OFFICE OF PREVENTION, PESTICIDES, AND TOXIC SUBSTANCES UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON, D. C. 20460 May 22, 2002 MEMORANDUM SUBJECT: Lactofen  Report of the Cancer Assessment Review Committee FROM: Sanjivani Diwan Executive Secretary Cancer Assessment Review Committee Health Effects Division ( 7509C)

TO: Robert Fricke, Toxicologist Reregistration Branch 2 Health Effects Division ( 7509C)

The Cancer Assessment Review Committee met on January 23, 2002 to evaluate the carcinogenic potential of Lactofen. Attached please find the Final Cancer Assessment Document.

cc: K. Dearfield R. Hill Y. Woo J. Pletcher CANCER ASSESSMENT DOCUMENT EVALUATION OF THE CARCINOGENIC POTENTIAL OF LACTOFEN ( SECOND REVIEW) P. C. CODE: 128888 FINAL REPORT 21 May 2002 TXR # 0050184 CANCER ASSESSMENT REVIEW COMMITTEE HEALTH EFFECTS DIVISION OFFICE OF PESTICIDE PROGRAMS ______________________________________________________________________________ LACTOFEN CANCER ASSESSMENT DOCUMENT FINAL REPORT DATA PRESENTATION: Robert F. Fricke DOCUMENT PREPARATION: Robert F. Fricke COMMITTEE MEMBERS IN ATTENDANCE: ( Signature indicates concurrence with the assessment unless otherwise stated). List the Committee members Karl Baetcke William Burnam Kerry Dearfield Vicki Dellarco Richard Hill Nancy McCarroll Esther Rinde Joycelyn Stewart Clark Swentzel Linda Taylor LACTOFEN CANCER ASSESSMENT DOCUMENT FINAL REPORT Duplicate Signature Page ( FAX Copy) contains Yin Tak Woo's signature LACTOFEN CANCER ASSESSMENT DOCUMENT FINAL REPORT CONTENTS Executive Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . iv I. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 II. Background Information . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 III. Studies Reviewed by the CARC . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 IV. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 V. Cancer Classification . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 Attachments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 LACTOFEN CANCER ASSESSMENT DOCUMENT FINAL REPORT EXECUTIVE SUMMARY On January 23, 2002, the Cancer Assessment Review Committee ( CARC) met to reevaluate the cancer classification of lactofen in light of the conclusions [ TXR No. 014590] of the Mechanism of Toxicity Assessment Review Committee ( MTARC). The MTARC concluded that lactofen acts via a mechanism involving peroxisome proliferation as a result of activation of peroxisome proliferatoractivated receptor   ( PPAR  ) activation.

On January 17, 2001, the MTARC reviewed the merits of the toxicological data supporting peroxisome proliferation as the proposed mode of action for lactofen. Based on the weight ofevidence from guideline, as well as non guideline mechanistic studies, the MTARC concluded that there are sufficient data to classify lactofen as a non genotoxic hepatocarcinogen in rodents with peroxisome proliferation being a plausible mode of action.

This conclusion is based on the results of a special study in rodents which evaluated the biochemical and histopathological markers for peroxisome proliferation in livers ( MRID No.: 45283904). In mice there was a dose dependent increase in relative liver weights and liver enzyme activities used as biomarkers for peroxisome proliferation. Histological evaluations of the livers also revealed dosedependent increases in nuclear enlargement, cytoplasmic eosinophilia, hypertrophy and peroxisomal staining. These results not only show dose dependent increases in the parameters measured, but more importantly, a non linear dose response curve.

The NOAEL for this study was established at 2 ppm ( 0.3 mg/ kg/ day), based on increased activities of liver enzymes and increased incidence of liver histopathological findings at the LOAEL of 10 ppm ( 1.5 mg/ kg/ day).

Based on the liver tumors seen in both sexes of the mouse, and in consideration of the mechanistic data provided, the CARC concluded that lactofen should be classified as likely to be carcinogenic to humans at high enough doses to cause these biochemical and histopathological effects in livers of rodents but unlikely to be carcinogenic at doses below those causing these changes. Further the margin of exposure ( MOE) approach should be used for estimating human cancer risk, using a NOAEL of 2 ppm ( 0.3 mg/ kg/ day). LACTOFEN CANCER ASSESSMENT DOCUMENT FINAL REPORT I. INTRODUCTION On January 23, 2002, the Cancer Assessment Review Committee ( CARC) met to evaluate the conclusions of the Mechanism of Toxicity Assessment Review Committee ( MTARC) and to reevaluate the cancer classification of lactofen.

The data were presented by Dr. Robert F. Fricke of Reregistration Branch 2 of the Health Effects Division.

II. BACKGROUND INFORMATION Initial evaluation of the carcinogenic potential of lactofen took place on February 12, 1987 by the Carcinogenicity Peer Review Committee ( CPRC). Based on liver tumors seen in both sexes of mice, the CPRC concluded that lactofen should be classified as a B2 ( Probable Human Carcinogen) [ Attachment 1, Peer Review of Lactofen, Memo from J. Hauswirth to R. Mountfort, dated April 08, 1987, TXR No. : none]. Subsequent quantitative evaluation of the tumor data resulted in a Q 1* of 0.119 ( mg/ kg/ day) 1 in human equivalents for lactofen.

The Registrant ( Valent U. S. A.) submitted a petition ( MRID No. 45160301) requesting that risk assessment for lactofen be based on the MOE approach rather than using a Q 1*. The petition reviewed and summarized earlier data submissions, which supported peroxisome proliferation as the mechanism of action of lactofen.

On January 17, 2001, the MTARC reviewed the merits of the toxicological data supporting peroxisome proliferation as the proposed mode of action for lactofen. Based on the weight ofevidence from guideline, as well as non guideline mechanistic studies, the MTARC concluded that peroxisome proliferation is the mode of activation of lactofen [ Attachment 2, TXR No. 014590]. The MTARC also recommended that the CARC reevaluate the carcinogenicity classification of lactofen in light of the mode of action of lactofen as it pertains to the formation of liver tumors in mice.

III. STUDIES REVIEWED BY THE CARC The CARC reviewed summaries of the mechanistic studies as presented in the report of the MTARC . These studies included several non guideline in vitro and in vivo mechanism studies that characterized lactofen induced peroxisome proliferation.

Of the studies evaluated by the CARC, a non guideline study, in which biochemical and histopathological markers for peroxisome proliferation were measured in both rat and mouse livers ( MRID No.: 45283904), was considered most pertinent.

In this study, male and female mice were exposed to technical lactofen at 0, 2, 10, 50, or 250 ppm or to nafenopin ( positive control for peroxisome proliferation) at 500 ppm. After 7 weeks of treatment, the mice were sacrificed and the livers examined biochemically and pathologically. Dose dependent increases were observed ( Table 1) in relative liver weights, catalase and acyl CoA oxidase, and carnitine acetyl transferase ( females only) was observed. Histological evaluations LACTOFEN CANCER ASSESSMENT DOCUMENT FINAL REPORT ( Table 2) also revealed dose dependent increases in nuclear enlargement, cytoplasmic eosinophilia, hypertrophy and peroxisomal staining in livers. Nafenopin treated mice showed significant increases in all of the parameters measured.

These results not only show dose dependent increases in the parameters measured ( see above), but more importantly, a non linear dose response curve with a NOAEL. A NOAEL of 2 ppm ( 0.3 mg/ kg/ day using a conversion factor of 1 ppm = 0.15 mg/ kg/ day) was based on increases in relative liver weight ( male mice), carnitine acetyl transferase and palmitoyl CoA oxidase ( female mice) at a LOAEL of 10 ppm ( 1.5 mg/ kg/ day).

The NOAEL for this study was established at 2 ppm ( 0.3 mg/ kg/ day), based on increased activities of liver enzymes and increased incidence of liver histopathological findings at the LOAEL of 10 ppm ( 1.5 mg/ kg/ day).

IV. CONCLUSIONS:

The CARC concluded that a NOAEL of 0.3 mg/ kg/ day should be used to calculate the MOE. The MOE approach should be used for quantification of risk and the acceptable MOEs will be risk management decisions.

The CARC also concluded that a NOAEL of 0.3 mg/ kg/ day can be used for chronic and reproductive NOAELs. The NOAEL of 0.3 mg/ kg/ day is also protective of carcinogenic effects, which has a NOAEL of 10 ppm ( 1.5 mg/ kg/ day).

Chronic Toxicological Effects: From the results of a chronic feeding study in the dog, the NOAEL was established at 40 ppm ( 0.8 mg/ kg/ day), based on increased incidence of proteinaceous casts in the kidneys and statistically significant decreases in the absolute weight of thyroid and adrenal glands in males at the LOAEL of 200 ppm ( 3.96 mg/ kg/ day). The chronic RfD is established at 0.008 mg/ kg/ day ( 100x uncertainty factor).

Reproductive Toxicity: Based on the results of a two generation reproduction study in the rat, the NOAELs for parental, reproductive and offspring toxicity were all established at 50 ppm ( 2.6 mg/ kg/ day). Effects observed at the LOAEL of 500 ppm ( 26 mg/ kg/ day) included parental toxicity consisting of deaths, decreased body weight/ gain and increased incidence of histopathological findings, reproductive toxicity consisting of decreased male fertility, and offspring toxicity consisting of decreased pup body weight, decreased liver weights, and decreased spleen weights.

Carcinogenicity: Based on the results of a carcinogenicity study in the mouse, the carcinogenic effects were seen at doses greater than 10 ppm ( 1.5 mg/ kg/ day) and there was an increased incidence of non neoplastic and neoplastic liver masses seen in both sexes at the LOAEL of 50 ppm ( 7.5 mg/ kg/ day). LACTOFEN CANCER ASSESSMENT DOCUMENT FINAL REPORT V. CANCER CLASSIFICATION In accordance with the EPA Draft Guidelines for Carcinogen Risk Assessment ( July 1999), based on the liver tumors seen in both sexes of the mouse, and in consideration of the mechanistic data provided, the CARC concluded that lactofen should be classified as " likely to be carcinogenic to humans at high enough doses to cause these biochemical and histopathological changes in the liver of rodents but unlikely to be carcinogenic to humans below those doses causing these changes." Furthermore, the CARC recommended using an MOE approach for estimating human cancer risk. Therefore, a NOAEL of 2 ppm ( 0.3 mg/ kg/ day) should be used for calculating the MOE.

