The Honorable John Shimkus

Mr. Cook, you testified that the regulatory level for barium is an arbitrary value, set in a time when there were no toxicology studies. Is it your opinion that there are other substances that are regulated using evaluations based on outdated or incomplete science?

Yes, I am of the strong opinion that a substantial number of other substances are also being regulated based upon bad science. In fulfilling Chemical Products Corporation's product stewardship obligations, I have found over-regulation based on bad science for both of the materials I have investigated. Not only have I encountered a resolute disregard for sound science at IRIS and failure by EPA to relax regulatory levels for barium consistent with sound science, but I have also encountered egregious scientific misconduct at the National Toxicology Program to support bad science concerning another of our products, Anthraquinone. I believe that it is beyond the realm of possibility that only the two substances I have evaluated are being over-regulated to the detriment of
U.S. manufacturers. Anthraquinone, another of Chemical Products Corporation's products, is a useful and benign industrial chemical. In the early-1990s, NTP obtained an Anthraquinone sample for animal testing which was contaminated with a potent mutagen. NTP did not become aware of this contamination until years after animal testing had been completed. Anthraquinone is not a mutagen; this fact was only acknowledged by NTP as a result of a Request for Correction and a subsequent Request for Reconsideration I submitted in 2003 under the Information Quality Act. In December 2004, highly significant false information was presented to peer reviewers to finally gain approval of the conclusions advocated by NTP staff. In 2006, NTP staff fabricated a document to support NTP's rejection

Page 1 of 5of my Request for Correction of the final Technical Report 494.

Anthraquinone has been an important raw material for the production of textile dyes for more than a century; more recently it has also found a use in the U.S. paper industry as a catalyst to increase pulp yields and thereby decrease energy usage and paper production costs. Anthraquinone has not been manufactured in the U.S. since the early 1980's; Chemical Products Corporation purchases imported Anthraquinone as a dry powder and formulates it into a stable slurry that our paper industry customers can easily store and pump into their papermaking processes. NTP incorrectly declared that Anthraquinone was a mutagen, based upon its own positive mutagenicity assay of a single contaminated sample, when it published the results of its animal studies in 1999. Even though several earlier published studies had reported that Anthraquinone is not mutagenic, NTP chose to dismiss those studies without investigating the issue. NTP reported in 1999 that it had found clear evidence that Anthraquinone caused cancer in rats and mice. When NTP's startling assertions were published for public review and comment in early 1999, I investigated further and found that a specific potent mutagenic contaminant had been identified in some Anthraquinone samples. This information was contained in the
International Uniform Chemical Information Database and also in EPA's TSCA file for Anthraquinone. The identified mutagenic contaminant came from an obsolete manufacturing process which is no longer practiced anywhere in the world. I obtained a sample of NTP's test material and had it analyzed in late 1999; I found this same potent mutagen in NTP's test material. NTP had unwittingly obtained contaminated test material produced by an obsolete, dirty manufacturing process; no commercial Anthraquinone anywhere in the world has been contaminated with this

Page 2 of 5potent mutagen for nearly two decades. I immediately informed NTP of

my findings. NTP took no action to correct its technical report for more than three years after it was informed that it had tested a contaminated Anthraquinone material. When the Information Quality Act came into effect in late 2002, I immediately submitted a Request for Correction which was promptly denied by NTP. I then submitted a Request for Reconsideration in 2003; it was adjudicated by the Deputy Director of the National Institute of Environmental Health Sciences. He concluded that the mutagenic contamination in the Anthraquinone sample tested by NTP made it impossible to be certain what had caused the cancers in the test animals; he withdrew NTP's 1999 Technical Report 494 on Anthraquinone in September 2003. In 2004 NTP staff issued a revised technical report which acknowledged that Anthraquinone is not a mutagen and that a mutagenic
contaminant had been found in the material that NTP had fed to rats and mice. However, NTP still insisted that its test results proved that Anthraquinone was solely responsible for the cancers found in rats and mice. The revised technical report was peer reviewed first in February 2004 and then reopened for additional peer review in December of 2004. In December 2004, NTP's present Associate Director orchestrated the removal of the restrictions placed in Technical Report 494 by the February 2004 peer review panel. “New” highly significant false information was presented to the peer review panel in December without the requisite prior publication for public review and comment. This false information was incorporated into the final technical report along with the same conclusions that had been in the 1999 technical report – those conclusions allowed NTP staff to proceed with publication of a paper characterizing Anthraquinone as a carcinogen in March 2005.

