March 13, 2002 MEMORANDUM: Response to Comment Document  Phase 2 DIURON: The HED Chapter of the Reregistration Eligibility Decision PC Code ( 035505). Case 0046. DP Barcode D281396 FROM: Carol Christensen, Risk Assessor Reregistration Branch II Health Effects Division ( 7509C)

THRU: Alan Nielsen, Branch Senior Scientist Reregistration Branch II Health Effects Division ( 7509C)

TO: Richard Dumas Team Leader Reregistration Branch II Special Review and Reregistration Division ( 7508W)

The attached document was generated in response to the comments received from the Diuron registrant Griffin Chemical on February 12th, 2002. This document was generated as part of Phase 2 ( error only) of the Interim Public Participation Process. The comments pertain to the 3( 3,4 dichlorophenyl) 1,1 dimethylurea ( diuron) RED document dated December 13, 2002. HED has acknowledged these comments in the Response to Comment document as well as in an updated version of the HED Chapter of the Diuron RED document and the Diuron Toxicology Chapter. The responses documented here reflect the Agency's current guidelines and policies concerning risk assessment. This document and updated HED chapters includes replies from John Punzi on residue chemistry and dietary risk assessment, Yung Yang concerning toxicology comments, and occupational and residential exposure responses from Renee Sandvig and Christina Jarvis, as well as risk assessment and characterization corrections by Carol Christensen.

The Environmental Fate and Effects Division ( EFED) revised the drinking water exposure assessment based upon Registrant comments. The new memorandum entitled " Drinking Water Reassessment for Diuron and its Degradates" dated March 11, 2002 has been incorporated into the Revised HED Chapter of the Reregistration Eligibility Decision Document ( RED) as appropriate. Specific comments pertaining to the Drinking Water Exposure Assessment for Diuron and its Degradates 2 are completed under a separate memo.

HED's Response to Registrant's Phase 1 Error Only Comments I. Toxicology Disciplinary Chapter Page 4. 1.0 Hazard Characterization: Para 1, Line 3.

However, a new 28 day inhalation toxicity study has been required to provide better hazard characterization.

Registrant's Comment: Although inhalation studies are preferred for the assessment of inhalation hazard, there is no triggering for a 28 day inhalation as outlined in the 40CFR regulation. The acute inhalation study shows no inhalation toxicity. The limit test showed no inhalation toxicity. There is no volatility of the diuron either as a solid formulation or as a liquid formulation. The use pattern does not suggest a particular inhalation risk to mixers or applicators. No use exceeds the short term inhalation designation of 1 30 days. Based on the regulations, there must be a mistake in this requirement. It was not triggered.

HED's Response: This is a policy issue and will be addressed in the phase 4 period.

Page 4. 1.0 Hazard Characterization: Para 3, Line 5.

Consistent observations of erythrocyte regeneration are seen in chronic toxicity studies in rats, mice and dogs.

Registrant's Comment: This implies incorrectly that the mice and dogs responded in a similar manner. The dose that resulted in similar effects was at substantially higher dosages of diuron. The phrase should be added for correctness, "   chronic toxicity studies in rats, mice and dogs but at significantly higher dosages of diuron than seen in the rat chronic study."

HED's Response: Hematological effects have been consistently observed in the rat, dog, and mouse chronic toxicity studies. No change is necessary.

Page 4. 1.0 Hazard Characterization: Para 6, Line 2.

Classified as " known/ likely" human carcinogen by all routes, based on urinary bladder .

Registrant's Comment: Data is only for the oral route. No studies were done to demonstrate that tumors resulted by other routes. The mechanism of action of diuron is specific for the oral route. Because the studies using other routes of exposure have not been done, other routes cannot be excluded at this time. However, for correctness the phase " by oral route only" needs to be added to the end of the sentence. It should read, "  in the female NMRI mouse by oral routes only."

HED's Response: The sentence is revised to " Classified as " known/ likely" human carcinogen based on urinary bladder ......"

Page 5. 1.0 Hazard Characterization: Para 1 ( cont.), Line 1.

There is no additional information to justify a reclassification of the cancer classification for diuron at this time. 3 Registrant's Comment: This statement was made based on a review of the mechanistic white paper that the MTARC concluded the " information was insufficient to support a mode of action on bladder carcinogenicity." However, one of the reasons that diuron was considered as a ` known' carcinogen was based on potential genotoxicity. Rereview of the mouse bone marrow chromosomal aberration study changed the conclusion of the study from positive to negative based on a review of the historical background data from the performing laboratory. This was the only positive genotoxicity result, but it carried much weight in the deliberation of the cancer classification of diuron. The change in the classification of diuron as a mutagen to a non mutagen is, in fact, new information that was not considered. The last sentence either needs to be deleted or should simply state " Diuron will not be reclassified at this time."

HED's Response: The sentence is revised to " Diuron will not be re classified at this time."

Page 6. Requirement 870.3465: 90 day Inhalation.

The HIARC determined that a 28 day inhalation toxicity is required.

Registrant's Comment: According to Section 158.340 of the 40CFR, a 90 day inhalation rat study is conditionally required. Footnote 6 of the Toxicology Data Requirements states, " Required if use may result in repeated inhalation exposure at a concentration likely to be toxic. A test with duration 21 days is required if the pesticide is used on tobacco."

The following agricultural use parameters were presented at the SMART meeting held on May 3, 2001.

Table 1. Diuron Agricultural Use Parameters Agricultural Acreage Treated Per Applicator Unit Application Max Acres/ Day Max Acre Apps/ Year ( Season)

On Farm Non Specialized Ground 150 3000 On Farm Specialized Ground 800 6000 Custom Ground 800 12000 Custom Aerial 1200 30000 Even in the worst case represented by aerial application, the maximum acre application per year averages to only 25 days of application. Diuron is a pre emergent herbicide. There is a small window between when the crop is planted and when the seed emerges in which the field is treated to kill weeds that emerge before the crop. The Occupational and Residential Exposure Assessment assumes 10 days of exposure for a private farmer and 30 days of exposure for a commercial applicator in a few large acreage crops. Therefore, no use exceeds the short term inhalation designation of 1 30 days. Diuron is not a volatile chemical either as a TGAI or as a TEP. Given the physical characteristics of the TEPs, there should be no respirable particles generated in the mixing, loading and application of the product.

Secondly, based on the inhalation data from the acute study, there is no reason to believe that the concentration of diuron in the spray mix is likely to be toxic. The LD50 in this study was 7.1 mg/ L. There is no trigger to require this study for this type of product. Therefore, the requirement for a 28 day inhalation study on diuron must be in error. 4 HED's Response: This is a policy issue and will be addressed in the phase 4 period.

Page 7. 4.2 Subchronic Toxicity: Para 1, Line 3.

Registrant's Comment: The 28 day inhalation study requirement should be conditional according to the 40CFR. Diuron does not meet the triggers for such a study. See discussion above.

HED's Response: This is a policy issue and will be addressed in the phase 4 period.

Page 8. Requirement 870.3100: 90 Day Oral Toxicity   Rat, Para 3. General Reticulocyte counts in the high dose females were increased at all intervals with statistical significance ( p< 0.05) attained at weeks 12 and 26 ( 150 165% of control values). Mean hemoglobin concentrations in the high dose females were slightly ( n. s.) depressed at all intervals as compared to the controls ( within 5% of control levels).

Registrant's Comment: Although the high dose females show increased reticulocyte counts, all except for the 3 month interval are within the control values for the study. The female control values range from 12   17. Historically in the conducting laboratory, the 1985 results show control animals to range between 0 34 in reticulocyte counts ( attached). The values of 28 at the 3 month interval of the 25 ppm dosed females and the value of 18 at the 6 month interval of the 25 ppm dosed females are well within the expected values observed in the performing laboratory during the time period in which the study was conducted.

Thus, despite statistical significance, there is little biological significance to the increase in reticulocyte counts at the 25 ppm dose level in the female rats. The same is true of the nonstatistically increased (< 5%) hemoglobin concentration. By discussing the statistical significance apart from the biological significance, it would appear that the effects as delineated by the statement in paragraph 3 have relevance to the assessment.

HED's Response: The hematological effects are consistently observed in other studies and are considered biologically significant. No change is necessary.

Page 8. Requirement 870.3100: 90 Day Oral Toxicity   Rat, Para 4, 5. General Increased incidences of gross lesions on the urinary bladder .

Microscopic examination and morphometric measurements of the urinary bladder ... .

Registrant's Comment: The discussion in these two paragraphs misrepresents the conclusions of the study authors. The effects as described were noted in the treated groups and not in the controls. However, a closer examination of the incidences in both males and females demonstrate little dose response relationship. On page 15 of the study report the authors state:

" The following alterations were noted at autopsy at the end of study. Part of the animals' urinary bladder walls exhibited dilation of blood vessels, increased consistency before filling with the fixative or reduced transparency after filling with fixative. These findings were mostly noted only in the treated animals, more frequently in the females than the males."

