OFFICE OF PREVENTION, PESTICIDES, AND TOXIC SUBSTANCES UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON, D. C. 20460 TXR No.: 0052862 MEMORANDUM DATE: September 17, 2004 SUBJECT: AMETRYN: Report of the Cancer Assessment Review Committee PC Code: 080801 FROM: Jessica Kidwell, Executive Secretary Cancer Assessment Review Committee Health Effects Division ( 7509C)

TO: John Doherty, Toxicologist ( RRB3) William Donovan, Risk Assessor ( RRB3) Health Effects Division ( 7509C)

Mark Howard, CRM Reregistration Branch 3 Special Review and Reregistration Division ( 7508C)

The Cancer Assessment Review Committee met on July 21, 2004 to evaluate the carcinogenic potential of Ametryn. Attached please find the Final Cancer Assessment Document.

cc: J. Pletcher Y. Woo CANCER ASSESSMENT DOCUMENT EVALUATION OF THE CARCINOGENIC POTENTIAL OF AMETRYN PC Code 080801 FINAL REPORT September 17, 2004 CANCER ASSESSMENT REVIEW COMMITTEE HEALTH EFFECTS DIVISION OFFICE OF PESTICIDE PROGRAMS AMETRYN CANCER ASSESSMENT DOCUMENT FINAL iii DATA PRESENTATION: John Doherty, Toxicologist DOCUMENT PREPARATION: Jessica Kidwell, Executive Secretary COMMITTEE MEMBERS IN ATTENDANCE: ( Signature indicates concurrence with the assessment unless otherwise stated).

Karl Baetcke Lori Brunsman, Statistician William Burnam, Chair Marion Copley Vicki Dellarco Abdallah Khasawinah Nancy McCarroll Esther Rinde Jess Rowland Linda Taylor NON COMMITTEE MEMBERS IN ATTENDANCE: ( Signature indicates concurrence with the pathology report and statistical analysis of data, respectively) AMETRYN CANCER ASSESSMENT DOCUMENT FINAL iv John Pletcher, Consulting Pathologist OTHER ATTENDEES: Karlyn Bailey ( HED/ RAB2), Kelly Schumacher ( HED/ RAB2), Gerome Burke ( HED/ RAB3), Zaida Tigueroa ( HED/ RAB2), Bridgett Bobowiec ( HED/ SIMB), Kimberly Kosick ( HED/ RAB2)

TABLE OF CONTENTS EXECUTIVE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 I. INTRODUCTION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 II. BACKGROUND INFORMATION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 III. EVALUATION OF CARCINOGENICITY STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . 3 1. Combined Chronic Toxicity/ Carcinogenicity Study with Ametryn . . . . . . . . . . . . . . . . 3 2. Carcinogenicity Study in Mice . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15 IV. TOXICOLOGY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16 1. Metabolism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16 2. Mutagenicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16 3. Structure Activity Relationship . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16 4. Subchronic and Chronic Toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17 5. Mode of Action Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19 V. COMMITTEE'S ASSESSMENT OF THE WEIGHT OF THE EVIDENCE . . . . . . . 20 1. Carcinogenicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20 2. Mutagenicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20 3. Structure Activity Relationship . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20 4. Mode of Action . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20 VI. CLASSIFICATION OF CARCINOGENIC POTENTIAL . . . . . . . . . . . . . . . . . . . . . . 21 VII. QUANTIFICATION OF CARCINOGENIC POTENTIAL . . . . . . . . . . . . . . . . . . . . . 21 VIII BIBLIOGRAPHY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21 AMETRYN CANCER ASSESSMENT DOCUMENT FINAL v AMETRYN CANCER ASSESSMENT DOCUMENT FINAL 1 EXECUTIVE SUMMARY On July 21, 2004, the Cancer Assessment Review Committee of the Health Effects Division of the Office of Pesticide Programs met to evaluate the carcinogenic potential of Ametryn.

John Doherty of Reregistration Branch 3 presented the chronic toxicity/ carcinogenicity studies in Sprague Dawley rats and HAM/ ICE Swiss mice. In the rat carcinogenicity study, ametryn was administered in the diet to groups of Sprague Dawley rats ( 70/ sex/ dose) at dose levels of 0, 50, 500, or 5000/ 4000/ 2000 ppm ( 0, 2, 20.9, 145.3 mg/ kg/ day for males; 0, 2.5, 26.2, 176.1 mg/ kg/ day for females) for 104 weeks. The high dose group rats received 5000 ppm that was reduced to 4000 ppm after 141 days and further reduced to 2000 ppm after 239 days because of reductions in weight gain. In the mouse study, ametryn was administered in the diet to groups of HAM/ ICE Swiss mice ( 60/ sex/ dose) at dose levels of 0, 10, 1000 or 2000 ppm ametryn for a period of 102 weeks. These doses corresponded to approximately 0, 1.5, 150 and 300 mg/ kg/ day.

The CARC concluded the following:

Rat

The CARC considered dosing at the high dose in male and female rats to be excessive and not adequate for the assessment of carcinogenicity. The tumor findings at the high dose cannot be interpreted because the animals were compromised due to large decreases in body weight/ body weight gain during the first 8 months of the study. Consequently, although statistical analyses were performed, the tumor data in rats were not discussed at this meeting. In addition, the 500 ppm dose group was not considered adequate for assessment of carcinogenicity since this was the NOAEL for the study, no tumors were seen at this dose, and the dose spread ( 500 ppm  5000 ( 10 fold)/ 4000 ( 8 fold)/ 2000 ppm ( 4 fold) was considered to be too large.

The high dose males weighed 29 38% less than controls when fed 5000 ppm from day 1 140, except for day 21 when they weighed 48% less than controls. They weighed 23 28% less than controls when fed the 4000 ppm diet from day 140 239 and the 2000 ppm diet for the remainder of the first year ( day 239 364), and 18 23% less than controls during the second year of the study. The males gained 38% less weight than controls when fed the 5000 ppm diet, 20% less when fed the 4000 ppm diet, and 29% more than controls when fed the 2000 ppm diet for the remainder of the first year. Although high dose males gained two times more weight than controls during the second year, the resulting overall weight gain was 22% below that of controls.

High dose females weighed 20 26% less than controls when fed the 5000 ppm diet, 24 AMETRYN CANCER ASSESSMENT DOCUMENT FINAL 2 34% less than controls when fed the 4000 ppm diet and the 2000 ppm diet for the remainder of the first year, and 25 28% less than controls during the second year of the study. High dose females gained 40% less weight than controls when fed the 5000 ppm diet, 57% less when fed the 4000 ppm diet, and 15% more weight than controls when fed the 2000 ppm diet for the remainder of the first year of the study. High dose females gained 51% less weight than controls during the second year, resulting in an overall weight gain 37% less than that of controls.

Mouse

No treatment related tumors were seen in male or female mice.

The CARC concluded that dosing at the high dose in both male and female mice was adequate and not excessive. Although the high dose of 2000 ppm ( 300 mg/ kg/ day) in the definitive mouse study did not result in systemic toxicity, the mouse 28 day range finding study demonstrated body weight gain decreases at 1000 (  12% in males and  17% in females) and 3000 (  24% in males and  46% in females) ppm which justified selection of 2000 ppm as the high dose for the definitive cancer study with mice.

There is no mutagenicity concern with ametryn.

Atrazine is a triazine herbicide. The chlorotriazine pesticides have been shown to increase mammary gland tumors in female rats. Because ametryn is not a chlorotriazine, SAR does not provide support for carcinogenic potential.

No specific mode of action studies were submitted with ametryn.

In accordance with the EPA Draft Guidelines for Carcinogen Risk Assessment ( July, 1999), the Committee classified ametryn into the category " Data Are Inadequate for An Assessment of Human Carcinogenic Potential". The carcinogenicity study in the rats is unacceptable because the high dose was considered to be excessive in both sexes. The animals in the high dose group were compromised due to large decreases in body weight/ body weight gain which render the neoplastic findings in this group uninterpretable. In addition, the 500 ppm dose group was not considered adequate for assessment of carcinogenicity since this was the NOAEL for the study, no tumors were seen at this dose, and the dose spread ( 500 ppm  5000 ( 10 fold)/ 4000 ( 8 fold)/ 2000 ppm ( 4 fold) was too large. The CARC requested that the carcinogenicity study in rats be repeated at a dose that was adequate to assess carcinogenicity. Quantification of carcinogenic potential is not applicable. AMETRYN CANCER ASSESSMENT DOCUMENT FINAL 3 I. INTRODUCTION On July 21, 2004, the Cancer Assessment Review Committee of the Health Effects Division of the Office of Pesticide Programs met to evaluate the carcinogenic potential of Ametryn.

II. BACKGROUND INFORMATION Chemical common name: Ametryn Type of pesticide: triazine herbicide PC Code: 080801 CAS Number: 834 12 8 Chemical name: 2 ethylamino 4 isopropylamino 6 methylthio s triazine. Structure:

III. EVALUATION OF CARCINOGENICITY STUDIES 1. Combined Chronic Toxicity/ Carcinogenicity Study with Ametryn References: Hazelette, J. and J. Green ( 1987) Ametryn: Combined chronic toxicity/ oncogenicity study in rats. CIBA GEIGY Corporation, Research Department, Pharmaceutical Division, Summit, New Jersey. Laboratory Report No. 842119. August 24, 1987. MRID 40349906. Unpublished.

Hazelette, J. and J. Green ( 1987) Ametryn: Supplement to combined chronic toxicity/ oncogenicity study in rats. CIBA GEIGY Corporation, Research Department, Pharmaceutical Division, Summit, New Jersey. Laboratory Report No. 842119. August 24, 1987. MRID 41184201. Unpublished.

Tai, C. 1987. Ametryn: 4 week range finding study in rats. CIBY GEIGY Corporation, Pharmaceuticals Division, Summit, NJ. Laboratory Report No. 842084. August, 11, 1987. MRID 40382001. Unpublished. AMETRYN CANCER ASSESSMENT DOCUMENT FINAL 4 A. Experimental Design In a combined chronic toxicity/ carcinogenicity study ( 1987, MRID 40349906), Ametryn ( 98.6% a. i., FL 840991) was administered to groups of 70 Sprague Dawley [ Crl: COBS ® CD ® ( SD) BR] rats per sex at concentrations of 0, 50, or 500 ppm for 104 weeks. Groups of 70 rats per sex received 5000 ppm that was reduced to 4000 ppm after 141 days and further reduced to 2000 ppm after 239 days because of reductions in weight gain. Ten rats/ sex/ group were sacrificed after 52 weeks for interim evaluation, and ten rats/ sex in the control and high dose groups were dosed for 52 weeks followed by control diet for 4 weeks to assess recovery, and sacrificed at 56 weeks ( recovery group).