Page 3 of 5NTP Technical Report 494 on Anthraquinone was published in

September 2005. California's Proposition 65 statute requires that any chemical identified as a carcinogen in a NTP technical report be added to the Proposition 65 list under the “Authoritative Bodies Mechanism”. Thus, U.S. papermakers have been faced with the dilemma of weighing the energy and cost savings achieved by using Anthraquinone in their pulping process against the risk that their myriad paper products entering California might be challenged under the Proposition 65 regulation. We feel certain that sales of our Anthraquinone product have been adversely impacted by the bad science contained in NTP Technical Report 494. Multiple Freedom of Information Act requests and a Freedom of Information Act appeal have permitted me to compile documentary evidence demonstrating that the new information presented to the December 2004 peer review panel and incorporated into the published NTP Technical Report 494 is false. By May 2006 I had determined that Technical Report 494 was fatally flawed; I submitted a Request for Correction under the Information Quality Act seeking its withdrawal. My Request was denied by NTP. I then submitted a Request for Reconsideration at the end of 2006; my submission included additional documents demonstrating conclusively that Technical Report 494 contains highly significant false information. My submission was adjudicated by the Director of the Office of Science Policy at the National Institute of Environmental Health Sciences. After an 18 month delay, my Request for Reconsideration was denied on September 22, 2008; the documentation I submitted had been ignored. I turned to the Office of Research Integrity for help and discovered
that ORI does not concern itself with evidence of scientific misconduct at NTP. Director John E. Dahlberg of the Division of Investigative Oversight stated in a letter to me dated January 16, 2009, “I also note that ORI does

Page 4 of 5not have authority to conduct the investigation you request. Our role is

limited by departmental policy to conducting oversight review of investigations conducted by the institutions where the alleged misconduct took place.” Thus, as long as NTP does not enforce scientific integrity by investigating alleged misconduct by its staff, ORI will not concern itself
with scientific misconduct at NTP. NIEHS and NTP Director Linda S. Birnbaum has refused to investigate. I have twice nominated Anthraquinone to NTP's Office of Chemical Nomination and Selection in an effort to obtain a valid scientific study to replace NTP's egregiously flawed existing technical report. These letters are attached as an appendix. I respectfully request this Subcommittee's assistance in obtaining a valid scientific evaluation of Anthraquinone to correct NTP Technical Report 494. Safeguards would certainly need to be put into place at NTP to insure the scientific validity of a new study
conducted there. In summary, I cannot imagine that I happened to stumble upon the only two instances of needlessly burdensome regulation based on bad science. I feel quite certain that many companies in many different industries in the United States are suffering under unnecessary regulatory burdens based upon the same indifference to sound science and lack of scientific integrity.

APPENDIX
Two letters submitted to NTP's Office of Chemical Nomination and Selection nominating Anthraquinone for a valid scientific study to replace NTP Technical Report 494 Each letter is 7 pages – a total of 14 pages appended.

Page 5 of 5December 5, 2008

Office of Chemical Nomination and Selection National Toxicology Program/NIEHS MD EC-31 P.O. Box 12233 Research Triangle Park, NC 27709

Subject: Nomination of Anthraquinone, CAS # 84-65-1,

for study - Replacement of scientifically untenable NTP Technical Report 494

Dear Sir or Madam:
The National Toxicology Program has demonstrated a strong interest in naturally occurring quinones containing the anthraquinone ring, as a class. Anthraquinone, CAS #84-6-1, also known as 9,10- anthraquinone or 9,10-dioxoanthracene, is the parent compound of this class.

