CANCER ASSESSMENT DOCUMENT EVALUATION OF THE CARCINOGENIC POTENTIAL OF LINDANE PC. Code: 009001 Final Report November 29, 2001 CANCER ASSESSMENT REVIEW COMMITTEE HEALTH EFFECTS DIVISION OFFICE OF PESTICIDE PROGRAMS ii DATA PRESENTATION: Suhair Shallal, Toxicologist DOCUMENT PREPARATION: Sanjivani Diwan, Executive Secretary COMMITTEE MEMBERS IN ATTENDANCE: (Signature indicates concurrence with the assessment unless otherwise stated).

Karl Baetcke William Burnam Marion Copley Kerry Dearfield Vicki Dellarco Virginia Dobozy Richard Hill Yiannakis Ioannou Tim McMahon Nancy McCarroll Esther Rinde Jess Rowland Joycelyn Stewart Clark Swentzel Linda Taylor Yin Tak Woo NON COMMITTEE MEMBERS IN ATTENDANCE (Signature indicates concurrence with the pathology report and statistical analysis of data, respectively) John M. Pletcher, Pathology Consultant Lori Brunsman, Statistical Analysis ii CONTENTS ExecutiveSummary............................................................. .iii I. Introduction............................................................... .. 1 II. BackgroundInformation ................................................... 1 III. Evaluation of Carcinogenicity ............................................... 2 1. CombinedChronicToxicity& CarcinogenicityStudyinCD 1Mice.............. 2 2. CarcinogenicityStudyinAgouti, PseudoAgoutiandBlackMice................ 7 3. NTPCarcinogenicityStudyinB6C3F1Mice ............................... 8 4. CarcinogenicityStudyinWistarRats .................................... 11 5. NTPChronicToxicity& CarcinogenicityStudyinOsborne MendelRats......... 13 IV. Toxicology............................................................ 14 1. Metabolism ....................................................... 14 2. Mutagenicity ...................................................... 15 3. StructureActivityRelationship......................................... 16 4. SubchronicandchronicToxicity ....................................... 16 5. ModeofActionStudies .............................................. 18 V. Committee'sAssessmentoftheWeight of theEvidence .......................... 19 VI. ClassificationofCarcinogenicPotential ....................................... 22 VII. QuantificationofCarcinogenicPotential....................................... 22 V. Bibliography........................................................... 23 LINDANE CANCER ASSESSMENT DOCUMENT FINAL REPORT iii EXECUTIVE SUMMARY Lindane (gamma isomer of hexachlorocyclohexane,   HCH) has been previously classified by the Cancer Assessment Group of the Office of Research and Development (CAG/ ORD, 1985) as a group "B2/ C" carcinogen based on an increased incidence of mouse liver tumors. In 1993, the RfD/ Peer Review Committee (1993) determined that the mouse carcinogenicity data were inadequate because of major deficiencies associated with the available studies. The Toxicology Endpoint Selection (TES) Committee concluded that a new carcinogenicity study in mice was needed to make a determination of the carcinogenic potential of lindane ( TES, 1994).

On May30, 2001, the Cancer Assessment ReviewCommittee (CARC) of the Health Effects Division (HED) of the Office of Pesticide Programs met to evaluate the carcinogenic potential of lindane. At this meeting, the CARC could not make a determination of the carcinogenic potential of lindane because the NTP studies were limited in value and it was uncertain if the study on Agouti, Pseudoagouti and Black mice with limited data could be used for regulatory purposes. In addition, the CARC was informed that new histopathology data would be submitted. The Committee also requested additional information including results of a 90 day subchronic range finding study in CD1 mice, an earlier RfD Committee report and analyses of the older studies on lindane.

At the September 13, 2001 meeting, the Committee reevaluated all the available information/ data including the old and the newly gathered information that was previously not available for review. [A list of CARC members who attended one or both meetings on lindane is presented on page # i. These meetings were held jointly by teleconference with Pesticide Management Regulatory Agency (PMRA), HealthCanada, Canada]. The chronic toxicity/ carcinogenicitystudies were conducted using 5 different strains of mice and two strains of rats. The dietary doses administered in these studies were as follows:

·  CD 1 mice (50/ sex/ dose): 0, 10, 40, or 160 ppm. for 78 weeks (0, 1.3, 5.2, and 21 mg/ kg/ day for males and 0, 1. 8, 7. 1, and 26. 8 mg/ kg/ day for females, respectively).

 Female Agouti, Pseudoagouti and Black mice (36 96 animals per strain): 0 or 160 ppm. for 24 months  B6C3F1 mice (50 /sex/ dose): 0, 80 or 160 ppm for 80 weeks  Wistar rats (50/ sex/ dose): 0, 1, 10, 100, or 400 ppm for 2 years ( 0, 0.05, 0.47, 4.81, and 19.66 mg/ kg/ day for males and 0, 0.06, 0.59, 6.00, and 24.34 mg/ kg/ day for females, respectively).

 Osborne Mendel rats (50/ sex/ dose): For males: 320 or 640 ppm for 38 weeks and 160 or 320 ppm for the remaining 42 weeks. For females: 320 or 640 ppm for 2 weeks and 160 or 320 ppm for 49 weeks then for the remaining 29 weeks the dose was lowered to 80 or 160 ppm. Matched controls consisted of 10/ sex. LINDANE CANCER ASSESSMENT DOCUMENT FINAL REPORT iv The CARC concluded that lindane was carcinogenic only to female CD 1 mice based on the following:

! CD 1 female mice had significant increasing trends, and significant differences in the pair wise comparisons of the 160 ppm( 26.8 mg/ kg/ day) dose group with the controls, for lung alveolarbronchiolar adenomas and combined adenomas/ carcinomas, all at p < 0. 05. The incidence of lung adenomas was slightly outside the historical control range. However, the increased incidence of carcinomas was not dose dependent and the tumor response was variable. Lindane was not carcinogenic to male mice. The dosing at the highest level was adequate and not excessive based on increased incidences of centrilobular hepatocellular hypertrophy and eosinophilic foci of cellular alteration in males and a slight increase in bronchiolar alveolar adenomas in females.

! At 160 ppm, both the treated female Agouti and Pseudoagouti mice had an increase in benign lung adenomas; the treated Agouti mice also had an increased incidence of liver adenomas. No statistical analyses of tumor data were conducted. There was no increase in the incidence or decrease in latency period for liver tumors in Black and Pseudoagouti strains of mice. There was evidence of increased liver weights and an increased incidence of Clara cell hyperplasia in Agouti and Black strains of mice. However, the study was conducted on few animals, only a single dose and sex were tested, no statistical analyses of tumor data were presented and the results of the study were not adequately reported. The Committee concluded that although the liver effects appear to suggest that a dose of 160 ppm was adequate, additional dose groups could have provided confirmatory information.

! The CARC could not assess the carcinogenicity of lindane in B6C3F1 male and female mice because the data reporting was inadequate and there were no indications of toxicity in high dose females. Moreover, the use of only 10 mice per sex for the control group compromised the usefulness of the study.

The Committee concluded that the increased incidence of lung tumors in female mice of three strains was treatment related because the statistically significant increase in lung adenomas in female CD 1 mice was corroborated with the increase in lung tumors in two genetically susceptible strains of mice. Although there is some evidence of liver tumor induction in these genetically susceptible strains of mice, no evidence of liver tumors was noted in CD 1 mice. Nevertheless, the evidence of hepatotoxicity (increased liver weight, hypertrophy and increased incidence of liver foci in both sexes) and promoting activity, indicates t hat t he liver, in addition to lung is a major target organ of toxicity.

! The CARC determined that lindane was not carcinogenic to male and female Wistar rats and the results of the study in Osborne Mendel rats were difficult to interpret and were not useful in determining the carcinogenic potential of lindane in that strain of rat.

! The results of a battery of acceptable mutagenicity assays indicate that lindane has a low LINDANE CANCER ASSESSMENT DOCUMENT FINAL REPORT v concern for mutagenicity. These studies satisfy pre 1991 FIFRAguideline requirements. The Committee recommended that the dominant lethal assay be repeated to determine if there is a genetic component to the reproductive (germ cell) effects reported for lindane.

! The technical HCH and the alpha isomer are classified as category "B2" (probable human carcinogen). The beta isomer is classified as a group "C "( possible human carcinogen) while the delta and epsilon isomers are classified as group "D" (not classifiable as to human carcinogenicity) .

! No mechanistic studies were submitted to support the mode of action for lung tumor induction in mice.

In accordance with the EPADraft Guidelines for Carcinogen Risk Assessment (July, 1999), the CARC classified lindane into the category "Suggestive evidence of carcinogenicity, but not sufficient to assess human carcinogenic potential" because lindane caused an increased incidence of benign lung tumors in female mice only. The Committee further recommended that quantification of human cancer risk is not required. LINDANE CANCER ASSESSMENT DOCUMENT FINAL REPORT 1 Cl Cl Cl Cl Cl Cl I. INTRODUCTION Lindane (gamma isomer of hexachlorocyclohexane,   HCH) was previously classified by the Cancer Assessment Group of the ORD (1985) as a group "B2/ C" carcinogen based on an increased incidence of mouse liver tumors; the calculated unit risk ( Q1*) was 1. 1 (mg/ kg/ day) 1 human equivalents. The other isomers of hexachlorocyclohexane are classified in IRIS. Technical HCH and the alpha isomer are classified as "B2", probable human carcinogens. The beta isomer is classified as "C", possible human carcinogen. The delta and epsilon isomers are classified as D, not classifiable as to human carcinogenicity.

In 1993, the RfD/ Peer Review Committee determined that the mouse carcinogenicity data were insufficient because of major deficiencies associated with all available studies. The TES committee concluded that a new carcinogenicity study in mice was needed to make a determination of the carcinogenic potential of lindane (TES, 1994).

On May 30, 2001, the HED Cancer Assessment Review Committee (CARC) of the Health Effects Division (HED) of the Office of Pesticide Programs met to evaluate the carcinogenic potential of lindane. At this meeting, the CARC could not make a determination of the carcinogenic potential of lindane because the NTP studies were limited in value and the published study on Agouti, Pseudoagouti and Black mice could not be used for regulatory purposes. The Committee, therefore, requested additional information including results of a 90 day subchronic range finding studyin CD 1 mice, an earlier RfD Committee report and analyses of the older studies on lindane. At the September 13, 2001 meeting, the Committee met to reevaluate the carcinogenic potential of lindane based on the available old and new information/ data. At this meeting, information/ data were presented by Dr. Suhair Shallal of Reregistration Branch 4. These data included a new mouse carcinogenicity study in CD 1 mice submitted by the registrant, a published study in Agouti, Pseudoagouti and Black mice, NCI studies in B6C3F1 mice and Osborne Mendel rats and a 2 year chronic/ carcinogenicity study in Wistar rats. In addition, carcinogenicity and genetic toxicology data on structurally related compounds were presented.

II. BACKGROUND INFORMATION Lindane (PC. Code is 009001 and CAS Number is 58 89 9) is a broad spectrum organochlorine compound used on a wide range of soil dwelling and plant eating (phytophagous) insects. Its chemical structure is provided below.