Microscopic examinations were also made. It was determined that 2 low dose females and 1 high dose female showed focal hyperplasia. The degree of severity was 1 ( slight) 5 on a scale of 1 to 5. One low dose male and 1 control female and 1 high dose female showed simple hyperplasia again scored as 1 or slight on the severity scale. One low dose female displayed simple hyperplasia with some vascularization; the added vascularization pushed the severity score to 2 or slight to moderate. Two low dose males and 1 high dose male showed a thickening of the epithelial cells but involved less than three cell layers; severity score of 1 or slight. There is no dose response and the severity of the lesions are slight in all cases. The microscopic observations did not correlate with the gross findings.

On the basis of these conflicting qualitative observations, the authors decide to make quantitative measurements of the bladder wall thickness. They measured only females because there were no effects that differed from the controls in the males. They state in the methods section on page 7 of the report:

Gross findings made in particular in treated females indicated possible thickening of the urinary bladder walls. For this reason the thickness of all the females' bladder walls was quantitatively measured with an automatic Omnicon screen unit ( Bausch & Lomb Co.). Equally long paramedian areas of the two wall portions of each bladder half were measured, that is four measurements per animal. The area contained a wall portion including epithelium and peritoneal tissue."

The results were clear. There was no thickening of the bladder walls. This can be seen in Table 2 below as taken from the study report on page 17.

Table 2. Females' relative bladder wall areas. Mean figures per group on measurement of 4 area portions of some length per animal ( area = paramedian bladder wall section).

Dose ( ppm) 0 4 10 25 Mean 437 492 448 486 Std Deviation 58 80 50 51 Based on the wide variation and absence of dose response relationship, no differences were assessed to these findings. The authors conclude on page 17 of the study report:

The gross findings obtained for the urinary bladders ( see Section 5.7) did not correlate with the histopathological results. In an attempt to obtain correlation for the reduced transparency and increased consistency of the bladder walls, automatic measurements of the bladder wall thickness were made. The results of these measurements are compiled in Table 5 ( given here as Table 2). In consideration of the wide variation and absence of dose correlation, no major differences were noted between the figures in any of the groups. No importance is therefore attached to the gross findings.

These observations are NOT EQUIVOCAL. There are no effects that can be attributed to any dose level, let alone the low dose of 4 ppm. The NOEL for this study can be defined by the blood effects for which the study was designed.

HED's Response: This nonguideline study was conducted in 1988 and reviewed by the HED in 1990. The scope of the study was primarily restricted to parameters associated 6 with effects on erythrocytes. However, the study did not evaluate the status of the bone marrow. Gross macroscopic observations revealed an increase of urinary bladder incidences related to blood vessel dilation, and reduced transparency and increased firmness in all treated groups as compared to the control. Quantitative evaluation of the urinary bladder wall revealed a slight increase of urinary wall thickening in all treated females as compared to the controls. Males were not evaluated in this study. In a chronic toxicity study ( MRID 40886501) ( dose levels of 0, 25, 250, or 2500 ppm), a treatment related urinary bladder thickening was observed in the 25 ppm males. The HED reviewer concluded that a NOAEL could not be determined because many parameters were not evaluated in this study. No change is necessary.

Page 8. Requirement 870.3100: 90 Day Oral Toxicity   Rat, Para 3, Line 2. Specific Mean hemoglobin concentrations in the high dose females were slightly ( n. s.) depressed at all intervals as compared to the controls ( within 5% of the control levels).

Registrant's Comment: This sentence either needs to be deleted or it needs to be made clear that this is not an effect as there is neither biological nor statistical significance in this finding.

HED's Response: By the weight of evidence, these hematological effects are considered biologically significant. No change is necessary.

Page 8. Requirement 870.3100: 90 Day Oral Toxicity   Rat, Para 5, Line 2. Specific Hyperplasia of the epithelium was observed in 1 low dose male, 1 control female, 2 low dose females and 2 high dose females.

Registrant's Comment: When the focal hyperplasia is separate from the totals as given in the EPA document, there is clearly no statistically significant hyperplasia at any dose level. Focal hyperplasia is given as 2 females at the low and 1 female at the high dose. Control and high dose females ( one each) demonstrate simple hyperplasia ( nonfocal Secondly, the degree of hyperplasia is given as the lowest scored. Severity is not discussed. It needs to be as it impacts the ` equivocal' judgment of the effect.

The dose response needs to be addressed. The lack of a dose correlation is omitted. It too impacts the ` equivocal' judgment of the effect.

Also omitted is the lack of correlation between the gross examination results and the histopathological results. It was this discordance that prompted the quantitative measurements of the female bladders.

These are all errors of omission that impact the assessment of the effect.

HED's Response: See above HED's response.

Page 8. Requirement 870.3100: 90 Day Oral Toxicity   Rat, Para 5, Line 7 ( last).

These observations are judged to be equivocal.

Registrant's Comment: The effects are not equivocal; there are no effects. No dose response was observed, no thickening of the bladder as demonstrated by either quantitative measurement or a correlation between gross observation and microscopic observation. This constitutes a negative effect and not ` equivocal'. 7 The results of the 2 year chronic oncogenicity study in rats are also in conflict with this assessment. The females displayed bladder carcinoma only at the high dose of 2500 ppm in contrast to the males, which showed effects at lower dosages of diuron. The EPA document states that focal hyperplasia was observed in the female only at the mid ( 250 ppm) and high ( 2500 ppm) dose groups at 12 and/ or 24 months. There were effects in the females at the 250 ppm dosage, but only at 24 months and not at 12 months. No effects at the 25 ppm dosage in the females were seen after either 12 or 24 months of exposure. These results should cast some interpretative light on the nature of the ` equivocal' effects in the 6 month study.

HED's Response: See above HED's response.

Page 8. Requirement 870.3100: 90 Day Oral Toxicity   Rat, Para 7, Line 1.

The NOEL cannot be determined because some findings were judged to be equivocal.

A NOEL is not defined by this study. No effects were biologically relevant including the reticulocyte count. The study authors give 10 ppm as the NOEL without an evaluation of the historical blood values.

HED's Response: See above HED's response.

Page 9. Requirement 870.3100: 90 Day Oral Toxicity   Rat, General Registrant Comment: A study has been omitted from this discussion. It is the " Study for Toxicity to Wistar Rats with Special Attention to Urothelial Alterations ( Administration in Diet for 2,4,12, and 26 Weeks with Recovery)." ( Reviewed in response to MRID 45494501).

Its significance is that it allows the bladder effects that EPA judged to be ` equivocal' to be placed into perspective.

In this study, male Wistar rats were administered diuron in their diet at a concentration of 2500 ppm for 2, 4, 12, or 26 weeks. Further animals were similarly treated for 4 or 26 weeks, and then observed for 4 or 8 weeks ( recovery). One control group ( each of 10 animals) was used per treatment group ( each of 10 animals).

Histopathological examination of the urinary bladders revealed a treatment related increased incidence of hyperplasia of the epithelium, and an increase in the degree of hyperplasia from treatment duration of four weeks onwards. Hyperplasia with exo and endophytic growth ( within 4 weeks) and marked squamous epithelial metaplasia ( after 26 weeks) were found. Morphometric measurements detected in addition an increase in the sub epithelial urinary bladder tissue ( already apparent after treatment fro two weeks). Examination of the animals in the recovery groups revealed a clear trend towards reversibility of the induced alterations after cessation of treatment.

Bladder thickening is measured and given in Table 3 below. The highest value of 492 seen in the blood study documented above is well within the normal values as shown in this study ( noting differences between sexes). Thickening of the bladder is readily observed and exceeds the error as expressed by the standard deviations. This is quite different than the rather small changes seen in the blood effect study above for which no dose effect exceeded the standard deviations.

Table 3. Areas of equally long wall regions from paramedian sections of the urinary bladder 8 ( relative units, mean and standard deviation, also number of animals examined per group).

Study Length Control Groups 2500 ppm Diuron Weeks Mean Std Dev n Mean Std Dev n 2 418 45 10 510 110 10 4 439 94 9 635 123 9 8* 521 84 9 565 89 9 12 590 92 10 847 99 9 26 307 110 10 778 115 7 34** 580 90 8 716 84 4 * 4 weeks diuron, 4 weeks recovery ** 26 weeks diuron, 8 weeks recovery This study is important in that it demonstrates a marked trend towards reversibility and should be included with the similar study that focuses on the blood effects.

HED Response: This study was submitted as part of the document entitled " Cancer Classification and Mechanism of Action of Diuron ( MRID 45494501)" for a proposed mode of action on bladder carcinogenicity. The HED's Mechanism of Toxicity Assessment Committee ( MTAC) reviewed the study and concluded that this study suggested a reversibility of possible precancerosis but did not present or propose a mode of action for assessment of mode of action on bladder carcinogenicity on diuron. No change necessary.

Page 9. Requirement 870.3465: 90 Day Inhalation   Rat The HIARC determined that a 28 day inhalation study is required to address the concern for inhalation exposure potential based on use pattern.

Registrant Comment: There is no need for a 28 day inhalation study based either on the use pattern or the inhalation toxicity. See discussion relating to this issue above.

HED Response: This is a policy issue and will be addressed in the phase 4 period.

Page 9. Requirement 870.3200: 21 Day Dermal  Rabbit, Para 1, Line 4.

Body weight, good consumption, clinical signs .

Registrant Comment: Typographical error: ` Good' consumption should be ` food'.

HED Response: Changed to " food".