Unfortunately, animal studies conducted by NTP in the mid-1990s employed an Anthraquinone test article contaminated with mutagenic 9-nitroanthracene (anthraquinone is not a mutagen). Uncorrected scientific misconduct on the part of individuals within NTP has resulted in publication of scientifically 

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untenable conclusions regarding the carcinogenic activity of Anthraquinone in NTP Technical Report 494 (TR494) 1 . Innes et al. (1969) 2 found no carcinogenic activity for Anthraquinone in mice, and Huff et al. (1996) 3 predicted that Anthraquinone would not be carcinogenic based upon structural characteristics of its primary metabolite, 2- hydroxyanthraquinone; the test article employed in the
TR494 studies was so contaminated as to confound the interpretation of the results of those studies.

The carcinogenic potential of anthraquinone was evaluated by Innes et al. (1969) in two strains of mice. At 7 days of age and continuing through 28 days of age, groups of 18 male or 18 female B6C3F 1 or B6AKRF 1 mice received 464 mg anthraquinone/kg body weight daily by gavage. After 28 days, these groups received 1,206 ppm anthraquinone in feed for 18 months. No increase in tumors in either strain of mice was associated with administration of anthraquinone.

1 Toxicology and Carcinogenesis Studies of Anthraquinone (CAS No. 84-65-1) In F344/N Rats and B6C3F 1 Mice (Feed Studies); National Toxicology Program Technical Report 494; NIH publication 05-3953. 2 Innes, J.R.M., Ulland, B.M., Valerio, M.G., Petrucelli, L., Fishbein, L., Hart, E.R., Pallotta, A.J., Bates, R.R., Falk, H.L., Gart, J.J., Klein, M., Mitchell, I., and Peters, J. (1969). Bioassay of pesticides and industrial chemicals for tumorigenicity in mice: A preliminary note. J. Natl. Cancer Inst. 42, 1101-1114. 3 Huff, James; Weisburger, Elizabeth; and Fung, Victor A.; “Multicomponent Criteria for Predicting Carcinogenicity: Dataset of 30 NTP Chemicals”; Environmental Health Perspectives Supplements Volume 104; Number S5; October 1996. Page 3 December 5, 2008

Huff et al. (1996) predicted that Anthraquinone would not be carcinogenic based upon multicomponent criteria for predicting carcinogenicity, including structural considerations of Anthraquinone's primary metabolite, 2- hydroxyanthraquinone.

In the mid-1990s NTP conducted animal tests using an Anthraquinone test article manufactured by the nitric acid
oxidation of anthracene which was contaminated with mutagenic 9-nitroanthracene (Anthraquinone is not a mutagen). A 1999 TR494, which incorrectly declared the test substance, Anthraquinone, to be a mutagen, and concluded that there was clear evidence of carcinogenic activity in both male and female mice, was withdrawn in September 2003 because it failed to recognize the mutagenic contamination in the non-mutagenic test article 4

.

A substantially revised February 2004 TR494 contained the same conclusions as the withdrawn 1999 report, but included new information that (1) “pure” anthraquinone is not mutagenic, (2) the TR494 test article was contaminated with mutagenic 9-nitroanthracene, (3) the TR494 test article had been found to be mutagenic to Salmonella typhimurium strains TA98 and TA100 without metabolic activation 5 , and

4 HHS Information Quality Web Site. Information Requests for Corrections and HHS' Responses. Item 5. 2003. http://aspe.hhs.gov/infoQuality/requests.shtml 5 Butterworth, B.E., Mathre, O.B., and Ballinger, K.; “The preparation of anthraquinone used in the National Toxicology Program cancer bioassay was contaminated with the mutagen 9-nitroanthracene”; Mutagenesis 16, 169-177; 2001. Page 4 December 5, 2008

(4) the primary anthraquinone metabolite, 2- hydroxyanthraquinone, had been found by NTP to be mutagenic to TA98 without S9 activation in a 2003 preincubation mutagenicity assay, thus, being cited as the mutagen potentially responsible for the observed tumors. NTP concealed an earlier negative preincubation assay for 2- hydroxyanthraquinone 6 7 in conflict with its finding. Nevertheless, on February 18, 2004 the NTP's Technical Reports Review Subcommittee restricted the conclusions in TR494 to “anthracene-derived anthraquinone”, in reference to the obsolete TR494 test article production method which contributed mutagenic contaminants. No anthracene-derived Anthraquinone has been available commercially within the U.S. for many years.