Figure 1. Chemical Structure of   HCH LINDANE CANCER ASSESSMENT DOCUMENT FINAL REPORT 2 The technical HCH consists of   isomer: 65 67% ,   isomer: 11 13%,  isomer: 13 15% ,   isomer: 3 5%,   isomer: 4 6% and other isomers: <1%. Lindane is a  isomer (1    2    3 4 , 5 , 6   hexachlorocyclohexane). The other isomers are:   isomer (1    2    3 4 , 5 , 6   hexachlorocyclohexane);   isomer (1    2 3    4 , 5 , 6   hexachlorocyclohexane);   isomer (1    2    3    4 , 5 , 6   hexachlorocyclohexane) and   isomer: (1    2    3    4 , 5 , 6   hexachlorocyclohexane).

Worldwide, lindane is commonly used on a wide variety of crops, in warehouses, in public health to control insect borne diseases, and (with fungicides) as a seed treatment. Lindane is also presently used in lotions, creams, and shampoos for the control of lice and mites (scabies) in humans; these pharmaceutical uses are regulated by FDA. In the U. S., the only registered food/ feed use is seed treatment for field and vegetable crops.

Lindane may be found in formulations with a host of fungicides and insecticides. Labels for products containing the chemical must bear the Signal Word WARNING. Some formulations of lindane are classified as Restricted Use Pesticides (RUP), and as such may only be purchased and used by certified pesticide applicators. Lindane is no longer manufactured in the U. S., and most agricultural and dairy uses have been canceled because of concerns about its potential carcinogenicity.

III. EVALUATION OF CARCINOGENICITY STUDIES 1. Combined Chronic Toxicity/ Carcinogenicity Study with Lindane in CD 1 Mice Reference: Lindane, carcinogenicity study by dietary administration to CD 1 mice for 78 weeks (2000), final report (vols. 1 4). Huntingdon Life Sciences Ltd., Woolley Road, Alconbury, Huntingdon, Cambridgeshire, PE28 4HS, England, Report no. 00 3512, Huntingdon Life Sciences Project identity no. CIL/ 021, MRID 45291402.

Experimental Design Lindane (99.78% a. i., batch no. HLS 96/ 1) was administered to groups of 50 Crl: CD 1 ®

(ICR) BR mice/ sex/ dose in the diet at concentrations of 0, 10, 40, or 160 ppm. The test diets were given for 78 weeks. The concentrations of 10, 40, or 160 ppm resulted in mean daily compound intakes for males of 1. 3, 5. 2, and 21 mg/ kg/ day and for females of 1.8, 7.1, and 27 mg/ kg/ day, respectively.

Discussion of Tumor Data Tumor Analyses As shown in Table 1. there was no statistically significant increase in tumors in male mice (Brunsman, 2001). The incidence of liver tumors was not statistically significant in either male or female CD 1 mice( Table 1).

Table 1. CD 1 Mice Male and Female Liver Tumor Rates + and Exact Trend Test and Fisher's LINDANE CANCER ASSESSMENT DOCUMENT FINAL REPORT 3 Exact Test Results (p values) (Brunsman 2001)

ppm 0 10 40 160 0 10 40 160 mg/ kg/ day 0 1. 3 5.2 20.5 0 1.8 7. 1 26.8 Males females Tumor Type Liver Tumor Adenoma % p = 10 a /48 (21) 0.1730 10/ 46 (22) 0.5570 9/ 43 (21) 0.5962 13/ 46 (28) 0.2752 0/ 47 (0) 0.2567 0/ 45 (0) 1.000 0/ 47 (0) 1.000 1 a /48 (2) 0.5053 Carcinoma % p = 4/ 48 (8) 0.4046 1/ 46 (2) 0.1943 1/ 43 (2) 0.2167 2 b /46 (4) 0.3592 No carcinomas were observed in females Combined % p = 13/ 48 (27) 0.1817 11/ 46 (24) 0.4543 10/ 43 (23) 0.4304 15/ 46 (33) 0.3594 + Number of tumor bearing animals/ Number of animals examined, excluding those that died before week 53. a First adenoma observed in males at week 67, dose 0 ppm; First adenoma observed in females at week 80, dose 160 ppm b First carcinoma observed in males at week 53, dose 10 ppm; no carcinomas were observed in females.

Note: 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.

Treatment for up to 78 weeks with lindane resulted in a statistically significant increase in the incidence of bronchiolar alveolar adenomas and an increased incidence of carcinomas in female Crl: CD 1 mice; however, the increased incidence of carcinomas was not dosedependent and tumor response was variable. Female mice had significant increasing trends and significant differences in the pair wise comparisons of the 160 ppm dose group with the controls for lung alveolar bronchiolar adenomas and combined adenomas/ carcinomas, all at p < 0. 05 (Table 2a). The incidence of pulmonary adenomas in the control group was at the low end of the range in historical controls (6%) and the incidence in females administered the high dose (23%) was slightly outside of the high end of the range for the historical controls (6% 19%) (MRID 45291402).

.

Table 2a. Male and Female Lung Alveolar Bronchiolar Tumor Rates + and Exact Trend Test and Fisher's Exact Test Results (p values) Initial Diagnosis (Brunsman, 2001) LINDANE CANCER ASSESSMENT DOCUMENT FINAL REPORT 4 ppm 0 10 40 160 0 10 40 160 mg/ kg/ day 0 1. 3 5.2 20.5 0 1.8 7. 1 26.8 males females Tumor Type Lung Alveolar Bronchiolar Tumors Adenoma % p = 16 a /49 (33) 0.0270* n 15/ 48 (31) 0.5278 11/ 49 (22) 0.1830 8/ 48 (17) 0.0554 3 a /48 (6) 0.0274 * 7/ 46 (15) 0.1412 7/ 47 (15) 0.1497 11/ 48 (23) 0.0200 *

Carcinoma % p = 0/ 49 (0) 0.3138 1/ 48 (2) 0.4948 3 b /49 (6) 0.1211 0/ 48 (0) 1.0000 1/ 48 (2) 0.4361 2 b /46 (4) 0.4839 2/ 47 (4) 0.4920 1/ 48 (2) 0.7526 Combined % p = 16/ 49 (33) 0.0186* n 16/ 48 (33) 0.5574 14/ 49 (29) 0.4134 8/ 48 (17) 0.0554 4/ 48 (8) 0.0389 * 8/ 46 (17) 0.1573 9/ 47 (19) 0.1080 12/ 48 (25) 0.0264 *

a first adenoma observed in males at week 33, dose 0 ppm and in females at week 44, dose 0 ppm b first carcinoma observed males at week 65, dose 40 ppm and in females at week 53, dose 10 ppm n Negative trend Note: 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.

A new report on the results of resectioning of lungs of female mice was later submitted by the Registrant (MRID 45470601). The results showed the presence of two additional pulmonary adenomas in the controls and two in the high dose group. The number of pulmonary adenomas and combined adenomas/ carcinomas in Group 4 remained still statistically significant (Table 2b), and was biologically significant, being well above the historical control range for this strain of mouse. The incidence in the controls and in the two intermediate dose groups was within the historical control range (6% 19%) for pulmonary adenomas in CD 1 females. It is, however, difficult to compare old tumor data versus the combined analyses based on the old and new findings without knowing the exact procedure involved in resectioning the lungs and why resectioning of the lung tissue was necessary. Therefore, without judging the validity of the new sectioning versus the original report, the end results appear to be the same.

Table 2b. Lindane  CD 1 Mouse Study Female Lung Alveolar Bronchiolar Tumor Rates + [Additional Histopathology PLUS LINDANE CANCER ASSESSMENT DOCUMENT FINAL REPORT 5 Original Diagnoses] and Exact Trend Test and Fisher's Exact Test Results (p values) Results of Re sectioning (Brunsman, 2001)

Dose (ppm)

0 10 40 160 Adenomas 5 a /48 7/ 46 7/ 47 13/ 48 (%) (10) (15) (15) (27)

p = 0.0165* 0.3492 0.3644 0.0326*

Carcinomas 1/ 48 2 b /46 2/ 47 1/ 48 (%) (2) (4) (4) (2)

p = 0.4361 0.4839 0.4920 0.7526 Combined 6/ 48 8/ 46 9/ 47 14/ 48 (%) (12) (17) (19) (29)

p = 0.0235* 0.3535 0.2723 0.0384*

+ Number of tumor bearing animals/ Number of animals examined, excluding those that died before week 44.

a First adenoma observed at week 44, dose 0 ppm.

b First carcinoma observed at week 53, dose 10 ppm.

Note: 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.

Non Neoplastic Lesions At 78 weeks, there were increases in the incidences of centrilobular hepatocyte hypertrophy (control, 6%; 160 ppm, 30%; p< 0. 01) and eosinophilic focus/ foci of hepatocellular alteration (control, 4%; 160 ppm, 16%; p< 0.05) in high dose males compared to the control group (Table 3). No microscopic liver changes were seen in females Table 3. Non Neoplastic Lesions in CD 1 Mice Fed Lindane LINDANE CANCER ASSESSMENT DOCUMENT FINAL REPORT 6 Dose (ppm) 0 10 40 160 0 10 40 160 mg/ kg/ day 0 1. 3 5.2 20.5 0 1.8 7. 1 26.8 males females centrilobular hepatocyte hypertrophy 3/ 50 2/ 50 7/ 50 15/ 50 0/ 50 0/ 50 0/ 50 0/ 50 eosinophilic focus/ foci of hepatocyte. alterations 2/ 50 1/ 50 5/ 50 8/ 50 0/ 50 0/ 50 0/ 50 0/ 50 lung epithelial hyperplasia 1/ 50 1/ 50 1/ 50 2/ 50 1/ 50 0/ 50 0/ 50 2/ 50 lung congestion 16/ 50 12/ 50 16/ 50 11/ 50 6/ 50 13/ 50 8/ 50 13/ 50 Thyroid dilated follicles 9/ 49 4/ 16 3/ 16 14/ 50 2/ 50 1/ 19 0/ 17 3/ 50 LN Bronchial increased cellularity 1/ 16 0/ 17 1/ 15 0/ 11 0/ 12 1/ 15 2/ 15 3/ 14 Adequacy of the Dosing for Assessment of Carcinogenicity There was no significant change in body weight and the survival analyses indicated no statistically significant incremental changes with increasing doses of lindane in male or female mice (Brunsman, 2001). All dose groups and controls had  68% survival at study termination.

Histopathologyrevealed an increased incidence of liver lesions in male mice. The LOAEL was 160 ppmfor males (20.5 mg/ kg/ day) and females (26.8 mg/ kg/ day) based on liver hypertrophy in males and a slight increase in bronchiolar alveolar adenomas in females.

The doses selected for the above chronic/ carcinogenicity study were based on the results of a range finding subchronic toxicity study (MRID 45424301). In this study, lindane (99.78% a. i.) was administered to 10 CD 1 mice/ sex/ dose at dietary levels of 0, 40, 80, 160, 320 ppm (0, 5. 7, 12.2, 22.8 and 46.2 and 0, 8.9, 16.0, 32.9, and 62.6 mg/ kg/ day in males and females, respectively). Body weight gain was reduced by 27% in males and 9% in females at the highest dose. The four females in the highest dose (320 ppm) group that died during treatment period had hepatocellular hypertrophy and karyomegaly in the liver and Clara cell hypertrophy as well as congestion in the lungs. These findings were also seen in treated animals in the 160 and 320 ppm dose groups that were sacrificed at study termination; therefore, these deaths were considered to be treatment related. The early deaths in the 320 ppmdose group indicate that this dose was excessive. Based on the results of this study the majority of the CARC concluded that the dose levels of 0, 10, 40 160 ppm selected for the two year carcinogenicity study in mice appeared to be adequate. However, a few members felt that the animals could have tolerated a higher dose, based on the results of chronic study.