Table 1: Evaluation of Liver Parameters in Male and Female Mice After 7 Weeks of Treatment with Lactofen ( Technical, 78.2%; pure, 99.8%) or Nafenopin ( NAF)

Sex Dose ( ppm) Relative Liver Wt ( g/ 100 g) Catalase Carnitine Acetyl Transferase Palmitoyl CoA Oxidase Male 0 3.9 0.34 2.92 3.1 2 ( Tech) 4.2 0.49 2.96 5.2 10 ( Tech) 5.0*** 0.41 3.87*** 6.1 50 ( Tech) 4.5** 0.49 3.27 7.2 250 ( Tech) 7.7*** 0.94*** 3.1 40***

250 ( pure) 6.2*** 0.93*** 6.77*** 29***

Female 0 4.0 0.22 3.21 2.1 2 ( Tech) 4.1 0.26 3.71 4.3 10 ( Tech) 4.4 0.21 4.27** 11***

50 ( Tech) 4.7** 0.30* 4.68*** 13***

250 ( Tech) 6.7*** 0.69*** 4.53** 35***

250 ( pure) 7.3*** 00.44*** 7.77*** 27***

Male 500 NAF 12.8*** 0.70*** 8.31*** 49***

Female 500 NAF 11.9*** 0.76*** 9.94*** 38***

** p

0.01; *** p

0.001 1 Data summarized from Tables 5 and 6 of MRID No. 452383904. LACTOFEN CANCER ASSESSMENT DOCUMENT FINAL REPORT Table 2: Evaluation of Histopathological Parameters in Male and Female Mice After 7 Weeks Treatment with Lactofen ( Technical, 78.2%; Pure, 99.8%) or Nafenopin ( NAF) 1 Sex Dose ( ppm) Nuclear Enlargement Cytoplasmic Eosinophilia Hypertrophy Peroxisomal Staining Male 0    +

2 ( Tech)    +

10 ( Tech) ± ± ± +

50 ( Tech) + + + ++

250 ( Tech) + ++ ++ ++

250 ( Pure) ++ +++ ++ ++

Female 0    +

2 ( Tech)    +

10 ( Tech) ±   +

50 ( Tech) + + + ++

250 ( Tech) ++ ++ ++ +++

250 ( Pure) ++ +++ +++ ++

Male 500 NAF ++ +++ +++ +++

Female 500 NAF +++ +++ +++ +++

1 Data summarized from Table 7 and 8 of MRID No. 452383904. LACTOFEN CANCER ASSESSMENT DOCUMENT FINAL REPORT Attachment 1 Peer Review of Lactofen, September 12, 1987 LACTOFEN CANCER ASSESSMENT DOCUMENT FINAL REPORT I(

APR 8, 1987 [ TXR NO. 0050971] Subject: Peer Review of Lactofen From: Judith W. Hauswirth, Ph. D. Acting Section Head, Section VI Toxicology Branch/ HED ( TS 769C)

To: Richard Mountfort Product Manger # 23 Registration Division ( TS 767C)

The Toxicology Branch Peer Review Ccumittee met on February 12, 1987 to discuss and evaluate the weight ot the evidence on Lactofen, with particular reference to its oncogenic potential.

. Individuals in Attendance:

1. Peer Review Committee: ( Signatures indicate concurrence with peer review unless otherwise stated).

Theodore M. Farber William L. Burnan Reto Engler John A. Quest Esther Rinde Judith W. Hauswirth Richard Levy Louis Kasza Richard Hill Robert Beliles 2. Reviewers:( Non panel members responsible for data presentation, signatures indicate technical accuracy of panel report).

Joycelyn E. Stewart ( Reviewer)

Albin B. Kocialski ( Section Head) LACTOFEN CANCER ASSESSMENT DOCUMENT FINAL REPORT Bernice Fisher ( Reviewer)

Allen Katz ( Reviewer)

3. Peer Review Members in Absentia: ( Committee members who were not able to attend the discussion; signatures indicate concurrence with the overall conclusions of the Committee.)

Anne Barton Stephen Johnson Diane Beal B. Material Reviewed:

The material available tor review consisted of DER's for mouse oncogenicity and lifetime rat feeding studies on Lactofen, summary tables on incidence of neoplastic and non neoplastic lesions tor both studies, historical control data on pertinent tumors and Toxicology branch " One Liners".

C. Background Information:

Registration for Cobra . Herbicide ( a. i., Lactofen) is being sought by PPG Industries. The herbicide is to be used pre and/ or post emergence for control of susceptible broadleaf weeds affecting soybeans, cotton and peanuts. There are no present or previous tolerances in the USA. Lactofen is supplied as a manufacturing use concentrate containing 60% a. i. and as an emulsifiable concentrate containing 2 pounds per gallon a. i.

The chemical name of Lactofen is 1( carboethyoxy) ethyl 5( 2 chloro 4 ( tri fluoromethyl) phenoxy) 2 nitrobenzoate. Lactofen is also referred to as PPG 844 in this report.

D. Evaluation of Oncogenicity Studies:

Oncogenicity study in mice PPG 844 Technical. Hazleton Laboratories America, Vienna, VA. Study No. 250 152, August 29, 1985. Accession No. 073848.

1. Mouse Oncogenicity Study:

a. Discussion of Study:

Lactofen ( 78.26% pure) was administered in the diet to groups of 60 male and 60 female Crl: CD 1 ( CP,)( SR) mice at levels of 10, 50 and 2 50 ppm for 78 weeks. The study was conducted by Hazleton Laboratories, LACTOFEN CANCER ASSESSMENT DOCUMENT FINAL REPORT America and was dated ( 3 August 29, 1985. The incidence of hepatocellular neoplasm is summarized in the following table.

Incidence of Hepatocellular Neoplasms Dose ( ppm)

Tumor Type 0 10 50 250 Males hepatocellular adenoma 2/ 50( 4) 2/ 50( 4) 5/ 50 ( 10) 6/ 50 ( 12) carcinoma 7/ 50( 15)** 7/ 50( 15) 1O/ 50 ( 20) 15/ 50( 30)* total tumor 9/ 50( 18)** 9/ 50( 18) 15/ 50( 31) 21/ 50( 42)** bearing animals females Hepatocellular adenoma. 0/ 5( 7( 0) 2/ 50( 4) 4/ 50( 8) 3/ 50 ( 6) carcinoma 2/ 50( 4)** 1/ 50( 2) 0/ 50( 0) 5/ 50( 10) total tumor 2/ 50( 4)** 3/ 50( 6) 4/ 50( 8) 8/ 50( 16)* bearing animals The number in parentheses is the percentage incidence. Cochran Armitage Trend test is indicated on Control and Fisher Exact test is indicated on Dose group as: ** p< 0.01 and * p< O. 05 No other tumor response related to Lactofen administration was seen.

Historical control data was provided on liver tumors in CD 1 mice sacrificed after 78 weeks. The data was derived from three studies conducted from 1979 1980 by the performing laboratory.

Historical Control Data Hepatocellular Tumors Total incidence Range(%)

males adenoma 3/ 140 0 4 carcinoma 19/ 140 3 17 females adenoma 3/ 156 0 7 carcinoma 5/ 156 0 14 The incidence of hepatocellular adenomas and carcinomas was well outside the historical control range tor male mice at the highest dose tested ( 250 ppm). In females, carcinomas and adenomas, considered alone, were within the historical control range. LACTOFEN CANCER ASSESSMENT DOCUMENT FINAL REPORT b. MTD Considerations:

Body weights and food consumption were unaffected by treatment. Survival was slightly affected at the high dose for males and mid and high dose for females but the differences were not statistically significant. Hemoglobin, hematocrit and RBC values were decreased in the high dose females when compared to controls at 58 weeks by 13, 16 and 11%, respectively. This effect was not seen at 78 weeks with the values being only 5, 3 and 2% lower, respectively than corresponding controls. Significantly increased liver/ body weight ratios were observed in all treated males an in mid and high dose females.

Non neoplastic liver pathology in treated groups consisted of the following:

1. Hepatocytomegaly was increased in all treated male groups and in the mid and high dose females; 2. necrosis of individual hepatocytes was increased in the high dose males; 3. Foci/ areas of cellular alteration were increased in mid and high dose males and high dose females; and 4. sinusoidal cell pigmentation was increased in all male and female treated groups ( Note: the control rate was 22% for males and 42% for females).

In a 90 day CD 1 mouse feeding study, all animals treated with 5000 and 10,000 ppm Lactofen were found dead by week three and week two, respectively. At 2000 ppm statistically significant lower body weights were seen. Also at 20OO ppm an increased incidence of hepatocytic vacuolization, necrosis of individual hepatocytes, hyperplasia of biliary epithelium, hepatocellular swelling and extramedullary hematopoiesis was seen in both sexes.

The Committee concurred that based upon the toxicity, as seen in both the 90 day and oncogenicity studies, that an MTD has not been reached in the latter study and that higher dosages (> 250 ppm) would have been tolerated chronically.

2. Two Year Rat feeding study:

Two Year feeding study of the oncogenicity and Chronic Toxicity of PPG 844 in Rats. Hazleton Laboratories, America, Madison, WI. Study N0. 6100 100, July 30, 1995. Accession Nos. 073837 073840.

a. Discussion of Study:

Lactofen ( 73.5  78.3% a. i.) was administered in the diet to Charles River CD Sprague Dawley derived rats at dosages of O, 50, 500,1000 and 200b. ppm for two years. A total of 84 animals per sex were started in each group. Clinical chemistry, blood chemistry and urinalysis were performed at 6, 12, 18 and 24 months on 8 rats/ sex/ group. At 6, 12, and 18 months 8 LACTOFEN CANCER ASSESSMENT DOCUMENT FINAL REPORT rats/ sex/ group were sacrificed and liver tissues were examined microscopically.

An increased incidence of " neoplastic" nodules ( sometimes referred to as proliferative nodules in the report but listed under neoplastic lesions) was seen in male and female rats at the highest dose tested.

Incidence of Proliferative Nodules ( Neoplastic) Dosages ( ppm) 0 50 500 1000 2000 Males 5+/ 63( 8) 1/ 59( 2) 3/ 60( 5) 5/ 61( 8) 15/ 59( 25)** Females 1/ 60( 2)** 0/ 59( 0) 2/ 60( 3) 2/ 58( 3) 7/ 60( 12)*

+ includes one hepatocellular carcinoma The number in parentheses indicates the percentage incidence. Cochran Armitage Trend test is indicated on Control and Fisher Exact test is indicated on dose group as: ** p < 0.01 and * p< 0.05.

Survival analysis of rat data in males indicated a survival disparity. Although the Cochran Armitage Trend analysis of tumor rates does not adjust for this fact, a more sensitive method of Trend analysis ( Peto's) would have resulted in a smaller p value, i. e. a more significant result. This is true because of the earlier occurrence or greater mortality in the highest dose group.

No evidence for early development of neoplastic lesions was apparent from the 6, 12 or 18 month interim sacrifices. The only hepatocellular carcinoma seen was one in the male control group.

Historical control data provided by the performing laboratory in untreated Sprague Dawley rats from 1980 to 1983 indicated that in males the total incidence of neoplastic nodules from four studies was 7/ 342 with a range of 1 2% and in females the total incidence of neoplastic nodules was 1/ 347 and the range was 0 1%.

An increased incidence of endometrial stromal polyps was observed in treated females ( p< 0.05 for all groups by Fisher's exact test) when compared to the controls; however, the incidence was within the historical control range of the performing laboratory and was not considered to be treatment related.

b. MTD Considerations:

The Committee concurred that the high dose in this study approached an MTD. This conclusion was based upon:

! a statistically significant decrease in body weight in both sexes when compared to control values ( 10 15% in males and 10 18% in females during the study); LACTOFEN CANCER ASSESSMENT DOCUMENT FINAL REPORT ! SGOT, SGPT and alanine phosphatase levels were increased in all high dose animals throughout the study; and ! basophilic and eosinophilic foci of cellular alteration were statistically significantly ( p< O. 05) increased in high close animals of both sexes.

E. Additional Toxicology Information:

1. Metabolism:

Lactofen is rapidly excreted after oral administration with 95% of the radiolabel excreted within 72 hours in rats. Male rats excreted the majority of the radioactivity in feces ( 56%), while female rats excreted most in the urine ( 52%).

In mice 65% to 69% of the orally administered radioactivity is excreted within 4 days; male mice excreted 50% and female mice excreted 34% of the absorbed dose in the feces. A small portion remained bound to mouse liver. In male rhesus monkeys fecal and urinary excretions of 14C Lactofen were each approximately 40% of the administered dose and were complete in 144 and 72 hours, respectively after oral administration.