Page 10. Requirement 870.3700a: Prenatal Developmental Toxicity Study   Rat, Para 3. General Registrant Comment: Paragraph 3 general comment on omission. Weight of both males and females rebounded to nearly normal in all dose groups after removal of diuron treatment. This should be noted. 9 HED Response: This observation confirmed a finding that the body weight decrease is treatmentrelated No change is necessary.

Page 11. Requirement 870.3700a: Prenatal Developmental Toxicity Study   Rat, Para 2, Line 2.

  Skeletal malformations/ variations was 288 ( 22), 305( 23),

Registrant Comment: Typographical error: ` 305' should be ` 306'.

HED Response: Changed to " 306".

Page 13. Requirement 870.3800: Reproduction and Fertility Effects   Rat, Para 1, Line 2.

Test substance intake for the treated .

Registrant Comment: Test substance intake should read ` Overall test substance intake'. The dosing reflects the entire dosing period.

HED Response: The intakes of test substance are estimated for F0 and F1 parental animals respectively by the reviewer. No change is necessary.

Page 13. Requirement 870.3800: Reproduction and Fertility Effects   Rat, Para 3, Line 8.

Significant reductions in food consumption were observed .

Registrant Comment: This is in error. There was not a significant difference in the 7 14 day interval for the females.

HED Response: The sentence stated that " ..... occasional significant differences from control .... were considered incidental to treatment." No change is necessary.

Page 14. Requirement 870.4300: Combined Chronic Toxicity/ Carcinogenicity   Rat, Para 1, Line 5.

.. dietary concentrations of 0, 1.7, 17, or 202 mg/ kg/ day

Registrant Comment: Typographical error: Should read ` 203 mg/ kg/ day'

HED Response: Changed to " 203."

Page 14. Requirement 870.4300: Combined Chronic Toxicity/ Carcinogenicity   Rat, Para 2, Line 2.

The only treatment related clinical sign was reddish discolored or bloody urine in high dose males.

Registrant Comment: This implies that all high dose males demonstrated this adverse effect. The sentence should read, "  some high dose males".

HED Response: Changed to " some high dose males".

Page 15. Requirement 870.4300: Combined Chronic Toxicity/ Carcinogenicity   Rat, Para 2, Line 2. 10 The hematopoietic system and urinary bladder ( and renal pelvis) were the primary diuron target organs. Erythrocyte damage resulted in hemolytic anemia and compensatory hematopoiesis which were manifested as significantly decreased... .

Registrant's Comment: The effects first outlined are for the 24 month interval. This needs to be noted. Also, in line 5 of the same sentence the parenthetical phrase that states (< 25% change for most parameters; 3 fold increase for reticulocytes) applies only to the high dose males and females. The mid dose animals do not show this degree of change. The low dose females show a very small increase of 33% in the erythrocyte count and no real change in the other parameters. ( Historical control data from the conducting laboratory during a similar time period, show that control animals can have the same 33% increase. See attached historical data.)

For accuracy, the second sentence should read, " Erythrocyte damage resulted in  . in mid and / or high dose males and females, and in low dose females. In the high dose groups there was < 25% change for most parameters with a 3 fold increase for reticulocytes. For the low dose females, only an increase of 33% was observed in erythrocyte count and no real change in the other parameters."

HED's Response: The DER indicated that significant hematological effects were observed in the mid and high dose males and females as early as 6 months. No change is necessary.

Page 15. Requirement 870.4300: Combined Chronic Toxicity/ Carcinogenicity   Rat, Para 3, Line 2.

Microscopic evaluation showed that epithelial focal hyperplasia of the urinary tract and renal pelvis increased in severity in both sexes at 12 and/ or 24 months, and increased in incidence ( p< 0.05) or 0.01) in high dose males at 12 months and in mid and high dose females at 12 and/ or 24 months.

Registrant's Comment: The mid dose females showed an increased incidence only at 24 months. The sentence should read:

` Microscopic evaluation showed that epithelial focal hyperplasia of the urinary tract and renal pelvis increased in severity in both sexes at 12 and/ or 24 months, and increased in incidence ( p< 0.01) in high dose males at 12 months and in high dose females at 12 and/ or 24 months with mid dose females showing an increased incidence at 24 months.'

HED's Response: Changed as Registrant's comment.

Page 17. 4.6 Carcinogenicity: Para 3.

There is no additional information to justify a re classification of the cancer classification for diuron at this time.

Registrant's comment: The change in classification of mutagenic to non mutagenic is enough information to re classify the chemical from known/ likely to likely. It should be enough to just indicate that diuron will not be re classified until the new guidelines are finalized.

HED' Response: The sentence is revised to " Diuron will not be re classified at this time."

Page 19. Requirement 870.4200b: Carcinogenicity ( feeding)  Mouse, Para 3, Line 1.

  and ovarian luteomas ( control, 6%; 2500 ppm, 14%) in female . 11 Registrant,' Comment: The reference to luteomas should be deleted. The CPRC made the decision ( May 8, 1997) that the effect was inconsequential. Combined sex cord stromal tumors are a better reflection of the system than ` luteomas'. There is no statistical difference between control and treated groups for ovarian combined sex cord stromal tumors.

HED' Response: Additional wording is added to the document to address this issue. " On December 18, 1996 the Carcinogenicity Peer review Committee ( CPRC) determined that the female mouse ovarian tumor rates table should reflect the more appropriate ' combined sex cord stromal tumors' nomenclature in lieu of the " luteoma" terminology used in the qualitative risk assessment ( Lori L. Brunsman to Linda L. Taylor, 11/ 20/ 96). Dr. Lucas Brennecke, EPA's consulting pathologist, confirmed that the combined tumor counts are more appropriate than the individual counts for ovarian tumors, as it is difficult to distinguish between the different types of ovarian tumors. The CPRC concluded that female mice do not have a significant increasing trend, or any significant differences in the pair wise comparisons of the dosed groups with the controls, for ovarian combined sex cord stromal tumors."

Page 19. 4.7 Mutagenicity: Para 1, Line 5.

  Sprague Dawley rats in one study and statistically significant increases in cells with structural aberrations in a second study conducted with the same rat strain. The data from the latter study, however, were shown to fall within the historical control range.

There is only one study for the rat bone marrow chromosomal aberration assay. It is HLR 366 85. It was assigned the MRID 00146611. This study was revised in 1995 to include the historical aberration frequencies that changed the assessment of the results. The revised report bears the same laboratory designation HLR 366 85 but was assigned a new MRID of 44350301. All references to the first study designated by MRID 00146611 can be deleted.

The reference to a second study showing statistically significant increases in structural aberrations was only at the 48 hour post treatment interval. Nothing was observed at either 6 or 24 hours.

Suggested wording: " There were marginal statistically significant increases in cells with structural aberrations in a Sprague Dawley rat in vivo bone marrow chromosomal aberration assay. However, the levels of aberrations were within the historical control range and assessed negative."

Note the type in the word evidence in the last sentence of the paragraph.

Typographical error: The word ` does' should be changed to ` dose.'

HED's Response: ( 1) Changed to " dose". ( 2) Deleted the study ( MRID 00146611) and revised wording as comment.

Page 20. Requirement 870.5385: Cytogenetics  Middle Row in Table.

Registrant's Comment: Guideline 870.5385 .. MRID # 00146611. This study is identical to the one above and should be deleted.

HED's Response: Deleted the study ( MRID 00146611) from the table.

Page 22. 5.3.1 Conclusions: Line 1 Treatment of diuron resulted in a significant increase in the incidences of urinary bladder carcinoma in both sexes of the Wistar rat, kidney carcinomas in the male rat ( a rare tumor) and mammary gland carcinomas in the female NMRI mouse.

Registrant's Comment: The way this sentence is phrased, it implies that the incidences of kidney carcinomas were also significant. There was no statistical significance attached to the incidences of renal pelvis tumors. Reference should either be deleted or the lack of statistical significance for this tumor should be referenced. 12 HED's Response: This is the conclusion of the HED's Carcinogenicity Peer Review Committee ( HED Doc. No. 012224). No change is necessary.

Page 28. 9.1.2 Subchronic, Chronic and Other Toxicity Tables: 870.3100 Results The NOEL cannot be determined based on equivocal findings in the urinary bladder including blood vessel dilation, reduced transparency, and increased firmness.

Registrant's Comment: A NOEL can be established. In the discussion of this study above, there was more than adequate evidence that the gross observations did not match either the histopathology or the measurement of bladder thickness. The pathologist dismissed the gross findings as not relevant to the assessment. The NOEL should be set based on the blood effects.

The doses should read " 0, 0.3, 0.8, 1.8", not " 0, 0, 0.3, 0.8, 1.8."

HED's Response: ( 1) See above HED's response on the NOAEL issue. ( 2) Corrected the doses as comment.

Page 29. 9.1.2 Subchronic, Chronic and Other Toxicity Tables: 870.5100 Results TA100 up to the highest does tested

Registrant's Comment: Typographical error: The word ` does' should be changed to ` dose.'

HED's Response: Changed to " dose".

Page 30. 9.1.2 Subchronic, Chronic and Other Toxicity Tables: 870.5375 Results Registrant's Comment: The description of results is quite long and inconsistent with the brevity of the rest of the Table. Would suggest deleting much of the material and matching it in content with the other mutagenicity experiments.