In an unprecedented action, NTP commissioned further mutagenicity testing in the summer of 2004 after theFebruary 2004 peer review. To remove the “anthracenederived anthraquinone” restriction from the conclusions presented in the final TR494, NTP presented a new negative mutagenicity assay conducted in the summer of 2004 to NTP's December 9, 2004 Technical Reports Review

6 Tikkanen, L.; Matsushima, T.; Natori, S.; “Mutagenicity of anthraquinones in the Salmonella preincubation test”; Mutation Research; 116(3-4):297-304; March 1983. This paper also presents a negative assay for Anthraquinone which NTP ignored in 1999, but later had to accept as accurate. 7 Page 91 in TR494 states specifically that Tikkanen et al. (1983) did not perform testing without S9; in fact, negative preincubation assays in strains TA98, TA100 and TA 2637 were reported without S9 activation. Page 5 December 5, 2008

Subcommittee for “Sample A07496”as a conclusive demonstration that the TR494 test article, “Anthraquinone, Lot 5893”, had not been mutagenic after all. False information was provided to the peer review panel to overcome a concern expressed by one of the reviewers that mutagenic impurities might have decomposed during the more than 7 years which had elapsed since the conclusion of
the animal studies 8 . This new information was incorporated
into the final TR494 and the “anthracene-derived anthraquinone” limitation on the conclusions was removed.

Investigation has revealed that “Sample A07496” has been falsely presented as being an aliquot of the TR494 test article “Anthraquinone Lot 5893”. The Test Article Receipt and Transfer Report from BioReliance Testing Laboratories (BTL), the laboratory which performed the 2004 mutagenicity assay for NTP, shows that “Sample A07496” was not labeled “Anthraquinone, Lot 5893”, the TR494 test article, when it was received by BTL and assigned sample number A07496 9

.

In a remarkable perpetuation of scientific misconduct, NIEHS's September 22, 2008 Information Quality response confirmed that any aliquot of the TR494 test article would be labeled “Anthraquinone, Lot 5893” when shipped from the

8 HHS Information Quality Web Site. Information Requests for Corrections and HHS' Responses. Item 28 at section c. http://aspe.hhs.gov/infoQuality/requests.shtml 9 BioReliance Testing Laboratories Test Article Receipt and Transfer Reports; Documents Responsive to NIH FOI No. 33011; 7 pages; attachment to item c2. at Item 28 in http://aspe.hhs.gov/infoQuality/requests.shtml Page 6 December 5, 2008

Battelle Columbus Laboratories test article repository, but ignored the BTL Test Article Receipt and Transfer Report submitted to document the fact that “Sample A07496” was not so labeled when it was received by BTL for mutagenicity

assay 10 . Enforcement of the HHS Information Quality Guidelines appears to be moribund; NIEHS is currently turning a blind eye to scientific misconduct within its own
ranks.

Scientific misconduct on the part of NTP staff resulted in the existing NTP Technical Report 494 (TR494) being approved at its third peer review on December 9, 2004.
A ccepted scientific and ethical standards have not been enforced within NTP, as demonstrated by NIH's September 22, 2008 Information Quality response regarding deficiencies in TR494 as described above. Materially false information remains an integral part of TR494, and the accuracy of the prediction by Huff et al. (1996) that anthraquinone is not a carcinogen has yet to be tested in a scientifically-sound study.