2. Combined Chronic Toxicity/ Carcinogenicity Study with Lindane in Agouti, Pseudoagouti and Black Mice LINDANE CANCER ASSESSMENT DOCUMENT FINAL REPORT 7 Reference: Wolff, G. L. et al. Tumorigenic responses to lindane in mice: potentiation by a dominant mutation, NCTR, Jefferson, AR ; Carcinogenesis 8( 12): 1889 97 (1987).

Experimental Design In an NCI study, three strains of female mice, Agouti, Pseudoagouti, and Black, were administered lindane at dietary concentrations of 0 or 160 ppm. Groups of 36 96 animals per strain were continuously fed treated or control diets for up to 24 months. Additional groups of 48 96 Agouti and Black mice were fed treated or control diets for 6 months and then fed control diet for 6 or 18 months (recovery).

Tumor Analysis:

No evidence for an increased incidence or a decreased latency of liver tumors was observed for the black strain at any time during the 24 months of study or for the Pseudoagouti strain through the 18 month sacrifice. At 18 months, 0/ 34 control and 12/ 36 (33%) of the treated Agouti mice developed hepatocellular adenomas; one carcinoma each in the treated and control groups was noted. Both the treated Agouti and Pseudoagouti strains had clear increases in adenomas and slight increases in carcinomas at 24 months. The incidence rates for the control and treated Agouti groups were 9% and 35%, respectively, for adenomas and 13% and 17%, respectively, for carcinomas. The incidence rates for the control and treated Pseudoagouti groups were 5% and 12%, respectively, for adenomas and 2% and 5%, respectively, for carcinomas.

Increases in Clara cell hyperplasia were noted in the lung at all sacrifice intervals for each strain and the incidence of lung tumors was increased in later months for the Agouti and Pseudoagouti strains. The percentage of mice with Clara cell hyperplasia in the control and treated groups was 6 31% and 72 92%, respectively, for the Agouti; 6 17% and 50 79%, respectively, for the Pseudoagouti; and 0 14% and 56 90%, respectively, for the Black strain. Lung tumors for the Agouti strain occurred in 0% of the control and 17% of the treated animals at 18 months and 4% of the control and 19% of the treat ed animals at 24 months. Lung tumors in the Pseudoagouti strain occurred in 6% of the controls and 14% of the treated animals at 24 months. After recovery, the incidences of Clara cell hyperplasia (Agouti and Black mice) and lung tumors (Agouti mice) remained slightly elevated as compared with the controls.

Non neoplastic lesions:

No clinical signs of toxicity and no survival information were reported. No apparent effects on body weights or food consumption were observed, but only limited data were presented. When compared with untreated controls at 6 and 12 months, benzo( a) pyrene monooxygenase activity in the liver was increased 1.61 1.84x in the Agouti, 2.71 2.78x in the Pseudoagouti, and 2. 07 2.09x in the Black strains. Liver weights were increased 14.7 31.2% in the Agouti, 13.5 22.0% in the Pseudoagouti, and 12.2 16.4% in the Black strains at sacrifice intervals up to 24 months. Following the recovery period, liver weights of the treated mice were similar to the controls. LINDANE CANCER ASSESSMENT DOCUMENT FINAL REPORT 8 Adequacy of the dose:

Only two dose groups were tested in this study, 0 and 160 ppm. The CARC concluded that although the liver effects appear to suggest that a dose of 160 ppm was adequate, additional dose groups may have provided confirmatory information. Amore thorough reporting of the clinical signs would have been useful in definitive determination of adequacy of dose.

3. NTP Combined Chronic Toxicity/ Carcinogenicity Study with Lindane in Mice Reference: NCI, Carcinogenesis Program, Bethesda, MD; DHEWPub # (NIH) 77 814, 1977.

Experimental Design:

Groups of 50 B6C3F1 mice/ sex were administered lindane at dietary concentrations of 80 or 160 ppm for 80 weeks then observed for an additional 10 11 weeks. Matched controls consisted of 10 mice/ sex. For statistical analysis, 40 untreated mice/ sex were pooled fromfour other bioassays of other test chemicals.

Discussion of tumor data:

The incidence of hepatocellular carcinoma in low dose males (19/ 49) was increased significantly (p= 0.001) when compared with pooled controls (5/ 49). The incidence of hepatocellular carcinoma in high dose male mice (9/ 46) was not significantly different than the matched (2/ 10) or pooled controls.

Non neoplastic lesions The non neoplastic lesions are presented in Table 4 below. There were only slight increases in liver inflammation in males and spleen hyperplasia in females. Higher incidences of microscopic changes in the uterus and ovaries of treated mice were noted; however, no clear dose response was found.

Table 4. Non neoplastic lesions in B6C3F1 male and female mice Dose 0 80 160 0 80 160 LINDANE CANCER ASSESSMENT DOCUMENT FINAL REPORT 9 males females liver, inflammation/ swelling 0/ 10 0/ 49 5/ 46 0/ 10 0/ 47 0/ 46 spleen, hyperplasia 0/ 10 1/ 50 0/ 47 0/ 8 2/ 49 4/ 48 uterus, hyperplasia N/ A 0/ 7 3/ 44 4/ 43 ovary , inflamation 3/ 7 14/ 42 10/ 46 Adequacy of Dosing for Assessment of Carcinogenicity Body weight was unaffected by the test material. No food or water consumption data was provided. The CARC concluded that the use of pooled controls compromised the usefulness of the study and the available data were inadequate to make an assessment of the carcinogenic potential of lindane.

Table 5 provides a comparison of other available mouse studies and their deficiencies.

Table 5. Mouse Carcinogenicity Studies, their Results and Deficiencies 1 Study design/ deficiencies/ classification Results 1. Carcinogenicity  CF 1 mouse Walker and Thorpe as published in Food Cosmetic Toxicology 11: 433 442,1973.

Supplementary. Data in summary tables were not supported by individual animal data. Test material cannot be validated. Only one dose level which produced severe toxicity was used. Study was run concurrently with dieldrin, DDT, phenobarbitone Considered positive for liver tumors. Males Females Control( 45) BHC( 29) Control( 44) BHC( 29) Adenoma 20% 38% 23% 34% Carcinoma 4% 55% 0 34% Total 24% 93%** 23% 69%** [data are % of animals with tumor, the number in( ) is the number of mice per sex examined.] ** P < 0.01 study author's statistics.

CFl strain mouse, Dose levels tested: 0, 400 ppm and beta BHC for 105 to 109 weeks.

2. Carcinogenicit dd mouse Hamada, Yutani and Miya as published in GANN 64: 511 3( 1973).

Supplementary. Data were available in summary form only. Very small number (only 3 or 4) of animals were dosed per group. The survival was poor and dosing period was only 32 weeks . Test material cannot be validated. Study was run concurrently with alpha, beta and gamma isomers of BHC. considered positive Three of f our males and one of three f emales receiving pure gamma isomer at 600 ppm were said to develop "hepatoma" or liver tumors. None of the controls or mice dosed with 100 or 300 ppm developed these tumors.

dd strain mice, dose levels 0, 100, 300 or 600 ppm of gamma, alpha or beta hexachlorocyclohexane or crude "BHC" for 36 to 38 weeks.

3. Oncogenicity  B6C3F1 mouse NCI, No.: NCI CG TR 14, 1977 Supplementary: Use of only 10 mice per sex for the control group compromised the usef ulness of the study. Data were in summary tables only. There were no indications of toxicity at high dose. Test material cannot be validated. Considered positive at low dose only. Hepatocellular Carcinomas Dose Level Males Females Control 10 2( 20%) 10 0 80 ppm 49 19( 39%) 47 2( 4%) 160 ppm 46 9( 20%) 46 4( 7%) NCI study conclusion is that the chemical is not positive for liver tumors. Conclusion corroborated by Vesselinovich and Carlborg. The CAG of ORD considers low dose group positive. Dose levels tested were 0, 80 and 160 ppm for 80 weeks with 10 weeks recovery. B6C3CF 1 strain mice. LINDANE CANCER ASSESSMENT DOCUMENT FINAL REPORT 10 4. Oncogenicity Chbb NMRI mouse Boehringer Sohn Ingelheim am Rhein, No Study No.: February 25. 1975 Supplementary: Insufficient raw data were used to support conclusions. There was no verif ication of identity of test material and no evidence of toxicity at high dose level. No evidence of liver neoplasms.

Dose levels tested 0, 12.5, 25 and 50 ppm.

Chbb NMRI strain mice.

5. Oncogenicity  mice (strain unspecified) Ito , Nagasaki, Arie, Sughara and Makiura, Nara Medical University No Study No.: as published in J. National Cancer Institute 51: 817 826, 1972 . Supplementary/ Invalid: No individual animal data were provided, test was conducted for only 24 weeks. There was no verif ication of the test material. gamma isomer was not shown to increase liver tumors. Alpha isomer was positive.

Dose levels tested 0, 100, 250 or 500 ppm for 24 weeks.

Strain was not specified.

6. oncogenicity  ICR JCL mouse Goto, Hattori, Miyagawa and Enomoto, Gakushin University, as published in Chemosphere 1( 6): 279 282 1972. No Study No., Supplementary: No individual animal data were available and there was no verif ication of the test material. Single dose level f or only 26 weeks. Other isomers were tested at the same time. No inf ormation on survival or reactions to treatment was available. Test material was not validated as lindane. considered positive Liver tumors developed in 5 of 10 mice dosed with gamma isomer after 26 weeks.

Dose level tested: 0 and 600 ppm, other isomers of HCH also tested.

ICR JCL strain mouse.

7. Carcinogenicit  dd mouse Nagasaki, Tonrii, Mega, Marugami and Ito, Nara Medical University, as published in Topics in Chemical Carcinogenesis, 1972 No Study No.: Supplementary: Technical ECCE (mixture of isomers) was used, not lindane. Data were available in summary tables only. Only males were tested. "Hepatoma" resulted in response to 660 ppm of the test material (mixture of isomers).

Doselevelstested: 0, 6. 6, 66and660ppm.

dd strain of mice, only males tested.

8. Carcinogenicity  mouse Wolff and colleagues. AS published in Carcinogenesis 8( 12): 1889 1892 , 1987 Supplementary: Data are in summary tables only. No verif ication of the test material. Only f emales tested. Only a single dose tested. No data on clinical observations, body weight or survival. This strain may metabolize lindane at a slower rate with resulting accumulation in tissue. Considered positive in two of three strains Liver and lung adenomas and liver carcinomas in "pseudoagouti" and "yellow" but not in black normal mice.

Dose levels tested 0 and 160 ppm.

Strains as indicated above.

1 This table developed by John Doherty (1993 RfD document) has been slightly modified.

5. Carcinogenicity Study in Rats Reference:

Aymes, S. J. 1993. Lindane: Combined carcinogenicity and toxicity study by dietary administration to Wistar rats for 104 weeks. Addendum to final report (Adrenal histopathology  additional investigations). Life Sciences Research, England. Study No. 90/ CIL002/ 0839. June 2, 1993. MRID 42891201. Unpublished. LINDANE CANCER ASSESSMENT DOCUMENT FINAL REPORT 11 Aymes, S. J. 1989. Combined carcinogenicity and toxicity study by dietary administration to Wistar rats for 104 weeks. Life Sciences Research, England. Study No. 90/ CIL002/ 0839. November 7, 1989. MRID 41853701. Unpublished.

Aymes, S. J. 1989. Lindane: Combined carcinogenicity and toxicity study by dietary administration to Wistar rats for 104 weeks  Interim report week 0 26. Life Sciences Research, England. Study No. 88/ CIL002/ 816. March 7, 1989. MRID 41094101. Unpublished.