B. Discussion of Survival and Tumor Data [ Note: Although statistical analyses were performed and are presented in this document, the results were not discussed at the CARC meeting.]

Survival Analyses The statistical evaluation of mortality indicated a statistically significant decreasing trend with increasing doses of Ametryn in both male and female rats ( Memo, J. Kidwell, 6/ 30/ 04, TXR No. 0052655) . See Table 1 for male mortality test results and Table 2 for female mortality test results showing the increase in survival in the groups dosed with ametryn.

The statistical evaluation of mortality was based upon the Thomas, Breslow and Gart computer program.

Tumor Analyses Males Testicular Interstitial Cell Tumors ( benign): Male rats had a significant increasing trend in benign interstitial cell tumors of the testes at p< 0.01. However, no significant differences in the pair wise comparisons of the dosed groups with the controls were seen for benign interstitial cell tumors of the testes ( Table 3).

Epididymides ( Mesothelioma): Male rats had a significant increasing trend in benign mesotheliomas of the epididymides at p< 0.05. However, no significant differences in the pairwise comparisons of the dosed groups with the controls were seen for benign mesotheliomas of the epididymides ( Table 4).

Thyroid Follicular Cell Tumors: There were no significant trends or pair wise comparisons of AMETRYN CANCER ASSESSMENT DOCUMENT FINAL 5 the dosed groups with the controls for thyroid follicular cell adenomas for male rats. Male rats had a significant increasing trend in thyroid follicular cell adenocarcinomas at p< 0.01, and a significant pair wise comparison of the 5000/ 4000/ 2000 ppm dose group with the control for this tumor at p< 0.05. There was a significant increasing trend in combined thyroid follicular cell adenomas and/ or adenocarcinomas at p< 0.01. No significant differences in the pair wise comparisons of the dosed groups with the controls were seen for combined thyroid tumors ( Table 5).

Females Liver Tumors: Female rats had a significant increasing trend in liver adenomas at p< 0.05, however, no significant differences in the pair wise comparisons were seen. There were no significant trends or pair wise comparisons of the dosed groups with the controls for liver carcinomas in female rats. There was a significant increasing trend in combined liver adenomas and/ or carcinomas in female rats at p< 0.05, however, there was no significant pair wise comparisons of the dosed groups with the controls ( Table 6).

Mammary Gland Tumors: Female rats had a significant increasing trend in mammary gland adenomas at p< 0.05, however no significant differences in the pair wise comparisons were noted for this tumor. There were significant increasing trends, and significant differences in the pairwise comparisons of the 5000/ 4000/ 2000 ppm dose group with the controls, for mammary gland adenocarcinomas and combined adenomas and/ or adenocarcinomas, all at p< 0.05 ( Table 7).

The statistical analyses of the male and female rats were based upon Peto's prevalence test due to significant differential mortality among the dose groups in both sexes ( Memo, J. Kidwell, 6/ 30/ 04, TXR No. 0052655). AMETRYN CANCER ASSESSMENT DOCUMENT FINAL 6 Table 1. Ametryn  Sprague Dawley Rat Study Male Mortality Rates+ and Cox or Generalized K/ W Test Results Weeks Dose ( ppm) 1 26 27 52 53 i 53 56 56r 57 78 79 106f Total 0 1/ 90 1/ 89 10/ 88 1/ 78 9/ 77 5/ 68 33/ 63 41/ 71** n ( 58)

50 0/ 80 3/ 80 10/ 77 1/ 67  7/ 66 21/ 59 32/ 70 ( 46)

500 0/ 80 1/ 80 10/ 79 0/ 69  10/ 69 23/ 59 34/ 70 ( 49)

5000/ 4000/ 2000 0/ 90 0/ 90 10/ 90 0/ 80 10/ 80 3/ 70 11/ 67 14/ 70** n ( 20)

+ Number of animals that died during interval/ Number of animals alive at the beginning of the interval. iInterim sacrifice at week 53. rRecovery group sacrifice at week 56. fFinal sacrifice at week 106. nNegative trend or negative change from control. ( ) Percent.

Note: Time intervals were selected for display purposes only. Significance of trend denoted at control. Significance of pair wise comparison with control denoted at dose level. If *, then p < 0.05. If **, then p < 0.01. AMETRYN CANCER ASSESSMENT DOCUMENT FINAL 7 Table 2. Ametryn  Sprague Dawley Rat Study Female Mortality Rates+ and Cox or Generalized K/ W Test Results Weeks Dose ( ppm) 1 26 27 52 53 i 53 56 56r 57 78 79 106f Total 0 0/ 90 2/ 90 10/ 88 1/ 78 9/ 77 10/ 68 27/ 58 40/ 71** n ( 56)

50 0/ 80 1/ 80 10/ 79 0/ 69  5/ 69 33/ 64 39/ 70 ( 56)

500 0/ 80 2/ 80 10/ 78 0/ 68  8/ 68 32/ 60 42/ 70 ( 60)

5000/ 4000/ 2000 1/ 90 3/ 89 10/ 86 1/ 76 9/ 75 1/ 66 17/ 65 23/ 71** n ( 32)

+ Number of animals that died during interval/ Number of animals alive at the beginning of the interval. iInterim sacrifice at week 53. rRecovery group sacrifice at week 56. fFinal sacrifice at week 106. nNegative trend or negative change from control. ( ) Percent Note: Time intervals were selected for display purposes only. Significance of trend denoted at control. Significance of pair wise comparison with control denoted at dose level. If *, then p < 0.05. If **, then p < 0.01. AMETRYN CANCER ASSESSMENT DOCUMENT FINAL 8 Table 3. Ametryn  Sprague Dawley Rat Study: Male Testes Tumor Rates+ and Peto's Prevalence Test Results Dose ( ppm) 0 50 500 5000/ 4000/ 2000 Benign Interstitial Cell Tumors (%)

p = 3a/ 49 ( 6)

0.0033** 0/ 51 ( 0)

0.9455n 3/ 48 ( 6)

0.4548 9/ 62 ( 15)

0.0557 Interstitial cell hyperplasia( a) 2/ 70 4/ 70 5/ 70 12/ 70**

+ Number of tumor bearing animals/ Number of animals examined, excluding those that died before observation of the first tumor. aFirst benign interstitial cell tumor observed at week 94, dose 0 ppm. nNegative change from control ( a) The non neoplastic condition is included to verify that the testis is affected by ametryn.

Note: Interim sacrifice and recovery animals are not included in these analyses. There were no tumors observed in any interim sacrifice animals.

Significance of trend denoted at control. Significance of pair wise comparison with control denoted at dose level. If *, then p < 0.05. If **, then p < 0.01.

The study report referenced a single study for historical control information which indicated that the frequency was 8.8%. Historical control information from the Charles River Company Bulletin ( March, 2001 for the Sprague Dawley Crl: COBS ® CD ® ( SD) BR strain rat) indicated that the range was from 1.43 to 7.14% for 23 studies. Thus, the incidence of testicular interstitial cell tumors at the high dose is in excess of the historical control range.

Table 3 also shows that at the highest dose there is an increase in interstitial hyperplasia, a possibly preneoplastic lesion. AMETRYN CANCER ASSESSMENT DOCUMENT FINAL 9 Table 4. Ametryn  Sprague Dawley Rat Study: Male Epididymides Tumor Rates+ and Peto's Prevalence Test Results Dose ( ppm) 0 50 500 5000/ 4000/ 2000 Benign Mesothelioma (%)

p = 0/ 20 ( 0)

0.0155* 0/ 28 ( 0)

  0/ 25 ( 0)

  3a/ 46 ( 7)

0.1230 + Number of tumor bearing animals/ Number of animals examined, excluding those that died before observation of the first tumor.

aFirst mesothelioma tumor observed at week 105, dose 5000/ 4000/ 2000 ppm.

Note: Interim sacrifice and recovery animals are not included in these analyses. There were no tumors observed in any interim sacrifice animals.

Significance of trend denoted at control. Significance of pair wise comparison with control denoted at dose level. If *, then p < 0.05. If **, then p < 0.01.

Mesothelioma in the epididymidis was not reported in either the single study for historical control data provided with the study report or in the historical control database for the Charles River Laboratory, meaning this tumor type is rare. There were no non neoplastic or pre neoplastic lesions in the epididymides. AMETRYN CANCER ASSESSMENT DOCUMENT FINAL 10 Table 5. Ametryn  Sprague Dawley Rat Study: Male Thyroid Follicular Cell Tumor Rates+ and Peto's Prevalence Test Results Dose ( ppm) 0 50 500 5000/ 4000/ 2000 Adenomas (%)

p = 6/ 65 ( 9)

0.1454 0/ 62 ( 0)

0.9945n 2/ 62 ( 3)

0.9226n 6a/ 68 ( 9)

0.6689 Adenocarcinomas (%)

p = 0/ 51 ( 0)

0.0009** 0/ 52 ( 0)

 0/ 49 ( 0)

 4b/ 63 ( 6)

0.0259*

Combined (%)

p = 6/ 65 ( 9)

0.0068** 0/ 62 ( 0)

0.9945n 2/ 62 ( 3)

0.9226n 10/ 68 ( 15)

0.2629 Follicular hypertrophy 0/ 70 0/ 70 0/ 70 1/ 70 + Number of tumor bearing animals/ Number of animals examined, excluding those that died before observation of the first tumor.

aFirst adenoma observed at week 74, dose 5000/ 4000/ 2000 ppm ( excluding interim sacrifice and recovery animals). bFirst adenocarcinoma observed at week 93, dose 5000/ 4000/ 2000 ppm. nNegative change from control Note: Interim sacrifice and recovery animals are not included in these analyses. One interim sacrifice animal in dose group 50 ppm had a thyroid follicular cell adenoma at week 52. One recovery group animal in dose group 5000/ 4000/ 2000 ppm had a thyroid follicular cell adenoma at week 57.

Significance of trend denoted at control. Significance of pair wise comparison with control denoted at dose level. If *, then p < 0.05. If **, then p < 0.01.