HED's Response: Revised as comment.

Page 31. 9.1.2 Subchronic, Chronic and Other Toxicity Tables: 870.5375 Results Registrant's Comment: This first item on page 31 of the Table can be deleted. The study was revised and the results are reflected in MRID# 44350301 on the last page.

HED Response: Deleted the study ( MRID 00146611).

II. HED Chapter Page 1. First Para, Line 15.

Application rates range from 0.8 lbs active ingredient ( ai)/ acre for corn to 87.1 lbs ai/ acre for non crop areas.

Registrant's Comment: The rate of 87.1 lbs ai/ acre is exaggerated. We can find no label to back these claims.

HED's Response: Registration 769 638 includes a label rate of 10 lbs per 1000 ft2. The label is for Granular Dy Kil 20 and is intended for use in irrigation and drainage ditches. It is manufactured by Southern Mill Creek Product Company. Using a standard conversion of 43,560 ft2 per acre and including a 20% a. i. concentration from the end use label the resulting application rate is 87.12 lbs 13 a. i. per acre. No change necessary.

Page 29. Last Para, Line 7.

Registrant's Comment: The word " mile" should be " mile2". Also, this use rate (> 1379 lb ai/ mile2/ yr) is not possible, both in this document and in the Drinking Water Assessment from which it is quoted. This rate is equivalent to 2.15 lb ai/ acre, a rate that is obtainable as an average only if every acre in the area was planted to cotton and 100% of those acres received the maximum annual diuron rate for clay soils, a treatment program that would also require all the acres to receive 2 treatments each year. In the subject area, soils are primarily sandy loam, the percentage of the crop treated averages about 50% and only about 30% of the acres received two treatments. These parameters would produce a maximum use rate of 1.2 lb ai/ treated acre/ yr or 827.4 lb ai/ mile 2/ yr for the whole area if it were 100% planted to cotton and 50% was treated.

HED's Response: The Environmental Fate and Effects Division will respond to this comment under separate cover memo.

III. Chronic Dietary Exposure Assessment Page 2. Table, Last row, 2nd column.

Registrant's Comment: The Q1 * should be " 1.91", not " 1.191."

HED's Response: This typographical error is noted. It is also noted that the correct value was included in the dietary exposure and risk assessment, 1.91.

IV. Drinking Water Assessment Registrant's Comment: The Agency used the PRZM/ EXAMS model that has never been adequately validated. Nevertheless, the model can produce results that predict residue levels in surface water reasonably well if used properly. The results produced by this model are very sensitive to the input parameters that drive the computations. When inappropriate input parameters are selected, as is the case in this assessment, the model grossly overestimates residues moving into surface water. Consequently, the results from the model are incorrect and misrepresents the diuron residues likely to occur in drinking water. Some of the incorrect input parameters are discussed below. A more thorough assessment, including results of the PRZM/ EXAMS model using the appropriate input parameters, will be filed during the public comment period. Some examples of inappropriate input parameters EPA used in the model are:

1. The Agency chose to model drinking reservoirs in Osceola County, FL, an area in which there are no large drinking reservoirs.

2. The wrong soil type was used for the area being modeled. The soil in the Osceola County, FL, area is loamy sand which has a good recharge capacity. In their use of the model, the Agency used high clay soil which has high runoff rates and little recharge capacity.

3. The Agency assumed that all of the chemical was deposited on the top of the soil. Diuron has measurable, but limited mobility in soil. Changes to the model that assume the chemical applied resides in the top 4 cm produce runoff estimates 10 to 40 fold lower than the levels produced when the chemical is assumed to reside on the surface.

The Agency has acknowledged that the results obtained from the PRZM/ EXAMS model are from 9 to 100 times higher than the data obtained from the various monitoring programs, including the 14 monitoring data from the US Geological Survey ( USGS) National Water Quality Assessment Program ( NAWQA) . It appears that the large difference between the modeling results and the results of the USGS program have contributed to the Agency's concern as to whether the USGS data are reasonably representative of residue levels of diuron in surface waters. EPA has expressed this concern in spite of the fact that the USGS results come from over 1400 samples from 62 streams over a 7 year period. Griffin fully expects that when appropriate input parameters are used, the PRZM/ EXAMS model will produce results that will give the Agency more confidence in the monitoring data from the US Geological Survey ( USGS) National Water Quality Assessment Program ( NAWQA).

The Agency has included in its Drinking Water Assessment the results of a monitoring study performed in the playa lakes of the high plains of western Texas. In characterizing the results of this study, the Agency failed to recognize that the playa lakes are temporary bodies of water with no natural outlets. Water from these " lakes" either evaporates or infiltrates into the soil. The area that becomes a playa lake may be planted to cotton or another crop in a previous year or even early in the same year in which runoff due to large rainfall events create the playa lake. Consequently, pesticide residues in these temporary water bodies may result, not only from surface water runoff from adjacent fields but from direct application to the area of the lake before flooding occurred. Water bodies such as the playa lakes are never used as sources of drinking water. Residue levels from such water bodies, while of academic interest, have no bearing on the levels of pesticides in drinking water.

In their lack of an outlet and their water source being runoff from a rather large area of heavily cropped land, the playa lakes bear some similarity to the Index Reservoir scenario EPA utilized in its use of the PRZM/ EXAMS model. The huge differences between the results of the model and the playa lakes results should have led the Agency to re examine the input parameters it used in the model.

In its discussion of the playa lakes study, EPA stated that diuron usage in the area of Texas that includes the playa lakes " reached and average of > 1379 lb ai/ mile 2/ yr.". This use rate is simply not possible. This rate is equivalent to 2.15 lb ai/ acre, a rate that is obtainable as an average only if every acre in the area was planted to cotton and 100% of those acres received the maximum annual diuron rate for clay soils, a treatment program that would also require all the acres to receive 2 treatments each year. In the subject area, soils are primarily sandy loam, the percentage of the crop treated averages about 50%, and only about 30% of the acres receive two treatments. These parameters would produce an maximum use rate of 1.2 lb ai/ treated acre/ yr or 827.4 lb ai/ mile 2/ yr for the whole area if it were 100% planted to cotton and 50% was treated.

The Agency stated that there is no aerobic and anaerobic aquatic studies available; however, DuPont has submitted both studies, MRID # s 42260501 and 42661901. The Agency assumed a one year half life in water which is contradictory to page 8, paragraph 3 of the Diuron Metabolism Committee Briefing Memo which agrees with our studies estimating a half life of 33 days in water and 1.2 days in sediment.

The Agency used a soil half life of 372 days and our data show half lives ranging from 20 to 372 days. MRID # s 41709305, 44654001, 44738001 and 44865001. The choice of the most extreme half life is just not a conservative choice as the Agency claims but is a worst case choice and is not representative of major diuron use areas.

HED's Response: The Environmental Fate and Effects Division will respond to this comment under separate cover memo.

Page 43.

Registrant's Comment: The references are misnumbered, appear to be incomplete and may be 15 misplaced.

HED's Response: No error noted.

V. Report of the HIARC Page 16. First Para, Line 5.

Registrant's Comment: The value " 0.8" should be " 0.88."

HED's Response: This typographical error is noted. However, no change is necessary in the revised HED chapter.

VI. RED, Residue Chemistry Considerations Registrant's Comment: The Table of Contents is not numbered correctly.

HED's Response: The error will be corrected in the next version of the Residue Chemistry Chapter.

Registrant's Comment: Studies have been submitted for the following crops: alfalfa  MRID # 45508703; lemons  MRID # 45509702; wheat  MRID # 45509703; and alfalfa  MRID # 45509704.

HED's Response: The study identified as MRID 45508703 is not a submission from the registrant that concerns diuron or alfalfa in any matter related to this assessment. We acknowledge that lemon MRID 45509702; wheat MRID 45509703; and alfalfa MRID 45509704 were inadvertently not included in the Chemistry Chapter and are currently in the Agency's review process. HED notes the MRID numbers quoted by the registrant for wheat and alfalfa are incorrect. The correct MRID for the wheat study is 45509704 and the correct MRID for the alfalfa study is 45509703.

Registrant's Comment: Portions of the residue data used by EPA in the memorandum entitled Chronic Dietary Exposure Assessment differs from those data submitted and cited in the Residue Chemistry Chapter, but apparently were not used. Below is a summary of the residue data in which we differ from EPA, along with an explanation for that difference, MRID numbers and references. These errors lead to a drastically overstated dietary risk, particularly in those processed commodities where the Agency has ignored the available data. The Agency has defaulted to their percent crop treated even though accurate crop treat data were presented by Griffin LLC.

HED's Response: The residue data that was used for the input to the chronic dietary assessment was taken from field trial data submitted by the registrant to support tolerances. As is the case for apple, banana, berries, grapefruit, grapes, lemons, limes, oranges, pineapples, and wheat processed commodities, there exists more than one field trial study. If the application rates and PHI's are appropriate to the current labeling and the study adheres to current Agency guidelines for geographic distribution and analytical methodology, any study could be used to develop the residue value( s) for the exposure computation.

With the exception of wheat and berries, the residue values are essentially non detectable and the difference between the studies are essentially in the limits of detection of the method. The studies referred to by the registrants will be examined to determination if the processing factors reported 16 therein are more appropriate than those presently used.