Two types of transformations were observed from the metabolism of PPG844. One route involved hydrolysis of the ethyl ester to form PPG 947. This reaction was followed by further hydrolysis to PPG 84; ( Acifluorfen, see # 4 below). The second route of metabolism involved reduction of the nitro group or PPG 844 to form PPG 1576, which was further hydrolyzed to PPG 2838 and finally to PPG 2053. The proposed metabolic pathway can be found in Figure 1 ( pg. 7).

2. Mutagenicity:

Lactofen did not cause an increase in chromosomal aberrations when tested with and without metabolic activation in CHU cells, was negative both with and without metabolic activation in the CHQ/ HGPRT mammalian cell forward mutation assay and did not induce unscheduled DNA synthesis in isolated rat hepatocytes. Lactofen did have a low covalent binding index to mouse liver DNA in vivo and was positive in the Ames Salmonella/ microsome plate test to tester strain TA 1538 without metabolic activation but at dosages that precipitated out in the medium ( 50O0 and 7500 ug/ plate).

3. Reproduction and Teratology:

Lactofen was not embryo/ fetotoxic when evaluated in rats and rabbits at dosages up to 400 mq/ kg and 20 M/ kg, respectively. In a 2 generation reproduction study at 500 ppm Lactofen administration resulted in decreased pup weight and increased pup heart and liver weights. The NOEL for these effects was 50 ppm. LACTOFEN CANCER ASSESSMENT DOCUMENT FINAL REPORT METABOLISM OF PPG 844 4. Structure Activity Relationship:

Lactofen and its metabolites are structurally related to four chemicals that are oncogenic in rodents:

Acifluorfen ( the major metabolite of Lactofen; see PPG 647 Fig. 1) induces hepatocellular adenomas and carcinomas in mice but is negative for oncogenicity in rat;

Nitrofen produces hepatocellular carcinomas in mice and pancreatic carcinomas in rats;

Oxyfluorfen produces marginally positive liver tumors in mice but is negative in the rat; and

Fomesafen produces hepatocellular adenomas and carcinomas in mice ( Category C oncogen).

5. Special Studies:

Lactofen is not an inducer of microsomal enzyme activity. Lactofen ( technical PPG 844, but not pure PPG 844) and Nafenopin, a known peroxisome proliferator, induce catalase activity and increased liver peroxisome and alkaline phosphatase staining in rats and mice. However, liver samples from Chimpanzees treated with Lactofen ( technical PPU 844, 5. and 75 mg/ kg/ day for 90 days) showed no increase in the activity of acyl Coenzyme A oxidase or catalase the increased levels of which are indicative of peroxisome proliferation.

e. Weight of Evidence Considerations:

The Committee, considered the following facts, regarding the toxicology data on Lactofen to be of importance in a weight of the evidence determination of oncogenic potential.

1. Administration of Lactofen in the diet of male and tamale Crl: CD 1( CR)( BR) mice was associated with an increased incidence of hepatocellular tumors ( adenomas, carcinomas and total hepatic tumor bearing animals in males and adenomas and total hepatic tumor bearing animals in females).

2. Historical control information from the performing laboratory for the incidence of hepatocellular. tumors in CD 1 mice at 78 weeks indicated that the incidence of hepatocellular adenomas and carcinomas was well outside the historical control range for male mice at the highest dose tested. In mice, carcinomas and adenomas at the highest dose tested were within the historical control range.

3. The MTD was not reached in the mouse oncogenicity study and doses higher than 250 ppm could have been tolerated chronically in CD 1 mice. LACTOFEN CANCER ASSESSMENT DOCUMENT FINAL REPORT 4. An increased incidence of " neoplastic" nodules ( sometimes referred to as proliferative nodules in the study report but listed under neoplastic lesions) was seen in male and female CD sprague Dawley derived rats at the highest dose tested ( 2000 ppm).

5. No evidence tor early development of neoplastic lesions in the liver was apparent from the 6,12 or l8 month interim sacrificers in the chronic rat feeding study.

6. The MTD was approached at the high dose in the rat study based upon increased body weight gain in both sexes (> 10%),. increased levels of SGOT, SGPT and alkaline phosphatase in both sexes and increased basophilic and eosinophilic foci of cellular alteration in the livers of both sexes.

7. Lactofen is rapidly excreted in the rat ( 95% in three days). Excretion in the mouse is slower since only b5 69% is excreted within four days. Some radioactivity remains bound to mouse liver.

8. Lactofen was negative in three short term assays for mutagenicity but was positive at high doses that precipitated in the medium in the Ames Salmonella assay ( strain TA 1538) and had, a low covalent binding index to mouse liver DNA in vivo. The latter result corroborates the finding in the mouse metabolism study showing binding radioactivity from 14C Lactofen in the liver.

9. Lactofen was not embryo/ fetotoxic when evaluated in rats andrabbits In a 2 generation reproduction study at 500 ppm Lactofen administration resulted in decreased pup weight and increased pup heart and liver weights. The NOEL for these effects was 50 ppm.

10. Lactofen and its metabolites are structurally related to four chemicals that are oncogenic in rodents. Acifluorfen, Nitrofen, Oxyfluorfen and Fomesafen all induce hepatocellular tumors in mice.

G. Classification of Oncogenic Potential:

The Committee concluded based upon the available evidence that Lactofen meets the criteria of a category B2 oncogen ( probable human carcinogen). Lactofen met criteria a for this category in that it induced " an increased incidence of malignant tumors or combined malignant and benign tumors a) in multiple species or strains..." In CD 1 mice an increased incidence of hepatocellular carcinomas in males and an increased incidence of combined hepatocellular adenomas and carcinomas in both males and females was associated with administration of Lactofen. In Charles River CD Sprague Dawley rats an increased incidence of liver neoplastic nodules was seen in both sexes. Although an increase in malignant tumors was not seen in rats, the Committee felt that a B2 classification was appropriate since a tumor response was seen in two species at the same site. Supportive information was provided by structure activity correlations. Four structurally similar chemicals, Acifluorfen,( the major metabolite of Lactofen), Nitrofen, LACTOFEN CANCER ASSESSMENT DOCUMENT FINAL REPORT 1 See for example the third edition of Casarett and Doull's Toxicology: The Basic Science of Poisons ( edited by C. D. Klaassen, M. 0. Amdur and J. Doull), 3rd edition Macmillan Publishing Company, New York, 1986. p. 136. Oxyfluorfen and Fomesafen, all produce hepatocellular tumors in rodents. Lactofen was negative in three short term assays for mutagenicity, but did have a low binding index, to mouse liver DNA in vivo. Results of the Ames/ Salmonella plate assay were positive in one strain, but only at doses that precipitated in the medium and, therefore, could not be interpreted as a definitive positive result.

Since an MTD was not reached in the mouse oncogenicity study on Lactofen, the Committee felt that the tumor response seen at, the highest could not be considered to be a high dose effect only and that it Lactofen had been tested at higher dosage levels, as well, induction of liver tumors would have been seen at multiple dosage levels.

The Committee discussed the registrant's contention that the mechanism of tumor induction by Lactofen is through peroxisome proliferation and that such a mechanism has a threshold in contrast to a non threshold mechanism attributed to direct acting carcinogens. The Committee felt that, although this could be part of the mechanism for liver tumor formation by Lactofen, such a mechanism has not been proven to be directly, but only indirectly, associated with liver tumor formation by this and other chemicals1.

1 LACTOFEN CANCER ASSESSMENT DOCUMENT FINAL REPORT Attachment 2 Lactofen  Report of the Mechanism of Toxicity Assessment Committee January 17, 2001 LACTOFEN CANCER ASSESSMENT DOCUMENT FINAL REPORT OFFICE OF PREVENTION, PESTICIDES, AND TOXIC SUBSTANCES UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON, D. C. 20460 TXR No.: 014590 March 12, 2001 MEMORANDUM SUBJECT: LACTOFEN: Report of the Mechanism of Toxicity Assessment Review Committee FROM: Robert F. Fricke Reregistration Branch II Health Effects Division ( 7509C)

THROUGH: Karl Baetcke, MTARC, Co chair, Health Effects Division ( 7509C)

and Pauline Wagner MTARC, Co chair, Health Effects Division ( 7509C)

TO: Christine Olinger, Risk Assessor Reregistration Branch I Health Effects Division ( 7509C)

EPA Identification Nos PC Code: 128888 DP Barcode: D267472 Submission: S582396 Case: 819544 Action Requested: The Registrant ( Valent U. S. A.) has submitted a petition ( MRID No. 45160301) requesting that risk assessment for lactofen be based on the MOE approach rather than using a Q 1* of 0.119 ( mg/ kg/ day) 1 in human equivalents ( HED Doc No.: 014237, July 12, 2000). The petition reviewed and summarized earlier data submissions, which supported peroxisome proliferation as the mechanism of action of lactofen. LACTOFEN CANCER ASSESSMENT DOCUMENT FINAL REPORT Conclusions: On January 17, 2001, the Mechanism of Toxicity Assessment Review Committee ( MTARC) reviewed the merits of the toxicological data supporting peroxisome proliferation as the proposed mode of action for lactofen. Based on the weight of evidence from guideline, as well as mechanistic studies , the MTARC concluded that the evidence presented on peroxisome proliferation indicates that lactofen operates via a mode of action involving PPAR activation.

Evaluation Criteria: Based on the International Life Sciences Institute ( ILSI) recommendations), the following criteria were used to assess the mode of action of lactofen:

1.) Changes in liver morphology indicating hepatomegaly as measured by increased relative liver weights and increased number of peroxisomes as measured by morphometric analysis.

2.) Evidence of cell proliferation as measured by increased relative liver weights and increased replicative DNA synthesis as measured by increased hepatocellular BrdU nuclear labeling in light microscopy.

3.) Increased levels of enzymes involved in peroxisomal fatty acid metabolism, especially CNinsensitive acyl ( palmitoyl) CoA oxidase activities.

Weakness of Submitted Data Supporting Mode of Action on Peroxisome Proliferation:

The only weakness in the submitted data was that BrdU labeling was not performed to evaluate replicative DNA synthesis. The MTARC concluded that this shortcoming did not impact on their conclusions; ample evidence was submitted which demonstrated hepatic hyperplasia after treatment with lactofen.

Strengths of the Submitted Data in Supporting Mode of Action on Peroxisome Proliferation:

1.) The results guideline studies showed that lactofen is neither mutagenic nor genotoxic. A non guideline study showed equivocal ( probably negative) binding of lactofen to DNA.

2.) Changes in liver morphology were observed in both rats and mice treated with lactofen. These effects include: dose dependent increase in relative liver weights and increased number of peroxisomes as measured by electron microscopic analysis. Further, in mice there was a dose dependent increase in nuclear enlargement, cytoplasmic eosinophilia, hypertrophy and peroxisomal staining.

3.) There was evidence of cell proliferation as measured by increased relative liver weights and histological evidence indicating hepatic hyperplasia. These effects were dose related with a clearly defined threshold.

4.) Dose dependent increases ( particularly in female mice) in the activities of hepatic CNinsensitive palmitoyl CoA oxidase and carnitine acetyl transferase. Dose dependent increase in CN insensitive palmitoyl CoA oxidase was also observed in primary rat hepatocytes treated with lactofen. LACTOFEN CANCER ASSESSMENT DOCUMENT FINAL REPORT 5.) The doses at which carcinogenicity was observed ( mouse, LOAEL = 50 ppm; rat, LOAEL = 2000 ppm) were consistent or higher than the doses which caused peroxisome proliferation.

