 Page 1 of 19 UNITED STATES ENVIRONMENTAL PROTECTION AGENCY Washington, DC 20460 OFFICE OF PREVENTION, PESTICIDES AND TOXIC SUBSTANCES M EMORANDUM DATE: 4/ 14/ 06 SUBJECT: Human Studies Review Board: CARBOFURAN Weight of the Evidence Presentation of Human and Animal Toxicity Studies PC Code: 090601 FROM: John J. Liccione, Toxicologist/ Risk Assessor Reregistration Branch 3 Health Effects Division ( 7509C)

THRU: Danette Drew, Branch Senior Scientist Reregistration Branch 3 Health Effects Division ( 7509C)

TO: Tina Levine, Director Health Effects Division ( 7509C)

The purpose of this weight of evidence ( WOE) report is to present the study design, methods, and results of three different human studies to the Human Studies Review Board ( HSRB) to evaluate them individually and collectively for their scientific validity. The human studies that will be presented are a single oral dose study and two single dose dermal studies. Relevant animal data are also summarized and conclusions as to how the Office of Pesticide Programs ( OPP) Health Effects Division ( HED) proposes to use these data in both the single chemical assessment and the N methyl carbamate cumulative assessments are presented.

Introduction Carbofuran ( 2,3 dihydro 2,2 dimethyl 7 benzofuranyl N methylcarbamate) is a broad spectrum Nmethyl carbamate ( see structure below) is an insecticide that can cause cholinergic toxicity through inhibition of the acetylcholinesterase( s) of the peripheral and/ or central nervous system. Similar to other N methyl carbamate pesticides, inhibition is followed by rapid recovery of acetylcholinesterase. Animal toxicity studies ( dog, rat, mouse) using both acute and chronic exposure conditions show that the primary toxicologic effect following carbofuran exposure by the oral route is cholinesterase ( ChE) activity inhibition, the most sensitive endpoint. Due to the rapid recovery of the inhibition, results of chronic studies in the dog, rat, and mouse indicate that the effects of carbofuran do not accumulate over time Page 2 of 19 Several toxicity studies involving direct dosing of humans with carbofuran ( including both the oral and dermal routes of exposure) have been conducted. ChE inhibition and associated clinical signs have been demonstrated in the submitted human volunteer studies.

TOXICITY STUDIES HUMAN 1) Human Single Dose Oral Study:

Arnold, J. D. ( 1976) Evaluation of the Safe Exposure Levels to Carbamate, Administered Orally to Healthy Adult Normal Male Volunteers. ( Unpublished study received Oct 24, 1979 under 279 2712; prepared by Quincy Research Center, submitted by FMC Corp., Philadelphia, Pa.; CDL: 241303 B) Accession no. 241303. MRID 00092826.

Study Description Laboratory: Quincy Research Center, Kansas City, MO Study Dates: Not reported; study report is dated 9/ 17/ 1976 Purpose of Study: " To determine the threshold toxicity level in normal male volunteers to single oral doses of carbamate."

General design: The protocol for this study called for an ascending dose schedule with the following doses: 0.05, 0.1, 0.25, 0.50, 1.0, and 2.0 mg/ kg. Part A was an " open" experiment ( assumed to mean that both investigator and subject were aware that carbofuran was being ingested) that started with two subjects each receiving 0.05 mg/ kg carbofuran with no placebo group. If no toxicity was observed after 24 hours, two more subjects were then given the next dose, and this was repeated until " intolerance was demonstrated". Then Part B of the experiment was performed in which one subject received a placebo and two subjects received the highest ( i. e., intolerable) dose observed in Part A. In Part B, the design was both randomized and double blind. Table 1 shows the study design up to the dose considered intolerable.

Subjects were admitted to the Quincy Research Ctr. by 4 pm the evening before the study began, and were dosed the following morning after a standard breakfast. According to the protocol, the placebo and carbofuran capsules were provided by the Midwest Research Institute [ MRI], but how they were consumed by the subjects is not recorded. The volunteers were confined to their beds from Page 3 of 19 0 hour to 2 hrs post dosing, and were permitted only minor ambulatory activity from 2 hours to 8 hours post dosing. The subjects remained under observation for 24 hours, and were permitted no alcohol or concomitant medications during the course of the study. When the observation period ended, the pre entry physical examinations and laboratory determinations were repeated and the subjects released from the center. Cigarette smoking was permitted during the study ( 2 of the 4 high dose subjects were the only non smokers).

Subjects: Nine healthy men " who fulfilled the selection criteria were selected to participate in the study." No information was provided about how or from what pool they were recruited. The age and body weight ranges were 23 47 and 60 95 kg, respectively.

.

Table 1: Single Oral Dose Study Design Dose ( mg/ kg) Study Phase ( Session) Control 0.05 0.1 0.25 ( 1) 2

( 2)   2   P a r t A ( 3) None     2 Part B 1     2 Measures: RBC and Plasma cholinesterase activity ( 0  hour/ pre dosing, and then 30 min., 1, 2, 3, 6 , and 24 hrs post dosing); EKG, blood pressure, heart rate, temperature, respiration, vestibular function, pupil size, eye accommodation, hematology, urinalysis and blood chemistry were measured at pre dosing and at various intervals up to 24 hours after dosing. During the observation period ( 24 hours) subjects were monitored for signs or symptoms of toxicity. The next highest dosing was not initiated until data from the 24 hour post treatment were evaluated.