Experimental Design Lindane (99.75% a. i., Lot no. DA433) was administered in the diet to groups of 50 male and 50 female Wistar rats at concentrations of 0, 1, 10, 100, or 400 ppm for 2 years. Corresponding delivered doses were 0, 0. 05, 0.47, 4.81, and 19.66 mg/ kg/ day, respectively, for males and 0, 0.06, 0.59, 6.00, and 24.34 mg/ kg/ day, respectively, for females. An additional 15 rats/ sex/ group were designated for interim sacrifices at 30 days and 26 weeks.

Discussion of Tumor Data Male rats were identified as having adrenal pheochromocytomas (Table 6). The percentages of animals with adrenal tumors in the 0, 1, 10, 100, and 400 ppm groups were 14, 16, 16, 6, and 24% for benign tumors, respectively, and 0, 0, 6, 8, and 2% for malignant tumors, respectively. Statistical significance was not reached by relevant tests.

When compared to historical controls, the incidence of adrenal pheochromocytomas in the current study slightly exceeded that of the historical control at the HDT (400 ppm). The range of adrenal pheochromocytomas observed in the historical control data was 4/ 50 to 11/ 50 (8%  22%) for male rats examined in four studies conducted in 1990. Of the 18 studies in the historical control data, 6 were performed in 1990; the other 12 were performed between 1986 and 1988.

Non Neoplastic Lesions The incidence rate of periacinar hepatocytic hypertrophy was significantly (p< 0.01) increased in the 100 and 400 ppm groups with 25/ 50 males and 19/ 50 females at 100 ppm and in 40/ 50 males and 43/ 50 females at 400 ppmcompared with the vehicle control. No treatment related histopathological lesions were observed in the spleen or bone marrow.

Kidney lesions in males indicative of alpha 2µ globulin accumulation were observed in animals treated with  10 ppm; but since this effect is species (rat) specific, it was not considered relevant to human health risk assessment.

Table 6. Percentage (%) of animals with adrenal pheochromocytomas LINDANE CANCER ASSESSMENT DOCUMENT FINAL REPORT 12 Control (ppm) Benign Malignant Both (B & M)

0 14014 1 16016 10 16 6 18 100 6 8 14 400 24 2 26 Adjusted Rates 1 0 29029 1 39039 10 33.5 15.2 38.6 100 12.1 21.4 31.0 400 52.9 2. 9 54.2 Historical controls: Benign 8 to 22% and Malignant 0 to 2% 1 Kaplan Meier estimated tumor incidence at the end of the study after adjusting for inter current mortality.

Adequacy of Dosing for Assessment of Carcinogenicity CARC concluded that the doses tested were considered to be adequate and not excessive in both sexes. This was based on decreased survival, decreased body weight gains, decreased food consumption, and increased spleen and liver weights correlated with periacinar hepatocyte hypertrophy in both sexes at the high dose, relative to the controls.

Final body weights of the high dose males were significantly ( 14%; p  0.05) less than the controls. Body weights and body weight gains for the treated females were similar to the controls throughout the study. Total food consumption for the entire study was similar to the control levels.

Platelet counts were significantly increased in males at 100 and 400 ppm at week 12 and in males and females at week 24, but not at later time points. High dose males and females had significant decreases in red blood cell parameters at week 104 as compared with the controls.

Significant changes in clinical chemistry parameters were observed in high dose males and females during the first year of the study. Inorganic phosphorous and calcium were increased in males and females; the cholesterol and urea were increased in females; and the albumin/ globulin ratio was decreased in females. All parameters were similar to the control LINDANE CANCER ASSESSMENT DOCUMENT FINAL REPORT 13 levels by week 104.

High dose males and females had increased absolute and relative liver weights at all interim sacrifices, although statistical significance was not always reached. At study termination, absolute and relative liver weights were significantly increased in high dose males and females. At 100 ppm, absolute and relative liver weights were increased for both sexes.

6. NTP Combined Chronic Toxicity/ Carcinogenicity Study with Lindane in Rats Reference: NCI, Carcinogenesis Program, Bethesda, MD; DHEWPub # (NIH) 77 814, 1977.

Experimental design:

Lindane was administered in the diet of 50 Osborne Mendel rats/ sex/ dose for a total of 80 weeks. Males received 320 or 640 ppm for 38 weeks and 160 or 320 ppm for the remaining 42 weeks. Females received 320 or 640 ppm for 2 weeks and 160 or 320 ppm for 49 weeks; then for the remaining 29 weeks, the dose was lowered to 80 or 160 ppm. After the initial 80 week treatment period, all animals were observed for an additional 29 30 weeks. Matched controls consisted of 10 rats/ sex. For statistical analysis 45 untreated rats/ sex were pooled from four other bioassays of other test chemicals.

Discussion of tumor data As shown in Table 7, there were three incidences of spleen hemangioma in the high dose male group only and none in the females. There were also increases in neoplastic lesions of the liver; however, these were within the historical control values in this tumor for this rat strain (0 12%, Goodman et al. 2000, personal communication). Other organs affected with primary tumors include: thyroid, pituitary, and mammary glands wit h only a few incidences and no clear dose response correlation. .

Non neoplastic Lesions Microscopic changes were seen in the liver of both males and females, including cirrhosis, degeneration and necrosis in a dose dependent manner. Cysts, hyperplasia and atrophy were seen in the endocrine and reproductive organs of these animals.

Table 7. Tumor data for Osborne Mendel rats fed lindane for 80 weeks Dose control low high control low high males females spleen hemangioma 0/ 8 0/ 44 3/ 44    LINDANE CANCER ASSESSMENT DOCUMENT FINAL REPORT 14 thyroid, adenoma carcinoma 1/ 6 5/ 37 0/ 37 0/ 8 1/ 44 1/ 42 0/ 6 1/ 37 4/ 37 0/ 8 1/ 44 0/ 42 liver, neoplastic nodule 0/ 10 3/ 45 2/ 45 0/ 10 4/ 48 2/ 45 pituitary, adenoma carcinoma 0/ 10 0/ 32 2/ 35 0/ 7 0/ 45 2/ 41 0/ 10 1/ 32 0/ 35 0/ 7 1/ 45 0/ 41 mammary, adenoma carcinoma 0/ 10 0/ 48 2/ 49 0/ 10 3/ 50 1/ 50 0/ 10 1/ 48 0/ 49 1/ 10 1/ 50 0/ 50 Adequacy of Dosing for Assessment of Carcinogenicity Mean body weight did not show consistent changes from the administration of lindane. The CARC concluded that the use of pooled controls compromised the usefulness of the study and the available data were inadequate to make an assessment of the carcinogenic potential of lindane.

IV. TOXICOLOGY 1. Metabolism Lindane is distributed to all organs at measurable concentrations within a few hours after oral administration. The highest concentrations are found in adipose tissue. The metabolism of lindane is initiated through one of the following pathways: dehydrogenation leading to  HCH, dehydrochlorination leading to formation of  PCCH, dechlorination leading to formation of  tetrachlorohexene, or hydroxylation leading to formation of hexachlorocyclohexanol. Further metabolism leads to a large number of metabolites. Volatilizalion appears to be an important route of its dissipation under the high temperature conditions oftropicalregions. Lindane is converted byenzymatic reactions, mainlyin the liver. In mammals, including humans, lindane is excreted very rapidly in urine and feces after metabolic degradation; only small amounts are eliminated unchanged. The half life of lindane administered to rats is 2 4 days depending on the frequency of exposures, single or repeated.

Other metabolites are also known to be associated with lindane exposure; these include 2,4,6 trichlorophenol and 2, 4, 5 trichlorophenol. Exposure to lindane in a residential setting is expected to be negligible except for use as a lice or scabies treatment. These uses are regulated by FDA and have not been evaluated in this document.

2. Mutagenicity As part of the Registration Standard prepared in 1985, the available literature and submitted mutagenicity studies were evaluated (HED Document No. 004704). Based on this evaluation, it was concluded that the weight of the evidence with conventional genotoxicity testing LINDANE CANCER ASSESSMENT DOCUMENT FINAL REPORT 15 indicated that lindane did not interact with DNA or interfere with genetic mechanisms. This position was reiterated in 1993 (memo by G. Ghali, 1993). Reviews prepared by IARC (1979/ 1987), IPCS (1990) and ATSDR( 1999) indicate that lindane and its associated isomers have mixed genotoxic potential. In addition, numerous mutagenicity studies have been evaluated by the European Commission (EU) in their draft monograph on lindane (2001). Representative studies were selected from the EU evaluation of lindane since they were performed according to OECD or EPA guidelines. These include:

1. A bacterial mutagenicity assay using Salmonella typhimurium with and without metabolic activation which was negative up to cytotoxic doses (5000 ug/ plate +S9) or insoluble doses (greater than or equal to 500 ug/ plate S9; greater than or equal to1500 ug/ plate +S9 ; Oesch, 1980).

2. An aerobic mammalian cell (V79) gene mutation assay was negative up to cytotoxic doses (greater than or equal to 50 ug/ mL S9; greater than or equal to 250 ug/ mL+ S9); the compound precipitated at greater than or equal to 250 ug/ mL (Glatt, 1984). EPA only received an anaerobic assay which had an acceptable aerobic portion (Glatt, 1985).

3. Mammalian cell cytogenetic assay was negative in CHO cells up to cytotoxic doses (greater than or equal to 33.2 ug/ mL S9; greater than 33.2 ug/ mL+ S9). (Murli, 1990).

4. UDS in primary rat hepatocytes was also found to be negative up to cytotoxic doses (15 ug/ mL) (Cifone, 1990).

There are no acceptable in vivo studies but they are not necessary to satisfy pre 1991 FIFRA guideline requirements. Newer published data shows that lindane induces oxidative stress in the liver of treated rats (Carrion et al., 2001; Cornnejo et al., 2001; Videla et al., 2000). In agreement with these findings, the 1999 ATSDR review states that oxidative stress may be a possible mechanism of liver toxicity.

The CARC has an additional concern related to possible genetic effects on germinal cells.

Although an old submitted dominant lethal assay (MRID 00062657) was negative, it was considered unacceptable and not upgradable because of technical deficiencies. Recent information found in the open literature indicates that topical application of lindane led to rapid absorption and accumulation in rat testes (Suwalsky et al., 2000). The investigators reported widespread damage to a "great number" of Leydig cells after the application of 1% lindane once daily for 4 consecutive days. These findings are consistent with the work of Walsh and Stocco (2000) showing inhibition of steroidogenesis by reductions in steroidogenic acute regulatory (StAR) protein expression in mouse Leydig cells in vitro. Since there is some evidence that lindane reaches and damages germ cells, the Committee recommends that the dominant lethal assay be repeated to determine if there is a genetic component to the reproductive (germ cell) effects reported above for lindane.

3. Structure Activity Relationship LINDANE CANCER ASSESSMENT DOCUMENT FINAL REPORT 16 Technical grade hexachlorohexane (HCH) which consists of alpha, beta, gamma, delta and epsilon isomers of HCH is a carcinogen. In rodents studies, the pure alpha isomer of HCH has been found to induce liver tumors; this is also true for the pure beta isomer of HCH.. These studies are found in the NTP, IARC and IPCS reports on hexachlorohexanes. Lindane shares its structure with at least four other isomers. They differ only with respect to the position of the chlorine atoms in the alpha or beta positions, above or below the plane of the hexane ring structure.