Other Issues Discussed:

The MTARC recommended that the cancer classification be reviewed by the Cancer Assessment Review Committee. Since the toxicological database for lactofen are relatively extensive, the MTARC further recommended that the Registrant submit the lactofen studies to ILSI as a case study. 1 Assessment of the Mode of Action for Lactofen I. Background A joint meeting ( March 29, 2000) of the Mechanism of Toxicity Assessment Review Committee ( MTARC) and Cancer Assessment Review Committee ( CARC) evaluated the adequacy of the toxicological database for diclofop methyl in support of peroxisome proliferation as the mechanism of action for liver carcinogenicity. The basis for the evaluation was two detailed literature reviews on the role of peroxisome proliferation in hepatocarcinogenesis. One review 1 by the International Life Sciences Institute ( ILSI) evaluated the human cancer risk of peroxisome proliferation, while the other 2 evaluated the human cancer risk of the plasticiser di( 2 ethylhexyl) phthalate ( DEHP).

As a result of this joint meeting of the MTARC and CARC, criteria ( based on the ILSI recommendations) were established which should be met before a non genotoxic hepatocarcinogenic substance can be classified as a peroxisome proliferator ( PP). These criteria are:

1.) Changes in liver morphology indicating hepatomegaly as measured by increased relative liver weights and increased number of peroxisomes as measured by morphometric analysis.

2.) Evidence of cell proliferation as measured by increased relative liver weights and increased replicative DNA synthesis as measured by increased hepatocellular BrdU nuclear labeling in light microscopy.

3.) Increased activity of enzymes involved in peroxisomal fatty acid metabolism, especially acyl ( palmitoyl) CoA oxidase activities.

II. Mechanism of Action of Peroxisome Proliferators PPs are a diverse group of chemicals and include synthetic ( industrial plasticisers and solvents and hypolipidemic drugs), as well as the naturally occurring compounds ( certain fatty acids, prostaglandins, and steroids). Although the synthetic PPs are structurally dissimilar, they share a similarity with fatty acids  a large hydrophobic region and an aliphatic chain with a terminal acidic group, usually carboxylic acid ( Figure 1).

Research over the past decade showed that the rodent is highly responsive to PPs and that the liver is the primary target organ. The action of PPs on rodent liver leads to specific and well characterized toxicological events. Short term effects ( as early as one week) on the liver include hepatomegaly due to hypertrophy and hyperplasia, increase in the number and size of peroxisomes, and the transcriptional induction of peroxisomal enzymes ( acyl CoA oxidase), endoplasmic reticulum ( cytochrome P450) and cytosol ( fatty acid binding protein). While these short term effects on the liver are reversible, long term exposure leads to the development of hepatic cancer.

Figure 1: Chemical Structures of Some Peroxisome Proliferators Lactofen Assessment of Mode of Action 2 C H 3 CH 3 NH N N Cl S OH O O OH O CH 3 C H 3 O O CH 3 CH 3 O O CH 3 CH 3 O O CH 3 O CH 3 CH 3 Wy 14,643 Nafenopin DEHP Clofibrate A receptor based mechanism for the proliferation of peroxisomes was established with the identification of peroxisome proliferator activated receptor   ( PPAR ) 3, which is a member of the nuclear receptor superfamily. The binding of PPAR  to the retinol X receptor ( RXR) produces a heterodimer which becomes fully active with the binding of a PP to the active site. The active PPAR  RXR PP complex is capable of regulating gene expression through interaction with the peroxisome proliferator responsive elements ( PPRE) of target genes.

In a recent review4, the large number of PPs preferentially activate PPAR ; several hypolilidemic drugs ( clofibrate) and Wy 14,643 have been shown to directly bind to PPAR . They further point out that the ability of a PP to bind to and/ or activate PPAR  correlated well with the hepatocarcinogenic potency of the PP. Further definitive evidence for the involvement of PPAR  in the development of hepatocellular tumors was demonstrated using transgenic mice which lacked expression of PPAR  mRNA.

The introduction of PPAR  null mice(/) by Lee et al. 5, the obligatory role of PPAR  in mediating the cellular effects of PP was established. Short term exposures to Wy 14,643 or clofibrate showed that while wild type (+/+) mice developed the classic hepatic effects, the effects in treated null (/) mice were comparable to the (/) controls. In a chronic toxicity study 6 (+/+) and (/) mice were fed either basal diet or diet containing 0.1% Wy 14,643. After one week of treatment, the (+/+) mice had a significant increase ( 93%) in relative liver weight; further increases in relative liver weights were observed at 5 weeks ( 245%) and 11 months ( 355%) of treatment. By contrast, the relative liver weights of treated (/) mice were comparable to control (/) mice at all timepoints. To evaluate replicative DNA synthesis, the BrdU labeling index was measured in both (+/+) and (/) mice. While the BrdU labeling index was significantly increased in (+/+) mice after 1 and 5 weeks of treatment compared to (+/+) controls, the BrdU labeling indexes of treated (/) mice were comparable to (/) controls at these same timepoints. Gross examination revealed multiple visible nodules in the livers of treated (+/+) mice; microscopic examination showed a 100% incidence of hepatocellular neoplasms. The livers of the treated (/) mice were grossly and microscopically comparable to (/) control mice. Lactofen Assessment of Mode of Action 3 These data firmly established the central, and necessary, role of PPAR  in nongenotoxic hepatocarcinogenesis.

III. Evaluation of Toxicity Database for Lactofen Both guideline and non guideline ( mechanistic) studies have been reviewed. Pertinent results of guideline studies relevant to the proposed mechanism of action of lactofen are summarized in Table 1.

A. Subchronic Toxicity Studies with Lactofen 1) 4 Week Feeding Study in the Rat ( MRID No: 00117563): In a 4 week rangefinding study, rats were fed diets at 0, 200,100, 5000 or 10000 ppm lactofen ( 76% a. i.). Animals in the high dose group had 100% mortality by day 7. Increased liver and kidney weights were observed at doses of 1000 ppm and higher.

2) Subchronic Feeding Study in the Rat ( MRID No: 00117564): In a 90 day subchronic toxicity study, rats were fed diets containing 0, 40, 200 or 1000 ppm lactofen ( males: 0, 2.9, 14, 74 mg/ kg/ day; females: 0, 3.5, 17, or 85 mg/ kg/ day). At the high dose level, increased relative ( to body weight) liver weights in males ( 3.4%, control 2.8%) and females ( 3.1%, control 2.7%) and absolute liver weights in males ( 18.4 g, control 15.0 g) were observed. Gross findings were observed only in high dose animals and included dark livers in high dose males ( 15/ 19) and females 4/ 21); darkened renal cortex was also observed in highdose males ( 15/ 19) and females ( 3/ 21). Histopathological evaluation of high dose animals revealed brown pigmentation in hepatocytes and/ or Kupffer cells ( males, 17/ 19; females, 7/ 21; none in controls), and acidophilic hepatocellular degeneration in males ( 10/ 19, none in control) and females ( 1/ 21, none in controls) and hyperplasia of bile ducts in males ( 6/ 19; controls, 1/ 20). Other microscopic lesions included brown pigment in tubular epithelium in the kidneys of high dose animals ( males, 12/ 19; females, 3/ 21; none in controls).

3) Subchronic Feeding Study in the Mouse ( MRID No: 00132882): In a 90 day subchronic toxicity study, mice were fed diets containing 0, 40/ 2000, 200, 1000, 5000, or 10000 ppm lactofen ( calculated doses: 0, 5.7, 29/ 286, 143, 714 or 1429 mg/ kg/ day). Further as a result of 100% mortality in 5000 and 10000 ppm males and females, the 40 ppm dose was increased to 2000 ppm at week 5. With the exception of one female, all of the 2000 ppm animals died between 5 and 10 weeks after the increase in the dose. Dose related increases in serum cholesterol and total protein levels, as well as liver enzymes ( ALP, ALT and AST) were observed in 200 and 1000 ppm males and females. Comparable increases in absolute and relative liver weights were seen at 200 ppm ( males, 43  48%; females, 45  53%) and 1000 ppm ( males, 198  221%; females, 189  190%). Gross examination revealed enlarged livers in 200, 1000 and 2000 ppm mice and enlarged spleens in 1000 and 2000 ppm mice. At 2000 and/ or 1000 ppm, microscopic examination of the liver showed hepatocytic vacuolization, necrosis of individual hepatocytes, bile retention, coagulative necrosis, hyperplasia of biliary epithelium and increased extramedullary hematopoiesis; the kidney showed nephrosis and cortical fibrosis/ scarring. Lactofen Assessment of Mode of Action 4 B. Chronic Toxicity, Carcinogenicity and Reproductive Toxicity Studies with Lactofen 1) Combined 2 Year Chronic Feeding/ Carcinogenicity Study in the Rat ( MRID No.: 00150329): In this study, rats were fed diets containing 0, 50, 500, 1000, or 2000 ppm ( 0, 2, 19, 38, and 76 mg/ kg/ day, based on 20 ppm = 1 mg/ kg) lactofen for 104 weeks. Effects seen at 1000 ppm included increased incidence of mottled diffusely dark livers and kidneys, increased aspartate aminotransferase, alanine aminotransferase and alkaline phosphatase activities, decreased cholesterol, blood urea nitrogen, and total protein globulin levels, and increased incidence in the pigmentation of hepatocytes, Kupffer cells and renal cortical tubule cells. Effects seen at the 2000 ppm were similar to those seen at 1000 ppm, but more severe. Other effects at 2000 ppm included increased incidence in basophilic or eosinophilic foci of cellular alteration and increased incidence of neoplastic liver nodules.

2) 18 Month Carcinogenicity Study in the Mouse ( MRID No. 00150343): In this study, mice were fed diets containing lactofen at 0, 10, 50, or 250 ppm ( 0, 1.4, 7.1, or 36 mg/ kg/ day, based on 1 ppm = 0.143 mg/ kg) for 78 weeks. Effects seen at 50 ppm included increased liver weight, increased incidence of dark colored and/ or enlarged livers, hepatocytomegaly ( also observed in males at 10 ppm); increased incidences of focal cell alteration ( females only), and hepatocellular adenomas ; sinusoidal cell pigmentation in the liver was observed in all dose groups. At the highest dose tested ( 250 ppm), the severity of these signs of toxicity was increased. Other effects noted at 250 ppm included increased incidence of non neoplastic and neoplastic liver masses and increased kidney pigmentation.

3) Chronic Feeding Study in the Dog ( MRID No: 41967901): In a one year toxicity study, dogs were fed diets containing 0, 40, 200, or 1000/ 3000 ( 0, 0.79, 4.0, 20/ 59 mg/ kg/ day based on 1 mg/ kg = 40 ppm) lactofen; because of lack of significant toxicity at 1000 ppm, the dose was increased to 3000 ppm after 4 months of treatment. Dogs fed the 1000/ 3000 ppm diet showed a slight increase in peroxisomal staining ( based on the intensity of brown stippling of D. A. B. stained slides) in the livers. Relative liver weight was increased in high dose females. There was no evidence of nuclear enlargement, increased mitotic activity, inflammation, or focal necrosis. Lactofen Assessment of Mode of Action 5 Table 1: Summary of Guideline Toxicity Studies with Lactofen Study ( MRID No.) Liver Weight Liver Enzymes Liver Histopathology 4 Week Feeding  Rat ( 00117563)

0, 200, 1000, 5000, 10000 ppm 100% lethality at 10000 ppm 5000 ppm

and   :

Increased relative wt Not measured Not measured 13 Week Feeding  Rat ( 00117564)

0, 40, 200, 1000 ppm

: 0, 2.9, 14, 74 mg/ kg/ day   : 0, 3.5, 17, 85 mg/ kg/ day 1000 ppm: Increased abs and rel in

and rel in   1000 ppm

: increased ALT, AST and ALK 1000 ppm,

and   : Brown pigmentation in hepatocytes and/ or Kupfer cells and acidophilic hepatocellular degeneration.