The cholinesterase assay used in this study ( Voss and Sachsse, 1970) was a modification of the Ellman colorimetric method. This method uses propionylthiocholine rather than acetylthiocholine as the substrate in the assay. According to the abstract ( see Appendix 1), this method was developed to assess cholinesterase activities in humans when a small volume of blood is collected for analysis.

Analysis: There was no statistical analysis of the data.

Study Results Page 4 of 19 Table 2 summarizes the results of the study. The lowest dose tested ( 0.05 mg/ kg) resulted in minimal RBC ChEI with no symptoms being reported. The second and third doses, however, showed a marked decrease in RBC ChEI and in symptoms ( both subjective and objective) in a dose related manner. The third dose ( 0.25 mg/ kg) was considered an " intolerable" dose in the first two subjects tested and so was tested in another two subjects as Part B of the experiment, along with a single control subject. Appendix 2 provides the individual RBC ChEI values ( in terms of percent change from baseline) for each subject at each time point ( from pre dose to 24 hours). The data show both the decrease in RBC at the 1 3 hour post dosing time period and the eventual return to " normal" values. Plasma ChEI values are not presented in Appendix 2 as they were more variable and the RBC ChEI is considered more important as a marker for carbofuran exposure.

I t should be noted that EPA performed a benchmark ( BMD) analysis of this human data as part of the Nmethyl cumulative assessment and calculated a BMDL10 of 0.026 mg/ kg ( BMD10 of 0.039 mg/ kg).

Table 2: Results of Single Oral Human Study with Carbofuran Dose RBC ChEI 1 Plasma ChEI Symptoms Control 10% 54%

0.05 mg/ kg 11%, 22% 2 32%, 36% No symptoms noted.

0.1 mg/ kg 33%, 31% 2 56%, 35% Headache ( 1 subject); lightheadedness ( the other subject). One subject had EKG anomalies ( 25% decrease in sinus rate, sinus arrhythmia, and sinus bradycardia   all at 4 hr and 24 hr post treatment time points). Same subject showed deterioration in vestibular mechanism ( but baseline was already abnormal and the subject was a smoker).

0.25 mg/ kg 46%, 63%, 62%, 59% 3 33%, 100%, 53%, 81% Symptoms usually attributed to cholinesterase inhibition ( drowsiness, nausea, dizziness, nervousness, vomiting, headache, weakness, dry mouth, salivation, unsteadiness 4 , abdominal pains, and diaphoresis) were seen in 3 of 4 subjects within 3 hrs of dosing. The fourth exhibited nausea within a 30 min. of dosing. Three of the subjects had changes in heart rate, lower body temperature, and lower respiration rates. EKG results showed anomalies in three subjects ( sinus bradycardia, 25% decrease in sinus rate)   one subject did not recover by the end of the monitoring period ( 24 hrs). 1 Percent decrease provided for each individual subject on study. Maximum inhibition presented for all subjects. 2 Seen at 1 hr; almost returned to normal by 3 hr in all subjects. 3 Seen at 1 [ one subject] and 3 [ three subjects] hrs post dosing; almost returned to normal by six hrs. 4 Vestibular mechanisms for 2/ 4 were abnormal and deteriorating one hr. post dosing. One of these subjects could not stand up after one hour postdosing

Strengths/ Uncertainties/ Limitations The following strengths of the single dose oral study in male human volunteers have been identified:

  Effects were observed in the treated subjects ( in terms of both subjective and objective measures).   Multiple doses were used. Page 5 of 19   All subjects were monitored ( they were kept at the center from the night before dosing up to 24 hours after dosing).   The ChEI effects observed ( and associated symptoms) occurred at or about the expected peak time ( 1 3 hours post dosing) and returned to almost normal within six hours of dosing.

The following uncertainties/ limitations have also been identified:

  There was no discussion of the rationale for dose selection.   The number of subjects is low ( 2 subjects) for the low ( 0.05 mg/ kg) and mid dose ( 0.1 mg/ kg) groups, and a placebo ( with only one subject) was only used in Part B of the experiment.   All tested subjects were males.   There was no statistical analysis.   Part A was " open"   assumed to mean that both the investigator and subject were aware that the subject( s) were receiving the treatment capsule.   There was potential confounding due to smoking ( all except two subjects   both in the 0.25 mg/ kg group   smoked). See Appendix 2 for number of cigarettes consumed by each subject during the study.   Duplicate blood samples were taken to analyze for carbofuran and/ or its metabolites but the data have not been submitted.   The RBC/ plasma ChEI method used was a different method than what is normally used. The study report is dated 1976 and it is assumed that the study was performed around that time. The method paper was published in 1970 ( Voss, G. and Sachsse, 1970). The Ellman method was published in 1961.   No justification or rationale of dose selection Conclusions The study authors considered the dose level of 0.1 mg/ kg as a " NOEL" whereas the OPP has considered the dose level of 0.1 mg/ kg as a " LOEL" in the past 1 .

There is some confidence in the high dose ( 0.25 mg/ kg) as a definitive effect level. Although there may be potential confounding due to smoking, this dose level had 4 subjects that demonstrated clear symptoms of cholinesterase toxicity, and moreover, the symptoms could be correlated in their severity and incidence with the extent and duration of RBC ChEI. Effects consisted of drowsiness, nausea, dizziness, nervousness, vomiting, headaches, weakness, dry mouth, salivation, unsteadiness, abdominal pains, and diaphoresis. Changes in heart rate, lower body temperatures, and lower respiration rate were also noted in these subjects. There were also effects on EKG, vestibular mechanisms, pupillary constriction and eye accommodation.