Structure of HCH (Lindane)::

 isomer: 1    2    3 4 , 5 , 6   hexachlorocyclohexane Other isomers:   isomer: 1    2    3 4 , 5 , 6   hexachlorocyclohexane   isomer: 1    2 3    4 , 5 , 6   hexachlorocyclohexane   isomer: 1    2    3    4 , 5 , 6   hexachlorocyclohexane   isomer: 1    2    3    4 , 5 , 6   hexachlorocyclohexane Isomers of hexachlorocyclohexane (HCH), other than lindane, have been classified as follows, according to IRIS: The technical HCH and the alpha isomer are classified as B2, probable human carcinogens. The beta isomer is classified as C, possible human carcinogen. The delta and epsilon isomers are classified as D, not classifiable as to human carcinogenicity.

Appendix A contains a summary of various studies which examine the carcinogenicity of the gamma isomer (Lindane) alone or in comparison with the other isomers.

4. Subchronic, and Chronic Toxicity Subchronic Toxicity Mice A range finding subchronic toxicity study (MRID 45424301) was conducted to determine the doses to be used in a two year carcinogenicity study. In this study, Lindane (99. 78% a. i.) was administered to 10 CD 1 mice/ sex/ dose in the diet at dose levels of 0, 40, 80, 160, 320 ppm (0, 5. 7, 12.2, 22.8 and 46.2 and 0, 8.9, 16.0, 32.9, and 62.6 mg/ kg/ day in males and females, respectively).

No treatment related clinical signs were observed. Five females died or were killed during the treatment period. Four were in the highest dose (320 ppm) group and one from the control group was a humane kill. These animals presented wit h no macroscopic changes. Histopathology revealed hepatocyte hypertrophy and karyomegaly in the liver and Clara cell hypertrophy and congestion in the lungs. These findings were also seen in treated animals in the 160 and 320 ppm dose groups that were sacrificed at study termination; therefore, these deaths were considered to be treatment related. Body weight was reduced by 6% in males and was unaffected in females in the highest dose tested (320 ppm). Body weight gain was reduced by 27% LINDANE CANCER ASSESSMENT DOCUMENT FINAL REPORT 17 in males and 9% in females.

In a subchronic inhalation toxicity study, Lindane (99.6% a. i., Batch no. DA433) was administered by inhalation to groups of 45 male and 45 female CD 1 mice at nominal concentrations of 0, 0.3, 1.0, 5.0 to 10 mg/ m3 (0, 0. 1, 0. 4, 2. 0 or 4.0 mg/ kg/ 6 hrs), for 14 weeks. Exposures were 6 hours/ day, 5 day/ week as described in the pilot study. During the first five exposures, the high dose group was exposed to a mean concentration of 9. 72 mg/ m3 (4. 0 mg/ kg/ 6 hrs), but due to excessive deaths, the mean concentration was lowered to 4. 94 mg/ m3 (2. 0 mg/ kg/ 6 hrs). No exposure related effects were noted for body weight gain, food consumption, water consumption, or ophthalmoscopic, hematology, clinical chemist ry, or urinalysis parameters. Bone marrow analysis did not show any time or concentration related changes. Brain, kidney, lung, spleen, thymus, and adrenal, and testes weights were similar between the treated and control animals. Liver weights of females exposed to 5 mg/ m3 were increased 14% (p  0.05) at week 20.

Rats In a subchronic oral neurotoxicity study (MRID 44781101), groups of 10 Crl: CD® BR rats/ sex/ group were administered lindane (Batch No. HLS96/ 1, Purity 99.78%) in the diet for 13 weeks at concentrations of 0 (control), 20, 100, or 500 ppm. Due to severe toxic reactions to treatment at 500 ppm, the dose was reduced to 400 ppm on day 11 of treatment thereafter. These doses resulted in average daily intake values of 0, 1.4, 7.1, and 28. 1 mg/ kg/ day for males and 0, 1.6, 7.9, and 30.2 mg/ kg/ day in females for 0, 20, 100, and 500/ 400 ppm, respectively.

Significant treatment related decreases (p< 0.05 or p< 0.01) in body weight were observed among males and females treated with 500/ 400 ppm of 14% and 23%, respectively. Decreases in body weight gains (70%  and 180%  ,p< 0. 01), food consumption (35%  and 50%  , p< 0.05 or p< 0.01, respectively), and food conversion ratios were observed for males and females in the 500 ppm groups compared to the control group for the first week of the study. Male rats tended to recover from these effects after the dose was lowered. Females, however, did not exhibit this same level of recovery as their food consumption remained slightly depressed throughout the remainder of the study.

Females in the 100 ppm group had significantly decreased body weight gains (40%, p< 0.05) compared to the control group during the first week of the study and this effect continued, although not at a level of significance throughout the remainder of the study. Females in the 100 ppm group had significantly decreased food consumption (16%, p< 0.01) for the first week of the study and this trend continued throughout the study. Liver weights were also found to be increased at 500/ 400 ppm for both sexes; no additional information was given.

Chronic Toxicity In the chronic toxicity/ carcinogenicity study (MRID41853701), lindane (99.75% a. i., Lot no. DA433) was administered in the diet to groups of 50 male and 50 female Wistar rats at concentrations of 0, 1, 10, 100, or 400 ppm for 2 years. Corresponding LINDANE CANCER ASSESSMENT DOCUMENT FINAL REPORT 18 delivered doses were 0, 0. 05, 0.47, 4.81, and 19.66 mg/ kg/ day, respectively, for males and 0, 0. 06, 0.59, 6.00, and 24.34 mg/ kg/ day, respectively, for females. An additional 15 rats/ sex/ group were designated for interim sacrifices at 30 days and 26 weeks.

Body weights were slightly less than the controls for the high dose males ( 6%) and females ( 8%) during weeks 1 5 of the study, but gradually increased to within 2% of the control level by week 26 for males and week 9 10 for females.

High dose females hadsignificantlydecreased hemoglobin, decreased RBCcounts, and decreased PCV. These red cell parameters were "marginally lower" for high dose males (non statistically significant). Platelet counts increased in mid and high dose males and females. White cell counts significantly increased in mid dose and in highdose females due to increases in neutrophils.

The liver appears to be the major target organ. Kidney lesions in male rats indicative of alpha 2µ globulin accumulation were observed in animals treated with  10 ppm, but are not considered relevant to human health risk assessment. Absolute kidney weights were significantly increased in high dose males. Absolute and relative kidney weights increased in mid dose males and high dose males and females. The incidence of periacinar hepatocytic hypertrophy was significantly increased in males at 100 and 400 ppm and in females at 400 ppm. This lesion was not seen in control animals of either sex. No treatment related histopathological lesions were observed in the spleen, adrenals, brain, or thymus. Bone marrow data presentation was inadequate for assessment.

5. Mode of Action Studies No mode of action studies have been submitted for lindane. There have been, however, several published studies which attempt to elucidate the initiator promoter activity of lindane. As discussed earlier lindane does not appear to have a clear mutagenic potential.

Lindane may act as a promoter as evidenced by studies with Agouti, Pseudoagouti and Black mice. Only Agouti and Pseudoagouti mice, which have a transformed genotype linked to tumorigenicity, were found to have an increased incidence of liver and lung tumors. The Black mice had no tumors in the 24 month period of the study. The Pseudoagouti and Black mice had a low rate of spontaneous tumor incidence in the liver and lung, but of these two only the Pseudoagouti responded to lindane. Therefore, lindane appears to augment the propensity of these genetically altered mice to develop tumors. It has been suggested that lindane has a similar mode of action to phenobarbital, which also increases the incidence of benign tumors in these mice. As discussed earlier on page 13, oxidative stress may be a possible mechanism of liver toxicity.

Suggestions have been made that the metabolites of lindane may contribute to its carcinogenic potential. One major urinary metabolite, 2,4,6 TCP, is considered to be a carcinogen. However studies indicate that TCP may have only a minimal effect on LINDANE CANCER ASSESSMENT DOCUMENT FINAL REPORT 19 the overall carcinogenic potential of lindane.

V. COMMITTEE'S ASSESSMENT OF THE WEIGHT OF THE EVIDENCE 1. Carcinogenicity The CARCconcluded that lindane is carcinogenic only to female mice and is not carcinogenic to male mice and male and female rats.

! CD 1 female mice had significant increasing trends and significant differences in pair wise comparisons of the 160 ppm( 26.8 mg/ kg/ day) dose group with the controls, for lung alveolar bronchiolar adenomas (23% vs 6% in controls) and combined adenomas/ carcinomas (25% vs 8% in controls), all at p < 0. 05; the incidence of lung adenomas (23%) was slightly outside the historical control range (6% 19%). The increased incidence of carcinomas was not dosedependent and tumor response was variable. Lindane was not carcinogenic to male mice. No non neoplastic liver changes were seen in females. The majority of the CARC considered the dosing to have been adequate and not excessive based on an increase in the incidence of centrilobular hepatocyte hypertrophy as well as eosinophilic foci of hepat ocellular alteration in high dose males compared to the control group; similar liver findings were also reported in a range finding subchronic toxicity study in which early deaths of four females were reported in the 320 ppm dose group indicating that this dose was excessive. However, based on the results of the chronic study a few members felt that the animals could have tolerated a higher dose.

! At 160 ppm, both the treated female Agouti and Pseudoagouti mice had an increased occurrence of benign lung tumors (19% vs 4% in controls and 14% vs 6% in controls, respectively). In addition, both the treated female Agouti and Pseudoagouti mice had increases in liver adenomas (35% vs 9% in controls and 17% vs 13% in controls, respectively) and slight increases in liver carcinomas (5% vs 2% in controls and 12% vs 5% in controls) at 24 months. No statistical analyses of tumor data were provided. There was no increase in incidence or decrease in latency period of liver tumors in Black and Pseudoagouti strains of mice. There was evidence of increased liver weights and increased incidence of Clara cell hyperplasia in Agouti and Black strains of mice. Increases in Clara cell hyperplasia were noted in the lung at all sacrifice intervals for each strain and the incidence of lung tumors was increased in later months for the female Agouti and Pseudoagouti mice. The percentage of mice with Clara cell hyperplasia in the treated and control groups was 72% 92% and 6% 31%, respectively, for the Agouti; 50% 79% and 6% 17 respectively, for the Pseudoagouti; and 56% 90% and 0% 14%, respectively, for the female Black mice. However, the study was conducted on few animals, only a single dose was tested, no statistical analyses of tumor data were presented; and the results of the studywere not adequately reported. The Committee concluded that although the liver effects appear to suggest that a LINDANE CANCER ASSESSMENT DOCUMENT FINAL REPORT 20 dose of 160 ppm was adequate, additional dose groups could have provided confirmatory information.

! The incidence of hepatocellular carcinoma in low dose B6C3F1 males (19/ 49) was significant (p= 0.001) when compared with that in pooled controls (5/ 49). The incidence of hepatocellular carcinoma in high dose male mice (9/ 46) was not significantly different than the matched (2/ 10) or pooled controls. The CARC could not assess the carcinogenicity of lindane in B6C3F1 male and female mice because the data reporting was inadequate, there were no indications of toxicity at the high dose and the test material could not be validated. Moreover, the use of only 10 mice per sex for the control group compromised the usefulness of the study.