The historical control data from a single study provided by Ciba Geigy reports an incidence of only 1.3%, whereas the Charles River historical control database reports a range of incidence of 0.87 to 3.85%, meaning the incidence in this study with ametryn exceeds the historical control range. There was no indication of increased thyroid follicular cell hyperplasia or hypertrophy that may have preceded the neoplastic lesions. AMETRYN CANCER ASSESSMENT DOCUMENT FINAL 11 Table 6. Ametryn  Sprague Dawley Rat Study: Female Liver Tumor Rates+ and Peto's Prevalence Test Results Dose ( ppm) 0 50 500 5000/ 4000/ 2000 Adenomas (%)

p = 1/ 64 ( 2)

0.0312* 0/ 67 ( 0)

0.8413n 2a/ 65 ( 3)

0.2932 4/ 66 ( 6)

0.1828 Carcinomas (%)

p = 0/ 21 ( 0)

0.2776 0/ 21 ( 0)

 1b/ 19 ( 5)

0.1466 1/ 38 ( 3)

0.2286 Combined (%)

p = 1/ 64 ( 2)

0.0236* 0/ 67 ( 0)

0.8413n 3/ 65 ( 5)

0.1579 5/ 66 ( 8)

0.1209 Hepatocellular Alteration Hyperplasia 20/ 90 18/ 90 24/ 90 21/ 90 28/ 90 21/ 90 59/ 90** 36/ 90**

+ Number of tumor bearing animals/ Number of animals examined, excluding those that died before observation of the first tumor.

aFirst adenoma observed at week 70, dose 500 ppm ( excluding recovery animal). bFirst carcinoma observed at week 105, dose 500 ppm. nNegative change from control.

Note: Interim sacrifice and recovery animals are not included in these analyses. One recovery group animal in dose group 0 ppm had an adenoma at week 56.

Significance of trend denoted at control. Significance of pair wise comparison with control denoted at dose level. If *, then p < 0.05. If **, then p < 0.01.

The historical control incidence for liver adenomas from the single study provided by Ciba Geigy was 3.8% and the historical control range for adenomas in the liver of females was 0.77 to 13.33% from the Charles River database. The incidence of liver adenomas at the high dose is within historical control range. Table 6 also shows increases in hepatocellular alterations and hyperplasia, possibly pre neoplastic lesions, which also demonstrate that the liver is a target AMETRYN CANCER ASSESSMENT DOCUMENT FINAL 12 organ.

Table 7. Ametryn  Sprague Dawley Rat Study: Female Mammary Gland Tumor Rates+ and Peto's Prevalence Test Results Dose ( ppm) 0 50 500 5000/ 4000/ 2000 Adenomas (%)

p = 0/ 90 ( 0)

0.0458* 2/ 79 ( 3)

0.1053 0/ 79 ( 0)

 3a/ 86 ( 3)

0.0534 Adenocarcinomas (%)

p = 12/ 90 ( 13)

0.0438* 14/ 79 ( 18)

0.3186 17/ 79 ( 22)

0.1299 24b/ 86 ( 28)

0.0342*

Combined (%)

p = 12/ 90 ( 13)

0.0303* 15c/ 79 ( 19)

0.2532 17/ 79 ( 22)

0.1299 25d/ 86 ( 29)

0.0210*

+ Number of tumor bearing animals/ Number of animals examined, excluding those that died before week 42. aFirst adenoma observed at week 91, dose 5000/ 4000/ 2000 ppm. bFirst adenocarcinoma observed at week 42, dose 5000/ 4000/ 2000 ppm. cOne animal in the 50 ppm dose group had both an adenoma and adenocarcinoma. dTwo animals in the 5000/ 4000/ 2000 ppm dose group had both an adenoma and adenocarcinoma.

Note: Interim sacrifice and recovery animals are included in these analyses.

Significance of trend denoted at control. Significance of pair wise comparison with control denoted at dose level. If *, then p < 0.05. If **, then p < 0.01.

The incidence in the single study provided by Ciba Geigy was only 8.8%, but it was not specified if this was for adenoma or adenocarcinoma. The Charles River data information bulletin indicates that there were 1.67% to 32% incidence of adenoma and 8.57% to 58.33% adenocarcinoma in their historical control database. Thus, the incidence of both adenoma and carcinoma in the study with ametryn is within the historical control range. There were no non neoplastic conditions in the mammary gland to indicate preneoplastic conditions.

c. Non neoplastic Lesions Non neoplastic lesions considered noteworthy are summarized in Table 8. AMETRYN CANCER ASSESSMENT DOCUMENT FINAL 13 TABLE 8. Notable microscopic lesions in male and female rats fed ametryn for 1 year and 2 years Organ/ Lesion Dietary concentration 0 50 500 5000/ 4000/ 2000a Males   1 year Pancreas [ No. animals examined] Acinar cell metaplasia [ 11] 0 [ 10] 0 [ 10] 0 [ 10] 1 Testes [ No. animals examined] Interstitial cell hyperplasia [ 11] 0 [ 10] 0 [ 10] 0 [ 10] 2 Males  1 year + recovery Testes [ No. animals examined] Interstitial cell hyperplasia [ 9] 0     [ 10] 1 Males   2 years Kidney ( pelvis) [ No. animals examined] Mineralization  concretions [ 70] 10 [ 70] 13 [ 70] 16 [ 70] 25**

Liver [ No. animals examined] Hepatocellular hyperplasia [ 70] 22 [ 70] 15 [ 70] 24 [ 70] 34*

Pancreas [ No. animals examined] Acinar cell metaplasia [ 68] 0 [ 70] 0 [ 70] 1 [ 70] 3 Pituitary [ No. animals examined] Hyperplasia [ 70] 13 [ 63] 13 [ 69] 5 [ 70] 26*

Testes [ No. animals examined] Interstitial cell hyperplasia [ 70] 2 [ 70] 4 [ 70] 5 [ 70] 12**

Females   1 year Liver [ No. animals examined] Hepatocellular alterations [ 10] 1 [ 10] 5 [ 10] 4 [ 11] 7*

Pancreas [ No. animals examined] Acinar cell metaplasia [ 10] 0 [ 10] 0 [ 10] 0 [ 11] 2 Females   1 year + recovery Liver [ No. animals examined] Hepatocellular alterations [ 10] 0     [ 9] 3 Females   2 years Liver [ No. animals examined] Hepatocellular alterations Hepatocellular hyperplasia [ 70] 19 18 [ 70] 19 21 [ 70] 24 21 [ 70] 49** 36**

Pancreas [ No. animals examined] Acinar cell metaplasia [ 70] 0 [ 69] 0 [ 70] 1 [ 70] 4 Data taken from pages 3572 3617, MRID 40349906. aThe dietary concentration was reduced to 4000 ppm on 1/ 22/ 85 ( Day 141) and to 2000 ppm on 4/ 30/ 85 ( Day 239) ( see footnote, page 202). * p

0.05, ** p

0.01, statistically significant, treated groups compared with the control group. AMETRYN CANCER ASSESSMENT DOCUMENT FINAL 14 D. Adequacy of the Dosing for Assessment of Carcinogenicity The CARC considered dosing at the high dose in male and female rats to be excessive and not adequate for the assessment of carcinogenicity. They concluded that the tumor findings at the high dose cannot be interpreted because the animals were compromised due to large decreases in body weight/ body weight gain during the first 8 months of the study. In addition, the 500 ppm dose group was not considered adequate for assessment of carcinogenicity since this was the NOAEL for the study, no tumors were seen at this dose, and the dose spread ( 500 ppm  5000 ( 10 fold)/ 4000 ( 8 fold)/ 2000 ppm ( 4 fold) was too large. The high dose group was initially started at 5000 ppm and dosed at this level for 141 days before being reduced to 4000 ppm and it was later reduced to 2000 ppm on day 239. High dose male and female rats weighed significantly ( p  0.01) less than controls throughout the entire study starting with day 7. The NOAEL and LOAEL for this study was 500 ppm and 5000/ 4000/ 2000 ppm, respectively. The high dose males weighed 29 38% less than controls when fed 5000 ppm from day 1 140, except for day 21 when they weighed 48% less than controls. They weighed 23 28% less than controls when fed the 4000 ppm diet from day 140 239 and the 2000 ppm diet for the remainder of the first year ( day 239 364), and 18 23% less than controls during the second year of the study. The males gained 38% less weight than controls when fed the 5000 ppm diet, 20% less when fed the 4000 ppm diet, and 29% more than controls when fed the 2000 ppm diet for the remainder of the first year. High dose males gained two times more weight than controls during the second year resulting in an overall weight gain 22% below that of controls.

High dose females weighed 20 26% less than controls when fed the 5000 ppm diet, 24 34% less than controls when fed the 4000 ppm diet and the 2000 ppm diet for the remainder of the first year, and 25 28% less than controls during the second year of the study. High dose males and females lost weight during the first 7 days of treatment. High dose females gained 40% less weight than controls when fed the 5000 ppm diet, 57% less when fed the 4000 ppm diet, and 15% more weight than controls when fed the 2000 ppm diet for the remainder of the first year of the study. High dose females gained 51% less weight than controls during the second year, resulting in an overall weight gain 37% less than that of controls.

Body weights of high dose males and females at the end of the recovery period showed a similar difference compared with the controls as did high dose rats continuing treatment during the same period. Low dose male and female rats had body weights similar to controls throughout the study. Mid dose male and female rats had body weights statistically significantly ( p  0.05) lower than controls during a few weeks during the study. Mid dose males weighed 4 7% ( p  0.05 or  0.01) less than controls during the first 63 days and at sporadic time points after day 63. Middose females weighed only 2 4% ( p  0.05 or  0.01) less than controls for almost all weeks during the first 91 days of the study.

Other indications of exposure to ametryn noted in the high dose group included hepatocellular AMETRYN CANCER ASSESSMENT DOCUMENT FINAL 15 hyperplasia in both males and females and hepatocellular " alterations" in females, interstitial cell hyperplasia in the testes, acinar cell metaplasia in the pancreas and mineralization in the kidneys.

2. Carcinogenicity Study in Mice Reference: Burdock, G., 1981, FINAL REPORT. 102 week Oncogenicity Study in Mice. Hazleton Laboratories. Virginia, Study No.: 483 128, March 20, 1981. MRID No.: 40349904.

A. Experimental Design Four groups of 60/ sex of HAM/ ICE Swiss, Charles River CD 1 strain mice were dosed as either 0, 10, 1000 or 2000 ppm ametryn ( technical, Batch No.: FL 761356, 98.9% purity) for a period of 102 weeks. These doses corresponded to approximately 0, 1.5, 150 and 300 mg/ kg/ day based on an estimate of 1 ppm = 0.15 mg/ kg/ day.

B. Discussion of Tumor Data The CARC concurred that there were no compound related increases in neoplasms.

C. Adequacy of Dosing for Assessment of Carcinogenicity The CARC concluded that dosing at the high dose in both male and female mice was adequate and not excessive. Although the high dose of 2000 ppm ( 300 mg/ kg/ day) in the definitive mouse study did not result in systemic toxicity, the mouse 28 day range finding study demonstrated body weight gain decreases at 1000 (  12% in males and  17% in females) and 3000 (  24% in males and  46% in females) ppm which justified selection of 2000 ppm as the high dose for the definitive cancer study with mice. AMETRYN CANCER ASSESSMENT DOCUMENT FINAL 16 IV. TOXICOLOGY 1. Metabolism The metabolism of ametryn demonstrates that ametryn is rapidly absorbed and excreted with distribution but little tissue retention ( MRIDs 41463301, 41463302, 41463303, 92002042). Most ametryn was excreted in the urine. Some thirteen water soluble metabolites were found.