At the 0.1 mg/ kg dose level, one subject had a headache, and the other was occasionally lightheaded. The study authors did not consider the headache and lightheadedness to be compound related. One subject exhibited a decrease in sinus rate. This subject also exhibited deterioration in the vestibular mechanism; although the baseline value for this parameter was abnormal to begin with. In addition, the one concurrent control in the second round of testing at 0.25 mg/ kg displayed decreased sinus rate and erratic vestibular function ( at baseline it was borderline between normal and abnormal, and at various time intervals was reported as abnormal and deteriorating). Therefore, the sinus rate and vestibular function effects are difficult to assess.

Using the BMD calculation, the BMDL10 of 0.026 mg/ kg is a reasonable Point of Departure ( PoD) for possible use in risk assessment.

1 In 1997, OPP requested an external peer review of this carbofuran study. Three academic scientists reviewed the study and determined it was an appropriate study to use to develop an RfD and also commented on the use of uncertainty factors in deriving an RfD ( Burnam, 1970). Page 6 of 19 2) Human Dermal Study:

A rnold, J. D. ( 1977) Carbamate ( Carbofuran) Human Dermal Study. Final rept. ( Unpublished study received Oct 24, 1979 under 279 2712; prepared by Quincy Research Center, submitted by FMC Corp., Philadelphia, Pa.; CDL: 241303 C), Accession no. 241303. MRID 00092827.

Study Description Laboratory: Quincy Research Center, Kansas City, MO Study Dates: Not reported; study report is dated 1977.

Purpose of Study: " To determine the threshold toxicity level to simple and multiple doses of Carbofuran under normal and elevated temperatures and/ or humidities"

General design: Like the single oral dose study described above, this dermal study was designed as an ascending dose study. The protocol proposed to begin with a dose of 0.5 mg/ kg, with dosing increasing in multiples of two up to 16 mg/ kg ( note that the study went up to 32 mg/ kg) until the " minimum effect level" is reached. The minimum effect level is defined as "  the level which produces mild but definitive clinical symptoms, as observed in the oral studies." After a standard breakfast, volunteers were dermally dosed with a 50% test article dilution ( undiluted test substance: Furadan 75 WP; 75% carbofuran) on a designated portion of their upper backs 2 , mildly exercised for 5 minutes, then allowed to rest for 15 minutes. This cycle was repeated 11 times over 4 hours. After four hours, the carbofuran was removed/ washed from the back. With each cycle, the dose was doubled until a " minimum effect level" was attained. After the 4 hour dosing interval, the dosages were removed and subjects monitored for the remainder of the 24 hour post treatment period. Cigarette smoking was permitted during the study Subjects: Eighteen healthy males ( 19 53 years of age) were chosen with a weight range of 63 102 kg.

Numbers/ Doses: This study was performed in three parts  A, B, and C. Eight subjects were assigned to part A, eight subjects were assigned to part B, and two subjects were assigned to part C ( see Table 3 below). Escalating doses were used in parts A ( 0, 0.5, 1.0, and 2.0 mg ai/ kg) and B ( 2.0, 4.0, 8.0, and 32.0 mg ai/ kg) over the course of one day ( 2 subjects per dose level; single dermal dose) using high temperature/ high humidity ( 85 95 degrees F and 68 89% relative humidity) in Part A and normal temperature/ normal humidity ( 70 75 degrees F and 35 40% relative humidity) in Part B. Part C consisted of treating two test subjects once daily at 1.0 mg ai/ kg/ day on three consecutive days ( multiple dermal doses) under the same high temperature/ high humidity conditions identified above for Part A.

Table 3: Acute Dermal Study Design ( Arnold, 1977)

Dose ( mg/ kg) Study Phase ( Session) Control 0.5 1.0 2.0 4.0 8.0 32.0 2 The submitted report is unreadable regarding specifics on this procedure ( see page 113 in the electronic copy of Accsn241303, also labeled as page 129 on the bottom right hand corner of the page). Page 7 of 19 A 1 2 2 2 2

B 2     2 2 2 2 C 1    2

1 High temperature/ high humidity conditions.

2 Normal temperature/ normal humidity conditions.

Measures: RBC and Plasma cholinesterase activity ( 0  hour/ pre dosing, 1, 2, 3, 6 , and 24 hours); EKG, blood pressure, heart rate, temperature, respiration, vestibular function, pupil size, eye accommodation, hematology and urinalysis were measured at pre dosing and at various intervals up to 24 hours after dosing. During the observation period ( 24 hours) subjects were monitored for clinical signs. As noted above for the oral study, the Voss and Sachsse method for ChEI determination was used.

Analysis: There was no statistical analysis of the data.

Study Results Tables 4 6 show the results from Parts A, B, and C; respectively. RBC Cholinesterase inhibition was compared to the self pre dose measurement. The subjects given the high dose of 2 mg/ kg in Part A were the only ones from any of the three experiments that showed both appreciable decreases in RBC ChEI and symptoms generally associated with a cholinergic response. Because this exposure scenario was under high heat/ high humidity conditions, it is likely that this contributed to the enhanced absorption and associated toxicity. This can be inferred given that the results of the same experiment performed under normal heat/ humidity conditions ( Part B) using much higher doses ( up to 32 mg/ kg) showed no effects. The three day dosing experiment summarized in Table 3 was inconclusive since there were no effects and no controls. In all three experiments, male volunteers were required to perform mild exercise activities which could be seen as enhancing the possible dermal absorption and possible toxicity of carbofuran. Page 8 of 19 Table 4: Results of Dermal Human Study ( Arnold, 1977) with Carbofuran: Part A 1 Dose RBC ChEI 2 Plasma ChEI 2 Symptoms Control 10%, 10% 0, 25%

0.5 mg/ kg 20%, 23% ( both @ 3 hrs.) 10%, 10% (@ 6 and 3 hrs)

1.0 mg/ kg 39%, 9% (@ 3 and 1 hrs) 5%, 11% ( both @ 3 hrs) No symptoms noted.