The Committee concluded that the increased incidence of benign lung tumors in female CD 1 mice was treatment related because the treatment related statistically significant increase in lung adenomas in female CD 1 mice was correlated with increases in lung tumors in two genetically susceptible strains of mice (Agouti and Pseudoagouti). Although there is some evidence of liver tumor induction in these genetically susceptible strains of mice, there was no evidence of liver tumors in CD 1 mice. Nevertheless, the evidence of hepatotoxicity (increased incidences of liver hypertrophy and liver foci in both sexes) and promoting activity suggests the liver as a major target organ of toxicity.

! The treated male Wistar rats developed adrenal pheochromocytomas. The percentages of animals with adrenal tumors in the 0, 1, 10, 100, and 400 ppm groups were 14%, 16%, 16%, 6%, and 24% for benign tumors, respectively, and 0%, 0%, 6%, 8%, and 2% for malignant tumors, respectively. Statistical significance was not reached by relevant tests and no dose response was evident. When compared to historical controls, the incidence of adrenal pheochromocytomas in the current studyslightlyexceeded that of the historical control at the HDT (400 ppm). The range of adrenal pheochromocytomas observed in the historical control data was 4/ 50 to 11/ 50 (8%  22%) for male rats examined in four studies conducted in 1990. Of the 18 studies in the historical control data, 6 were performed in 1990; the other 12 were performed between 1986 and 1988. The Committee concluded that the adrenal tumors in male rats were not treatment related. The doses tested were considered to be adequate and not excessive in both sexes based on decreased survival, decreased body weight gains and decreased food consumption; the increased spleen and liver weights correlated with increased occurrence of periacinar hepatocyte hypertrophy in both sexes at the high dose.

! There were three spleen hemangiomas in 44 high dose male Osborne Mendel rats only (0/ 8 in controls) and none in the females. There were also non dose related increases in neoplastic lesions of the liver (3/ 45 and 2/ 45 in males and 4/ 48 and 2/ 45 in females in the low and high dose groups compared to 0/ 10/ sex in control groups) which were within the historical control values (0% 12%). Other organs with primary tumors include: thyroid, pituitary, and mammary LINDANE CANCER ASSESSMENT DOCUMENT FINAL REPORT 21 glands with only a few incidences but there was no clear dose response. Dosing at the highest level was considered to be adequate based on microscopic changes seen in the liver of both males and females, including cirrhosis, degeneration, necrosis in a dose dependent manner. Cysts, hyperplasia and atrophy were seen in the endocrine and reproductive organs of these animals. Survival of the animals was adequate for meaningful statistical analyses of the incidence of tumors.

The CARC concluded that lindane was not carcinogenic to male and female Wistar rats and that the results of the study in Osborne Mendel rats were difficult to interpret and were not useful in determining the carcinogenic potential of lindane in that strain of rat.

2. Mutagenicity ! Lindane has been tested in a battery of pre 1991 mutagenicity assays which satisfies the guideline requirements. The review of both the guideline and literature studies suggests that lindane does not interact with DNAor interfere with genetic mechanisms. However, since there is some evidence that lindane reaches and damages germ cells, the Committee recommended that the dominant lethal assay be repeated to determine if there is a genetic component to the reproductive (germ cell) effects reported for lindane.

3. Structure Activity Relationship ! Isomers of hexachlorocyclohexane (HCH), other than lindane, have been classified for carcinogenic potential. The technical HCH and the alpha isomer are classified as B2, probable human carcinogens. The beta isomer is classified as C, possible human carcinogen. The delta and epsilon isomers are classified as D, not classifiable as to human carcinogenicity.

4. Mode of Action ! The tumor initiating activity reported in the literature has been discounted due to the lack of morphologic alterations in liver foci after treatment with lindane. Lindane appears to augment the propensity of genetically altered mice to develop tumors. However, no definitive studies have established the mode of action for liver tumor induction by lindane. There is a suggestion that oxidative stress may play a role in the liver toxicity of lindane.

VI. CLASSIFICATION OF CARCINOGENIC POTENTIAL In accordance with the Agency's Draft Guidelines for Carcinogen Risk Assessment (July, 1999), the Committee classified lindane into category: "Suggestive evidence of carcinogenicity, but not sufficient to assess human carcinogenic potential" based on the occurrence of benign lung tumors in one sex of one species (i. e., female CD 1 mice). LINDANE CANCER ASSESSMENT DOCUMENT FINAL REPORT 22 VII. QUANTIFICATION OF CARCINOGENIC POTENTIAL The Committee recommended that quantification of human cancer risk is not required.

VIII BIBLIOGRAPHY MRID No. CITATIONS 00160863 Koenig, GR, Rexroat, MA and Probst, GS (1985) The effect of benefin EL110 compound 54521) on the induction of reverse mutations of Salmonella typhimirium using the Ames test. Study Laboratory: Toxicology Div Lilly Research Laboratories, Laboratory# 85624UB2598 and 850708UB 2598, August 13, 1985.

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00160866 Koenig, G. R., Oberly, T. J., Bewsey, B. J., (1985) The Effect of Benefin EL110 Compound 54521) onthe Inductionof Forward Mutation at the Thymidine Kinase Locus of L5178Y Mouse Lymphoma Cells. Toxicology Division, Lilly Research Laboratories, Greenfield, IN. Laboratory Study Numbers LINDANE CANCER ASSESSMENT DOCUMENT FINAL REPORT 23 850612MLA2598 and 850724MLA2598, October 1985. Unpublished.

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40693203 Koenig, G. R., Byrd, T. K., Pohland, R. C. (1988) Radiocarbon Disposition in Fischer 344 Rats Given Single Oral Doses of 14 C Benefin (EL 110, Compound 54521): Pharmacokinetics, Excretion, and Residual Tissue Levels. Lilly Research Laboratories, Greenfield, IN. Laboratory Project Id. R16687, May 25, 1988. Unpublished.

40693204 Koenig, G. R., Byrd, T. K., Pohland, R. C. (1988) Biliary Excretion of Radioactivity by Fischer 344 Rats Given Single Oral Doses of 14 C Benefin EL110 Compound 54521). Lilly Research Laboratories, Greenfield, IN. Laboratory Project Id. R09887 and R23887, May 25, 1988. Unpublished.

40693205 Koenig, G. R., Byrd, T. K., Pohland, R. C. (1988) Tissue Distribution of Radioactivity in Fischer 344 Rats Given Single Oral Doses of 14 C Benefin EL110 Compound 54521). Lilly Research Laboratories, Greenfield, IN. Laboratory Project Id. R09887, May 25, 1988. Unpublished.

45291402. Chase, K. (2000) Lindane, carcinogenicity study by dietary administration to CD 1 mice for 78 weeks, final report (vols. 1 4). Huntingdon Life Sciences Ltd., Woolley Road, Alconbury, Huntingdon, Cambridgeshire, PE28 4HS, England, Report no. 00 3512, Huntingdon Life Sciences Project identity no. CIL/ 021, December 20, 2000.

42891201. Aymes, S. J. 1993. Lindane: Combined carcinogenicit and toxicity study by dietary administration to Wistar rats for 104 weeks. Addendum to final report (Adrenal histopathology  additional investigations). Life Sciences Research, England. Study No. 90/ CIL002/ 0839. June 2, 1993 . 45470601 Huntingdon Life Sciences Ltd. Additional histopathology investigations of female mouse lung tissues conducted by Huntingdon Life Sciences Ltd., Cambridgeshire, England, for C. I. E. L. (Centre International Etudes du Lindane), Brussels, Belgium, and completed July31, 2001 (Project Identity No. CIL/ 027.

00162724. Huntington Research Center (Lindane toxicity study in beagle dogs) report #3720/ 70/ 532, 1970 LINDANE CANCER ASSESSMENT DOCUMENT FINAL REPORT 24  Boehringer C. H. Sohn Ingelheim am Rhein.; (Testing of the substance Lindane for carcinogenic effects in mice using oral administration duration 80 weeks) translated from German (1975).

 Brunsman, L. L. ; Lindane: Qualitative Risk Assessment Based On Crl: CD 1 (ICR) BR Mouse Dietary Study. Memorandum from Lori Brunsman, Science Information Management Branch, to Suhair Shallal, Reregistration Branch 4, Health Effects Division, Office of Pesticide Programs, Environmental Protection Agency, dated May 1, 2001. HED Doc.# 014556.

 Brunsman, L. L. ; ADDENDUMTo Lidane: Qualitative Risk Assessment Memo of 5/ 1/ 2001 Based OnAdditional HistopathologyInvestigations of Female Lung Tissues of Crl: CD 1( ICR) BR Mouse Dietary Study. MemorandumfromLori Brunsman, Science Information Management Branch, to Suhair Shallal, Reregistration Branch 4, Health Effects Division, Office of Pesticide Programs, Environmental ProtectionAgency, dated August 16, 2001. HEDDoc.# 014652.

 Fitzhugh, O. G.; Nelson, A. A.; and Frawley, J. P.; The chronic toxicities of technical benzene hexachloride and its alpha, beta and gamma isomers J. Pharmacol. Expt. Therapeutics. 100: 59 (1950)..

 Goto, M.; Hattori, M.; Miyagawa, T.; and Enomoto, M..; Contributions to ecological chemistry II. Hepatoma development in mice after administration of HCH isomers in high dosage Chemosphere 1( 6): 279 282 (1972).

 Hanada, M.; Yutani, C.; and Miya, T.; Induction of hepatoma in mice with benzene hydrochloride GANN 64: 511 513 (1973).

 Ito, N.; Nagasaki, H.; Arai, M.; Sugihara, S.; and Makiura, S.; Pathologic and ultrastructural studies in the hepatocarcinogenicity of benzene hexachlooride in mice J. NCI 51: 817 826 (1973).

 Ito, N.; Nagasaki, H.; et al.; Brief communication: development of hepatocellular carcinomas in rats treated with benzene hexachloride J. NCI 54: 801 805 (1975).

 Lindane, Environmental HealthCriteria 124, IPCS, WHO, Geneva, Switzerland (1991).

 Nagasaki, H.; Tonrii, S.; et al. ; Carcinogenicity of Benzene Hexachloride (BHC) Proc. of 2 nd Intern Symp of Princess Tokamatsu Cancer Center Res. Fund in Topics in Chem. Carcino. 1972  NCI.; NTP Combined Chronic Toxicity/ Carcinogenicity Study with Lindane in Mice. National Cancer Institute, Carcinogenesis Program, Bethesda, MD; DHEW Pub # (NIH) 77 814 (1977). 25  NCI; NTP Combined Chronic Toxicity/ Carcinogenicity Study with Lindane in Rats. National Cancer Institute, Carcinogenesis Program, DHEWPub # (NIH) 77 814 (1977).

 Ortega, P.; Hayes, W. J.; and Durham, W. F.; Pathologic changes in the liver of rats after feeding low levels of various insecticides A. M. A. Archives of Pathology, 64: 614, (1957).

 Thorpe and Walker; The toxicology of dieldrin (HEOD). II. Comparitive longt erm oral toxicity studies in mice with dieldrin, DDT, phenobarbitone, betaBHC and gamma BHC Fd. Cosmet. Toxicol, 11: 433 442 (1973).

 Wolff, G. L., Roberts, D. W., Morrissey, R. L., Greenman, D. L., Allen, R. R., Campbell, W. L., Bergman, H., Nesnow, S., and Firth, C. H. 1987. Tumorigenic responses to lindane in mice: potentiation by a dominant mutation. Carcinogenesis 8: 1889 1897 (1987). National Center for Toxicological Research, Jefferson, AK.