We respectfully submit that the February 18, 2004 NTP Technical Reports Review Subcommittee was correct in its de facto determination that mutagenic impurities confounded the results of the TR494 animal studies (hence, therestriction of the conclusions presented to only “anthracenederived anthraquinone”). We nominate Anthraquinone, CAS

10 HHS Information Quality Web Site. Information Requests for Corrections and HHS' Responses. Item 28 at section c. http://aspe.hhs.gov/infoQuality/requests.shtml Page 7 December 5, 2008

# 84-65-1, produced by either of the dominant present industrial manufacturing processes – the Friedel-Crafts process or the Diels-Alder process - for study to obtain a scientifically-sound determination of the carcinogenic potential of anthraquinone containing only biologically innocuous impurities.

Chemical Products Corporation markets Anthraquinone to the pulp and paper industry.

Sincerely,

Jerry A. Cook Technical Director

### November 24, 2009

Office of Chemical Nomination and Selection National Toxicology Program/NIEHS MD EC-31 P.O. Box 12233 Research Triangle Park , NC 27709

Subject: Nomination of Anthraquinone, CAS # 84-65-1, for long-term bioassay – NTP Technical Report 494 has been recognized as deficient

Dear Sir or Madam:
The international scientific community has recognized that NTP Technical Report 494 does not represent sound science. Professor Alan R. Boobis et al. state in the October 2009 issue of Toxicologic Pathology

, “The data for anthraquinone are considered suspect because other carcinogenicity studies were negative, and the NTP carcinogenicity study used a batch of 

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# C orporation 102 Old Mill Road S E P.O. Box 2470 Cartersville, Georgia 30120-1692

Phone: 770-382-2144 Fax: 770-386-6053 e-mail: jcook@cpc-us.comNomination of Anthraquinone for study to correct Technical Report 494

Page 2 November 25, 2009


### anthraquinone contaminated with the potent mutagen 9-nitroanthracene at a level of 1,200 ppm (Butterworth, Mathre, and Ballinger 2001). (A purified sample was negative in the Ames test.) Certainly, it can be said that the material used by the NTP was mutagenic...” (“A DataBased Assessment of Alternative Strategies for Identification of Potential Human Cancer Hazards”; Alan R. Boobis, Samuel M. Cohen, Nancy G. Doerrer, Sheila M. Galloway, Patrick J. Haley, Gordon C. Hard, Frederick G. Hess, James S. Macdonald, Stéphane Thibault, Douglas C. Wolf and Jayne Wright; Toxicol Pathol; 37; 714-732; 2009 - at page 719 ).

The deficient NTP carcinogenicity study referenced by Professor Boobis et al. is reported in NTP Technical Report 494 (TR494); this report contains a negative mutagenicity assay falsely
attributed to the contaminated NTP test material. This false assay was presented as “new information” at the third peer review of this technical report on December 9, 2004 and resulted in acceptance of scientifically untenable conclusions by the Technical Reports Review Subcommittee on that date. Documentary evidence (obtained through a FreedomNomination of Anthraquinone for study to correct Technical Report 494

Page 3 November 25, 2009



### of Information Act appeal ) of misconduct on the part of NTP scientists Dr. Richard Irwin, Dr. Cynthia Smith, and Dr. John Bucher was willfully ignored by Dr. Joyce
Martin when she denied Chemical Products Corporation's Request for Reconsideration under the DHHS Information Quality Guidelines in September
2008.

Rigorous scientific analysis led Professor Boobis et al. to conclude, “Certainly, it can be said that the material used by the NTP was mutagenic”

, based on knowledge of the potency of the 9-
nitroanthracene contaminant. Professor Boobis at Imperial College London has published over 200 original research papers and is an Editor-in-Chief of Food and Chemical Toxicology. He was deputy chairman of the U.K. Advisory Committee on Pesticides (1999-2002) and is a member of a number of national and international grant review and advisory committees, including the UK Committees on Carcinogenicity and on Toxicity. He was awarded the Order of the British Empire for his work on the risk assessment of pesticides in 2003. He is an Honorary Member of EUROTOX, a Fellow of the British Toxicology Society, and a Fellow of the Institute ofNomination of Anthraquinone for study to correct Technical Report 494

Page 4 November 25, 2009


### Biology. Fortunately, a commitment to research integrity and correction of the scientific record exists within the international scientific community.

