a direct violation of the
protocol. Further, he did not verify the purported signatures of the
independent radiologist reports and, instead, failed to disclose to
GlaxoSmithKline and/or FDA that the signatures were unverified and
possibly

forged, with the intent to create a false impression of a state of
facts. Dr. Hendrick was paid by GlaxoSmithKline approximately $116,800
in X-ray fees for his participation in the clinical research trial. In
so doing he caused a check to be mailed to him through the Postal
Service at the direction of GlaxoSmithKline as partial payment for his
participation in the clinical trial for the purpose of executing the
scheme to defraud.
    As a result of this conviction, FDA sent Dr. Hendrick by certified
mail on May 4, 2009, a notice proposing to permanently debar him from
providing services in any capacity to a person that has an approved or
pending drug product application. The proposal was based on a finding,
under section 306(a)(2)(A) and (a)(2)(B) of the act, that Dr. Hendrick
was convicted of a felony under Federal law for conduct relating to the
development or approval of a drug product, including the process for
development or approval of a drug product, and conduct otherwise
relating to the regulation of a drug product under the act. The
proposal also offered Dr. Hendrick an opportunity to request a hearing,
providing him 30 days from the date of receipt of the letter in which
to file the request, and advised him that failure to request a hearing
constituted a waiver of the opportunity for a hearing and of any
contentions concerning this action. Dr. Hendrick did not request a
hearing and has, therefore, waived his opportunity for a hearing and
any contentions concerning his debarment (21 CFR part 12).

II. Findings and Order

    Therefore, the Acting Director, Office of Enforcement, Office of
Regulatory Affairs, under section 306(a)(2)(A) and (a)(2)(B) of the
act, and under authority delegated to the Acting Director (Staff Manual
Guide 1410.35), finds that Dr. Hendrick has been convicted of a felony
under Federal law for conduct relating to the development or approval
of a drug product, including the process for development or approval,
of a drug product, and conduct otherwise relating to the regulation of
a drug product under the act.
    As a result of the foregoing finding, Dr. Hendrick is permanently
debarred from providing services in any capacity to a person with an
approved or pending drug product application under sections 505, 512,
or 802 of the act (21 U.S.C. 355, 360b, or 382), or under section 351
of the Public Health Service Act (42 U.S.C. 262), effective (see DATES)
(see sections 306(c)(1)(B) and (c)(2)(A)(ii) and 201(dd) of the act (21
U.S.C. 335a(c)(1)(B) and (c)(2)(A)(ii), and 321(dd)). Any person with
an approved or pending drug product application who knowingly employs
or retains as a consultant or contractor, or otherwise uses the
services of Dr. Hendrick, in any capacity, during Dr. Hendrick's
permanent debarment, will be subject to civil money penalties (section
307(a)(6) of the act (21 U.S.C. 335b(a)(6))). If Dr. Hendrick, during
his period of debarment, provides services in any capacity to a person
with an approved or pending drug product application, he will be
subject to civil money penalties (section 307(a)(7) of the act). In
addition, FDA will not accept or review any abbreviated new drug
applications submitted by or with the assistance of Dr. Hendrick during
his permanent debarment (section 306(c)(1)(B) of the act).
    Any application by Dr. Hendrick for special termination of
debarment under section 306(d)(4) of the act should be identified with
Docket No. FDA-2008-N-0582 and sent to the Division of Dockets
Management (see ADDRESSES). All such submissions are to be filed in
four copies. The public availability of information in these
submissions is governed by 21 CFR 10.20(j).
    Publicly available submissions may be seen in the Division of
Dockets Management between 9 a.m. and 4 p.m., Monday through Friday.

    Dated: July 15, 2009.
Alyson L. Saben,
Acting Director, Office of Enforcement, Office of Regulatory Affairs.
[FR Doc. E9-18621 Filed 8-3-09; 8:45 am]

BILLING CODE 4160-01-S


[Federal Register: February 8, 2006 (Volume 71, Number 26)]
[Notices]
[Page 6464-6465]
[DOCID:fr08fe06-72]

-----------------------------------------------------------------------

DEPARTMENT OF ENERGY

Federal Energy Regulatory Commission

[Docket No. RP06-192-000]

Southern Natural Gas Company; Notice of Proposed Changes in FERC
Gas Tariff

February 2, 2006.
    Take notice that on January 31, 2006, Southern Natural Gas Company
(Southern) tendered for filing as part of its FERC Gas Tariff, Seventh
Revised Volume No. 1, the following revised sheets to become effective
March 1, 2006:

Sixth Revised Sheet No. 26
Fifth Revised Sheet No. 27
Fifth Revised Sheet No. 28
Forty-Fifth Revised Sheet No. 29
Twenty-Seventh Sheet No. 30

    Any person desiring to intervene or to protest this filing must
file in accordance with Rules 211 and 214 of the Commission's Rules of
Practice and Procedure (18 CFR 385.211 and 385.214). Protests will be
considered by the Commission in determining the appropriate action to
be taken, but will not serve to make protestants parties to the
proceeding. Any person wishing to become a party must file a notice of
intervention or motion to intervene, as appropriate. Such notices,
motions, or protests must be filed in accordance with the provisions of
Section 154.210 of the Commission's regulations (18 CFR 154.210).
Anyone filing an intervention or protest must serve a copy of that
document on the Applicant. Anyone filing an intervention or protest on
or before the intervention or protest date need not serve motions to
intervene or

protests on persons other than the Applicant.
    The Commission encourages electronic submission of protests and
interventions in lieu of paper using the ``eFiling'' link at http://www.ferc.gov.
 Persons unable to file electronically should submit an

original and 14 copies of the protest or intervention to the Federal
Energy Regulatory Commission, 888 First Street, NE., Washington, DC
20426.
    This filing is accessible on-line at http://www.ferc.gov, using the

``eLibrary'' link and is available for review in the Commission's
Public Reference Room in Washington, DC. There is an ``eSubscription''
link on the Web site that enables subscribers to receive e-mail
notification when a document is added to a subscribed docket(s). For
assistance with any FERC Online service, please e-mail
<EMAIL_ADDRESS>or call<PHONE_NUMBER> (toll free). For

TTY, call<PHONE_NUMBER>.

Magalie R. Salas,
Secretary.
[FR Doc. E6-1703 Filed 2-7-06; 8:45 am]

BILLING CODE 6717-01-P


Comment Info: =================

General Comment:After smoking nearly 1 pack of cigarettes a day, for close to twenty years, I have drastically cut back to nearly zero cigarettes.  I had tried various forms of smoking cessation in the past with no avail.  Between patches, gums, lozenges, and prescription medication, I had spent hundreds of dollars, and plenty of time and countless side affects on my body.  Nothing was ever able to match the need of what a cigarette could give me.
Two years ago, a friend of mine introduced me to electronic cigarettes, which contradictory to the name, were not nearly as harmful to the body as tobacco, but with the same feeling use of a cigarette.  I was able to gradually "swap" my regular tobacco cigarettes for my vaporizer.  I now feel better, breath easier, and know that I can control the level of nicotine that I am putting into my body.
These devices are in no way any more harmful than tobacco, alcohol, or 90% of the OTC medications that are available in a convenience or grocery store on every street corner in america.
 A 75 day comment period is insufficient time for the vaping industry and the wider vaping community to comment on the proposed deeming regulations. I would respectfully request that the period for comment be extended to 180 days.