2. Mutagenicity The mutagenicity data base does not indicate a concern for mutagenicity/ genetic toxicity. As per memo from I. Mauer ( July 2, 2004), there are acceptable and negative mutagenicity studies ( Ames test in Salmonella, UDS in rat hepatocyte, and mouse micronucleus tests). A forward gene mutation assay in mammalian cell cultures is required to complete the current requirement for mutagenicity/ genetic toxicity testing.

MRID Type of Assay Concentrations Reported Results EPA Classification 40995820 41189701 Ames Assay 0, 20, 80, 320, 1280, 5120 ug/ 0.1 mL No evidence of mutagenicity in Salmonella strains TA 98, TA 100, TA 1535, and TA 1537, up to cytotoxicity. Acceptable/ guideline 41067904 Unscheduled DNA Synthesis in rat hepatocytes 1. 0.41 to 100 ug/ mL 2. 0.137 to 33.3 ug/ mL Negative for increased UDS up to cytotoxicity Acceptable/ guideline 41067903 Mouse Micronucleus Test 1. 800 mg/ kg; harvest at 16, 24, 48 hrs. 2. 200, 400, 800 mg/ kg; harvest at 24 hrs. Negative. for increased MPCEs up to clinical toxicity ( death). Acceptable/ guideline 3. Structure Activity Relationship Ametryn is a methylthio triazine herbicide. HED recently completed a comprehensive structure activity assessment for a model for the common mechanism of action for triazine compounds such as atrazine to induce mammary gland tumors. Rather than attempt to write a synopsis of this document here, the interested readers can refer to the document entitled " The Grouping of a Series of Triazine Pesticides Based on a Common Mechanism of Toxicity" ( HED Document, March, 2002). Atrazine is a triazine herbicide. The chlorotriazine pesticides have been shown to increase mammary gland tumors in female rats. Because ametryn is not a chlorotriazine, SAR does not provide support for carcinogenic potential. AMETRYN CANCER ASSESSMENT DOCUMENT FINAL 17 4. Subchronic and Chronic Toxicity a) Subchronic Toxicity The subchronic toxicity data base for ametryn rat and mouse studies is considered old and the chronic studies replace the subchronic studies in the data base.

28 day range finding mouse: In a 28 day range finding study ( MRID 92002041), mice ( 5/ sex/ group) were fed ametryn technical at dietary dose levels of 0, 30, 100, 300, 600, 1000, 3000, 10,000, and 30,000 ppm.. All 30,000 ppm animals died by the end of week 3. At 10,000 ppm 1 male and 2 females also died. At 3000 ppm clinical signs ( hunched posture, labored breathing and thin appearance) were observed in one of five females. At 1000 and 3000 ppm decreased mean body weight gain was observed in males (  12%,  24%) and females (  17%,

 46%), respectively. The NOEL was 600 ppm, with minimal effects occurring at 1000 and marked effects occurring at 3000 ppm.

b) Chronic Toxicity Rat In a combined chronic toxicity/ carcinogenicity study ( MRID 40349906), Ametryn ( 98.6% a. i., FL 840991) was administered in the feed to groups of 70 Sprague Dawley [ Crl: COBS ® CD ® ( SD) BR] rats per sex at concentrations of 0, 50, or 500 ppm for 104 weeks. Groups of 70 rats per sex received a 5000 ppm diet that was reduced to 4000 ppm after 141 days and further reduced to 2000 ppm after 239 days because of extreme reductions in weight gain at the higher doses. Ten rats/ sex/ group were administered the same diets under the same protocol for 52 weeks for interim evaluation, and ten rats/ sex/ group were administered the control and the high dose diets for 56 weeks followed by control diet for 4 weeks to assess recovery.

Survival rates for high dose male and female rats were significantly greater than those of controls; 80% of males and 69% of females in the high dose group were alive at study termination compared with only 43% and 44% of controls, respectively. The only treatment related clinical sign was loose feces observed in high dose males during the time they were fed the 5000 ppm diet.

High dose male and female rats weighed significantly less than controls throughout the study. High dose males weighed 29 48% less than controls when fed the 5000 ppm diet and 18 26% less when fed the 4000 ppm diet followed by the 2000 ppm diet. High dose females weighed 20 34% less than controls regardless of the concentration of test material in the diet. High dose males and females lost weight during the first week of treatment and gained 38% and 40% less weight, respectively, when fed the 5000 ppm diet, 20% and 57% less weight, respectively, when fed the 4000 ppm diet, and 29% and 15% more weight, respectively, when fed the 2000 ppm diet AMETRYN CANCER ASSESSMENT DOCUMENT FINAL 18 for the remainder of the first year. During the second year, high dose males gained two times more weight than controls and high dose females gained 51% less weight than. High dose males and females consumed 18 41% and 30 45% less food when fed the 5000 ppm diet, 12 17% and 18 22% less when fed the 4000 ppm diet, and 6 14% and 7 12% less when fed the 2000 ppm diet up to day 560 and 532, respectively. No toxicologically significant effects were observed on body weight or food consumption in mid dose males and females. Food efficiency for the first 91 days was reduced by 22% and 17% for high dose males and females, respectively. Water consumption was inconsistent during the study and showed no treatment related effect.

No toxicologically significant effects were observed on hematology or clinical chemistry parameters except for elevated alkaline phosphatase activity ( 68 94% increase) in high dose females. No treatment related effects were observed on urinalysis parameters in male or female rats.

Postmortem examination showed no treatment related effect on organ weights; tissue masses in the testes of high dose male rats and the skin of high dose female rats probably correlated with neoplastic lesions. Treatment related microscopic lesions were observed in the testes, pancreas, renal pelvis, liver, and pituitary in high dose males and liver and pancreas in high dose females. High dose male rats had significantly increased incidences of mineralization/ concretions in the renal pelvis ( 25/ 70 vs 10/ 70 for controls), pituitary hyperplasia ( 26/ 70 vs 13/ 70 for controls), and interstitial cell hyperplasia in the testes ( 12/ 70 vs 2/ 70 for controls). High dose male and female rats had a significant increase in the incidence of hepatocellular hyperplasia ( males: 34/ 70 vs 22/ 70; females: 36/ 70 vs 18/ 70) and a non significant increase in the incidence of acinar cell metaplasia ( hepatocyte like cells) in the pancreas ( 3/ 70 for males, 4/ 69 for females vs 0/ 70 for controls in both sexes). High dose females had a significantly increased incidence of hepatocellular alterations ( 49/ 70 vs 19/ 70 for controls). Acinar metaplasia in both sexes, interstitial cell hyperplasia in the testes, and hepatocellular alterations in females were observed in the high dose groups after only 1 year of treatment. The incidences of lesions after 1 year were reduced after the 4 week recovery period.

The lowest observed adverse effect level ( LOAEL) for ametryn in rats is 5000/ 4000/ 2000 ppm ( 145.3 and 176.1 mg/ kg/ day for males and females, respectively) based on decreased body weight and weight gain in both sexes and histopathologic lesions in the kidney, testes, and pituitary in male rats and in the liver and pancreas in male and female rats. The corresponding no observed adverse effect level ( NOAEL) is 500 ppm ( 20.9 and 26.2 mg/ kg/ day, for males and females, respectively) AMETRYN CANCER ASSESSMENT DOCUMENT FINAL 19 Mouse In a mouse carcinogenicity study ( 1992, MRID No.: 40349904), four groups of 60/ sex mice ( HAM/ ICE, Swiss, CD 1) were dosed as 0, 10, 1000 or 3000 ppm of ametryn ( Batch FL 761356, 98.9% purity) for a scheduled 102 weeks. These dose levels correspond to 0, 1.5, 150 and 300 mg/ kg/ day based on a conversion factor of 1 ppm = 0.15 mg/ kg/ day.

There were no systemic effects of treatment at the highest dose tested. There were also no treatment related increases in neoplasms. The dose levels were, however, considered adequate because the dose range finding study ( 1990, MRID # 92002041) demonstrated that there was significant weight gain decrease at 1000 ppm ( 12 to 17%) and 3000 ppm ( 24 to 46%).

This study is classified as Acceptable/ Guideline and satisfies the guideline ( 870.4200) requirement for a carcinogenicity study in mice.

5. Mode of Action Studies There were no data submitted on the possible mode of action of ametryn. AMETRYN CANCER ASSESSMENT DOCUMENT FINAL 20 V. COMMITTEE'S ASSESSMENT OF THE WEIGHT OF THE EVIDENCE 1. Carcinogenicity Rat The CARC considered dosing at the high dose in male and female rats to be excessive and not adequate for the assessment of carcinogenicity. They concluded that the tumor findings at the high dose cannot be interpreted because the animals were compromised due to large decreases in body weight/ body weight gain during the first 8 months of the study. Consequently, although statistical analyses were performed, the tumor data in rats were not discussed at this meeting. In addition, the 500 ppm dose group was not considered adequate for assessment of carcinogenicity since this was the NOAEL for the study, no tumors were seen at this dose, and the dose spread ( 500 ppm  5000 ( 10 fold)/ 4000 ( 8 fold)/ 2000 ppm ( 4 fold) was too large.

Mouse No treatment related tumors were seen in male or female mice.

The CARC concluded that dosing at the high dose in both male and female mice was adequate and not excessive. Although the high dose of 2000 ppm ( 300 mg/ kg/ day) in the definitive mouse study did not result in systemic toxicity, the mouse 28 day range finding study ( MRID 92002041) demonstrated body weight gain decreases at 1000 (  12% in males and  17% in females) and 3000 (  24% in males and  46% in females) ppm which justified selection of 2000 ppm as the high dose for the definitive cancer study with mice.

2. Mutagenicity There is no mutagenicity concern with ametryn.

3. Structure Activity Relationship Atrazine is a triazine herbicide. The chlorotriazine pesticides have been shown to increase mammary gland tumors in female rats. Because ametryn is not a chlorotriazine, SAR does not provide support for carcinogenic potential.