It is presently HED policy to use the percent crop treated data provided by BEAD.

Registrant's Comment: MRID # 43434301  Apples = 0.007 ppm = Mean of Field Trial data ( All samples were less than LOD ( 0.0145 ppm) so ½ LOD was used) Residue Factor of 2. In a processing study, all residues in pomace and juice were less than 0.013 at a 3X treatment rate.

Food Name Anticipated Residues from Residue Studies Anticipated Residues from EPA Adj # 1 Adj # 1 EPA Adj # 2 Adj # 2 EPA Concentration Factor % Crop Treated Apples 0.007 0.016 1 1 0.11 0.13 Apples Dried 0.007 0.016 8 8 0.11 0.13 Apples Juice 0.007 0.016 1 1.3 0.11 0.13 Apple Juice Conc 0.007 0.016 3 3.9 0.11 0.13 HED's Response: The percent of crop treated are weighted averages provided by the Biological and Economic Analysis Division ( BEAD) in a Quantitative Usage Analysis issued 3 20 01 and supplemented for miscellaneous usage sites on 04 27 2001.

Registrant's Comment: MRID # 44583001  Bananas = 0.005 ppm = Mean of Field Trial data. All values were less than LOQ, but were reported as actual values. The two reported values above LOQ ( i. e. 0.005 ppm) were used while the values reported below 0.005 ppm were replaced with 0.005 ppm. This led to a mean value of 0.005 ppm.

Food Name Anticipated Residues from Residue Studies Anticipated Residues from EPA Adj # 1 Adj # 1 EPA Adj # 2 Adj # 2 EPA Concentration Factor % Crop Treated Bananas 0.005 0.025 1 1 0.05 0.14 Bananas Dried 0.005 0.025 3.9 3.9 0.05 0.14 Bananas Juice 0.005 0.025 1 1 0.05 0.14 HED's Response: The percent of crop treated are weighted averages provided by the Biological and Economic Analysis Division ( BEAD) in a Quantitative Usage Analysis issued 3 20 01 and supplemented for miscellaneous usage sites on 04 27 2001.

Registrant's Comment: MRID # 44797701  Blackberries = 0.02 ppm = Mean of Field Trial data. The LOQ was 0.04 ppm and all values were reported as either 0 or 0.017 ppm. We used ½ LOQ ( i. e. 0.02 ppm) for all the samples, which gives an average residue of 0.02 ppm. MRID # 44544101  Blueberries = 0.02 ppm = Mean of Field Trial data. The LOQ was 0.04 ppm and all values were reported as zero, therefore ½ LOQ was used. Boysenberries, Currants, Dewberries, Huckleberries and Loganberries = 0.02 ppm = Mean of field trial data. Value taken from blackberry/ blueberry study.

Food Name Anticipated Residues from Residue Studies Anticipated Residues from EPA Adj # 1 Adj # 1 EPA Adj # 2 Adj # 2 EPA Concentration Factor % Crop Treated Blackberries 0.02 0.1 1 1 0.53 0.53 17 Blackberries Juice 0.02 0.1 1 1 0.53 0.53 Blueberries 0.02 0.1 1 1 0.29 0.29 Boysenberries 0.02 0.1 1 1 0.53 0.07 Currants 0.02 0.1 1 1 0.29 0.31 Dewberries 0.02 0.1 1 1 0.53 0.53 Huckleberries 0.02 0.1 1 1 0.29 0.29 Loganberries 0.02 0.1 1 1 0.53 0.33 HED's Response: The percent of crop treated are weighted averages provided by the Biological and Economic Analysis Division ( BEAD) in a Quantitative Usage Analysis issued 3 20 01 and supplemented for miscellaneous usage sites on 04 27 2001.

Registrant's Comment: MRID # 43339201  Grapefruit = 0.006 ppm = All Field Trial values are less than LOD of 0.0110 ppm, therefore ½ of the LOD was used. A processed commodity study accepted by the Agency which demonstrated no concentration in juice was ignored.

Food Name Anticipated Residues from Residue Studies Anticipated Residues from EPA Adj # 1 Adj # 1 EPA Adj # 2 Adj # 2 EPA Concentration Factor % Crop Treated Grapefruit Juice 0.006 0.012 1 2.1 0.36 0.47 Grapefruit Juice Concentrate 0.006 0.012 1 8.26 0.36 0.47 Grapefruit Peeled Fruit 0.006 0.012 1 1 0.36 0.47 HED's Response: The percent of crop treated are weighted averages provided by the Biological and Economic Analysis Division ( BEAD) in a Quantitative Usage Analysis issued 3 20 01 and supplemented for miscellaneous usage sites on 04 27 2001.

Registrant's Comment: MRID # 43421501  Grapes = 0.008 ppm. All Field Trial values are less than the LOD of 0.0160 ppm, therefore ½ LOD was used. A processing study which demonstrates no concentration in raisins has been ignored.

Food Name Anticipated Residues from Residue Studies Anticipated Residues from EPA Adj # 1 Adj # 1 EPA Adj # 2 Adj # 2 EPA Concentration Factor % Crop Treated Grapes 0.008 0.021 1 1 0.1 0.1 Grapes Juice 0.008 0.021 1 1.2 0.1 0.1 Grapes Juice Concentrate 0.008 0.021 1 3.6 0.1 0.1 Grapes Leaves 0.008 0.021 1 1 0.1 0.1 Grapes Raisins 0.008 0.021 1 4.3 0.1 0.1 Grapes Wine 0.008 0.021 1 1 0.1 0.1 HED's Response: The percent of crop treated are weighted averages provided by the 18 Biological and Economic Analysis Division ( BEAD) in a Quantitative Usage Analysis issued 3 20 01 and supplemented for miscellaneous usage sites on 04 27 2001.

Registrant's Comment: MRID # 45509702  Lemons = 0.09 ppm = Mean of Field Trial data. Four of 6 samples were less than LOQ, so ½ LOQ ( i. e. 0.005 ppm) was used for those samples. The other two samples were at 0.2 ppm and 0.32 ppm. When taken all together, this gives a mean of 0.09 ppm.

Food Name Anticipated Residues from Residue Studies Anticipated Residues from EPA Adj # 1 Adj # 1 EPA Adj # 2 Adj # 2 EPA Concentration Factor % Crop Treated Lemons Juice 0.09 0.05 2 2 0.2 0.26 Lemons Juice Concentrate 0.09 0.05 11.4 11.4 0.2 0.26 Lemons Peeled Fruit 0.09 0.05 1 1 0.2 0.26 HED's Response: The percent of crop treated are weighted averages provided by the Biological and Economic Analysis Division ( BEAD) in a Quantitative Usage Analysis issued 3 20 01 and supplemented for miscellaneous usage sites on 04 27 2001.

Registrant's Comment: MRID # 45509702  Limes = 0.09 ppm = Lemon Field Trial data used for lime. A processed commodity study accepted by the Agency which demonstrated no concentration in juice was ignored.

Food Name Anticipated Residues from Residue Studies Anticipated Residues from EPA Adj # 1 Adj # 1 EPA Adj # 2 Adj # 2 EPA Concentration Factor % Crop Treated Limes Juice 0.09 0.05 1 2 0.2 0.33 Limes Juice Concentrate 0.09 0.05 1 6 0.2 0.33 Limes Peel 0.09 0.05 1 1 0.2 0.33 Limes Peeled Fruit 0.09 0.05 1 1 0.2 0.33 HED's Response: The percent of crop treated are weighted averages provided by the Biological and Economic Analysis Division ( BEAD) in a Quantitative Usage Analysis issued 3 20 01 and supplemented for miscellaneous usage sites on 04 27 2001.

Registrant's Comment: MRID # 43339201 Oranges = 0.007 ppm = Mean orange Field Trial residue was used. Orange juice processing factor of 0.96 was calculated from MRID # 43260101. To get orange juice concentrate, the ratio of the orange juice concentrate and orange juice default processing factors ( 6.7/ 1.8) were multiplied by 0.96, which equals 3.6. The default processing factors was used by EPA. A processed commodity study accepted by the Agency which demonstrated no concentration in juice was ignored.

Food Name Anticipated Residues from Residue Studies Anticipated Residues from EPA Adj # 1 Adj # 1 EPA Adj # 2 Adj # 2 EPA Concentration Factor % Crop Treated 19 Oranges Juice 0.007 0.03 0.96 1.8 0.46 0.51 Oranges Juice Concentrate 0.007 0.03 1 6.7 0.46 0.51 Oranges Peel 0.007 0.03 1 1 0.46 0.51 Oranges Peeled Fruit 0.007 0.03 1 1 0.46 0.51 HED's Response: The percent of crop treated are weighted averages provided by the Biological and Economic Analysis Division ( BEAD) in a Quantitative Usage Analysis issued 3 20 01 and supplemented for miscellaneous usage sites on 04 27 2001.

Registrant's Comment: MRID # 42798501  Pineapples = 0.004 ppm = Average residue data from RAC portion of Processing study. These were used because they were from a 4 5X application rate. 0.25 is juice processing factor from processing study. 0.93 = 0.25 x the ratio of the juice concentrate to juice default processing factors ( 6.3/ 1.7), which = 0.93. Five is the default processing factor for dried pineapples.

