National Institutes of Health
National Institute of
Environmental Health Sciences
P. O. Box 12233
Research Triangle Park, NC 27709
September 22, 2008
Mr. Jerry A. Cook
Chemical Products Corporation
P.O. Box 2470
Cartersville, Georgia 30120
Dear Mr. Cook:
On behalf of the National Institute of Environmental Health Sciences (NIEHS), National Institutes of Health (NIH), we are responding to your January 5, 2007, Request for Reconsideration, as amended on March 1, 2007, submitted for Chemical Products Corporation (CPC) under the NIH's “Guidelines for Ensuring the Quality of Information Disseminated to the Public” (NIH Guidelines). Your request appealed the National Toxicology Program's (NTP's) December 22, 2006 decision regarding the CPC's Request for Correction of Information regarding the NTP Technical Report on anthraquinone (TR 494). A summary of the background information on the study that culminated in TR 494, the process we used to consider the appeal and the conclusions reached are provided as follows:
The basis of the appeal on TR 494 NIH Publication Number 05-3953 (National Toxicology Program Technical Report on Anthraquinone [CAS#84-65-1] is that the mutagenic properties of the test material are dependent on its route of synthesis. Anthraquinone is used in the dye, pigment and pulp and paper industries as well as a bird repellent. NTP considered its risk to human health through occupational or environmental exposures as part of its mission “to evaluate agents of public health concern by developing and applying tools of modern toxicology and molecular biology,. . . to provide toxicological evaluations on substances of public health concern, . . . [and to] use scientific data in making decisions about the safety of agents routinely encountered by humans . . . [with the goal of] provid[ing] the best science possible for preventing disease due to human exposures.”
On May 31, 2006 you submitted a Request for Correction of Information, amended on July 13 and July 17 in compliance with NIH's Guidelines for Ensuring the Quality of Information Disseminated to the Public. That request was for the withdrawal of NTP's Technical Report 494 Publication Number 05-3953. Dr. Allen Dearry, Interim Associate Director of NTP, denied that request on December 22, 2006. However, Dr. Dearry did acknowledge that there was a misstatement made at the December 2004 meeting and, thus, the meeting minutes were amended in light of the concern you brought to our attention.
On January 5, 2007, you appealed Dr. Dearry's decision in compliance with HHS “Information Quality Guidelines for Information Disseminated to the Public.” On March 1, 2007 you submitted an Addendum to the Request for Reconsideration dated January 5, 2007.
In considering your request, we reviewed the NIH and HHS “Guidelines for Ensuring the Quality of Information Disseminated to the Public” (http://aspe.hhs.gov/infoquality/Guidelines/index.shtml and http://aspe.hhs.gov/infoquality/Guidelines/NIHinfo2.shtml), read the draft and final Technical Report 494: Toxicology and Carcinogenesis Studies of Anthraquinone [CAS No. 84-65-1], your May 31, 2006 Request for Correction of Information and the July 13 and July 17, 2006 addenda, the December 22, 2006 NTP response from Dr. Allen Dearry, your January 5, 2007 Request for Reconsideration and your March 1, 2007 Addenda. Furthermore, we reviewed the records related to handling of samples in this matter. Those records indicated that Battelle, the analytical chemistry laboratory, shipped 2 g of 4 different lots of anthraquinone to BioReliance, the study laboratory, on June 1, 2004. NTP materials are occasionally shipped overnight. The samples were labeled by lot number, the standard information that is included on samples. BioReliance received the materials on June 2, 2004. You were sent this record previously. Battelle sent NTP the Bulk Chemical Shipment Report dated June 22, 2004 verifying it had shipped samples of the 4 anthraquinone lots to BioReliance on June 1, 2004. This document also was provided by NTP to you in NTP's Response to the Request for Correction. BioReliance confirmed assignment of each test article aliquot number to the correct lot of anthraquinone. You were sent this document previously. The review of these records provided assurance that the samples were handled appropriately and in conformity with routine procedures.
We consulted with NIH and HHS staff familiar with the Information Quality process. The NIEHS Office of the Deputy Director and the NIEHS Office of Policy, Planning and Evaluation assisted in these efforts.
Request that TR 494 be Withdrawn and Rewritten
We concluded that there is no evidence of noncompliance with NIH and HHS Information Quality Guidelines for TR 494. We would like to clarify that the NIH and HHS Guidelines do not address meetings of advisory committees. The members of the Technical Reports Review Subcommittee (TRRS) act as independent scientists and are free to raise scientific issues for discussion at their meetings.