APPENDIX A Carcinogenicity Studies comparing the toxicity of gamma HCH with other isomers Study # of animals doses results for lindane (gamma HCH) results for other isomers Carcinogenicityrat (The chronic toxicities of technical benzene hexachloride and its alpha, beta and gamma isomers) published: 1950 10  /10  Wistar rat 0, 5, 10, 50, 100, 400, 800 or 1600 ppm of    ,    , or    HCH. At 100 ppm of    HCH , liver wt. incr no frank liver tumors induced by    HCH 26 CarcinogenicityRats (Pathologic changes in the liver of rats after feeding low levels of various insecticides) published: 1957 6  / 6  0, 50, 100 ppm for 8 months. One 50 ppm  , and one each 100 ppm  and  developed centrilobular hypertrophy, peripheral migration of basophilic cytoplasmic granulations and cytoplasmic inclusion bodies.

Carcinogenicity rats (Brief communication: development of hepatocellular carcinomas in rats treated with benzene hexachloride) published: 1975. 9 groups of  W rats (Japanese strain) 0, 500, 1000 or 1500 ppm of    ,

   ,    , or    BHC        BHC : cell hypertrophy        BHC: cell hypertrophy, nodular hyperplasia (27/ 41 dosed w/

 1000 ppm for 48 72 wks), hepatocellular carcinoma (4/ 29 dosed w/  1000 ppm for 72 wks)

   , , ,        :cell hypertrophy Carcinogenicity rats (Bioassay of lindane for possible carcinogenicity) NCI (NCI RG TR 14) 1977 10  /10  Osborne Mendel rats 50

50

0 ppm;

320 or 640 ppm for 38 wks, 160 or 320 ppm for 42 wks, then 0 ppm for 30 wks 320 or 640 for 2 wks, 160 or 320 ppm for 49 wks, 80 or 160 ppm for 29 wks, then 0 ppm for 30 wks. Incidence of liver neoplasia is within historical control levels Carcinogenicity mice (Bioassay of lindane for possible carcinogenicity) NCI (NCI RG TR 14) 1977 10  /10  BGC3F1 hybrid mice 50  /50  0 ppm 80 or 160 ppm for 80 wks then control diet for 10 wks hepatocellular carcinoma: 0 ppm (20%), 80 ppm (39%), 160 ppm (20%) 27 Carcinogenicitymouse (The toxicology of dieldrin (HEOD). II. Comparitive long term oral toxicity studies in mice with dieldrin, DDT, phenobarbitone, beta BHC and gamma BHC) Thorpe and Walker (1973). CF1 mice 45  /45  30  /30  0 ppm (24/ 23%)

400 ppm (gamma BHC) 10 ppm (dieldrin) 100 ppm (DDT) 500 ppm (phenobarbitone) 200 ppm betaBHC  /  % of liver tumors (gamma BHC) 93/ 69%  /  % of liver tumors (dieldrin) 100/ 87% (DDT) 77/ 87 % (phenobarbitone) 80/ 75% (beta BHC) 73/ 43 %

Carcinogenicitymouse (Testing of the substance Lindane for carcinogenic effects in mice using oral administrationduration 80 weeks) translated from German 1975 SPF mice ChbbNMRI 100  / 100  50  /50  0 ppm 12.5, 25 or 50 ppm for 80 wks incidences (  /

 ) liver cell adenomas: 4/ 1, 1/ 1, 0/ 0, 2/ 0 lung tumor: 13/ 8, 10/ 1, 5/ 3, 6/ 4 lymphosarcoma : 5/ 12, 0/ 7, 1/ 3, 2/ 5, respectively Carcinogenicitymouse (Pathologic and ultrastructural studies in the hepatocarcinogenic ity of benzene hexachlooride in mice) published (1973) 19 groups (20 40/ group)    ,    ,    or    BHC at 100, 250, or 500 ppm and combos of 250 ppm ea. of    with    ,    , or    BHC. Only mice that were dosed w/    BHC in combo. or alone developed nodular hyperplasia and hepatocellular carcinoma Carcinogenicitymouse (Contributions to ecological chemistry II. Hepatoma development in mice after administration of HCH isomers in high dosage. Published: (1972). 8 groups of 20  ICR JCL mice 600 ppm of technical HCH (I),    HCH (II) ,

   HCH (III),    HCH (IV), a mix of    /    HCH (V), or 300 ppm of    HCH (IX) 5/ 10 in gp IX developed liver tumors and incr. Liver wgt. all of group I and II developed hepatomas 8/ 10 in gp V developed liver tumors and incr. Liver wgt. 28 Carcinogenicitymouse (Carcinogenicity of Benzene Hexachloride (BHC)) published: (1972) 4 groups of dd mice 0, 6.6, 66, 660 ppm of technical BHC    (67%),

   (11%),    (15%) or    (6%) BHC and other isomers < 1% for 24 wks at all doses:  liver wgt, cellular hyperplasia, nodular hyperplasia, all 660 ppm mice developed hepatoma Carcinogenicitymouse (Induction of hepatoma in mice with benzene hydrochloride) published: (1973). 4 groups of dd mice 0, 100, 300 or 600 ppm with crude BHC, or pure    ,    , or    isomer for 36 38 wks No control and 100 or 300 ppm    isomer mice developed hepatomas many mice in crude BHC, or pure    isomer developed hepatoma,

Chronic feeding Dogs (Lindane toxicity study in beagle dogs) 1970 4 group of 4 beagles/ sex 0, 25, 50, or 100 ppm for 104 wks NOAEL: 50 ppm LOAEL: 100 ppm liver changes, slight inc liver wt.


[Federal Register Volume 80, Number 198 (Wednesday, October 14, 2015)]
[Notices]
[Page 61887]
[FR Doc No: 2015-26019]

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DEPARTMENT OF TRANSPORTATION

Pipeline and Hazardous Materials Safety Administration

[Docket No. PHMSA-2015-0188, Notice No. 15-19]

International Standards on the Transport of Dangerous Goods

AGENCY: Pipeline and Hazardous Materials Safety Administration (PHMSA).

ACTION: Notice of public meetings.

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

SUMMARY: This notice is to advise interested persons of two public
meetings occurring on Thursday, November 12, 2015, both held at the
Department of Transportation (DOT) headquarters. PHMSA will conduct a
public meeting to discuss proposals in preparation for the 48th session
of the United Nations Sub-Committee of Experts on the Transport of
Dangerous Goods (UNSCOE TDG), to be held November 30 to December 09,
2015, in Geneva, Switzerland. During this meeting, PHMSA is also
requesting comments relative to potential new work items that may be
considered for inclusion in its international agenda.
    Also on Thursday, November 12, 2015, the Occupational Safety and
Health Administration (OSHA) will conduct a public meeting (Docket No.
OSHA-H022k-2006-0062) to discuss proposals in preparation for the 30th
session of the United Nations Sub-Committee of Experts on the Globally
Harmonized System of Classification and Labelling of Chemicals
(UNSCEGHS), to be held December 9 to December 11, 2015, in Geneva,
Switzerland.
    Time and Location: Both the PHMSA and OSHA public meetings will
take place on Thursday, November 12, 2015 at the DOT Headquarters in
the West Building, which is located at 1200 New Jersey Avenue SE.,
Washington, DC 20590-0001. The times are:

    PHMSA pubic meeting: 9:00 a.m. to 12:00 noon EST.
    OSHA public meeting: 1:00 p.m. to 4:00 p.m. EST.

    Advanced Meeting Registration: The DOT requests that attendees pre-
register for these meetings by completing the form at https://www.surveymonkey.com/r/LVXNWYT. Attendees may use the same form to pre-
register for both the PHMSA and the OSHA meetings. Failure to pre-
register may delay your access into the DOT Headquarters building.
Additionally, if you are attending in-person, arrive early to allow
time for security checks necessary to access the building.
    Conference call-in and ``live meeting'' capability will be provided
for both meetings. Specific information on call-in and live meeting
access will be posted when available at http://www.phmsa.dot.gov/hazmat/regs/international under Upcoming Events and at http://www.osha.gov/dsg/hazcom/.

FOR FURTHER INFORMATION CONTACT: Mr. Steven Webb or Mr. Aaron Wiener,
Office of Hazardous Materials Safety, Department of Transportation,
Washington, DC 20590,<PHONE_NUMBER>.
    Supplementary Information on the PHMSA Meeting: The primary purpose
of PHMSA's meeting will be to prepare for the 48th session of the
UNSCOE TDG, which is the second of four meetings scheduled for the
2015-2016 biennium. The UNSCOE will consider proposals for the 20th
Revised Edition of the United Nations Recommendations on the Transport
of Dangerous Goods Model Regulations, which may be implemented into
relevant domestic, regional, and international regulations from January
1, 2019. Copies of working documents, informal documents, and the
meeting agenda may be obtained from the United Nations Transport
Division's Web site at http://www.unece.org/trans/main/dgdb/dgsubc3/c3age.html. General topics on the agenda for the UNSCOE TDG meeting
include:
     Explosives and related matters;
     Listing, classification, and packing;
     Electric storage systems;
     Transport of gases;
     Global harmonization of transport of dangerous goods
regulations with the Model Regulations;
     Guiding principles for the Model Regulations;
     Electronic data interchange for documentation purposes;
     Cooperation with the International Atomic Energy Agency
(IAEA);
     New proposals for amendments to the Model Regulations;
     Issues relating to the Globally Harmonized System of
Classification and Labeling of Chemicals (GHS); and
     Miscellaneous pending issues.
    Following the 48th session of the UNSCOE TDG, a copy of the Sub-
Committee's report will be available at the United Nations Transport
Division's Web site at http://www.unece.org/trans/main/dgdb/dgsubc3/c3rep.html. PHMSA's Web site at http://www.phmsa.dot.gov/hazmat/regs/international provides additional information regarding the UNSCOE TDG
and related matters.
    Supplementary Information on the OSHA Meeting: The Federal Register
notice and additional detailed information relating to OSHA's public
meeting will be available upon publication at http://www.regulations.gov (Docket No. OSHA-H022k-2006-0062) and on the OSHA
Web site at http://www.osha.gov/dsg/hazcom/.

    Signed at Washington, DC, on October 7, 2015.
Magdy El-Sibaie,
Associate Administrator for Hazardous Materials Safety.
[FR Doc. 2015-26019 Filed 10-13-15; 8:45 am]
BILLING CODE 4910-60-P


[Federal Register Volume 85, Number 119 (Friday, June 19, 2020)]
[Rules and Regulations]
[Pages 37011-37013]
[FR Doc No: 2020-12227]

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DEPARTMENT OF HOMELAND SECURITY

Coast Guard

33 CFR Part 165

[Docket Number USCG-2020-0039]
RIN 1625-AA00

Safety Zone; Illinois River, Miles 10 to 187, Grafton, IL to
Peoria, IL

AGENCY: Coast Guard, DHS.

ACTION: Temporary final rule.

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SUMMARY: The Coast Guard is establishing a temporary safety zone on the
navigable waters of the Illinois River from mile marker (MM) 10 to MM
187 between Grafton, IL and Peoria, IL. This action is necessary to
provide for the safety of persons, vessels, and the marine environment
on these navigable waters as a result of increasing flood conditions on
the river that threaten to overtop levees. Entry of vessels or persons
into this zone is prohibited unless specifically authorized by the
Captain of the Port Sector Upper Mississippi River (COTP) or a
designated representative.

DATES: This rule is effective without actual notice from June 19, 2020
through June 20, 2020. For the purposes of enforcement, actual notice
will be used from May 21, 2020 through June 19, 2020.