Food Name Anticipated Residues from Residue Studies Anticipated Residues from EPA Adj # 1 Adj # 1 EPA Adj # 2 Adj # 2 EPA Concentration Factor % Crop Treated Pineapples dried 0.04 0.1 5 5 0.8 0.13 Pineapples juice 0.04 0.07 0.25 1.7 0.8 0.13 Pineapples juice Concentrate 0.04 0.07 0.93 6.3 0.8 0.13 Pineapples peeled fruit 0.04 0.1 1 1 0.8 0.13 HED's Response: The percent of crop treated are weighted averages provided by the Biological and Economic Analysis Division ( BEAD) in a Quantitative Usage Analysis issued 3 20 01 and supplemented for miscellaneous usage sites on 04 27 2001.

Registrant's Comment: MRID # 42740401  Wheat = 0.025 ppm = Mean Field Trial residue ( All residues less than LOQ of 0.05 ppm, so 0.025 ppm was used). Wheat bran and wheat flour processing factors calculated from wheat processing study.

Food Name Anticipated Residues from Residue Studies Anticipated Residues from EPA Adj # 1 Adj # 1 EPA Adj # 2 Adj # 2 EPA Concentration Factor % Crop Treated Wheat Bran 0.025 0.3 2 1 0.01 0.01 Wheat Flour 0.025 0.019 0.33 1 0.01 0.01 Wheat Germ 0.025 0.3 1 1 0.01 0.01 Wheat Germ Oil 0.025 0.3 1 1 0.01 0.01 Wheat Rough 0.025 0.136 1 1 0.01 0.01 HED's Response: The percent of crop treated are weighted averages provided by the 20 Biological and Economic Analysis Division ( BEAD) in a Quantitative Usage Analysis issued 3 20 01 and supplemented for miscellaneous usage sites on 04 27 2001.

In addition to this review of the Human Health Risk Assessment for diuron, several discrepancies were noted in the previous review of the RED for diuron. These comments are reiterated below:

Diuron: 2nd Report of the Hazard Identification Assessment Review Committee 1.1 Acute Reference Dose ( RfD)  No errors noted.

1.2 Chronic Reference Dose ( RfD)

Registrant's Comment: Paragraph 1, Line 5, of Executive Summary. The high dose female group, according to the text of the study report, is listed as " 203 mg/ kg/ day" rather than " 202 mg/ kg/ day."

Paragraph 2, Lines 1 2, of Executive Summary. The sentence, " The only reported related clinical sign was reddish discolored or bloody urine in high dose males." This implies all high dose males showed this effect which was not the case. This sentence should read, "  in some high dose males."

Paragraph 3, Line 1, of Executive Summary. The first sentence should be prefaced with, " At 24 months," to be correct. Also in line 5 of the same sentence, the parenthetical phrase that states (< 25% change for most parameters; 3 fold increase for reticulocytes) applies only to the high dose males and females. The mid dose animals do not show this degree of change. The low dose females show a very small increase of 33% in the erythrocyte count and no real change in the other parameters.

For accuracy, the first sentence of the second paragraph should read:

At 24 months, diuron affected hematopoietic system resulting in hemolytic anemia and compensatory hematopoiesis, which were manifested as significantly decreased ( P< 0.05 or 0.01) erythrocyte counts, hemoglobin levels, and hematocrit and increased MCV, MCH, abnormal erythrocyte forms, reticulocyte counts, and leukocyte counts ( with no effects on differential counts) in mid and/ or high dose males and females, and in low dose females. In the high dose groups there was < 25% change for most parameters with a 3 fold increase for reticulocytes. For the low dose females only an increase of 33% was observed in erythrocyte count and no real change in the other parameters.

Paragraph 4, Second Sentence, of the Executive Summary states, " Microscopic evaluation showed that epithelial focal hyperplasia of the urinary tract and renal pelvis increased in severity in both sexes at 12 and/ or 24 months, and increased in incidence ( p< 0.01) in high dose males at 12 months and in mid and high dose females at 12 and/ or 24 months." The mid dose females showed an increased incidence only at 24 months. The sentence should read:

Microscopic evaluation showed that epithelial focal hyperplasia of the urinary tract and renal pelvis increased in severity in both sexes at 12 and/ or 24 months, and increased in incidence ( p< 0.01) in high dose males at 12 months and in high dose females at 12 and/ or 24 months with mid dose females showing an increased incidence at 24 months.

HED's Response: See above HED's response in the toxicology chapter section.

Dose and Endpoint for Establishing RfD Registrant's Comment: This analysis provides a 1.0 mg/ kg/ day LOAEL and no NOAEL. The dose of 1.0 mg/ kg/ day represents a LOEL and not a LOAEL because of the compensatory response to the minor changes seen in the females at the low dose ( only 33% increase in erythrocytes). In fact, a NOAEL could be established as distinct from a NOEL or LOEL. Because the anemia is compensated 21 by an increase in erythrocytes, the end effect is not adverse. We would suggest that the Agency consider the LOAEL as a NOAEL.

HED's Response: The LOAEL was established based on evidence of hemolytic anemia and compensatory hematopoiesis. No change is necessary.

1.3 Occupational/ Residential Exposure 1.3.1 Registrant's Comment: Paragraph 3, Line 3, of the Executive Summary states the absolute body weight of the high dose does were significantly less than the controls on GD 20. Although this is accurate, it is worth noting that the weight rebounded on GD20 24 and GD 24 29.

HED's Response: This observation also support the finding that body weight decrease is treatment related. No change is necessary.

1.3.2 Comments about Study/ Endpoint: A note in passing. There were no effects observed at 6 months for the NOEL of 1.0 mg/ kg/ d. There were also no effects for this dose at the 12 month interval as well.

1.3.3 No errors noted.

1.3.4 No errors noted.

1.3.5 No errors noted.

1.3.6 Long Term Dermal ( Longer than 6 Months) Exposure Registrant's Comment: Dose and Endpoint for Risk Assessment. There were also no effects at the 1.0 mg/ kg/ d females at 12 months exposure. The effects seen at 24 months at this dose in the female group were compensatory and should be classified as a NOAEL rather than a LOAEL.

HED's Response: The LOAEL was based on evidence of hemolytic anemia and compensatory hematopoiesis ( decreased erythrocyte counts, increased reticulocyte counts, increased spleen weight and bone marrow activation). No change is necessary.

1.3.7 No errors noted.

1.3.8 Registrant's Comment: If the LOAEL were corrected to a NOAEL, then an MOE of 100 would be appropriate.

HED's Response: The LOAEL will not be changed to a NOAEL.

2. Classification of Carcinogenic Potential 2.1 Combined Chronic Toxicity/ Carcinogenicity Study in Rats No errors. Although these tumors are dose related, they are due to a secondary mechanism that is not relevant to humans.

2.2 Carcinogenicity Study in Mice Registrant's Comment: Line 1, Paragraph 1, of Discussion of Tumor Data: Treatment was for 104 weeks. Animals were treated and sacrificed after 104 weeks ( excluding early mortality). Some confusion may have resulted since mortality tables were developed at 102 weeks, body weights and clinical parameters were recorded at 103 weeks. 22 Line 3, Paragraph 1, of Discussion of Tumor Data: The reference to ovarian luteomas should be deleted. This effect was determined to be inconsequential by the CPRC report ( May 8, 1997) which states:

The female mouse ovarian tumor rates table should reflect the more appropriate ' combined sex cord stromal tumors' nomenclature in lieu of the ' luteoma' terminology used in the qualitative risk assessment ( Lori L. Brunsman to Linda L. Taylor, 11/ 20/ 96). Dr. Lucas Brennecke, EPA's consulting pathologist, confirmed that the combined tumor counts are more appropriate than the individual counts for ovarian tumors, as it is difficult to distinguish between the different types of ovarian tumors. Since only the luteoma tumor counts have been verified, the counts for the combined sex cord stromal tumors have been taken from Table 2, page 3, of the Diuron data package, which was extracted from the registrant's analysis.   Female mice do not have a significant increasing trend, or any significant differences in the pair wise comparisons of the dosed groups with the controls, for ovarian combined sex cord stromal tumors. ( from page7).

Therefore, Sentence 1 should read:

" Treatment of up to 104 weeks with 2500 ppm diuron resulted in a significant increase in the incidences of mammary adenocarcinomas ( control, 4%; 2500 ppm, 12%, p # 0.05) in female NMRI ( SPF HAN) mice under the conditions of this study."

HED's Response: Additional wording has been added to the document. See above HED's response in the " Requirement 870.4200b: Carcinogenicity ( feeding) mouse".

2.3 Classification of Carcinogenic Potential Registrant's Comment: When the HED CPRC met on December 18, 1996, they classified diuron as a ` known/ likely' carcinogen. Since then, mechanistic studies and additional genotoxicity studies have been submitted. These need to be evaluated in light of the cancer assessment. In addition, the classification ` known/ likely' is no longer used. We would encourage the CARC to re evaluate the cancer classification of diuron. We believe the classification of ` known/ likely' to be incorrect.

HED's Response: The HED Mechanism of Toxicity Assessment Review Committee ( MTARC) has evaluated a proposed mode of action submitted by the Registrant and concluded that the submitted information is insufficient to support a mode of action on bladder carcinogenicity for diuron. Diuron will not be re classified at this time.