13 Week Feeding  Mice ( 00132882)

0, 40/ 2000, 200, 1000, 5000, 10000 ppm 0, 5.7/ 286, 29, 143, 714 mg/ kg/ day 40 ppm increased to 2000 ppm at wk 7 100% lethality at HDT

200 ppm

and   :

Increased relative and absolute wt

200 ppm: Increased ALK in

and   , increased ALT and AST in

1000 ppm: Increased ALT and AST in   ,

increased total cholesterol in

and

200 ppm: Enlarged liver in

and   , extramedullary hematopoiesis in   ,

1000 ppm

and   : Hepatocellular vacuolation,

bile retention, hepatocellular swelling, and extramedullary hematopoiesis

1000 ppm

: Necrosis of individual hepatocytes,

Carcinogenicity  Mouse ( 00150343)

0, 10, 50 , 250 ppm 0, 1.4, 7.1, 36 mg/ kg/ day

10 ppm

,

50 ppm   : Increased abs and rel wts Not measured Hepatomegaly:

10 ppm

and

50 ppm   Focus/ Area of Cell Alteration: 50 ppm

and 250 ppm   Sinusoidal cell pigmentation.:

10 ppm in

and   Necrosis of individual hepatocytes: 250 ppm

Hepatocellular Adenoma:

50 ppm

and   Carcinoma: 250 ppm

and   Combined: 250 ppm

and   Lactofen Assessment of Mode of Action Study ( MRID No.) Liver Weight Liver Enzymes Liver Histopathology 6 2 year Combined Chronic/ Onco  Rat ( 00150329)

0, 50, 500, 1000, 2000 ppm 0, 2, 19, 38, 76 mg/ kg/ day

1000 ppm,

,

500 ppm   : Increased relative wt

500 ppm,

and   :

Increased AST, ALT and ALK at 18 mo.

1000 ppm,: Pigmentation in hepatocytes(   only) and Kupfer cells (

and   )

2000 ppm: Increased basophilic and eosinophylic (

only) foci of cellular alteration and proliferative nodules 1 Year Chronic Feeding Study  Dog ( 41967901)

0, 40, 200, and 1000/ 3000 ppm 0, 0.8, 4, 20/ 59 mg/ kg/ day 1000/ 3000 ppm   :

Statistically significant increases in the relative liver weight; absolute liver weight not affected. Not measured No histopathological findings observed in the liver 2 Generation Reproduction  Rat ( 00132885)

0, 50 500, 2000 ppm F1 Adults

500 ppm   and 2000 ppm

: Increased relative wt 2000 ppm   :

Increased absolute wt.

F1 Pups

500 ppm

:

Increased absolute wt 2000 ppm   :

Increased relative wt. Not measured F1 Adults 2000 ppm

and   : Centrilobular necrosis/ degeneration, brown pigmentation [ hemosiderin] in hepatocytes and reticuloendothelial cells Lactofen Assessment of Mode of Action 7 4) Reproductive Toxicity Study in the Rat ( MRID No: 00132885): In this study, rats were fed diets containing lactofen at 0, 50, 500, or 2000 ppm ( F0 males/ females: 0, 2.6/ 3.1, 26.2/ 31.8, 103.5/ 121.3 mg/ kg/ day; F1 males/ females: 0, 2.7/ 3.3, 26.732.9, or 115.4/ 138.9 mg/ kg/ day). For parental groups at the high dose level, there was increases in spleen and liver weights; increased incidence of liver [ hepatocytic centrilobular degeneration and necrosis] and spleen [ extramedullary hematopoiesis] microscopic lesions. For offspring groups no liver toxicity was noted C. Mutagenicity and Genotoxicity Studies with Lactofen The guideline and non guideline studies indicate that lactofen is neither genotoxic nor mutagenic. Equivocal ( probably negative) results were observed in an in vivo DNA binding assay with radiolabeled lactofen. Results are summarized in Table 2.

Table 2: Summary of Mutagenic and Genotoxic Effects of Lactofen Assay Results Salmonella typhimurium/ mammalian microsome mutagenicity assay ( MRID No. 00150346, 00150346) Negative: ± S9 including Salmonella typhimurium/ mammalian microsome mutagenicity assay ( MRID No. 00150347) Negative ± S9 In vitro cytogenetic assay with Chinese hamster ovary ( CHO) cells ( MRID No. 00150348) Negative for clastogenic effects ± S9 In vitro cytogenetic assay with Chinese hamster ovary ( CHO) cells ( MRID No. 00150626) Negative for clastogenic effects ± S9 In vitro unscheduled DNA synthesis in primary mouse hepatocytes ( MRID No. 00150349 and 00162141) Negative In vitro unscheduled DNA synthesis in primary rat hepatocytes ( MRID No. 00150627) Negative In vivo DNA covalent binding in mouse liver ( MRID No. 00150350) Equivocal ( probably negative) Low level of binding D. Mechanistic Studies with Lactofen Several non guideline in vitro and in vivo mechanism studies have been submitted which further characterized lactofen induced peroxisome proliferation. These studies include the measurement of biochemical markers for peroxisome proliferation in the mouse and rat, as well as in primary rat hepatocytes, and a DNA binding study in the mouse. A summary of the results of these mechanistic studies is summarized in the Table 3. Lactofen Assessment of Mode of Action 8 Table 3: Summary of Results for Mechanistic Studies with Lactofen Study ( MRID No) Liver Weights Enzyme Pathology/ histopathology Electron Microscopy Analysis of biochemical and microscopic parameters in Chimpanzee liver ( 45283901, 45283905)

5 and 75 mg/ kg/ day Not measured Aryl CoA oxidase, catalase and carnitine acetlytransferase activities not affected by treatment No nuclear enlargement, cytoplasmic eosinophilia or hepertrophy observed in liver biopsies after 0, 1, and 3 months of treatment Slight + response for peroxisomal staining ( brown stippling)

Results of the Analysis of Biochemical Parameters in Mouse and Rat Liver Following Exposure to PPG 844 ( 45283904)

Mouse: 0, 2, 10, 50, 250 technical 250 ppm pure Rat: 0 and 2000 ppm technical Mice at 7 Weeks:

10 ppm

and

50 ppm   Increased rel wt Catalase and CN insensitive palmiloyl CoA oxidase increased in

at 250 ppm and   at

50 ppm. Pathology: Rats ( 2000 ppm) and mice (

50 ppm) showed increased nuclear enlargement,

cytoplasmic eosinophilia, hypertrophy and peroxisomes in number of peroxisomes.

EM: Rats ( 2000 ppm) and mice ( 250 ppm)

showed quantitative increase in the number of peroxisomes Measurement of Peroxisome Proliferation in Primary Rat Hepatocytes Induced by PPG 844 and Five of its Metabolites ( 45283902) Not applicable Concentration dependent increase in CN insensitive palmitoyl CoA oxidase activities with each of the metabolites. EM: Lactofen ( 0.01 mM) increased number of peroxisomes and glycogen aggregates.

Other metabolites showed occasional peroxisomes Lactofen Assessment of Mode of Action 9 1) Subchronic Toxicity Study in Male Chimpanzees ( MRID No.: 45283901, 45283905): In this study, three male chimpanzees per dose group were orally dosed with lactofen at 5 and 75 mg/ kg/ day for three months, followed by a two month recovery period. Whole blood was collected before and during treatment for clinical pathological evaluations; liver biopsies were obtained before and after 30 and 90 days of treatment. Compared to pretreatment values, the activities of acetyl CoA oxidase, catalase and carnitine acetyl transferase in the liver were not affected by treatment. Histopathological evaluation of the liver biopsies did not show any evidence of nuclear enlargement, cytoplasmic eosinophilia, or hypertrophy; peroxisome content in the liver biopsies did not show any change in the pre and posttreatment evaluations. Further, electron microscopic evaluation of liver did not reveal any evidence of peroxisome proliferation. Based on the results of this study lactofen was not a peroxisome proliferator in chimpanzees.

2) Measurement of Biochemical and Histopathological Markers for Peroxisome Proliferation in Rat and Mouse Livers ( MRID No.: 45283904): In a dietary study male and female Crl: CD( S) Br rats and Crl: CD1 mice were fed diets containing lactofen or nafenopin, a positive control for peroxisome proliferation. Biochemical markers of peroxisomal proliferation included measurement of hepatic acyl CoA oxidase, catalase and carnitine acetyl transferase activities. Light and electron microscopic were used to evaluate livers for evidence of peroxisome proliferation Male and female mice were exposed to technical lactofen at 0, 2, 10, 50, or 250 ppm, pure lactofen at 250 ppm, or nafenopin, at 500 ppm. After 7 weeks of treatment, male and female mice showed significant biochemical and pathological effects on the liver. Dosedependent increases in relative liver weights, catalase and acyl CoA oxidase were observed in males and females; females also showed a significant increase in carnitine acetyl transferase ( Table 4). Liver histology ( Table 5) revealed significant, dose dependent increases in nuclear enlargement, cytoplasmic eosinphilia, hypertrophy and peroxisomal staining. Nafenopintreated mice showed significant increases in all of the parameters measured.

Similar findings were also observed in an 8 week study, in which rats were fed diets containing lactofen at 0 or 2000 ppm or nafenopin at 500 ppm. Lactofen treated rats had significantly increased relative liver weights, carnitine acetyl transferase and acyl CoA oxidase ( Table 6). Histological examination revealed increased incidence of nuclear enlargement, cytoplasmic eosinophilia, hypertrophy and peroxisomal staining ( Table 7); catalase activity was not affected by treatment. Nafenopin treated rats showed significant increases in all of the parameters indicative of peroxisome proliferation Electron microscopic analysis was performed on the livers of male rats and mice. As a quantitative measurement of peroxisome proliferation, the ratio of peroxisomes to mitochondria were determined. The ratios were 1/ 4.7 ( 21%) and 1/ 3.0 ( 33%) for control and treated ( 2000 ppm, 8 weeks) male rats, respectively, and 1/ 4.8 ( 21%) and 1/ 1.5 ( 66%) for control and treated ( 250 ppm, 7 weeks) mice, respectively.

Table 4: Evaluation of Liver Parameters in Male and Female Mice After 7 Weeks of Treatment with Lactofen ( Technical, 78.2%; pure, 99.8%) or Nafenopin ( NAF) Lactofen Assessment of Mode of Action 10 Sex Dose ( ppm) Relative Liver Wt ( g/ 100 g) Catalase Carnitine Acetyl Transferase Palmitoyl CoA Oxidase Male 0 3.9 0.34 2.92 3.1 2 ( Tech) 4.2 0.49 2.96 5.2 10 ( Tech) 5.0*** 0.41 3.87*** 6.1 50 ( Tech) 4.5** 0.49 3.27 7.2 250 ( Tech) 7.7*** 0.94*** 3.1 40***

250 ( pure) 6.2*** 0.93*** 6.77*** 29***

Female 0 4.0 0.22 3.21 2.1 2 ( Tech) 4.1 0.26 3.71 4.3 10 ( Tech) 4.4 0.21 4.27** 11***

50 ( Tech) 4.7** 0.30* 4.68*** 13***

250 ( Tech) 6.7*** 0.69*** 4.53** 35***

250 ( pure) 7.3*** 00.44*** 7.77*** 27***

Male 500 NAF 12.8*** 0.70*** 8.31*** 49***

Female 500 NAF 11.9*** 0.76*** 9.94*** 38***

** p

0.01; *** p

0.001 1 Data summarized from Tables 5 and 6 of MRID No. 452383904.