Professor Boobis et al. have provided an essential correction of the scientific record regarding Anthraquinone. The REACH Substance Information Exchange Forum (SIEF), of which I am a member, will disregard the conclusions presented in TR494 when preparing the REACH registraion dossier for anthraquinone on the basis that they are scientifically untenable. The European Chemicals Agency has been formally requested by the REACH SIEF to confirm the SIEF's determination that TR494 does not represent sound science.

The final TR494, published in September 2005, also misrepresents the scientific record concerning the mutagenicity of anthraquinone's primary metabolite, 2-hydroxyanthraquinone. After the 1999
TR494 had been withdrawn because “the presence of this contaminant [9-nitroanthracene] raises doubt as to the effect(s) of anthraquinone itself, or its metabolites, and confounds interpretation of the NTP studies...” (NIEHSNomination of Anthraquinone for study to correct Technical Report 494

Page 5 November 25, 2009


### Deputy Director Samuel H. Wilson's determination in September 2003), NTP conducted a mutagenicity assay of 2-hydroxyanthraquinone which purported to show that it was mutagenic to Salmonella typhimurium TA98 without metabolic activation. Thus, Dr. Irwin at al. presented 2-hydroxyanthraquinone as a direct acting mutagen produced in situ which could be responsible for the carcinogenicity observed in the TR494 studies through a mechanism inv olving mutagenicity. A c onflicting earlier negative preincubation assay of 2-hydroxyanthraquinone in TA98 without metabolic activation was withheld from peer reviewers and its existence is specifically denied in TR494; a t page 91, TR494 incorrectly states that Tikkanen et al. (1983) did not perform mutagenicity assays in the absence of S9 metabolic activation; in fact, Tikkanen et al. (1983) reported negative assays of 2-hydroxyanthraquinone in 3 strains - TA98, TA100
and TA 2637 – in the absence of S9 metabolic activation ( Tikkanen, L.; Matsushima, T.; Natori, S.; Mutagenicity of anthraquinones in the Salmonella preincubation test; Mutation Research ; 116(3-4):297- 304; March 1983).Nomination of Anthraquinone for study to correct Technical Report 494

Page 6 November 25, 2009



### An additional negative assay of 2- hydroxyanthraquinone in TA98 without metabolic activation was reported by Butterworth et al. in August 2004 ( Butterworth, B.E., Mathre, O.B., and Ballinger, K.E., Adalsteinsson, O. ; Contamination is a Frequent Confounding Factor in Toxicology Studies with Anthraquinone and Related Compounds; Int J
Toxicol ; 23; No. 5; 335-344; 2004).

In summary, Anthraquinone is not a mutagen, but the test article employed in the studies conducted by NTP in the mid-1990s contained biologically significant mutagenic contamination – it was found to be mutagenic to Salmonella typhimurium strains TA98 and TA100 without S9 metabolic activation (less so with metabolic activation). Misconduct on the part of NTP scientists resulted in publication of a final technical report which contains a false negative mutagenicity for the TR494 test article and misrepresents the scientific record concerning the mutagenicity of the primary anthraquinone metabolite, 2-hydroxyanthraquinone. The international scientific community has recognized that the conclusions presented in TR494 are scientifically untenable.Nomination of Anthraquinone for study to correct Technical Report 494

Page 7 November 25, 2009



### We reiterate our nomination of anthraquinone, CAS # 84-65-1, for long-term bioassay by NTP. The
failure of NIEHS to withdraw TR494 after being presented conclusive documentation that it is scientifically deficient demonstrates that NIEHS and NTP lack a functioning mechanism to insure research integrity. Thus, a repeated anthraquinone study should be overseen by an impartial scientific body outside of NIEHS.

Anthraquinone, CAS #84-65-1, should be chosen by NTP's Board of Scientific Counselors for study in 2010 for the same reasons that it was chosen by NTP for study in the early 1990s.

Sincerely,

Jerry A. Cook Technical Director