2.0 mg/ kg 46%, 65% ( both @ 4 hrs) 12%, 16% ( both @ 24 hrs) One subject ( 46% peak RBC ChEI) reported feeling weak and shaky 3 hrs, 30 min. postdosing and was administered atropine at 5 hrs post dose. The other subject had more severe symptoms ( lightheadedness, hazy vision, hunger, vomiting, defecation with muscular cramps, chills) from 2 hrs, 30 min. to 4 hrs post dosing. Atropine was administered at three different times ( 4 hrs 20 min, 5 hrs, 5 min; and 5 hrs, 15 min. post dosing. The carbofuran solution was washed off his back prior to atropine administration. Both subjects had changes in pulse and vestibular function. EKGs were normal and pupil size/ accommodation measurements could not be made. Both subjects were asymptomatic at 24 hrs postdosing 1 Single dose of carbofuran applied to backs of volunteers. Subjects were placed in an enclosed environment with high temperature/ high humidity conditions one hour before dosing and then for four hours post dosing. During the four hour exposure period, they exercised for 5 minutes, rested for 15 minutes and then continued this cycle 11 times. 2 Percent decrease provided for each individual. Maximum inhibition presented for all individuals and the time point associated with that maximum. Page 9 of 19 Table 5: Results of Dermal Human Study ( Arnold, 1977) with Carbofuran: Part B 1 Dose RBC ChEI 2 Plasma ChEI 2 Symptoms 2.0 mg/ kg 10%, 20% ( both @ 6 hrs.) 6%, 5% (@ 6 and 3 hrs)

4.0 mg/ kg 13%, 11% (@ 6 and 2 hrs.) 26%, 33% ( both @ 2 hrs)

8.0 mg/ kg 7%, 17% (@ 3 and 6 hrs) + 7%, 4% (@ 3 and 1/ 6 hrs)

32.0 mg/ kg 24%, 16% (@ 8 and 4 hrs) 0, 2% ( both @ 10 hrs) No symptoms noted.

1 Single dose of carbofuran applied to backs of volunteers. Subjects were placed in an enclosed environment with normal temperature/ normal humidity conditions one hour before dosing and then for four hours post dosing. They then exercised for 5 minutes, rested for 15 minutes and then continued this cycle 11 times ( four hours). 2 Percent decrease provided for each individual. Maximum inhibition presented for all individuals and the time point associated with that maximum.

Table 6: Results of Dermal Human Study ( Arnold, 1977) with Carbofuran: Part C 1 Dose RBC ChEI 2 Plasma ChEI 2 Symptoms 1.0 mg/ kg 26%, 29% ( both @ 24 hrs. on day 2) 43%, 49% ( both @ 4 hrs on day 1) No symptoms noted.

1 Single dose of carbofuran applied to backs of volunteers for three successive days. Subjects were placed in an enclosed environment with high temperature/ high humidity conditions one hour before dosing and then for four hours post dosing. They then exercise for 5 minutes, rest for 15 minutes and then continued this cycle 11 times ( four hours). 2 Percent decrease provided for each individual. Maximum inhibition presented for all individuals and the time point associated with that maximum.

Strengths/ Uncertainties/ Limitations:

The following strengths of the Arnold, 1977 dermal study in male human volunteers have been identified:

  Effects were observed in the treated subjects in Part A of the study ( in terms of both subjective and objective measures). Page 10 of 19   Multiple doses were used.   All subjects were monitored ( they were kept at the center from the night before dosing up to 24 hours after dosing).   The ChEI effects observed occurred at or about the expected peak time for dermal exposure ( 3 4 hours post dosing; a lag associated with dermal exposure vs. oral) and returned to almost normal within six hours of dosing.

The following uncertainties/ limitations have also been identified:

  The number of subjects is low ( 2 subjects) and placebos were only used in one of the three experiments ( Part A).   All tested subjects were males.   There was no statistical analysis.   All three experiments appear to have been " open"   assumed to mean that both the investigator and subject were aware that the subject( s) were receiving either the placebo or the treatment capsule.   There was potential confounding due to smoking because it was permitted, but unlike the oral study described above, no details were provided on which subject smoked or how much they may have smoked.   The RBC/ plasma ChEI method used was a different method than what is normally used ( as mentioned above as an uncertainty in the oral study).   Duplicate blood samples were taken to analyze for carbofuran and/ or its metabolites but the data have not been submitted.   Individual data missing from the study report included clinical signs, pupil size and eye accommodation, pulse rate, blood pressure, EKG, respiration rate, body temperature, vestibular function, and clinical pathology.   No rationale or justification for doses selected Conclusions Although effects were observed in Part A of this study, it is important to note that the subjects were under atypical conditions ( high temperature and high humidity) and were asked to perform mild exercise ( stationary bike) for five minutes eleven times over a four hour period while the carbofuran was on their backs. The effects observed at the highest dose tested ( 2 mg/ kg) resulted in both marked RBC ChEI and cholinergic symptoms that required intervention with the antidote atropine in both of the subjects tested at this dose. Similar symptoms were not observed under normal temperature/ humidity conditions   at much higher doses ( up to 32 mg/ kg) but following the same exercise regimen. However, it is believed that the study has value in that it attempts to understand dermal absorption and possible toxicity to carbofuran under high heat/ humidity   conditions that may exist in certain occupational settings ( e. g., outdoor agricultural working conditions). Thus, OPP/ HED believes these data may be useful in a hazard assessment as a PoD ( with a LOAEL of 0.5 mg/ kg given the RBC ChEI observed in Part A   see Table 4). Page 11 of 19 2b) Arnold, J. D. ( 1978) Comparison of Cholinesterase Inhibition and Effects of Furadan 4F and FMC 35001 4 EC ( ACT 152.03). Rev. final rept. ( Unpublished study received Oct 24, 1979 under 279 2712; prepared by Quincy Research Center, submitted by FMC Corp., Philadelphia, Pa.; CDL: 241305 A) Accession no. 241305, MRID no. 00092829.