4. Mode of Action No specific mode of action studies were submitted with ametryn.

VI. CLASSIFICATION OF CARCINOGENIC POTENTIAL AMETRYN CANCER ASSESSMENT DOCUMENT FINAL 21 In accordance with the EPA Draft Guidelines for Carcinogen Risk Assessment ( July, 1999), the Committee classified ametryn into the category " Data Are Inadequate for An Assessment of Human Carcinogenic Potential". The carcinogenicity study in the rats is unacceptable because the high dose was considered to be excessive. The animals in the high dose group were compromised due to large decreases in body weight/ body weight gain which render the neoplastic findings in this group uninterpretable. In addition, the 500 ppm dose group was not considered adequate for assessment of carcinogenicity since this was the NOAEL for the study, no tumors were seen at this dose, and the dose spread ( 500 ppm  5000 ( 10 fold)/ 4000 ( 8 fold)/ 2000 ppm ( 4 fold) was too large. The CARC requested that the carcinogenicity study in rats be repeated at a dose that was adequate to assess carcinogenicity.

Note: A few members of the CARC felt that ametryn should be classified as " Suggestive Evidence of Carcinogenicity, but not sufficient to Assess Human Carcinogenic Potential" based on the tumor findings in male and female rats at an excessive dose ( based only on body weight gain decrements). However, there was no systemic toxicity and survival was significantly increased relative to concurrent controls in both males and females.

VII. QUANTIFICATION OF CARCINOGENIC POTENTIAL Not applicable.

VIII BIBLIOGRAPHY MRID No. Citation 40349904 Burdock, G., 1981, Final Report. 102 week Oncogenicity Study in Mice. Hazleton Laboratories. Virginia, Study No.: 483 128, March 20, 1981.

40349906 Hazelette, J. and J. Green ( 1987) Ametryn: Combined chronic toxicity/ oncogenicity study in rats. CIBA GEIGY Corporation, Research Department, Pharmaceutical Division, Summit, New Jersey. Laboratory Report No. 842119. August 24, 1987. Unpublished.

40382001 Tai, C. 1987. Ametryn: 4 week range finding study in rats. CIBY GEIGY Corporation, Pharmaceuticals Division, Summit, NJ. Laboratory Report No. 842084. August, 11, 1987. Unpublished.

40995820 Deparade, E. ( 1984) Ametryn Technical: Gene Mutations Test: Salmonella Mammalian Microsome Mutagenicity Test: Study No. 840802. Unpublished study prepared by Ciba Geigy Corp. 25 p. ( duplicate of MRID No. 41189701)

41067903 Hertner, T. ( 1989). Ametryn Technical: Structural Chromosomal Aberration AMETRYN CANCER ASSESSMENT DOCUMENT FINAL 22 Test; Micronucleus Test, Mouse, performed at CIBA GEIGY Limited, Basle ( Switzerland), February 20, 1989. Laboratory Study No. 881548. Unpublished.

41067904 Hertner, T. ( 1989). Ametryn Technical: Tests for Other Genotoxic Effects; Autoradiographic DNA Repair Test on Rat Hepatocytes, performed at CIBAGEIGY Limited, Basle ( Switzerland), February 17, 1989. Laboratory Study Number 881549. Unpublished.

41184201 Hazelette, J. and J. Green ( 1987) Ametryn: Supplement to combined chronic toxicity/ oncogenicity study in rats. CIBA GEIGY Corporation, Research Department, Pharmaceutical Division, Summit, New Jersey. Laboratory Report No. 842119. August 24, 1987. Unpublished.

41189701 Deparade, E. ( 1984) Ametryn Technical: Gene Mutations Test: Salmonella Mammalian Microsome Mutagenicity Test: Study No. 840802. Unpublished study prepared by Ciba Geigy Ltd. 23 p. ( duplicate of MRID No. 40995829)

41463301 Wu, D. ( 1990) Analysis, Quantitation, and Structure Elucidation of Metabolites in Urine and Feces from the Rat Dosed with ? Carbon 14| Ametryn: XRL Report No.: RPT0022. Unpublished study prepared by Xenobiotic Laboratories, Inc. 215 p.

41463302 Reynolds, J. ( 1990) Ametryn Metabolism of ? Carbon 14| Ametryn in Rats Phase I Preliminary Study: XBL Report No.: RPT0007. Unpublished study prepared by XenoBiotic Laboratories, Inc. 41 p.

41463303 Braun, R. ( 1990) Absorption, Distribution and Excretion Studies of ? Carbon 14| Ametryn in the Rat: BTC Protocol No.: P01744. Unpublished study prepared by Biological Test Center. 169 p.

92002041 Piccirillo, V. ( 1990) Ciba Geigy Corp. Phase 3 Reformat of MRID 00068169 and Related MRIDs 40349903. 28 Day Pilot Feeding Study in Mice: Study No. 483 126. Prepared by Hazleton Laboratories America, Inc. 26 p.

92002042 Schabacker, D. ( 1990) Ciba Geigy Corp. Phase 3 Summary of MRID 41463301. Analysis, Quantification and Structure Elucidation of Metabolites in Urine and Feces from the Rat Dosed with ( Triazine ( U) Carbon14 Ametryn: Report No. RPT0022. Prepared by Xenobiotic Labs, Inc. 20 p.

 J. Kidwell. 2004. Ametryn: Qualitative Risk Assessment Based on a Sprague Dawley Rat Dietary Study. June 30, 2004. TXR No. 0052655.

 I. Mauer. 2004. Ametryn Technical Mutagenicity. July 2, 2004. TXR No. 0052157.


									OSWER 9200.3-54

REVIEW OF INTERNATIONAL SOIL LEVELS FOR DIOXIN

Prepared by:

U.S. Environmental Protection Agency

Office of Superfund Remediation and Technology Innovation

Washington, D.C.

with technical assistance from:

SRC, Inc.

Denver, CO

December 28, 2009

EXECUTIVE SUMMARY

A number of foreign nations have evaluated the toxicity of dioxin and
have established concentration values in soil that are intended to
provide protection to humans who may be exposed under residential or
commercial/industrial land uses.  Two types of soil levels have been
established:

Screening Levels are generally interpreted as concentrations below which
health concern is minimal and no further investigations or evaluations
are needed.

Action Levels are generally interpreted as concentrations above which
concern is likely to exist and where some sort of response action is
likely to be needed.

Because dioxin is a carcinogen, the method used to derive screening
levels or action levels depends on the assumed mode of action of dioxin.
 The World Health Organization (WHO) has evaluated the available data
for dioxin, and has determined that cancer effects of dioxin are caused
by a non-linear threshold mode of action.  Consequently, human health
will be protected from both cancer and non-cancer effects if the average
daily ingested dose of dioxin does not exceed the Tolerable Daily Dose
(TDI).

In 1990, the WHO estimated the TDI to be 10 pg/kg-day.  In 1998, the WHO
revised this estimate and identified a range of 1-4 pg/kg-day, with 1
pg/kg-day being the goal.  In 2001, this range was re-evaluated using
several new studies, and a range of 2-2.3 pg/kg-day was identified.
Nearly all foreign nations have followed the approach recommended by the
WHO for evaluating dioxin toxicity, and have selected TDI levels in the
1-10 pg/kg-day range.  Each of these TDI values or ranges is a suitable
candidate for consideration in EPA’s determination of soil PRG levels,
with preference for the most recent values.

The method for deriving a soil level from a TDI depends upon which soil
exposure pathways are considered (ingestion, inhalation, dermal), and on
the exposure parameters for each pathway.  In some cases, other factors
may also be considered.  Table ES-1 lists soil screening levels and
action levels that were located for foreign nations, indicating the TDI
values that were considered, and the exposure pathways that were
included.  As shown, screening levels range from 1 to 250 ppt, with most
values of about 10 ppt.  Residential action levels range from 10 to
1,500 ppt, with most values in the 100 to 1,000 ppt range.
Commercial/industrial action levels range from 100 to 18,000 ppt, with
most values in the 1,000 to 10,000 ppt range.  Unfortunately, based on
the information presently located, the detailed basis for the derivation
of these soil levels is not clear except for the Netherlands.

TABLE OF CONTENTS

  TOC \o "1-3" \h \z \u    HYPERLINK \l "_Toc238874963"  1.0	OVERVIEW
PAGEREF _Toc238874963 \h  1

  HYPERLINK \l "_Toc238874964"  2.0	BASIC STRATEGIES FOR DERIVING SOIL
LEVELS	  PAGEREF _Toc238874964 \h  1

  HYPERLINK \l "_Toc238874965"  2.1	Linear Non-Threshold Cancer Risk
Model	  PAGEREF _Toc238874965 \h  1

  HYPERLINK \l "_Toc238874966"  2.2	Non-Linear Threshold Cancer Risk
Model	  PAGEREF _Toc238874966 \h  2

  HYPERLINK \l "_Toc238874967"  2.3	Exceedence of “Background”
PAGEREF _Toc238874967 \h  2

  HYPERLINK \l "_Toc238874968"  3.0	SEARCH OBJECTIVES AND METHODS
PAGEREF _Toc238874968 \h  3

  HYPERLINK \l "_Toc238874969"  3.1	Search Objectives	  PAGEREF
_Toc238874969 \h  3

  HYPERLINK \l "_Toc238874970"  3.2	Search Methods	  PAGEREF
_Toc238874970 \h  3

  HYPERLINK \l "_Toc238874971"  4.0	RESULTS	  PAGEREF _Toc238874971 \h
4

  HYPERLINK \l "_Toc238874972"  4.1	Nations that Use the Linear
No-Threshold Risk Model	  PAGEREF _Toc238874972 \h  4

  HYPERLINK \l "_Toc238874973"  4.2	Nations that Use the Non-Linear
Threshold Risk Model	  PAGEREF _Toc238874973 \h  6

  HYPERLINK \l "_Toc238874974"  4.2.1	TDI Values	  PAGEREF _Toc238874974
\h  6

  HYPERLINK \l "_Toc238874975"  4.2.2	Derivation of Soil Levels
PAGEREF _Toc238874975 \h  8

  HYPERLINK \l "_Toc238874976"  4.3	Nations that Use the Exceedence of
Background Approach	  PAGEREF _Toc238874976 \h  10

  HYPERLINK \l "_Toc238874977"  5.0	EVALUATION	  PAGEREF _Toc238874977
\h  10

  HYPERLINK \l "_Toc238874978"  6.0	REFERENCES	  PAGEREF _Toc238874978
\h  11

LIST OF ABBREVIATIONS AND ACRONYMS

BMD	Benchmark Dose

COT	Committee on the Toxicity of Chemicals in Food

EC	European Commission

ECEH	European Centre for Environmental Health Safety

IPCS 	International Programme on Chemical

JECFA 	Joint FAO/WHO Expert Committee on Food Additives

LOAEL	Lowest Observed Adverse Effect Level

oSF	Oral Slope Factor

OSWER	Office of Solid Waste and Emergency Response

PBPK	Physiologically-based pharmacokinetic

PCDD	Polychlorinated dibenzodioxins

PCDF	Polychlorinated dibenzofurans

RfD	Reference Dose

SCF	Scientific Committee on Food

TCDD	2,3,7,8-tetrachloro-p-dibenzodioxin

TDI	Tolerable daily intake

TEQ	TCDD Equivalents

USEPA	United States Environmental Protection Agency

WHO	World Health Organization

REVIEW OF INTERNATIONAL SOIL LEVELS FOR DIOXIN

OVERVIEW

Regulatory agencies in many nations have sought to identify a default
concentration of dioxin (2,3,7,8-TCDD) and related polychorinated
dibenzodioxins (PCDDs) and dibenzofurans (PCDFs) in soil that does not
pose an unacceptable health risk to humans.  These values are generally
expressed in terms of TCDD-equivalent (TEQ) concentrations, which
include the contributions from all of the relevant PCDD and PCDF
congeners.