Table 5: Evaluation of Histopathological Parameters in Male and Female Mice After 7 Weeks Treatment with Lactofen ( Technical, 78.2%; Pure, 99.8%) or Nafenopin ( NAF) 1 Sex Dose ( ppm) Nuclear Enlargement Cytoplasmic Eosinphilia Hypertrophy Peroxisomal Staining Male 0    +

2 ( Tech)    +

10 ( Tech) ± ± ± +

50 ( Tech) + + + ++

250 ( Tech) + ++ ++ ++

250 ( Pure) ++ +++ ++ ++

Female 0    +

2 ( Tech)    +

10 ( Tech) ±   +

50 ( Tech) + + + ++

250 ( Tech) ++ ++ ++ +++

250 ( Pure) ++ +++ +++ ++

Male 500 NAF ++ +++ +++ +++

Female 500 NAF +++ +++ +++ +++

1 Data summarized from Table 7 and 8 of MRID No. 452383904. Lactofen Assessment of Mode of Action 11 Table 6: Evaluation of Liver Parameters in Male and Female Rats After 8 Weeks of Dietary Treatment with Lactofen ( Technical, 78.2%) or Nafenopin ( NAF)

Sex Dose ( ppm) Relative Liver Wt ( g/ 100 g) Catalase Carnitine Acetyl Transferase Palmitoyl CoA Oxidase Male 0 3.0 0.37 3.5 3.4 2000 4.3*** 0.36 6.4*** 8.6**

Female 0 2.8 0.20 7.3 5.3 2000 3.8*** 0.19 2.4*** 18.3***

Male 500 NAF 5.4*** 0.60*** 2.9 13.3***

Female 500 NAF 3.7*** 0.30*** 10.2*** 12.5**

** p

0.01; *** p

0.001 1 Data summarized from Table 11 of MRID No. 452383904.

Table7: Evaluation of Histopathological Parameters in Male and Female Rats After 8 Weeks Treatment with Lactofen ( Technical, 78.2%) or Nafenopin ( NAF) 1 Sex Dose ( ppm) Nuclear Enlargement Cytoplasmic Eosinphilia Hypertrophy Peroxisomal Staining Male/ 0    +

2000 ++ ++ ++ ++

Female 0    +

2000 ++ ++ ++ ++

Male 500 NAF ++ ++ ++ +++

Female 500 NAF ++ ++ ++ ++

1 Data summarized from Table 12 of MRID No. 452383904.

3.) Measurement of Biochemical Markers for Peroxisome Proliferation in Primary Rat Hepatocytes ( MRID No.: 45283902): In this study, primary cultures of rat hepatocytes were exposed to PPG 844 ( lactofen, 99.8%) or five of its principal animal metabolites ( structures Figure 2): PPG 947 ( desethyl lactofen 98.9% purity), PPG 847 ( acrifluorfen, 100% purity), PPG 1576 ( amino lactofen, 95.6% purity), and PPG 2053 ( amino acifluorfen, 94.6% purity), PPG 2838 ( desethyl amino lactofen, 70.6% purity). Because of the low purity of PPG 2838, it was excluded from the definitive study. CN insensitive palmitoyl CoA oxidase activity, a biomarker for peroxisome proliferation was measured after 68 hr of exposure. Solvent ( DMSO) and positive ( clofibrate) were also evaluated.

Additionally, control, lactofen, metabolite and clofibrate treated hepatocyte were examined using an electron microscope.

CN insensitive palmitoyl CoA oxidase data are summarized in Table 8. Of the test chemicals evaluated, treatment with lactofen resulted in greater than 5 fold, concentrationdependent increase in palmitoyl CoA oxidase activity compared to the solvent control. the highest increase for the metabolites was approximately 3 fold. Decending order of potency, based on palmitoyl CoA oxidase activity, was PPG 844,  947,  847,  1576 and  2053. Lactofen Assessment of Mode of Action 12 C H 3 O O CH 3 O Cl F F F O O N +

O O C H 3 OH O O C l F F F O O NH 3 +

C H 3 OH O O Cl F F F O O N+ O O C H 3 O O CH 3 O Cl F F F O O NH 3 +

O Cl F F F OH O N+ O O O Cl F F F OH O NH 3 + Clofibrate produced significant increases ( 6.9 to 7.7 fold) in enzyme activity at both of the concentrations test.

Electron micrographs of lactofen and clofibrate treated hepatocytes revealed an increased numbers of dense, anucleoide peroxisomes compared to the solvent control. Additionally, lactofen treated hepatocytes showed increased amounts of cytoplasmic glycogen aggregates. Treatment with the metabolites did not cause any increase in the number of peroxisomes relative to the control.

Figure 2: Structures of Lactofen and Primary Metabolites Lactofen ( PPG 844) Desethyl amino lactofen ( PPG 2838)

Desethyl Lactofen ( PPG 947) Amino Lactofen ( PPG 2838 )

Acifluorfen ( PPG 847 ) Amino Acifluorfen ( PPG 2053) Lactofen Assessment of Mode of Action 13 Table 8: Effect of Lactofen and Metabolites on CN Insensitive Palmitoyl CoA Oxidase Activity ( nmol/ min/ mg protein) in Primary Rat Hepatocytes Addition Concentration, mM 0.003 0.01 0.03 0.10 PPG 844 ( Lactofen) 1.55* 2.47* NT 2.63*

PPG 947 1.61* 1.68* NT 1.74*

PPG 847 NT 2 1.35* 1.35* 1.75*

PPG 1576 NT 1.26* 0.743 1.573 PPG 2053 NT 0.86 0.983 1.46*

Controls Solvent Control ( DMSO) 0.50 Positive Control Clofibrate, 0.16 mM 3.46*

Clofibrate, 0.50 mM 3.86*

1 Data summarized from Table 2 of MRID No. 45283902. 2 NT = not tested 3 Mean of two observations, significance not determined. * Significantly different from solvent control, p

0.05.

IV. Other Modes of Action Studies with transgenic mouse confirmed that essentially all of the of the effects of PPs in rodent liver are mediated by PPAR .

V. Recommendations to the MTARC Based on the weight of the evidence of the toxicity database, there are sufficient data to classify lactofen as a non genotoxic hepatocarcinogen in rodents with peroxisome proliferation being a plausible mode of action.

VI. Relevancy to Humans The human relevancy of the role of peroxisome proliferators was not addressed, and will be deferred pending a proposed ILSI evaluation of pertinent data.

VI. References Cattly, R. C., DeLuca, J., Elcombe, C., Fenner Crisp, P., Lake, B. G., Marsman, D. S., Pastoor, T. A., Popp, J. A., Robinson, D. E., Schwetz, B., Tugwood, J., and Wahli, W., Do peroxisome proliferating compounds pose a hepatocarcinogenic hazard to humans? Regulatory Toxicology and Pharmacology 27: 47 60 ( 1998).

Doull, J., Cattley, R., Elcombe, C., Lake, B. G., Swenberg, J., Wilkinson, C., Wiliams, G., and van Gemert, M. A cancer risk assessment of di( 2 ethylhexyl) phthaltae: Application of the new U. S. EPA Risk Assessment Guidelines, Regulatory Toxicology and Pharmacology 29: 327 357 ( 1999). Lactofen Assessment of Mode of Action 14 1. Cattly, R. C., DeLuca, J., Elcombe, C., Fenner Crisp, P., Lake, B. G., Marsman, D. S., Pastoor, T. A., Popp, J. A., Robinson, D. E., Schwetz, B., Tugwood, J., and Wahli, W., Do peroxisome proliferating compounds pose a hepatocarcinogenic hazard to humans? Regulatory Toxicology and Pharmacology 27: 47 60 ( 1998).

2. Doull, J., Cattley, R., Elcombe, C., Lake, B. G., Swenberg, J., Wilkinson, C., Wiliams, G., and van Gemert, M. A cancer risk assessment of di( 2 ethylhexyl) phthaltae: Application of the new U. S. EPA Risk Assessment Guidelines, Regulatory Toxicology and Pharmacology 29: 327 357 ( 1999).

3. Issemann, I. And Green, S., Activation of a member of the steroid hormone receptor superfamily by peroxisome proliferators. Nature ( London) 347: 645 650 ( 1990).

4. Corton, J. C., Lapinskas, P. J. and Gonzalex, F. J., Central role of PPAR  in the mechanism of actions of hepatocrcinogenic peroxide proliferators, Mutation Research, 448: 139 151 ( 2000).

5. Lee, S. S., Pineau, T., Drago, J., Lee, E. J., Owens, J. W., Kroetz, D. L., Fernandez Saluguero, P. M., Westphal, H., and Gonzalez, F. J., Targeted disruption of the   isoform of the peroxisome proliferator activated receptor gene in mice results in abolishment of the pleiotropic effects of peroxisome proliferators, Mol. Cell. Biol., 15: 3012 3022 ( 1995).

6. Peters, J. M., Cattley, R. C. and Gonzalez, F. J., Role of PPAR

in the mechanism of action on nongenotoxic carcinogen and peroxisome proliferator Wy 14,643, Carcinogenesis, 18, 2029 2033 ( 1997). Issemann, I. And Green, S., Activation of a member of the steroid hormone receptor superfamily by peroxisome proliferators. Nature ( London) 347: 645 650 ( 1990).

Corton, J. C., Lapinskas, P. J. and Gonzalex, F. J., Central role of PPAR  in the mechanism of actions of hepatocrcinogenic peroxide proliferators, Mutation Research, 448: 139 151 ( 2000).

Lee, S. S., Pineau, T., Drago, J., Lee, E. J., Owens, J. W., Kroetz, D. L., Fernandez Saluguero, P. M., Westphal, H., and Gonzalez, F. J., Targeted disruption of the   isoform of the peroxisome proliferatoractivated receptor gene in mice results in abolishment of the pleiotropic effects of peroxisome proliferators, Mol. Cell. Biol., 15: 3012 3022 ( 1995).

Peters, J. M., Cattley, R. C. and Gonzalez, F. J., Role of PPAR

in the mechanism of action on nongenotoxic carcinogen and peroxisome proliferator Wy 14,643, Carcinogenesis, 18, 2029 2033 ( 1997).


PAPERWORK REDUCTION ACT SUBMISSION Please read the instructions before completing this form. For additional forms or assistance in completing this form, contact your agency's Paperwork Clearance Officer. Send two copies of this form, the collection instrument to be reviewed, the Supporting Statement and any additional documentation to: Office of Information and Regulatory Affairs, Office of Management and Budget, Docket Library, Room 10102, 725 17th Street NW Washington, DC 20503.