Laboratory: Quincy Research Center, Kansas City, MO Study Dates: Not reported; study report is dated 1978.

Purpose of Study: " The objective of this study was to compare the effects of single cutaneous applications of Furadan 4F ( 4F) and FMC 35001 4EC ( EC) in men exposed to high temperature and humidity. Specific goals were: [ to determine] .( 1) effects of treatment on plasma and erthyrocyte cholinesterase activity, ( 2)  . the minimal dose level   which induces symptoms of cholinesterase inhibition, ( 3) . the effects of the two treatments on neurovegetative signs ".

( NOTE: Furadan 4F is carbofuran and FMC 35001 4EC is carbosulfan, a carbofuran analog   see structure below).

General design: In an open, parallel study design, volunteers were dermally dosed with a 50% test article dilution [ undiluted test substance: carbofuran or carbosulfan] on a designated portion of their upper backs ( 0.5 mg per square centimeter) approximately 1 ½ hours after a standard breakfast. Subjects received Furadan 4F or FMC 35001 4EC in groups of two; no subject received more than one treatment of either chemical. From 0 4 hours post treatment, subjects mildly exercised for 5 minutes, then were allowed to rest for 15 minutes. The exercise/ rest cycle was repeated 11 times over 4 hours. Subjects were kept in environmentally controlled rooms of high temperature and high humidity ( 91 96 degrees F and relative humidity 70 80%). After the 4 hour dosing interval, the dosages were removed ( soap and water) and subjects monitored for the remainder of the 24 hour post treatment period. Cigarette smoking was not allowed 1/ 2 hour before treatment and until 2 ¼ hours after dose administration.

Subjects: Twenty males ( eight received carbofuran and 12 received carbosulfan) were used with an age range of 18 53 years old; and had a weight range of 1??   188 pounds [ lower value unreadable in submitted data].

Numbers/ Doses: Groups of 2 subjects were dosed with carbofuran at 0.5, 1.0, 2.0, or 4.0 mg/ kg. Groups of 2 subjects were dosed with carbosulfan at 0.5, 1.0, 2.0, 4.0, 8.0, or 16.0 mg/ kg. Page 12 of 19 Table 7: Acute Dermal Study Design: Arnold, 1978 1 Dose ( mg/ kg) Study Phase ( Session) Control 0.5 1.0 2.0 4.0 8.0 16.0 Carbofuran  2 2 2 2

Carbosulfan  2 2 2 2 2 2 1 All subjects were placed in a room under high temperature/ high humidity conditions for the four hour exposure period.

Measures: RBC and Plasma cholinesterase activity ( 0  hour/ pre dosing, ½ , 1, 2, 4, 6 , and 24 hours); EKG, blood pressure, heart rate, temperature, respiration, pupil size, eye accommodation, hematology and urinalysis were measured at pre dosing and at various intervals up to 24 hours after dosing. During the observation period ( 24 hours) subjects were monitored for clinical signs. As noted above for the oral study, the Voss and Sachsse method for ChEI determination was used.

Analysis: There was no statistical analysis of the data.

Study Results For the purposes of this WOE, only the carbofuran data are presented in Table 8. RBC ChE inhibition values were based on self pretest levels. The data show clear cholinergic effects ( decrease in RBC ChEI and associated symptoms) at the high dose of 4 mg/ kg. As with the dermal study described above, both treated subjects at this dose received an antidote due to the severity of the response. Although the 4 mg/ kg reported here represents a two fold difference in carbofuran amount as compared to the 2 mg/ kg reported for the other dermal study ( Arnold, 1977), the differences are likely due to the fact that Arnold ( 1978) uses a formulation ( includes a higher concentration of inert ingredients) with 4% carbofuran and the previously reported dermal study uses a product that contains 75% carbofuran. Page 13 of 19 Table 8: Results of Carbofuran Data From Comparative Dermal Study 1 Dose RBC ChEI 2 Plasma ChEI 2 Symptoms 0.5 mg/ kg 22%, 7% 33%, 46% (@ 1 and 4 hrs) One subject reported nausea [ at 40 min and 2 hrs 10 min. post dosing]. The first episode lasted 10 min and the second about 40 min. The other subject reported a burning sensation at application site that lasted about 5 min [ at 1 hr, 50 min. post dosing].