1. On December 9, 2004, the TRSS vacated the restrictions placed upon their conclusions at their February 17-18, 2004 meeting. The reasons for this determination are as follows:The TRRS restriction of some of its conclusions about anthraquinone in February 2004 was based on a concern about manufacturing process not sample purity. The Subcommittee decided to precisely identify the material in terms of the manufacturing process used to produce it. The recommendation was made to limit the TR 494 to “anthracene-derived anthraquinone.” The Summary Minutes of the NTP Board of Scientific Counselors (BSC) held on June 29, 2004 indicate that Board members Roberts, Klaunig, Boekelheide, Storer and Piegorsch discussed in open meeting the fact that the title “anthracene-derived anthraquinone “ (as added at the Feb. 17-18, 2004 TRRS meeting) had the unintended outcome of suggesting that all other sources of anthraquinone were safe. (Summary Minutes, BSC, June 29, 2004, p. 6-8). When TR 494 was brought back to the TRRS at its meeting on December 9, 2006, the TRRS decided to “ . . .absolutely have no reference to anthracene-derived anywhere in the conclusion.”(Transcript, TRRS, December 9, 2007, p. 151). The Summary Minutes of the Technical Reports Review Subcommittee meeting on December 9, 2007 further record the vote:The motion to retain the amended title was defeated by two yes votes in favor . . . and seven no votes. Dr. Birt then moved and Dr. Elwell seconded that anthracene-derived be removed from the title. The motion was approved by seven yes votes and two no votes.(Summary Minutes, TRRS, December 9, 2004, p 9 )
2. The TR 494 test article assayed for bacterial mutagenicity using the Ames test showed no evidence of mutagenic activity in this assay. (Technical Report 494, Table E3, p. 252. See also Results, p. 73; Discussion and Conclusions, p. 91; Table E3 was also referenced in this context in the Dr. Dearry's Final Response to Mr. Cook's Request for Correction of Information, December 22, 2006, p. 1). As reported in TR 494 and presented at the Subcommittee meeting in February, 2004, the NTP found that irrespective of the manufacturing process for anthraquinone, the major urinary metabolite is 2-hydroxyanthraquinone which is more mutagenic in the Ames test than 9-nitroanthracene at comparable doses (Technical Report 494, Tables E8 and E11, pp. 257-258 and 261, respectively; and also found in the February 17-18, 2004 TRRS minutes, p.9, available at http://ntp.niehs.nih.gov/go/15849). Based upon data in TR 494 and shown in the table below, 2-hydroxyanthraquinone is approximately 7-fold more mutagenic than 9-nitroanthracene at 100 µg.
|Comparison of Mutagenicity in Salmonella typhimurium T98|
To compare the relative mutagenicity of 9-nitroanthracene and 2-hydroxyanthraquinone, induced revertants were calculated for each trial by subtracting the zero dose revertants from the revertants observed at 100 µg, averaging the induced mutants, and dividing by the dose.
3. Bulk chemical shipment reports recommended that anthraquinone be stored at room temperature in amber glass vials. TR 494 describes in Appendix J the in-depth purity analyses of anthraquinone using several methods at different times. As Dr. Dearry explained in his December 22, 2006 letter: “[t]he purity analyses described above and in Appendix J of TR 494 were all conducted on aliquots of the anthraquinone test article lot 5893 stored at room temperature. Each of these analyses conducted at different times over a 10-year period gave purity values for the anthraquinone test article: 1995: 99.9% by GC-FID using the area % approach, 2002:99.9% by GC-FID using the area % approach; 2002: 99.5 % by HPLC-UV using the area % approach and, 2004: 99.8% by both GC-FID and HPLC-UV using the method of standard addition.”
4. The misstatement by Dr. Smith that the sample assayed in the genetic toxicology testing was frozen rather than maintained at room temperature has been corrected by electronic and text erratum at page 20, column 2, paragraph 3 of TR 494. As reported to you previously in Dr, Dearry's letter, storing the anthraquinone at room temperature (approximately 25 degrees C) in amber glass bottles is the recommended storage condition.
5. While the documents released by NIH FOI No. 33011 indicate variability in the colors of samples, color is determined subjectively by the technician receiving the sample. As stated by Dr. Dearry in his letter to you and also provided in response to the FOIA request, the laboratory confirmed assignment of the test aliquot numbers to the mutagenicity assay results.
We concluded that there is no evidence of noncompliance with NIH and HHS Information Quality Guidelines for TR 494. Thank you for your comments.
Thank you for your comments.
Joyce M. Martin
Director, Office of Science Policy