3. Mutagenicity Registrant's Comment:

In addition to the five studies previously submitted to the Agency, Griffin LLC has supplied seven additional studies on June 4, 2001:

1) Salmonella typhimurium: Line 3. Typographical error: Highest ` does' should be ` dose'.

2) Chinese Hamster Ovary. No errors 3) Chromosome Aberrations: Paragraph 1. This study is the same as the study given as 4) In vivo Bone Marrow Cytogenetics Assay ( MRID # 44350301). This study ( MRID# 00146611) was revised with additional information on historical background frequencies. This study can be removed completely.

4) In Vivo Bone Marrow Cytogenetics Assay ( MRID # 44350301), Line 6. A sentence should be 23 inserted after the sentence beginning Cytotoxicity to the target organ ... and ending ... decreased at 24 hours. It should read:

There were no statistical significant dose related increases observed in the diuron treated groups at either 6 or 24 hours.

Numerical designation of 4) will become 3) after deletion of the replicate/ revised study.

5) Unscheduled DNA Synthesis. No errors noted.

Conclusions: Line 2 6. Because these ` two' studies are actually the same study, this sentence needs to be corrected. It should read:

Diuron was not clastogenic when evaluated by the in vivo chromosomal assay in Sprague Dawley rats.

The additional studies submitted in June further document the negative genotoxic response of diuron. These studies evaluated in vivo mouse bone marrow micronucleus formation, mouse dominant lethal response and mouse spermatogonial chromosomal aberrations. All were negative. ( MRID # s 45494501, 45494502, 45494503, 45494504, and 45494505)

HED's Response: All studies have been reviewed and put into consideration for evaluation of mutagenicity.

4.3 Developmental Toxicity Registrant's comment: Paragraph 3, General Comment: Weight of both males and females rebounded to nearly normal in all dose groups after removal of diuron treatment. This should be mentioned.

Line 2, Paragraph 6: The number of fetuses examined in the low dose was 306 and not 305. This should read 288( 22), 306( 23), 297( 22) and 279( 20).

HED's Response: See above HED's response in the toxicology chapter.

4.4 Reproductive Toxicity Registrant's Comment: Line 3, Paragraph 1: Test substance intake should read " Overall test substance intake". The dosing reflects the entire dosing period.

Line 9, Paragraph 4: There was not a significant difference in the 7 14 day interval for the females.

HED's Response: See above HED's response in the toxicology chapter.

4.5 Additional Information  No errors noted.

4.6 Determination of Susceptibility  No errors noted.

4.7 Recommendation for a Developmental Neurotoxicity Study  No errors noted.

5. Hazard Characterization Registrant's Comment: Line 3, Paragraph 3: The NOAELS for the maternal/ parental toxicity were less than the NOAELS for fetal or reproductive toxicity. The reference to equal can be deleted.

HED's Response: No error noted. 24 Registrant's Comment: Paragraph 4, General Comment: There needs to be a reassessment of the cancer classification of diuron. It is inconsistent with the care that was taken by the HIARC to evaluate this chemical using current classifications of risk and exposure. The cancer classification of " known/ likely" no longer exists. This assessment was also performed without consideration of the mechanism of action of diuron. The urinary bladder and renal tumor ( not statistically significant) carcinoma is induced by irritation of the urinary system. The mouse mammary tumors observed are consistent with the historical background incidences. The use of the low dose linear extrapolation model under these circumstances is not warranted. A threshold approach with benchmark reference doses is more appropriate given the scientific data.

HED's Response: See above HED's response in the toxicology chapter.

6. Data Gaps  No errors noted.

7. Acute Toxicity  No errors noted.

8. Summary of Toxicological Endpoint Selection Registrant's Comment:

Acute dietary: No errors noted.

Chronic Dietary: The LOAEL = 1.0 should read LOEL. There was an absolute effect. The effect of anemia was compensated for by increased hematopoiesis. This dose should be considered an NOAEL and not an LOAEL. With the establishment of an NOAEL, a UF of 100 could be set.

Cancer: As indicated in discussions above, the classification of " known/ likely" is incorrect. Based on the new guidelines, diuron should be classified as either ` unlikely' or ` suggestive'. The guidelines properly assert that application of a descriptor is a matter of judgement and subject to gray areas and borderline cases. The final classification depends on the weight that is given to the mode of action and its human relevance. A new assessment needs to be made that considers the mechanism of action.

The reference to the kidney carcinoma needs to indicate that the incidence observed was not statistically significant.

The reference to the mammary gland carcinoma in female NMRI mice should be deleted. The incidence is within the historical range.

Dermal, Long term: As indicated in the Chronic Dietary exposure scenario, the LOAEL should be a NOAEL.

Inhalation, Long term: As indicated in the Chronic Dietary exposure scenario, the LOAEL should be a NOAEL.

HED'S Response: These issues will be addressed in the Phase 4 period.


[Federal Register Volume 78, Number 239 (Thursday, December 12, 2013)]
[Proposed Rules]
[Page 75542]
[FR Doc No: 2013-29660]

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DEPARTMENT OF HOMELAND SECURITY

Federal Emergency Management Agency

44 CFR Part 67

[Docket ID FEMA-2013-0002; Internal Agency Docket No. FEMA-B-1147]

Proposed Flood Elevation Determinations for Fayette County,
Pennsylvania (All Jurisdictions)

AGENCY: Federal Emergency Management Agency, DHS.

ACTION: Proposed rule; withdrawal.

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SUMMARY: The Federal Emergency Management Agency (FEMA) is withdrawing
its proposed rule concerning proposed flood elevation determinations
for Fayette County, Pennsylvania (All Jurisdictions).

DATES: This withdrawal is effective on December 12, 2013.

ADDRESSES: You may submit comments, identified by Docket No. FEMA-B-
1147 to Luis Rodriguez, Chief, Engineering Management Branch, Federal
Insurance and Mitigation Administration, Federal Emergency Management
Agency, 500 C Street SW., Washington, DC 20472,<PHONE_NUMBER>, or
(email<EMAIL_ADDRESS>
FOR FURTHER INFORMATION CONTACT: Luis Rodriguez, Chief, Engineering
Management Branch, Federal Insurance and Mitigation Administration,
Federal Emergency Management Agency, 500 C Street SW., Washington, DC
20472,<PHONE_NUMBER>, or (email<EMAIL_ADDRESS>
SUPPLEMENTARY INFORMATION: On October 5, 2010, FEMA published a
proposed rulemaking at 75 FR 61377, proposing flood elevation
determinations along one or more flooding sources in Fayette County,
Pennsylvania. Because FEMA has or will be issuing a Revised Preliminary
Flood Insurance Rate Map, and if necessary a Flood Insurance Study
report, featuring updated flood hazard information, the proposed
rulemaking is being withdrawn. A Notice of Proposed Flood Hazard
Determinations will be published in the Federal Register and in the
affected community's local newspaper.

    Authority:  42 U.S.C. 4104; 44 CFR 67.4.

    Dated: November 20, 2013.
Roy E. Wright,
Deputy Associate Administrator for Mitigation, Department of Homeland
Security, Federal Emergency Management Agency.
[FR Doc. 2013-29660 Filed 12-11-13; 8:45 am]
BILLING CODE 9110-12-P


[Federal Register: January 26, 2007 (Volume 72, Number 17)]
[Notices]
[Page 3829-3830]
[DOCID:fr26ja07-96]

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DEPARTMENT OF ENERGY

Federal Energy Regulatory Commission

Combined Notice of Filings 1

January 18, 2007.
    Take notice that the Commission received the following electric
corporate filings:

    Docket Numbers: EC07-47-000.
    Applicants: Wabash Valley Power Association, Inc; Duke Energy,
Indiana, Inc.
    Description: Wabash Valley Power Assoc., Inc, et al. submits an
Application for authorization of disposition of jurisdictional assets.
    Filed Date: 01/12/2007.
    Accession Number: 20070117-0148.
    Comment Date: 5 p.m. Eastern Time on Friday, February 02, 2007.
    Take notice that the Commission received the following electric
rate filings:

    Docket Numbers: ER02-1330-007.
    Applicants: Pacific Gas and Electric Company.
    Description: Pacific Gas and Electric Company submits a compliance
refund report pursuant to the Commission's 12/8/06 order.
    Filed Date: 01/17/2007.
    Accession Number: 20070117-5079.
    Comment Date: 5 p.m. Eastern Time on Wednesday, February 07, 2007.

    Docket Numbers: ER05-1065-006.
    Applicants: Entergy Services Inc.
    Description: Entergy Services, Inc, agent for the Entergy Operating
Companies submits a compliance filing pursuant to the Commission's 10/
18/06 order.
    Filed Date: 01/16/2007.
    Accession Number: 20070117-0231.
    Comment Date: 5 p.m. Eastern Time on Tuesday, February 06, 2007.

    Docket Numbers: ER06-819-004.
    Applicants: ConEdison Energy Massachusetts, Inc.
    Description: Consolidated Edison Energy Massachusetts Inc submits a
revised Reliability Agreement with ISO New England Inc, pursuant to the
Commission's 8/25/06 order.
    Filed Date: 01/16/2007.
    Accession Number: 20070117-0229.
    Comment Date: 5 p.m. Eastern Time on Tuesday, February 06, 2007.