1.0 mg/ kg 29%, 21% 4%, 15% (@ 6 and 1 hrs)

2.0 mg/ kg 42%, 40% 44%, 6% (@ 2 and 24 hrs) No symptoms reported 4.0 mg/ kg 61%, 49% 6%, 9% (@ 30 min and 1 hr) Both subjects reported nausea, dizziness and weakness. One also reported " swollen tongue", increased salivation, and stomach cramps; and the other experienced vomiting and tremors. Most symptoms began about 3 hrs. post dosing and disappeared within 2 hrs of onset. In both cases atropine was administered as an antidote [ in the first case, at 4 hours and in the second at 3 hrs]. In addition, the second subject's back was washed to remove the treatment at 3 hrs [ 1 hour early] and the subject was removed from the high temp/ high humid room. 1 Single dose of carbofuran applied to backs of volunteers. Volunteers are placed in an enclosed environment under high temperature/ high humidity conditions. They then exercise for 5 minutes, rest for 15 minutes and then continue this cycle 11 times ( four hours). 2 Percent decrease provided for each individual. Maximum inhibition presented for all individuals. For RBC values, the maximum inhibition was seen at the 4 hr time point in all cases.

Strengths/ Uncertainties/ Limitations:

The following strengths of the Arnold, 1978 dermal study in male human volunteers have been identified:

  Effects were observed in the treated subjects ( in terms of both subjective and objective measures).   Multiple doses were used.   All subjects were monitored ( they were kept at the center from the night before dosing up to 24 hours after dosing).   The ChEI effects observed occurred at or about the expected peak time ( 4 hours post dosing; a lag associated with dermal exposure vs. oral and in agreement with the values measured in Arnold, 1977) and returned to almost normal within six hours of dosing.

The following uncertainties/ limitations have also been identified:

  Only two volunteers were treated at each dose level. Page 14 of 19   The study design was open ( so both investigators and subjects knew that all volunteers were receiving carbofuran).

  There were no control subjects.

  There were no statistical analyses.

  Only males were tested.

  All subjects were placed in a high temperature/ high humidity environment and were required to exercise   The carbofuran product used was a formulation ( i. e., 4% carbofuran) and so contains other ingredients at high concentrations that confound the results of this study ( especially when compared with the Arnold ( 1977) study described earlier which used a 75% technical produce).

Conclusions The comparative dermal toxicity study showed apparent cholinergic effects at 4 mg/ kg, but not at 2 mg/ kg. However, comparison of RBC ChE inhibition data from the two dermal studies show similar degrees of inhibition at the same doses ( 0.5, 1.0, and 2.0 mg/ kg). The dermal study described earlier showed effects at 2 mg/ kg ( the highest dose tested in that study). The study designs were essentially similar between the two studies, with the major difference between the two being the use of a technical product ( 75% carbofuran in the first study) and the use of a formulation ( 4% carbofuran) in this study may explain the different results since the carbofuran formulation that contains numerous inert or other ingredients that could inhibit dermal absorption.

Together, the two dermal studies suggest a dermal LOAEL of 0.5 mg/ kg based on RBC ChEI at the expected peak time ( 3 4 hours) with the appropriate recovery over the next six hours. Thus, this dose may be used as a PoD for an appropriate occupational dermal exposure scenario.

ANIMAL Consistent with the other N methyl carbamates, the effects from carbofuran exposure do not accumulate over time. This lack of accumulation is due to the rapid recovery of the acetylcholinesterase. Therefore, the most appropriate exposure route is via gavage while dietary studies are less appropriate.

There are several studies available where acute ChE inhibition was measured at or near peak time of inhibition ( 15 45 min) and which inform the derivation of the acute RfD in the rat. These include two studies performed by the registrant: 1) time course study ( MRID no. 45675701) where male and female rats were dosed at 0.5 and 1.0 mg/ kg and 2) recently submitted comparative ChE study where adult and juvenile ( post natal day 11, PND) rats were dosed at 0.3, 0.6, and 1.0 mg/ kg ( MRID no. 46688914). Clinical signs were also reported for adults and PND11 pups in the comparative ChE study. In support of the Agency's cumulative risk assessment for the N methyl carbamates, scientists from the National Health and Environmental Effects Research Laboratory ( NHEERL) performed dose response studies in male rat where brain and RBC ChE inhibition along with motor activity were measured. For carbofuran, the Agency's study included doses ranging from 0.1 mg/ kg up to 1.5 mg/ kg ( USEPA, 2005).

Table 9. Benchmark estimates for carbofuran from the comparative ChE study and the Preliminary Cumulative Risk Assessment for the N methyl carbamate pesticides.

Brain RBC Source Male Female Male Female Page 15 of 19 BMD10 0.11 0.12 Adult ( CCA) BMDL10 0.05 0.06 Data provides no dose response relationship BMD10 0.15 0.03 Preliminary Cumulative RA BMDL10 0.13 N/ A 0.01 N/ A BMD10 NA NA 0.038 NA Human Oral BMDL10 NA NA 0.025 NA PROPOSED USE IN SINGLE CHEMICAL ASSESSMENT OPP HED proposes that the single oral dose human study ( BMDL10 of 0.026) be used directly as a point of departure. Based on RBC ChE inhibition at the lowest dose tested ( 0.5 mg/ kg) in both dermal studies, and using a LOAEL to NOAEL extrapolation factor of 3X, the point of departure is 0.17 mg/ kg for worker exposure.