1. Agency/ Subagency originating request USEPA/ Office of Enforcement and Compliance Assurance 2. OMB control number b. G None a. 2060  0114 __ __ __ __

3. Type of information collection ( check one) a. G New collection b. G Revision of a currently approved collection c. X Extension of a currently approved collection d. G Reinstatement, without change, of a previously approved collection for which approval has expired e. G Reinstatement, with change, of a previously approved collection for which approval has expired f. G Existing collection in use without an OMB control number 4. Type of review requested ( check one) a. X Regular b. G Emergency  Approval requested by: / / c. G Delegated 5. Small entities Will this information collection have a significant economic impact on a substantial number of small entities? G Yes X No For b f, note item A2 of Supporting Statement Instructions 6. Requested expiration date a. X Three years from approval date b. G Other Specify: / /___

7. Title NSPS for Wool Fiberglass Insulation Manufacturing Plants ( 40 CFR part 60, subpart PPP) and NESHAP for Wool Fiberglass Manufacturing Plants ( 40 CFR part 63, subpart NNN)

8. Agency form number( s) ( If applicable) EPA ICR Number 1160.07 9. Keywords wool fiberglass, particulates, formaldehyde, insulation, glass melting 10. Abstract This ICR includes two Clean Air Act standards for the wool fiberglass industry; NSPS subpart PPP and NESHAP subpart NNN. Both the NSPS and NESHAP standards include basic recordkeeping and reporting including initial notifications, performance testing, semiannual excess emission reports, and occurrence of any startup, shutdown, or malfunction in the operation of an affected facility.

11. Affected public ( Mark primary with " P" and all others that apply with " X") a. Individuals or households d. Farms b. P Business or other for profit e. Federal Government c. Not for profit institutions f. State, Local or Tribal Government 12. Obligation to respond ( Mark primary with " P" and all others that apply with " X") a. G Voluntary b. G Required to obtain or retain benefits c. P Mandatory 13. Annual reporting and recordkeeping hour burden a. Number of respondents 61 b. Total annual responses 180 1. Percentage of these responses collected electronically 10 % c. Total hours requested 18,216 d. Current OMB inventory 19,098 e. Difference ( 882) f. Explanation of difference 1. Program Change 2. Adjustment ( 882) 14. Annual reporting and recordkeeping cost burden ( in thousands of dollars) a. Total annualized capital/ startup costs 0 b. Total annual costs ( O& M) 489 c. Total annualized cost requested 489 d. Current OMB inventory 689 e. Difference ( 200) f. Explanation of difference 1. Program change 2. Adjustment ( 200)

15. Purpose of information collection ( Mark Primary With " P" and all others that apply with " X") a. Application for benefits e. Program planning or management b. Program evaluation f. Research c. General purpose statistics g. P Regulatory or compliance d. __ Audit 16. Frequency of recordkeeping or reporting ( check all that apply) a. X Recordkeeping b. Q Third party disclosure c. X Reporting 1. Q On occasion 2. Q Weekly 3. Q Monthly 4. Q Quarterly 5. X Semi annually 6. Q Annually 7. Q Biannually 8. X Other ( describe) Initial 17. Statistical methods Does this information collection employ statistical methods?

Q Yes X No 18. Agency contact ( person who can best answer questions regarding the content of this submission) Name: Gregory Fried Phone: ( 202) 564 7016 OMB 83 I 10/ 95 19. Certification for Paperwork Reduction Act Submissions On behalf of this Federal agency, I certify that the collection of information encompassed by this request complies with' 5 CFR 1320.9.

NOTE: The text of 5 CFR 1320.9, and the related provisions of 5 CFR 1320.8( b)( 3), appear at the end of the instructions. The certification is to be made with reference to those regulatory provisions as set forth in the instructions.

The following is a summary of the topics, regarding the proposed collection of information, that the certification covers:

( a) It is necessary for the proper performance of agency functions;

( b) It avoids unnecessary duplication;

( c) It reduces burden on small entities;

( d) It uses plain, coherent, and unambiguous terminology that is understandable to respondents;

( e) Its implementation will be consistent and compatible with current reporting and recordkeeping practices;

( f) It indicates the retention periods for recordkeeping requirements;

( g) It informs respondents of the information called for under 5 CFR 1320.8( b)( 3):

( i) Why the information is being collected; ( ii) Use of information; ( iii) Burden estimate; ( iv) Nature of response ( voluntary, required for a benefit, or mandatory); ( v) Nature and extent of confidentiality; and ( vi) Need to display currently valid OMB control number;

( h) It was developed by an office that has planned and allocated resources for the efficient and effective management and use of the information to be collected ( see note in Item 19 of the instructions);

( i) It uses effective and efficient statistical survey methodology; and ( j) It makes appropriate use of information technology.

If you are unable to certify compliance with any of these provisions, identify the item below and explain the reason in Item 18 of the Supporting Statement.

Signature of Program Official Michael S. Alushin, Director Compliance Assessment and Media Programs Division Office of Compliance Office of Enforcement and Compliance Assurance Date Signature of Senior Official or designee Oscar Morales, Director Collection Strategies Division Office of Environmental Information Date OMB 83 I 10/ 95


? Need to return call by / at/ between and . Signature: Project No.: 0<IP_ADDRESS> DISTRIBUTION Page __ 1_ of _ 1_

Project Name: 304( m) OCPSF Detailed Study TELEPHONE CALL RECORD Outgoing Call Date: 11/ 17/ 03 Time: 2 p. m.

Company Name: Koppers Dolomite Dolomite, AR Company Number: 205 744 9660 Contact Name: Ellie Ku Codding Phone No.: 703 633 1673 Name: Ron Rutledge Eastern Research Group, Inc.

GENERAL SUBJECT : PACs at Tar Sites TOPICS DISCUSSED AND ACTION TAKEN I called Mr. Rutledge to discuss the PACs reported as discharged in the 2000 TRI. He said that he monitors quarterly for benzo( a) anthracene, benzo( a) pyrene, benzo( k) fluoranthene, and 3,4 benzofluoranthene. The first two parameters are monitored at the internal outfall, and the latter two are monitored from an outfall that contains a lot of storm water. He didn't know about 2000, but in 2002 ( December), all the compounds were tested BDL (< 5 ppb), except for chloroform, which measured at 10 ppb. He said he wasn't sure why they even monitored for chloroform since they don't use it in their process. Mr. Rutledge uses consultants to complete his annual TRI forms, and he was not sure how the consultants calculated the 2000 TRI releases, but they could have been based on concentrations BDL.

I asked him about his products, and he explained that they use coal tar feedstock from coke plants, which they put through a still. The bottoms are recovered and sold as industrial pitches, phenols, and anodes for primary aluminum manufacturers. They also recover creosote and naphthalene as by products.


[Federal Register Volume 83, Number 119 (Wednesday, June 20, 2018)]
[Proposed Rules]
[Pages 28553-28555]
[FR Doc No: 2018-13126]

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DEPARTMENT OF TRANSPORTATION

Federal Aviation Administration

14 CFR Part 39

[Docket No. FAA-2018-0546; Product Identifier 2017-NM-171-AD]
RIN 2120-AA64

Airworthiness Directives; Bombardier, Inc., Airplanes

AGENCY: Federal Aviation Administration (FAA), DOT.

ACTION: Notice of proposed rulemaking (NPRM).

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

SUMMARY: We propose to adopt a new airworthiness directive (AD) for
certain Bombardier, Inc., Model BD-700-1A10 and BD-700-1A11 airplanes.
This proposed AD was prompted by reports of multiple in-flight
departures of the aft belly fairing access panels. This proposed AD
would require modification of the aft belly fairing access panels. We
are proposing this AD to address the unsafe condition on these
products.

DATES: We must receive comments on this proposed AD by August 6, 2018.

ADDRESSES: You may send comments, using the procedures found in 14 CFR
11.43 and 11.45, by any of the following methods:
     Federal eRulemaking Portal: Go to http://www.regulations.gov. Follow the instructions for submitting comments.
     Fax:<PHONE_NUMBER>.
     Mail: U.S. Department of Transportation, Docket
Operations, M-30, West Building Ground Floor, Room W12-140, 1200 New
Jersey Avenue SE, Washington, DC 20590.
     Hand Delivery: Deliver to Mail address above between 9
a.m. and 5 p.m., Monday through Friday, except Federal holidays.
    For service information identified in this NPRM, contact
Bombardier, Inc., 400 C[ocirc]te-Vertu Road West, Dorval, Qu[eacute]bec
H4S 1Y9, Canada; telephone<PHONE_NUMBER>; fax<PHONE_NUMBER>; email
[email protected]; internet http://www.bombardier.com. You
may view this service information at the FAA, Transport Standards
Branch, 2200 South 216th St., Des Moines, WA. For information on the
availability of this material at the FAA, call<PHONE_NUMBER>.

Examining the AD Docket

    You may examine the AD docket on the internet at http://www.regulations.gov by searching for and locating Docket No. FAA-2018-
0546; or in person at the Docket Management Facility between 9 a.m. and
5 p.m., Monday through Friday, except Federal holidays. The AD docket
contains this NPRM, the regulatory evaluation, any comments received,
and other information. The street address for the Docket Operations
office (telephone<PHONE_NUMBER>) is in the ADDRESSES section. Comments
will be available in the AD docket shortly after receipt.

FOR FURTHER INFORMATION CONTACT: Andrea Jimenez, Aerospace Engineer,

Airframe and Mechanical Systems Section, FAA, New York ACO Branch, 1600
Stewart Avenue, Suite 410, Westbury, NY 11590; telephone<PHONE_NUMBER>;
fax<PHONE_NUMBER>.

SUPPLEMENTARY INFORMATION:

Comments Invited

    We invite you to send any written relevant data, views, or
arguments about this proposal. Send your comments to an address listed
under the ADDRESSES section. Include ``Docket No. FAA-2018-0546;
Product Identifier 2017-NM-171-AD'' at the beginning of your comments.
We specifically invite comments on the overall regulatory, economic,
environmental, and energy aspects of this NPRM. We will consider all
comments received by the closing date and may amend this NPRM based on
those comments.
    We will post all comments we receive, without change, to http://www.regulations.gov, including any personal information you provide. We
will also post a report summarizing each substantive verbal contact we
receive about this NPRM.

Discussion

    Transport Canada Civil Aviation (TCCA), which is the aviation
authority for Canada, has issued Canadian AD CF-2017-31, dated
September 22, 2017 (referred to after this as the Mandatory Continuing
Airworthiness Information, or ``the MCAI''), to correct an unsafe
condition for certain Bombardier, Inc., Model BD-700-1A10 and BD-700-
1A11 airplanes. The MCAI states:

    There have been multiple in-service occurrences where operators
reported in-flight departure of the aft belly fairing access panels,
185CL and/or 186CR. There has been no damage reported to the
affected aircraft to date, however departure of the panels in any
phase of flight could create runway hazards or a hazard to persons
and property on the ground.
    Bombardier Inc. has issued Service Bulletins (SBs) to
incorporate new self-locking nutplates with associated hardware
(retaining rings and studs) to improve fastener engagement. A
bracket has also been added to provide two additional panel
attachment points.
    This [Canadian] AD requires the incorporation of these design
changes to prevent departure of the two aft belly fairing access
panels in flight and the associated risk on the ground.

    You may examine the MCAI in the AD docket on the internet at http://www.regulations.gov by searching for and locating Docket No. FAA-2018-
0546.