In general, one or both of two types of soil level have been
established:

Screening Levels are generally interpreted as concentrations below which
health concern is minimal and no further investigations or evaluations
are needed.

Action Levels are generally interpreted as concentrations above which
concern is likely to exist and where some sort of response action is
likely to be needed.

The purpose of this report is to review the methods that have been used
by other countries to derive screening levels and/or action levels for
dioxin in soil, and to characterize the values that have been
established.

BASIC STRATEGIES FOR DERIVING SOIL LEVELS

Review of the approaches used by various nations for deriving soil
levels for dioxin have identified three basic strategies.  These are
discussed below.

Linear Non-Threshold Cancer Risk Model

Dioxin is a carcinogen.  If the risk of cancer from dioxin is assumed to
be linear in the low-dose range and to have no threshold, then the basic
equation for calculating the soil level that corresponds to some
specified acceptable "target cancer risk" is as follows:

As seen, the soil level for cancer depends on the slope factor, the
intake rate of soil, and the target cancer risk.  The slope factor is
usually derived by fitting the linearized multistage model to an
appropriate set of cancer exposure-response data (animal data), while
intake rate is based on default assumptions about residential or worker
exposure to soil.  Target cancer risk is a risk management choice, and
is typically in the 1E-04 to 1E-06 range.

Because dioxin also causes non-cancer as well as cancer effects, it is
also appropriate to calculate a soil level that will protect against
non-cancer effects, as follows:

As seen, the soil level for non-cancer effects depends only on the ratio
of the threshold dose (an intake level that does not cause any adverse
effects) to the soil intake rate.

Given the cancer and non-cancer soil levels, the lower of the two is
generally selected to ensure protection against both types of effect.

Non-Linear Threshold Cancer Risk Model

If the cancer effects of dioxin are assumed to occur via a non-linear
threshold mode of action, then exposures that are below the threshold
for non-cancer effects are assumed to be safe for both cancer and
non-cancer effects.  In this case, the soil level is calculated using
the non-cancer equation described above:

The threshold dose is usually referred to as a Reference Dose (RfD) in
the United States, and as a Tolerable Daily Intake (TDI) in Europe and
Asia.  These two terms are conceptually equivalent and both describe the
total amount of dioxin/TEQ that may be ingested per day that will not
result in an adverse health effect.

The value of the TDI or RfD can be derived in several ways, including:

Direct observation of no-effect dose levels in reliable studies

Benchmark dose (BMD) modeling of reliable non-cancer dose-response data

Calculations from a tissue-based no-effect level, using an appropriate
physiologically based pharmacokinetic (PBPK) model

Exceedence of “Background”

If it is assumed that any excess exposure to dioxin is undesirable
because of its high potency for both non-cancer and cancer effects, then
the soil level may be set equal to the “background” level of dioxin
in soil.  This approach does not require any data on toxicity or
exposure, but does require robust data on the distribution of
concentration values in soils that are considered to be
“background”.  Because dioxin can be released from a variety of
sources (ATSDR 1998), soil “background” levels may vary as a
function of location and setting (rural, industrial, urban, pristine,
etc.).

SEARCH OBJECTIVES AND METHODS

3.1	Search Objectives

The goal of this search effort was to identify soil action levels for
dioxin that have been adopted by various nations.  In addition, the
primary objective was to document the underlying basis of these soil
levels (e.g., toxicity value, derivation approach, exposure parameters)
with regard to the following criteria.  The resulting objective was to
identify international soil levels based on the most recent, sound
science and evaluate the levels based on the following criteria:

Nature of peer review

Transparency/reproducibility & public availability

Scientific basis

These criteria are consistent with those recommended for Tier 3 human
health toxicity value sources indicated in USEPA Office of Solid Waste
and Emergency Response (OSWER) Directive 9285.7-53, Human Health
Toxicity Values in Superfund Risk Assessments (USEPA 2003).

3.2	Search Methods

Searches for information on international soil levels for dioxin were
primarily performed using web-based search engines.  These searches were
initially quite broad in scope in an attempt to locate any
publicly-available information on dioxin (or TEQ) toxicity assessments
and/or soil levels.  These initial searches did not target specific soil
level types (e.g., residential/commercial, screening/action level), and
did not attempt to target specific nations or regions.  Information on
dioxin soil levels for European nations was initially located in two key
summary reports:

Carlon, C. (ed.).  2007.  Derivation Methods of Soil Screening Values in
Europe.  A Review and Evaluation of National Procedures Towards
Harmonization.  European Commission, Joint Research Centre, Ispra, EUR
22805-EN, 306 pp.    HYPERLINK
"http://www.nicole.org/news/downloads/EUR22805-EN%20(3)_27_AUG.pdf"
http://www.nicole.org/news/downloads/EUR22805-EN%20(3)_27_AUG.pdf

AEA Technology.  1999.  Summary Report: Compilation of EU Dioxin
Exposure and Health Data.  Task 1 - Member State Legislation and
Programmes.  Produced for European Commission DG Environment, UK
Department of the Environment Transport and the Regions.  October.
HYPERLINK "http://ec.europa.eu/environment/dioxin/download.htm"
http://ec.europa.eu/environment/dioxin/download.htm

When potentially relevant dioxin information was located for a
particular nation, a more focused search of specific agency websites and
peer-reviewed literature was performed to identify and gather the
underlying documents providing the detailed information on the basis and
derivation of the specified soil levels.

4.0	RESULTS

4.1	Nations that Use the Linear No-Threshold Risk Model

Only one foreign nation (Germany) evaluated the cancer effects of dioxin
assuming a linear no-threshold mode of action.  Based on information
reported in Carlon (2007), both oral exposure and inhalation exposure
are considered, and both cancer and non-cancer effects are evaluated.
Two types of values are identified:

“Trigger levels” are concentrations in soil that warrant further
investigation to determine if the concentration of the contaminant in
soil is hazardous.

“Action levels” are concentrations in soil that, as a rule, indicate
that a hazard is present that must be addressed.  Further investigation
is usually not necessary.

Equations for calculating “Trigger Levels” utilized by Germany are
as follows:

Effect	Pathway	Equation

Cancer	Oral	TL = Dtb ∙ frc ∙ 8.75 / IR

	Inhalation	TL = Dtb ∙ frc ∙ 8.75 / (IR ∙ AF)

Non-Cancer	Oral	TL = Dtb ∙ (frc - 0.8) / IR

	Inhalation	TL = Dtb ∙ frc  / (IR ∙ AF)

where:

	TL = Trigger Level in soil (pg/g)

	Dtb = Tolerable body dose (pk/kg-day)

	frc = risk connecting factor

	8.75 = ratio of averaging time to assumed exposure duration for cancer
(70 yrs/8 yrs)

	0.8 = fraction of total daily dioxin intake that is derived from the
diet

	IR = average daily soil intake (g/kg-day)

	AF = accumulation factor of dioxin in dust

Default values employed by Germany in the computation of Trigger Levels
for dioxin for residential land use are as follows (Carlon 2007):

Parameter	Cancer	Non-cancer

	Oral	Inhal	Oral	Inhal

Dtc (pg/kg-day)	6.7E-02	6.0E-02	1.0	--

frc	5	5	3.2	--

IR (g/kg-day)	1.65E-02	4.1E-05	1.65E-02	--

AF	--	10	--	--

Note that the soil ingestion rate (16.5 mg/kg-day) used by Germany is
substantially higher than the default value used by the United States
Environmental Protection Agency (USEPA) (3.81 mg/kg-day).  Likewise, the
soil inhalation rate used by Germany (4.1E-02 mg/kg-day) is also higher
than the USEPA default (2.3E-04 mg/kg-day), although the air pathway
remains minor in both cases.  Also note that the exposure duration for
cancer effects (8 years) is much shorter than assumed by USEPA (30
years), and that for non-cancer effects, only 20% of the allowable daily
intake is allocated to soil.

For cancer effects, the oral slope factor (oSF) utilized by Germany may
be calculated as follows:

	oSF = Target Risk / Dtc = 1E-05 / 6.7E-02 = 1.5E-04 (pg/kg-day)-1

This is the same value utilized by the United States.

Based on the inputs provided above, the derived soil Trigger Levels for
dioxin are as shown below:

Effect	Toxicity

Value	Target Risk	Trigger Level (pg/g)

	Oral	Inhal.	Combined

Cancer	1.5E-04 (pg/kg-day)-1	1E-05	178	6400	173

Non-cancer	1.0 pg/kg-day	HQ = 1	145	--	145

As seen, the Trigger Level for cancer effects (1E-05) is 173 ppt, and
the Trigger Level for non-cancer effects is 145 ppt.  Presuming that the
lower of the two values is selected as the final value, the final soil
Trigger Level for dioxin would be 145 ppt.  However, no information was
located on the selected Trigger Level for dioxin in the literature.

As noted above, Germany utilizes an approach in which both a Trigger
Level and an Action Level are identified.  The residential Action Level
for dioxin selected by Germany is 1,000 ppt.  No information was located
on the process used by Germany to derive the selected soil Action Level.

4.2	Nations that Use the Non-Linear Threshold Risk Model

4.2.1	TDI Values

Most foreign nations for which information was located follow the
approach in which the cancer effects of dioxin are believed to be
mediated by a non-linear threshold mode of action.  This approach has
been developed mainly by the World Health Organization (WHO) and several
other international health groups.  Table 1 provides a summary of TDI
values that have been derived by WHO and others.  These are discussed in
greater detail below.

WHO 1990

In 1990, the World Health Organization (WHO) Regional Office for Europe
organized several expert consultations and working groups to perform a
toxicological evaluation for TCDD (WHO 1991, 1992).  It was concluded
that TCDD was carcinogenic in animals, acting as a non-genotoxic
promoter-carcinogen.  Therefore, the consultation decided to establish a
TDI based on general toxicological effects.  The no-effect dose was
estimated to be about 1,000 pg/kg-day in various laboratory animals,
which was adjusted to an equivalent human dose of 100 pg/kg-day using
toxicokinetic data.  After applying an uncertainty factor of 10 to
account for insufficient data on reproductive effects in humans, a TDI
of 10 pg/kg-day was recommended.