PROPOSED USE IN N METHYL CARBAMATE CUMULATIVE ASSESSMENT 1. Background:

The Food Quality Protection Act ( FQPA) was passed by Congress in 1996. The FQPA made key changes to the approaches used by EPA to assess pesticide chemicals. One of these changes was the requirement to consider cumulative risk to those pesticides which act by a common mechanism of toxicity. Pesticides are determined to have a " common mechanism of toxicity" if they act the same way in the body that is, the same toxic effect occurs in the same organ or tissue by essentially the same sequence of major biochemical events. OPP established the N methyl carbamate pesticides ( NMCs) as a common mechanism group and in accordance with FQPA has developed a preliminary cumulative risk assessment for this group of pesticides ( USEPA, 2005). Carbofuran is a member of the NMC common mechanism group.

OPP has developed a guidance document for developing cumulative risk assessments under FQPA ( USEPA, 2002). This guidance indicates that when developing a multi chemical hazard assessment, comparison of toxic potency should be made using a uniform basis of comparison, by using to the extent possible a common response derived from a comparable measurement methodology, species, and sex for all the exposure routes of interest. In the preliminary cumulative risk assessment, the Agency considered RBC and brain ChE inhibition as potential endpoints. Plasma cholinesterase data were not considered since the primary enzyme in plasma is butylcholinesterase and not acetylcholinesterase. Ultimately, brain ChE data from acute rat toxicity studies measured at or near the time of peak effect have been used by EPA to estimate a relative potency factor ( RPF) and to develop the points of departure ( PoD) for extrapolating cumulative risk. For instance, the brain BMD10 has been used to calculate the RPF while the brain BMDL10 establishes the PoD in the preliminary cumulative risk assessment. Brain data have been selected over RBC data as brain ChE inhibition represents a direct measure of the target tissue ( as opposed to blood data which is considered a surrogate measure) and brain ChE inhibition data tend to have less variation and thus confer less uncertainty on cumulative risk estimates. Page 16 of 19 Because data from rat studies provide the basis for potency determination, the Agency must consider interspecies extrapolation ( i. e., animal to human) in its cumulative risk assessment. As such, human data may be used by the Agency to inform the pesticide specific interspecies extrapolation. In the specific case of carbofuran, MRID 00092826 is available.

2. Carbofuran Human Study Summary:

The single oral human toxicity study for carbofuran does not provide brain ChE data, for obvious reasons, but does provide RBC ChE data for male volunteers. The blood ChE activity ( RBC) provided in the human study is considered appropriate surrogate measures of potential effects on peripheral nervous system ( PNS) acetylcholinesterase ( AChE) activity, and of potential effects on the central nervous system ( CNS) when brain ChE data are lacking ( USEPA 2000). AChE is the target enzyme for the cumulative risk assessment and is the primary form of ChE found in RBCs. Butylcholinesterase ( BChE), on the other hand, is the primary for of ChE found in plasma. BChE is considered a measure of exposure but has not been shown to be of toxicological significance. As with the RBC ChE data from the aldicarb, methomyl, and oxamyl human studies that were presented to the HSRB in April 2006, the RBC ChE data from the single oral carbofuran human study also is being utilized by the Agency to inform the pesticide specific interspecies extrapolation.

The measured RBC ChE activity from the oral human study is adequate for estimation of BMD and BMDL estimates. The RBC ChE data from the carbofuran human study was utilized in the model in the same manner as the RBC data from the oral human studies for aldicarb, methomyl, and oxamyl. The BMD10 and BMDL10 estimates for both rat ( RBC, brain) and human ( RBC) are included in Table 9 . It should be noted that the BMD estimates for the rat include both sexes while the BMD estimates from the human study only include male subjects.

Based on the FIFRA SAP ( 2005) approval of statistical analyses for the BMD model, the single RBC BMD estimate for carbofuran indicates similar ChE activity in males and females ( 0.031 mg/ kg, M and F). Comparison of the rat BMD estimates from the two compartments indicates the RBC compartment is slightly more sensitive than the brain. The RBC ChE data from the human study, therefore, would also be expected to be protective of brain ChE inhibition. As such, the BMD estimate from the carbofuran human study provides useful information into the sensitivity of RBC ChE inhibition of rats compared to humans.

3. Discussion Several studies for carbofuran are available that provide quality dose response and ChE inhibition data from both the rat and human. As presented for aldicarb, methomyl, and oxamyl at the April 2006 HSRB, the cumulative risk assessment for carbofuran also must extrapolate information across compartments ( blood brain). The preliminary NMC cumulative risk assessment relies on rat brain ChE data for the relative potency factors ( RPFs) and points of departure ( PoDs). The FIFRA SAP supported the Agency's use of brain ChE data in August 2005 ( FIFRA SAP 2005).

Similar to the approach proposed by the Agency at the April, 2006 for aldicarb, methomyl, and oxamyl for informing the interspecies extrapolation factor in the cumulative risk assessment, the carbofuran human study may also inform the interspecies extrapolation factor for the preliminary cumulative risk assessment. The ratio of the rat BMD10 to the human BMD10 was proposed at the April 2006 HSRB. The Agency is proposing to use the same approach for carbofuran. The Agency is in the process of analyzing both the rat and human BMD10 data to determine the central estimate and 95% confidence interval for use as the interspecies extrapolation factor. A rough estimate of the interspecies extrapolation factor for carbofuran may be made by comparing the RBC BMD10 values for the rat and human from Table X above. This ratio is approximately 1X. The interspecies extrapolation factor resulting from the formal BMD ratio analysis would be in addition to the other uncertainty factors for the cumulative risk assessment that includes intraspecies variability ( human variability) and FQPA. Page 17 of 19 References Voss, G and K Sachsse. 1970. Red cell and plasma cholinesterase activities in microsamples of human and animal blood determined simultaneously by a modified acetylthiocholine/ DTNB procedure Toxicology and Applied Pharmacology, 16: 764 777.