    Docket Numbers: ER07-150-001,
    Applicants: Public Service Company of New Mexico
    Description: Public Service Company of New Mexico submits a revised
OATT, FERC Electric Tariff Original Volume No. 6, to replace the 11/2/
06 Joint OATT of PNM and Texas-New, Mexico Power Co.

    Filed Date: 01/16/2007.
    Accession Number: 20070117-0225.
    Comment Date: 5 p.m. Eastern Time on Tuesday, February 06, 2007.

    Docket Numbers: ER07-370-001.
    Applicants: TexRep2 LLC.
    Description: TexRep2, LLC submits an amended version of its 12/26/
06 petition for acceptance of initial tariff, FERC Electric, Original
Volume 1, waivers and blanket authority.
    Filed Date: 01/16/2007.
    Accession Number: 20070117-0226.
    Comment Date: 5 p.m. Eastern Time on Tuesday, February 06, 2007.

    Docket Numbers: ER07-434-000.
    Applicants: Pennsylvania Electric Company; Metropolitan Edison
Company; Pennsylvania Power Company; Jersey Central Power & Light
Company; FirstEnergy Solutions Corporation.
    Description: Pennsylvania Power Company et al submits its proposed
amendments to their market-based rate tariffs.
    Filed Date: 01/11/2007.
    Accession Number: 20070117-0228.
    Comment Date: 5 p.m. Eastern Time on Thursday, February 01, 2007.

    Any person desiring to intervene or to protest in any of the above
proceedings must file in accordance with Rules 211 and 214 of the
Commission's Rules of Practice and Procedure (18 CFR 385.211 and
385.214) on or before 5 p.m. Eastern time on the specified comment
date. It is not necessary to separately intervene again in a subdocket
related to a compliance filing if you have previously intervened in the
same docket. Protests will be considered by the Commission in
determining the appropriate action to be taken, but will not serve to
make protestants parties to the proceeding. Anyone filing a motion to
intervene or protest must serve a copy of that document on the
Applicant. In reference to filings initiating a new proceeding,
interventions or protests submitted on or before the comment deadline
need not be served on persons other than the Applicant.
    The Commission encourages electronic submission of protests and
interventions in lieu of paper, using the FERC Online links at http://www.ferc.gov.
 To facilitate electronic service, persons with Internet

access who will eFile a document and/or be listed as a contact for an
intervenor must create and validate an eRegistration account using the
eRegistration link. Select the eFiling link to log on and submit the
intervention or protests.
    Persons unable to file electronically should submit an original and
14 copies of the intervention or protest to the Federal Energy
Regulatory Commission, 888 First St., NE., Washington, DC 20426.
    The filings in the above proceedings are accessible in the
Commission's eLibrary system by clicking on the appropriate link in the
above list. They are also available for review in the Commission's
Public Reference Room in Washington, DC. There is an eSubscription link
on the Web site that enables subscribers to receive e-mail notification
when a document is added to a subscribed dockets(s). For assistance
with any FERC Online service, please e-mail<EMAIL_ADDRESS>
or call<PHONE_NUMBER> (toll free). For TTY, call<PHONE_NUMBER>.

Magalie R. Salas,
Secretary.
[FR Doc. E7-1156 Filed 1-25-07; 8:45 am]

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[Federal Register Volume 76, Number 145 (Thursday, July 28, 2011)]
[Notices]
[Pages 45271-45272]
[FR Doc No: 2011-19140]

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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. FDA-2011-N-0002]

Review and Qualification of Clinical Outcome Assessments; Public
Workshop

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice of public workshop.

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SUMMARY: The Food and Drug Administration (FDA) is announcing a public
workshop to discuss measurement principles for clinical outcome
assessments (COAs) for use in clinical trials for new drugs. COAs
include patient-reported outcome (PRO) measures, clinician-reported
outcome (ClinRO) measures, and observer-reported outcome (ObsRO)
measures. This public workshop is intended to provide information for
and gain perspectives from patient advocates, health care providers,
researchers, regulators, individuals from academia, industry, and other
interested persons on various aspects of the development and
implementation of COAs in the evaluation of treatment benefit.
Regulatory review issues regarding context of use and documentation of
the measurement properties of a COA will be covered during panel
discussions. The input from this public workshop will be published in
the form of a white paper or a series of manuscripts.

DATES:  Date and Time: The public workshop will be held on October 19,
2011, from 8:30 a.m. to 5 p.m. Participants are encouraged to arrive
early to ensure time for parking and routine security check before the
workshop.
    Location: The public workshop will be held at the FDA White Oak
Campus, 10903 New Hampshire Ave., Building 31 Conference Center, the
Great Room (rm. 1503), Silver Spring, MD 20993-0002. Entrance for the
public meeting participants (non-FDA employees) is through Building 1
where routine security check procedures will be performed. For parking
and security information, please refer to http://www.fda.gov/AboutFDA/WorkingatFDA/BuildingsandFacilities/WhiteOakCampusInformation/ucm241740.htm. Attendees are responsible for their own accommodations.
    The public workshop will also be available to be viewed online via
Web cast at https://collaboration.fda.gov/coaworkshop/. Persons
interested in participating by Web cast must register online by October
17, 2011.
    Contact Person: Shauna Shupe, Center for Drug Evaluation and
Research, Food and Drug Administration, 10903 New Hampshire Ave., Bldg.
22, rm. 6417, Silver Spring, MD 20993-0002,<PHONE_NUMBER>, e-mail:
<EMAIL_ADDRESS>    Registration: Registration is free for the public workshop.
Interested parties are encouraged to register early because space is
limited to 150 attendees. Workshop space will be filled in order of
receipt of registration. Those accepted into the workshop will receive
confirmation. Registration will close after the workshop is filled.
Registration at the site is not guaranteed but may be possible on a
space available basis on the day of the public workshop beginning at
7:30 a.m.
    To register electronically, e-mail registration information
(including name, title, firm name, address, telephone, and FAX number)
to<EMAIL_ADDRESS>For those without Internet access, please
call Shauna Shupe (see Contact Person) to register.
    If you need special accommodations due to a disability, please
contact Shauna Shupe at least 7 days in advance.

SUPPLEMENTARY INFORMATION: The Center for Drug Evaluation and Research
(CDER) reviews COAs including PRO measures, (ClinRO) measures, and
ObsRO measures when submitted with an investigational new drug
application, a new drug application, or a biologics licensing
application. The FDA guidance for industry entitled ``Patient-Reported
Outcome Measures: Use in Medical Product Development to Support
Labeling Claims,'' available at http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM193282.pdf,
explains how FDA reviews PRO measures.
    CDER also reviews a COA when submitted for qualification as a drug
development tool (DDT). Qualification of a COA is a regulatory
determination that the COA is well-suited for a specific context of use
in drug development. Following a public announcement of the
qualification decision by FDA, the COA will be publicly available for
use in any appropriate drug development program. Because the
qualification process is separate from the drug marketing application
process, qualification is conducive to public-private partnerships
engaging in this COA development effort. Such collaborative approaches
may increase the efficiency of COA development when more than one
entity is interested in the use of a COA for a specific context of use.
The FDA draft guidance for industry entitled ``Qualification Process
for Drug Development Tools,'' available at http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM230597.pdf, provides the draft process for CDER participation in the
consultation, advice, and qualification review for COAs and other DDTs.
    This workshop will focus on FDA review principles specific to all
type of COAs, i.e., PRO, ClinRO, and ObsRO measures. More specifically,
the workshop will provide researchers involved in the drug development
process with information on the following topics concerning FDA review
of COAs for treatment benefit evaluation:
     COA measurement principles;
     COA nomenclature;

     Determination of COA context of use;
     Practical considerations to develop and implement COAs to
document treatment benefit; and
     Description of interagency collaborations and public-
private partnerships for COA development.
    The Agency encourages patient advocates, health care providers,
researchers, regulators, individuals from academia, industry, and other
interested persons to attend this public workshop.
    Transcripts: Please be advised that as soon as a transcript is
available, it will be accessible at http://www.regulations.gov. It may
be viewed at the Division of Dockets Management (HFA-305), Food and
Drug Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20857.
A transcript will also be available in either hardcopy or on CD-ROM,
after submission of a Freedom of Information request. Written requests
are to be sent to Division of Freedom of Information (ELEM-1029), Food
and Drug Administration, 12420 Parklawn Dr., Element Bldg., Rockville,
MD 20857. Transcripts will also be available on the Internet at http://www.fda.gov/Drugs/NewsEvents/ucm206132.htm approximately 45 days after
the workshop.
    The workshop helps to achieve objectives set forth in section 406
of the Food and Drug Administration Modernization Act of 1997 (21
U.S.C. 393) which includes working closely with stakeholders and
maximizing the availability and clarity of information to stakeholders
and the public. The workshop also is consistent with the Small Business
Regulatory Enforcement Fairness Act of 1996 (Pub. L. 104-121), as
outreach activities by government Agencies to small businesses.

    Dated: July 20, 2011.
David Dorsey,
Acting Deputy Commissioner for Policy, Planning and Budget.
[FR Doc. 2011-19140 Filed 7-27-11; 8:45 am]
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