WHO 1998

In 1998, the WHO European Centre for Environmental Health (WHO-ECEH) and
International Programme on Chemical Safety (IPCS) performed a
re-assessment of the available information on the toxicity of dioxin
(WHO 1998), and reached the following key conclusions:

the cancer effects of dioxin are mediated by a non-genotoxic mode of
action that is mediated via a receptor binding mechanism.  Consequently,
cancer risk has a threshold, and exposures that do not cause non-cancer
effects will not increase cancer risk.

the most sensitive non-cancer effects caused by dioxin included
developmental and reproductive effects in rats and monkeys.

the most reliable metric of exposure for use in risk evaluation is
tissue burden rather than ingested dose.

Based on these key conclusions, WHO (1998) estimated the TDI (pg/kg-day)
for lifetime exposure in a series of 3 steps, as follows:

Step 1:  Identify the tissue burden effect level for the most sensitive
(and relevant) adverse responses.  Based on studies in rats and monkeys,
the WHO estimated that the lowest observed adverse effect level (LOAEL)
tissue burdens ranged from 28-73 ng/kg (28,000-73,000 pg/kg).

Step 2:  Given the tissue burden range, calculate the TDI that would
yield this tissue burden range.  The WHO computed the TDI using a simple
steady-state pharmacokinetic model of the following form:

		TDI (pg/kg-d) = Tissue Burden (pg/kg) · [1-exp(-ln(2)/t1/2)] / f

where:

		t1/2 = half-time of dioxin in the body (days)

		f = fraction of an ingested dose that is absorbed

WHO utilized a half-time of 7.5 years (2,738 days), and an assumed
fractional absorption of 0.5 (50%).  Based on this, the TDI was
estimated to range from 14-37 pg/kg-day.

Step 3:  Adjust the TDI to account for uncertainties.  A factor of 10
was applied to address the following uncertainties: a) the use of a
range of LOAELs instead of a no-effect level, b) the possible
differences in susceptibility between humans and experimental animals,
c) the potential differences in susceptibilities within the human
population, and d) differences in half-lives of elimination for the
compounds of a complex TEQ mixture.  After application of the
uncertainty factor, the TDI (rounded) was estimated to range from 1-4
pg/kg-day.

The WHO (1998) consultation stressed that the upper range of the TDI of
4 pg/kg-day should be considered a maximal tolerable intake on a
provisional basis and that the ultimate goal is to reduce human intake
levels to below 1 pg/kg bw-day.

EC-SCF and JECFA 2001

In 2001, the European Commission Scientific Committee on Food (EC-SCF)
and the Joint FAO/WHO Expert Committee on Food Additives (JECFA)
incorporated several new studies published since the 1998 WHO
re-assessment and estimated the TDI to be 2.0-2.3 pg/kg-day,
respectively, using an approach similar to the one described above.

Table 1a summarizes the TDI values recommended by these various
international organizations.

TDI Values Selected by Various Nations

Table 2 provides a summary of the information that was located for
nations that follow the TDI approach for evaluating dioxin toxicity.  As
indicated, a majority of nations have chosen to adopt TDI values
recommended by WHO.  This includes:

WHO (1990)

TDI = 10 pg/kg-day	WHO (1998)

TDI = 1-4 pg/kg-day	JECFA (2001)

TDI = 2.3 pg/kg-day

Austria

Italy	France

Germany

Netherlands

New Zealand	Australia

Canada

However, several nations (see Table 1b) have performed their own
re-assessment of the available toxicity data for dioxin to derive a TDI,
rather than adopting TDI values derived by others.  Japan derived a TDI
of 4 pg/kg-day, which is equivalent to the maximum TDI established by
WHO (1998).  For the United Kingdom, the Government’s independent
advisory Committee on the Toxicity of Chemicals in Food (COT)
recommended a TDI of 2 pg/kg-day, which is equivalent to the TDI
identified by EC-SCF (2001).  In August 2000, several countries
(Denmark, Finland, Sweden) considered revising the Nordic Council TDI
value of  5 pg/kg-day to a value of 4 pg/kg-day in accord with WHO
(1998), but it was determined that no change was appropriate (Johansson
and Hanberg 2000).

4.2.2	Derivation of Soil Levels

As noted above, given a TDI, the soil level is computed as follows:

The soil intake rate may be computed in a number of different ways,
depending on which exposure pathways are considered (ingestion, dermal
contact, inhalation of particulates, and/or ingestion of crops or
livestock that have been impacted by soil).  The general form of the
equation is:

where:

	TDI = Tolerable daily intake

	ki = Ratio of dioxin concentration in medium “i” to concentration
in soil

	IRi = Intake rate of medium “i”

For example, if only the soil ingestion pathway is considered, the basic
equation is:

where:

TDI = Tolerable daily intake (pg/kg-day)

IRs = 	Average soil intake rate (g/kg-day)

If dermal contact, inhalation exposure and intake of foods (e.g., garden
vegetables) grown in contaminated soil are considered, the equation is:

where:

	IRd = Intake rate of soil from dermal exposure (g/kg-day)

	kair = Concentration in air (pg/m3) divided by concentration in soil
(pg/g)

	IRPM10 = Intake rate of air (m3/kg-day)

	kveg = Concentration in vegetable (pg/g) divided by concentration in
soil (pg/g)

	IRgv = Intake rate of garden vegetables (g/kg-day)

Note that inhalation exposure from PM10 particles usually contributes
only a small dose compared to oral exposure (typically <1%).
Consequently, whether the inhalation pathway is included or not
generally has little influence on the result.

Soil Levels Identified by Various Nations

Not all nations that utilize the TDI approach have derived soil levels.
Table 2 provides the detailed information for all soil levels located
for various nations.  This table includes a variety of different soil
levels and nomenclature in describing these levels.  As described above,
the various soil levels reported by the nations were stratified into two
broad categories – screening levels and action levels.  Screening
levels are soil values below which no further investigation is likely to
be needed.  Usually these screening values are not land use specific,
but are applied to all land use types.  Action levels are soil values
above which cleanup actions are warranted.  These values are often
effects-based (i.e., derived from a TDI) and land use specific.  The
most common land use types are residential and commercial/industrial,
although some nations also derive action levels for agricultural and
recreational land uses.

Table 3 summarizes the screening levels and action levels for
residential and commercial/ industrial soils that have been derived.
Figure 1 presents these soil levels in a graphical format.  As shown,
screening levels (Panel A) range from 1 to 250 ppt, with most values of
about 10 ppt.  Residential action levels (Panel B) range from 10 to
1,500 ppt, with most values in the 100 to 1,000 ppt range.
Commercial/industrial action levels (Panel C) range from 100 to 18,000
ppt, with most values in the 1,000 to 10,000 ppt range.

Figure 2 presents the soil action levels for residential (Panel A) and
commercial/industrial (Panel B) grouped by the selected TDI.  As shown,
there is a wide range of soil levels within each TDI value (e.g.,
residential action levels range from 100 to 1,000 ppt for a TDI of 1
pg/kg-day).  This suggests that the primary reason for the differences
in the derived soil levels is due to differences in the exposure
parameters utilized.

Unfortunately, the basis of these soil levels is not always clear.
Carlon (2007) sought to determine the methods that had been used by each
nation to establish the soil levels, and concluded that, in most cases,
the basis of the soil levels was not well documented.  Even in cases
where documentation is available, derived soil values are not always
reproducible.  Therefore, it is suspected that most soil values reflect
risk management decisions that are not based solely on risk-based
exposure-response models.

4.3	Nations that Use the Exceedence of Background Approach

Two nations (Canada and Czech Republic) were identified in which the
soil screening level is stated to be based on background levels of
dioxin.  For Canada, the soil screening level identified as the average
background level is 4 ppt, and this value is intended to apply to all
land use types (i.e., agricultural, residential, commercial,
industrial).  For the Czech Republic, there are two soil screening
levels identified:  1 ppt, which was identified as the 95th percentile
of background, and 100 ppt, which is a value selected between background
and the “limit of pollution”.  Most nations, including the United
States (USEPA 2007), report background concentrations within range of
1-10 ppt.

5.0	EVALUATION

In order for the USEPA to consider a human health toxicity value (TDI,
slope factor) for use in risk calculations or in the derivation of a
soil level, it must meet the criteria of a Tier 3 value established by
USEPA OSWER Directive 9285.7-53 (USEPA 2003).  As noted above, these
criteria are as follows:

Nature of peer review – in accord with USEPA (2003), “draft
assessments are not appropriate for use until they have been through
peer review, the peer review comments have been addressed in a revised
draft, and the revised draft is publicly available”.

Transparency/reproducibility and public availability – in accord with
USEPA (2003), values should be “available to the public,
and…transparent about the methods and processes used to develop the
values”.  In addition to being transparent, values should be
reproducible (i.e., able to be derived based on the provided
information).

Scientific basis – in accord with USEPA (2003), values should be
“based on similar methods and procedures” as USEPA guidance (e.g.,
cancer risk assessment guidelines, soil screening guidance).

Table 4 presents a matrix of the evaluation criteria for the TDI values
(top panel) and soil action levels (bottom panel) currently utilized by
various nations.  In general, most of the TDI values derived by the WHO
and other international health groups have been peer reviewed, are
transparent/reproducible and publically available, and are based on
science that is consistent with current USEPA guidance procedures
(assuming that a threshold mode of action is accepted).  Thus, all of
these TDI values would rank as appropriate for use as Tier 3 human
health toxicity values.  TDI values developed by various nations (e.g.,
Japan), do not meet all of the specified criteria in full.

For the soil action levels (Table 4, lower panel), with the exception
the Netherlands, no nations provided sufficient detail to document the
underlying basis of the adopted soil values and no information was
located on the peer review process associated with the adopted values.
For the Netherlands, soil levels were derived using an exposure model
called CSOIL.  Detailed information on this model and the underlying
exposure parameters and assumptions are documented in the Technical
Evaluation of the Intervention Values for Soil/Sediment and Groundwater
(RIVM 2001).  The derived soil values are subject to review by the
Netherland Technical Soil Protection Committee and Health Council.

6.0	REFERENCES

ATSDR (Agency for Toxic Substances and Disease Registry).  1998.
Toxicological Profile

for Chlorinated Dibenzo-p-dioxins (CDDs).  Agency for Toxic Substances
and Disease Registry.  December 1998.

Carlon, C. (Ed.) (2007). Derivation methods of soil screening values in
Europe. A review and evaluation of national procedures towards
harmonization. European Commission, Joint Research Centre, Ispra, EUR
22805-EN, 306 pp.