ADDRESSES: To view documents mentioned in this preamble as being
available in the docket, go to https://www.regulations.gov, type USCG-
2020-0039 in the ``SEARCH'' box and click ``SEARCH.'' Click on Open
Docket Folder on the line associated with this rule.

FOR FURTHER INFORMATION CONTACT: If you have questions about this
notice of enforcement, call or email Chief Warrant Officer 4 Eric
Kvistad, Sector Upper Mississippi River Waterways Management Division,
U.S. Coast Guard; telephone<PHONE_NUMBER>, email
<EMAIL_ADDRESS>
SUPPLEMENTARY INFORMATION:

I. Table of Abbreviations

CFR Code of Federal Regulations
COTP Captain of the Port
DHS Department of Homeland Security
FR Federal Register
NPRM Notice of proposed rulemaking
Sec.  Section
U.S.C. United States Code

II. Background Information and Regulatory History

    The Coast Guard is issuing this temporary rule without prior notice
and opportunity to comment pursuant to authority under section 4(a) of
the Administrative Procedure Act (APA) (5 U.S.C. 553(b)). This
provision authorizes an agency to issue a rule without prior notice and
opportunity to comment when the agency for good cause finds that those
procedures are ``impracticable, unnecessary, or contrary to the public
interest.'' Under 5 U.S.C. 553(b)(B), the Coast Guard finds that good
cause exists for not publishing a notice of proposed rulemaking (NPRM)
with respect to this rule because it is impracticable. Actual notice is
impracticable because of the unpredictable martime environmental
conditions. Delaying this safety zone would be contrary to waterway
users best interest because of the amount of danger and risk associated
with high water. It is impracticable because we must establish this
safety zone immediately and lack sufficient time to provide a
reasonable comment period and then consider those comments before
issuing this rule. The NPRM process would delay the establishment of
the safety zone and compromise public safety.
    Under 5 U.S.C. 553(d)(3), the Coast Guard finds that good cause
exists for making this rule effective less than 30 days after
publication in the Federal Register. Delaying this rule would be
contrary to public interest because immediate action is necessary to
respond to the potential safety hazards associated with floodwaters
threatening to overtop levees along the river.

III. Legal Authority and Need for Rule

    The Coast Guard is issuing this rule under authority in 46 U.S.C.
70034 (previously 33 U.S.C. 1231). The COTP has determined that
potential hazards associated with flood waters threaten to overtop
levees along the river due to reports that vessel traffic in the
affected area is causing water to overtop levees resulting in increased
damage to the levees and flooding impacts to local communities and
residential areas. This rule is necessary to ensure the safety of
persons, vessels, and the marine environment on these navigable waters
due to the flood impacts to USACE levees.

IV. Discussion of the Rule

    The COTP has determined that the sudden increase in flood waters
approaching the tops of levees along the Illinois River poses a hazard
to the safety of persons, vessels, the marine environment, and the
structural stability of the levees as a result of floodwaters
overtopping the levees. This rule establishes a temporary safety zone
from May 21, 2020 until June 20, 2020, or until cancelled by the COTP,
whichever occurs first. The safety zone will cover all navigable waters
of the Illinois River from MM 10 to MM 187, unless reduced in scope by
the COTP as flood conditions warrant.
    No vessel or person will be permitted to enter the safety zone
without obtaining permission from the COTP or a designated
representative. A designated representative is a commissioned, warrant,
or petty officer of the U.S. Coast Guard (USCG) assigned to units under
the operational control of USCG Sector Upper Mississippi River. To seek
permission to enter, contact the COTP or a designated representative
via VHF-FM channel 16, or through USCG Sector Upper Mississippi River
at<PHONE_NUMBER>. Persons and vessels permitted to enter the safety zone
must comply with all lawful orders or directions issued by the COTP or
designated representative. The COTP or a designated representative will
inform the public of the effective period for the safety zone as well
as any changes in the dates and times of enforcement, as well as
reductions in size of the safety zone as flood conditions improve,
through Local Notice to Mariners (LNMs), Broadcast Notices to Mariners
(BNMs), and/or Marine Safety Information Bulletins (MSIBs), as
appropriate.

V. Regulatory Analyses

    We developed this rule after considering numerous statutes and
Executive orders related to rulemaking. Below we summarize our analyses
based on a number of these statutes and Executive orders, and we
discuss First Amendment rights of protestors.

A. Regulatory Planning and Review

    Executive Orders 12866 and 13563 direct agencies to assess the
costs and benefits of available regulatory alternatives and, if
regulation is necessary, to select regulatory approaches that maximize
net benefits. Executive Order 13771 directs agencies to control
regulatory costs through a budgeting process. This rule has not been
designated a ``significant regulatory action,'' under Executive Order
12866. Accordingly, this rule has

not been reviewed by the Office of Management and Budget (OMB), and
pursuant to OMB guidance it is exempt from the requirements of
Executive Order 13771.
    This regulatory action determination is based on the emergency
nature of the action. Moreover, the Coast Guard will issue a BNM via
VHF-FM marine channel 16 about the zone, and the rule allows vessels to
seek permission to enter the zone on a case-by-case basis to minimize
the impacts of this rule.

B. Impact on Small Entities

    The Regulatory Flexibility Act of 1980, 5 U.S.C. 601-612, as
amended, requires Federal agencies to consider the potential impact of
regulations on small entities during rulemaking. The term ``small
entities'' comprises small businesses, not-for-profit organizations
that are independently owned and operated and are not dominant in their
fields, and governmental jurisdictions with populations of less than
50,000. The Coast Guard certifies under 5 U.S.C. 605(b) that this rule
will not have a significant economic impact on a substantial number of
small entities.
    While some owners or operators of vessels intending to transit the
safety zone may be small entities, for the reasons stated in section
V.A above, this rule will not have a significant economic impact on any
vessel owner or operator.
    Under section 213(a) of the Small Business Regulatory Enforcement
Fairness Act of 1996 (Pub. L. 104-121), we want to assist small
entities in understanding this rule. If the rule would affect your
small business, organization, or governmental jurisdiction and you have
questions concerning its provisions or options for compliance, please
contact the person listed in the FOR FURTHER INFORMATION CONTACT
section.
    Small businesses may send comments on the actions of Federal
employees who enforce, or otherwise determine compliance with, Federal
regulations to the Small Business and Agriculture Regulatory
Enforcement Ombudsman and the Regional Small Business Regulatory
Fairness Boards. The Ombudsman evaluates these actions annually and
rates each agency's responsiveness to small business. If you wish to
comment on actions by employees of the Coast Guard, call 1-888-REG-FAIR
(1-888-734-3247). The Coast Guard will not retaliate against small
entities that question or complain about this rule or any policy or
action of the Coast Guard.

C. Collection of Information

    This rule will not call for a new collection of information under
the Paperwork Reduction Act of 1995 (44 U.S.C. 3501-3520).

D. Federalism and Indian Tribal Governments

    A rule has implications for federalism under Executive Order 13132,
Federalism, if it has 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. We have analyzed this rule under that Order and have
determined that it is consistent with the fundamental federalism
principles and preemption requirements described in Executive Order
13132.
    Also, this rule does not have tribal implications under Executive
Order 13175, Consultation and Coordination with Indian Tribal
Governments, because it does not have a substantial direct effect on
one or more Indian tribes, on the relationship between the Federal
Government and Indian tribes, or on the distribution of power and
responsibilities between the Federal Government and Indian tribes.

E. Unfunded Mandates Reform Act

    The Unfunded Mandates Reform Act of 1995 (2 U.S.C. 1531-1538)
requires Federal agencies to assess the effects of their discretionary
regulatory actions. In particular, the Act addresses actions that may
result in the expenditure by a State, local, or tribal government, in
the aggregate, or by the private sector of $100,000,000 (adjusted for
inflation) or more in any one year. Though this rule will not result in
such an expenditure, we do discuss the effects of this rule elsewhere
in this preamble.

F. Environment

    We have analyzed this rule under Department of Homeland Security
Directive 023-01 and Commandant Instruction M16475.1D, which guide the
Coast Guard in complying with the National Environmental Policy Act of
1969 (42 U.S.C. 4321-4370f), and have determined that this action is
one of a category of actions that do not individually or cumulatively
have a significant effect on the human environment. This rule involves
a temporary safety zone prohibiting entry on a one hundred eighty one
mile stretch of the Illinois River that is experiencing significant
flooding that is impacting levees. It is categorically excluded from
further review under paragraph L60(d) of Appendix A, Table 1 of DHS
Instruction Manual 023-01-001-01, Rev. 01. Because this regulation is
for a temporary safety zone established to deal with an emergency, and
which is longer than one week in duration, a Record of Environmental
Consideration is not required at this time, but will be made available
in the Docket after the issuance of this rule.

G. Protest Activities

    The Coast Guard respects the First Amendment rights of protesters.
Protesters are asked to call or email the person listed in the FOR
FURTHER INFORMATION CONTACT section to coordinate protest activities so
that your message can be received without jeopardizing the safety or
security of people, places or vessels.

List of Subjects in 33 CFR Part 165

    Harbors, Marine safety, Navigation (water), Reporting and
recordkeeping requirements, Security measures, Waterways.

    For the reasons discussed in the preamble, the Coast Guard amends
33 CFR part 165 as follows:

PART 165--REGULATED NAVIGATION AREAS AND LIMITED ACCESS AREAS

0
1. The authority citation for part 165 continues to read as follows:

    Authority: 46 U.S.C. 70034, 70051; 33 CFR 1.05-1, 6.04-1, 6.04-
6, and 160.5; Department of Homeland Security Delegation No. 0170.1.

0
2. Add Sec.  165.T08-0171 to read as follows:

Sec.  165.T08-0171   Safety Zone; Illinois River, Miles 0-187, Grafton,
IL to Peoria, IL.

    (a) Location. The following area is a safety zone: All navigable
waters of the Illinois River from mile marker (MM) 10 to MM 187, unless
reduced in scope by the Captain of the Port Sector Upper Mississippi
River (COTP) as flood conditions warrant.
    (b) Effective period. This rule is effective without actual notice
from June 19, 2020 until June 20, 2020, or until cancelled by the COTP,
whichever occurs first. For the purposes of enforcement, actual notice
will be provided from 5 p.m. on May 21, 2020 until June 19, 2020.
    (c) Regulations. (1) In accordance with the general safety zone
regulations in Sec.  165.23, entry of persons or vessels into this
safety zone described in paragraph (a) of this section is prohibited
unless authorized by the COTP or a designated representative. A
designated representative is a commissioned, warrant, or petty officer
of the U.S. Coast Guard (USCG) assigned to units

under the operational control of USCG Sector Upper Mississippi River.
    (2) To seek permission to enter, contact the COTP or a designated
representative via VHF-FM channel 16, or through USCG Sector Upper
Mississippi River at<PHONE_NUMBER>. Persons and vessels permitted to
enter the safety zone must comply with all lawful orders or directions
issued by the COTP or designated representative.
    (d) Informational broadcasts. The COTP or a designated
representative will inform the public of the effective period for the
safety zone as well as any changes in the dates and times of
enforcement, as well as reductions in size of the safety zone as flood
conditions improve, through Local Notice to Mariners (LNMs), Broadcast
Notices to Mariners (BNMs), and/or Marine Safety Information Bulletins
(MSIBs) as appropriate.

    Dated: May 28, 2020.
R.M. Scott,
Commander, U.S. Coast Guard, Captain of the Port Sector Upper
Mississippi River.
[FR Doc. 2020-12227 Filed 6-18-20; 8:45 am]
BILLING CODE 9110-04-P