Related Service Information Under 1 CFR Part 51

    Bombardier has issued the following service information:
     Service Bulletin 700-1A11-53-025, Revision 01, dated
December 16, 2016;
     Service Bulletin 700-53-050, Revision 01, dated December
16, 2016;
     Service Bulletin 700-53-5009, Revision 01, dated December
16, 2016; and
     Service Bulletin 700-53-6008, Revision 01, dated December
16, 2016.
    The service information describes actions to modify the aft belly
fairing access panels by replacing the attachments. These documents are
distinct since they apply to different airplane models in different
configurations. This service information is reasonably available
because the interested parties have access to it through their normal
course of business or by the means identified in the ADDRESSES section.

FAA's Determination and Requirements of This Proposed AD

    This product has been approved by the aviation authority of another
country, and is approved for operation in the United States. Pursuant
to our bilateral agreement with the State of Design Authority, we have
been notified of the unsafe condition described in the MCAI and service
information referenced above. We are proposing this AD because we
evaluated all pertinent information and determined an unsafe condition
exists and is likely to exist or develop on other products of the same
type design.

Costs of Compliance

    We estimate that this proposed AD affects 110 airplanes of U.S.
registry. We estimate the following costs to comply with this proposed
AD:

                                                 Estimated Costs
----------------------------------------------------------------------------------------------------------------
                                                                                Cost per       Cost on U.S.
                          Labor cost                              Parts cost        product         operators
----------------------------------------------------------------------------------------------------------------
4 work-hours x $85 per hour = $340...........................          $2,640           $2,980         $327,800
----------------------------------------------------------------------------------------------------------------

    According to the manufacturer, some of the costs of this proposed
AD may be covered under warranty, thereby reducing the cost impact on
affected individuals. We do not control warranty coverage for affected
individuals. As a result, we have included all costs in our cost
estimate.

Authority for This Rulemaking

    Title 49 of the United States Code specifies the FAA's authority to
issue rules on aviation safety. Subtitle I, section 106, describes the
authority of the FAA Administrator. ``Subtitle VII: Aviation
Programs,'' describes in more detail the scope of the Agency's
authority.
    We are issuing this rulemaking under the authority described in
``Subtitle VII, Part A, Subpart III, Section 44701: General
requirements.'' Under that section, Congress charges the FAA with
promoting safe flight of civil aircraft in air commerce by prescribing
regulations for practices, methods, and procedures the Administrator
finds necessary for safety in air commerce. This regulation is within
the scope of that authority because it addresses an unsafe condition
that is likely to exist or develop on products identified in this
rulemaking action.
    This proposed AD is issued in accordance with authority delegated
by the Executive Director, Aircraft Certification Service, as
authorized by FAA Order 8000.51C. In accordance with that order,
issuance of ADs is normally a function of the Compliance and
Airworthiness Division, but during this transition period, the
Executive Director has delegated the authority to issue ADs applicable
to transport category airplanes to the Director of the System Oversight
Division.

Regulatory Findings

    We determined that this proposed AD would not have federalism
implications under Executive Order 13132. This proposed AD would not
have a substantial direct effect on the States, on the relationship
between the national Government and the States, or on the distribution
of power and responsibilities among the various levels of government.
    For the reasons discussed above, I certify this proposed
regulation:
    1. Is not a ``significant regulatory action'' under Executive Order
12866;

    2. Is not a ``significant rule'' under the DOT Regulatory Policies
and Procedures (44 FR 11034, February 26, 1979);
    3. Will not affect intrastate aviation in Alaska; and
    4. Will not have a significant economic impact, positive or
negative, on a substantial number of small entities under the criteria
of the Regulatory Flexibility Act.

List of Subjects in 14 CFR Part 39

    Air transportation, Aircraft, Aviation safety, Incorporation by
reference, Safety.

The Proposed Amendment

    Accordingly, under the authority delegated to me by the
Administrator, the FAA proposes to amend 14 CFR part 39 as follows:

PART 39--AIRWORTHINESS DIRECTIVES

0
1. The authority citation for part 39 continues to read as follows:

    Authority:  49 U.S.C. 106(g), 40113, 44701.

Sec.  39.13   [Amended]

0
2. The FAA amends Sec.  39.13 by adding the following new airworthiness
directive (AD):

Bombardier, Inc.: Docket No. FAA-2018-0546; Product Identifier 2017-
NM-171-AD.

(a) Comments Due Date

    We must receive comments by August 6, 2018.

(b) Affected ADs

    None.

(c) Applicability

    This AD applies to Bombardier, Inc., Model BD-700-1A10 and BD-
700-1A11 airplanes, certificated in any category, serial numbers
9002 through 9770 inclusive, 9772 through 9781 inclusive, and 9998.

(d) Subject

    Air Transport Association (ATA) of America Code 53, Fuselage.

(e) Reason

    This AD was prompted by reports of multiple in-flight departures
of the aft belly fairing access panels. We are issuing this AD to
prevent in-flight departures of the aft belly fairing access panels,
which could result in runway hazards or hazards to people on the
ground.

(f) Compliance

    Comply with this AD within the compliance times specified,
unless already done.

(g) Access Panel Modification

    Within 15 months after the effective date of this AD, modify the
aft belly fairing access panels by replacing the attachments, in
accordance with the Accomplishment Instructions of the applicable
service information identified in paragraphs (g)(1) and (g)(2) of
this AD.
    (1) For Model BD-700-1A10 airplanes: Bombardier Service Bulletin
700-53-050, or 700-53-6008, both Revision 01, both dated December
16, 2016.
    (2) For Model BD-700-1A11 airplanes: Bombardier Service Bulletin
700-1A11-53-025, or 700-53-5009, both Revision 01, both dated
December 16, 2016.

(h) Credit for Previous Actions

    This paragraph provides credit for actions required by paragraph
(g) of this AD, if those actions were performed before the effective
date of this AD using the applicable service information identified
in paragraphs (h)(1) through (h)(4) of this AD.
    (1) Bombardier Service Bulletin 700-1A11-53-025, dated July 14,
2016.
    (2) Bombardier Service Bulletin 700-53-050, dated July 14, 2016.
    (3) Bombardier Service Bulletin 700-53-5009, dated July 14,
2016.
    (4) Bombardier Service Bulletin 700-53-6008, dated July 14,
2016.

(i) Other FAA AD Provisions

    The following provisions also apply to this AD:
    (1) Alternative Methods of Compliance (AMOCs): The Manager, New
York ACO Branch, FAA, has the authority to approve AMOCs for this
AD, if requested using the procedures found in 14 CFR 39.19. In
accordance with 14 CFR 39.19, send your request to your principal
inspector or local Flight Standards District Office, as appropriate.
If sending information directly to the manager of the certification
office, send it to ATTN: Program Manager, Continuing Operational
Safety, FAA, New York ACO Branch, 1600 Stewart Avenue, Suite 410,
Westbury, NY 11590; telephone<PHONE_NUMBER>; fax<PHONE_NUMBER>. Before
using any approved AMOC, notify your appropriate principal
inspector, or lacking a principal inspector, the manager of the
local flight standards district office/certificate holding district
office.
    (2) Contacting the Manufacturer: For any requirement in this AD
to obtain corrective actions from a manufacturer, the action must be
accomplished using a method approved by the Manager, New York ACO
Branch, FAA; or Transport Canada Civil Aviation (TCCA); or
Bombardier Inc.'s TCCA Design Approval Organization (DAO). If
approved by the DAO, the approval must include the DAO-authorized
signature.

(j) Related Information

    (1) Refer to Mandatory Continuing Airworthiness Information
(MCAI) Canadian Airworthiness Directive CF-2017-31, dated September
22, 2017, for related information. This MCAI may be found in the AD
docket on the internet at http://www.regulations.gov by searching
for and locating Docket No. FAA-2018-0546.
    (2) For more information about this AD, contact Andrea Jimenez,
Aerospace Engineer, Airframe and Mechanical Systems Section, FAA,
New York ACO Branch, 1600 Stewart Avenue, Suite 410, Westbury, NY
11590; telephone<PHONE_NUMBER>; fax<PHONE_NUMBER>.
    (3) For service information identified in this AD, contact
Bombardier, Inc., 400 C[ocirc]te-Vertu Road West, Dorval,
Qu[eacute]bec H4S 1Y9, Canada; telephone<PHONE_NUMBER>; fax 514-855-
7401; email [email protected]; internet http://www.bombardier.com. You may view this service information at the
FAA, Transport Standards Branch, 2200 South 216th St., Des Moines,
WA. For information on the availability of this material at the FAA,
call<PHONE_NUMBER>.

    Issued in Des Moines, Washington, on June 8, 2018.
Michael Kaszycki,
Acting Director, System Oversight Division, Aircraft Certification
Service.
[FR Doc. 2018-13126 Filed 6-19-18; 8:45 am]
 BILLING CODE 4910-13-P


[Federal Register: November 29, 2010 (Volume 75, Number 228)]
[Notices]
[Page 73069-73070]
[DOCID:fr29no10-66]

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

DEPARTMENT OF ENERGY

Federal Energy Regulatory Commission

[Docket No. PR10-97-001; Docket No. PR10-101-001; Docket No. PR10-125-
001; Docket No. PR10-83-001]

Enstor Grama Ridge Storage and Transportation, LLC, Enstor Katy
Storage and Transportation, LP, et al.; Notice of Baseline Filings

November 18, 2010.

Enstor Grama Ridge Storage     Docket No. PR10-97-001.
 and Transportation, LLC.
Enstor Katy Storage and        Docket No. PR10-101-001.
 Transportation, LP.
NorthWestern Corporation.....  Docket No. PR10-125-001.
New York State Electric & Gas  Docket No. PR10-83-001.
 Corporation.
                               Not Consolidated.

    Take notice that on November 10, 2010, November 12, 2010, and
November 17, 2010, the applicants listed above submitted a revised
baseline filing of their Statement of Operating Conditions for services
provided under Section 311 of the Natural Gas Policy Act of 1978
(``NGPA'').
    Any person desiring to participate in this rate proceeding must
file a motion 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 on or before the date as indicated below. 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 7 copies of the protest or
intervention to the Federal Energy Regulatory Commission, 888 First
Street, NE., Washington, DC 20426.
    This filing is accessible online 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>.
    Comment Date: 5 p.m. Eastern Time on Monday, November 29, 2010.

Kimberly D. Bose,
Secretary.
[FR Doc. 2010-29844 Filed 11-26-10; 8:45 am]
BILLING CODE 6717-01-P


[Federal Register Volume 76, Number 84 (Monday, May 2, 2011)]
[Notices]
[Page 24472]
[FR Doc No: 2011-10509]

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

DEPARTMENT OF ENERGY

Federal Energy Regulatory Commission

[Docket No. PR11-101-000]

UGI Central Penn Gas, Inc.; Notice of Petition for Rate Approval
Take notice that on April 8, 2011, UGI Central Penn Gas, Inc. (CPG)
filed a petition pursuant to section 284.123(b)(1)(ii) of the
Commission's regulations a rate election for interruptible
transportation service. CPG states the rate election consists of the
applicable interruptible component of its currently effective Large
Volume Daily Delivery Service rate contained in Rate Schedule L on file
with the Pennsylvania Public Utility Commission. In addition, CPG
submits a revised Statement of Operating Conditions and General Terms
and Conditions, as more fully described in the petition.

    Any person desiring to participate in this rate 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 on or before the date as indicated below. 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 7 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>.
    Comment Date: 5 p.m. Eastern Time on Friday, April 22, 2011.

    Dated: April 12, 2011.
Kimberly D. Bose,
Secretary.
[FR Doc. 2011-10509 Filed 4-29-11; 8:45 am]
BILLING CODE 6717-01-P