  HYPERLINK
"http://eusoils.jrc.ec.europa.eu/esdb_archive/eusoils_docs/other/EUR2280
5.pdf"
http://eusoils.jrc.ec.europa.eu/esdb_archive/eusoils_docs/other/EUR22805
.pdf

Johansson, N. and A Hanberg. 2000. Report from a Nordic meeting on the
1998 WHO consultation on assessment of the health risks of dioxins;
re-evaluation of the tolerable daily intake (TDI). Organohalogen
Compounds. 48:252-255.

Kimbrough RD, Falk H, Stehr P.  1984.  Health Implications of
2,3,7,8-tetrachloro-dibenzodioxin (TCDD) Contamination of Residential
Soil.  J. Toxicol. Environ. Health 14:47-93.

Kociba RJ, Keyes DG, Beyer JE, et al . 1978.  Results of a Two-Year
Chronic Toxicity and oncogenicity Study of
2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) in rats.  Toxicol. Appl.
Pharmacpol. 46:279-303.

NTP (National Toxicology Program).  1982.  Carcinogenesis Bioassay of
2,3,7,8-tetrachlorodibenzo-p-dioxin (CAS No. 1746-01-6) in
Osborne-Mendel rats and B6C3F1 Mice (Gavage Study).  National Toxicology
Program Technical  Report Series, Issue 209:195.

RIVM.  2001.  Technical Evaluation of the Intervention Values for
Soil/Sediment and Groundwater: Human and ecotoxicological risk
assessment and derivation of risk limits for soil, aquatic sediment and
groundwater.  National Institute of Public Health and the Environment
(RIVM).  RIVM report 711701 023.  February 2001.

  HYPERLINK
"http://rivm.openrepository.com/rivm/bitstream/10029/9660/1/711701023.pd
f"
http://rivm.openrepository.com/rivm/bitstream/10029/9660/1/711701023.pdf

USEPA (U.S. Environmental Protection Agency).  1985.  Health Assessment
Document for Polychlorinated Dibenzo-p-Dioxins.  U.S. Environmental
Protection Agency, Office of Health and Environmental Assessment,
Environmental Criteria and Assessment Office.  Cincinnati, OH.  EPA
600/8-84-014F.

USEPA.  1997.  Health Effects Assessment Summary Tables (HEAST).  U.S.
Environmental Protection Agency, Office of Solid Waste and Emergency
Response.  EPA-540-R-97-036.  July 1997.

USEPA.  1998.  Approach for Addressing Dioxin in Soil at CERCLA and RCRA
Sites.  Memo from Timothy Fields, USEPA Acting Administrator, to
Regional Directors.  OSWER Directive 9200.4-26.  April 13, 1998.

USEPA.  2003.  Human Health Toxicity Values in Superfund Risk
Assessments. OSWER

Directive 9285.7-53.  U.S. Environmental Protection Agency, Office of
Solid Waste and Emergency Response, Washington, DC.  December 5, 2003.

  HYPERLINK "http://www.epa.gov/oswer/riskassessment/pdf/hhmemo.pdf"
http://www.epa.gov/oswer/riskassessment/pdf/hhmemo.pdf

USEPA.  2005.  Guidelines for Carcinogen Risk Assessment.  U.S.
Environmental Protection Agency, Risk Assessment Forum. Washington, DC.
EPA/630/P-03/001B.  March 2005.

USEPA.  2007.  Pilot Survey of Levels of Polychlorinated
Dibenzo-P-Dioxins (PCDDs), Polychlorinated Dibenzofurans (PCDFs),
Polychlorinated Biphenyls (PCB) and Mercury in Rural Soils of the U.S.
U.S.   Environmental Protection Agency, Washington, DC.
EPA/600/R-05/043F.    HYPERLINK
"http://cfpub.epa.gov/ncea/CFM/recordisplay.cfm?deid=150944"
http://cfpub.epa.gov/ncea/CFM/recordisplay.cfm?deid=150944

WHO (World Health Organization).  1991.  Summary Report – Consultation
on Tolerable Daily Intake from Food of PCDDs and PCDFs.  Bilthoven, the
Netherlands, December 1990, EUR/ICP/PCS 030(S) 0369n, World Health
Organization, Regional Office for Europe, Copenhagen.

WHO.  1992.  Tolerable daily intake of PCDDs and PCDFs.  Toxic
Substances Journal 12:101-128.

WHO.  1998.  Assessment of the Health Risk of Dioxins: A Re-evaluation
of the Tolerable Daily Intake (TDI), Consultation, May 1998, World
Health Organization, Geneva.  Available on-line at:   HYPERLINK
"http://www.who.int/pcs/docs/dioxin-exec-sum/exe-sum-final.html"
http://www.who.int/pcs/docs/dioxin-exec-sum/exe-sum-final.html

 EC-SCF recommended a tolerable weekly intake (TWI) of 14 pg/kg, while
JECFA recommended a tolerable monthly intake (TMI) of 70 pg/kg.  These
values correspond to TDI values of 2.0 to 2.3 pg/kg-day.

•

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7 New Zealand has recently adopted the WHO 1998 TDI values; however, the
soil action levels identified utilize WHO 1990 TDI values.

 PAGE

ES- PAGE   1

 PAGE   ii

 PAGE   13


[Federal Register: May 18, 2010 (Volume 75, Number 95)]
[Rules and Regulations]
[Page 27637]
[DOCID:fr18my10-2]

=======================================================================
-----------------------------------------------------------------------

DEPARTMENT OF TRANSPORTATION

Federal Aviation Administration

14 CFR Part 71

[Docket No. FAA-2009-0538; Airspace Docket No. 09-ASW-15]

Amendment of Class E Airspace; Claremore, OK

AGENCY: Federal Aviation Administration (FAA), DOT.

ACTION: Final rule.

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

SUMMARY: This action amends Class E airspace for Claremore, OK, adding
additional controlled airspace to accommodate Area Navigation (RNAV)
Standard Instrument Approach Procedures (SIAPs) at Claremore Regional
Airport, Claremore, OK. The FAA is taking this action to enhance the
safety and management of Instrument Flight Rule (IFR) operations at the
airport.

DATES: Effective date 0901 UTC, July 29, 2010. The Director of the
Federal Register approves this incorporation by reference action under
1 CFR part 51, subject to the annual revision of FAA Order 7400.9 and
publication of conforming amendments.

FOR FURTHER INFORMATION CONTACT: Scott Enander, Central Service Center,
Operations Support Group, Federal Aviation Administration, Southwest
Region, 2601 Meacham Blvd., Fort Worth, TX 76137; telephone (817) 321-
7716.

SUPPLEMENTARY INFORMATION:

History

    On February 5, 2010, the FAA published in the Federal Register a
notice of proposed rulemaking to amend Class E airspace for Claremore,
OK, reconfiguring controlled airspace at Claremore Regional Airport (75
FR 5905) Docket No. FAA-2009-0538. Interested parties were invited to
participate in this rulemaking effort by submitting written comments on
the proposal to the FAA. No comments were received. Class E airspace
designations are published in paragraph 6005 of FAA Order 7400.9T
signed August 27, 2009, and effective September 15, 2009, which is
incorporated by reference in 14 CFR 71.1. The Class E airspace
designations listed in this document will be published subsequently in
the Order.

The Rule

    This action amends Title 14 Code of Federal Regulations (14 CFR)
part 71 by amending Class E airspace for the Claremore, OK area, adding
additional controlled airspace extending upward from 700 feet above the
surface to accommodate SIAPs at Claremore Regional Airport. Adjustment
to the geographic coordinates will be made in accordance with the FAA's
National Aeronautical Charting Office. With the exception of this
change, this action is the same as that published in the NPRM. This
action is necessary for the safety and management of IFR operations at
the airport.
    The FAA has determined that this regulation only involves an
established body of technical regulations for which frequent and
routine amendments are necessary to keep them operationally current.
Therefore, this regulation: (1) Is not a ``significant regulatory
action'' under Executive Order 12866; (2) is not a ``significant rule''
under DOT Regulatory Policies and Procedures (44 FR 11034; February 26,
1979); and (3) does not warrant preparation of a regulatory evaluation
as the anticipated impact is so minimal. Since this is a routine matter
that will only affect air traffic procedures and air navigation, it is
certified that this rule, when promulgated, will not have a significant
economic impact on a substantial number of small entities under the
criteria of the Regulatory Flexibility Act.
    The FAA's authority to issue rules regarding aviation safety is
found in Title 49 of the U.S. Code. Subtitle 1, section 106, describes
the authority of the FAA Administrator. Subtitle VII, Aviation
Programs, describes in more detail the scope of the agency's authority.
This rulemaking is promulgated under the authority described in
subtitle VII, part A, subpart I, section 40103. Under that section, the
FAA is charged with prescribing regulations to assign the use of
airspace necessary to ensure the safety of aircraft and the efficient
use of airspace. This regulation is within the scope of that authority
as it amends controlled airspace at Claremore Regional Airport,
Claremore, OK.

List of Subjects in 14 CFR Part 71

    Airspace, Incorporation by reference, Navigation (air).

Adoption of the Amendment

0
In consideration of the foregoing, the Federal Aviation Administration
amends 14 CFR part 71 as follows:

PART 71--DESIGNATION OF CLASS A, B, C, D, AND E AIRSPACE AREAS; AIR
TRAFFIC SERVICE ROUTES; AND REPORTING POINTS

0
1. The authority citation for 14 CFR part 71 continues to read as
follows:

    Authority:  49 U.S.C. 106(g), 40103, 40113, 40120; E.O. 10854,
24 FR 9565, 3 CFR, 1959-1963 Comp., p. 389.

Sec.  71.1  [Amended]

0
2. The incorporation by reference in 14 CFR 71.1 of the Federal
Aviation Administration Order 7400.9T, Airspace Designations and
Reporting Points, signed August 27, 2009, and effective September 15,
2009, is amended as follows:
* * * * *
Paragraph 6005 Class E airspace areas extending upward from 700 feet
or more above the surface.
* * * * *

ASW OK E5 Claremore, OK [Amended]

Claremore Regional Airport, OK
    (Lat. 36[deg]17'34'' N., long. 95[deg]28'47'' W.)
Claremore Regional Hospital Heliport, OK
Point In Space Coordinates
    (Lat. 36[deg]18'23'' N., long. 95[deg]38'26'' W.)

    That airspace extending upward from 700 feet above the surface
within a 6.4-mile radius of Claremore Regional Airport and that
airspace within a 6-mile radius of the Point In Space serving
Claremore Regional Hospital Heliport.

    Issued in Fort Worth, Texas, on May 7, 2010.
Anthony D. Roetzel,
Manager, Operations Support Group, ATO Central Service Center.
[FR Doc. 2010-11714 Filed 5-17-10; 8:45 am]
BILLING CODE 4910-13-P


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