Burnam, W. 1997. " Discussion of Outside Peer Review Comments on the Carbofuran RfD". Memorandum to Tina Levine entitled "

FIFRA SAP ( 2005). Meeting Minutes of the FIFRA Scientific Advisory Panel Held August 23 26, 2005. SAP Minutes No. 2005 04. Preliminary N Methyl Carbamate Cumulative Risk Assessment. October 13, 2005.

USEPA ( 2000). " The Use of Data on Cholinesterase Inhibition for Risk Assessments of Organophosphorous and Carbamate Pesticides"; August 18, 2000. Available: http:// www. epa. gov/ pesticides/ trac/ science/ cholin. pdf USEPA ( 2002). " Guidance on Cumulative Risk Assessment of Pesticide Chemicals That Have a Common Mechanism of Toxicity." January 14, 2002. ( 67 FR 2210; January 16, 2002) http:// www. epa. gov/ oppfead1/ trac/ science/# common USEPA ( 2005). Preliminary N Methyl Carbamate Cumulative Risk Assessment. Office of Pesticide Programs, U. S. Environmental Protection Agency. Washington, DC. http:// www. epa. gov/ scipoly/ sap/ index. htm# sept Page 18 of 19 APPENDIX 1 Red cell and plasma cholinesterase activities in microsamples of human and animal blood determined simultaneously by a modified acetylthiocholine/ DTNB procedure Guenther Voss and Klaus Sachsse Agrochemical Division of CIBA Ltd, Basle, Switzerland Received 3 March 1969. Available online 27 September 2004.

Abstract A modification of the acetylthiocholine/ DTNB method has been developed for the simultaneous determination of red cell and plasma cholinesterases in samples of only 0.01  0.03 ml of whole human and animal blood, using a relatively short incubation period of 10 min and an incubation temperature of 30 ° C. In contrast to many other micromethods, these test conditions allow activity determinations of cholinesterases inhibited by insecticidal carbamates in vivo, because decarbamylation of the enzymes after dilution is comparatively low after 10 min at 30 ° C. Human blood cholinesterases are assayed with propionylthiocholine, whereas for blood samples of various laboratory animals acetylthiocholine was found to be the better substrate. The experimental procedure of this micromethod is based on two cholinesterase measurements, of which the first determines total activity in whole blood, and the second, plasma cholinesterase activity alone. Erythrocyte cholinesterase activity is determined by subtraction. Normal activity values of the enzymes in red cells, plasma, and brain are given for a variety of species, and a few in vivo inhibition data after organophosphate and carbamate poisoning are also presented. Page 19 of 19 APPENDIX 2 Appendix 2: RBC ChEI Data ( Percent Change from Baseline) in Human Single Oral Dose Study 1 1 2 3 4 5 6 7 8 9 Time of Blood Sample 0.05 mg/ kg 0.1 mg/ kg 0.25 mg/ kg Placebo Pre          30 min  8 + 5  29  15  21  5 + 12 ?? 2 + 6 1 hr  22  11  33  31  58  63  46  59  10 2 hr      46  49 ??? 2  52 + 3 3 hr + 5 + 3  4  2  62  57  12  26  1 6 hr + 8 + 7 0 + 12  8 0 + 6 + 5 + 28 24 hr + 12 + 5 + 1 + 5 + 24 + 27 + 51 + 44 + 40 1 Subject number. Subjects 1 and 2 received 0.05 mg/ kg, subjects 3 and 4 received 0.1 mg/ kg, subjects 5 through 8 received 0.25 mg/ kg and subject 9 was the lone placebo in the study. 2 Value unreadable on data table in submitted report.

Appendix 2: Number of Cigarettes Consumed During the Human Single Oral Dose Study 1 1 2 3 4 5 6 7 8 9 Time Post Dosing 0.05 mg/ kg 0.1 mg/ kg 0.25 mg/ kg Placebo 0 1 hr 0 0 0 0 0 0 0 0 0 1 2 hr 3 2 2 0 0 0 0 1 1 2 3 hr 2 2 0 2 0 0 1 1 1 3 4 hr 1 0 1 2 0 0 0 0 1 4 5 hr 1 2 1 1 0 0 0 1 2.5 5 6 hr 1 2 0 0 0 0 0 0 2 6 7 hr 0 2 2 0 0 0 1 1 1 7 8 hr 1 1 1 2 0 0 1 2 3 TOTAL 9 11 7 7 0 0 3 6 11.5 1 Subject number. Subjects 1 and 2 received 0.05 mg/ kg, subjects 3 and 4 received 0.1 mg/ kg, subjects 5 through 8 received 0.25 mg/ kg and subject 9 was the lone placebo in the study.


[Federal Register Volume 80, Number 11 (Friday, January 16, 2015)]
[Notices]
[Pages 2432-2433]
[FR Doc No: 2015-00596]

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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. FDA-2014-D-2300]

Evaluating Drug Effects on the Ability To Operate a Motor
Vehicle; Draft Guidance for Industry; Availability

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice.

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SUMMARY: The Food and Drug Administration (FDA) is announcing the
availability of a draft guidance for industry entitled ``Evaluating
Drug Effects on the Ability to Operate a Motor Vehicle.'' The purpose
of this guidance is to assist sponsors in the evaluation of the effects
of psychoactive drugs on the ability to operate a motor vehicle.
Driving is a complex activity involving a wide range of cognitive,
perceptual, and motor activities. Reducing the incidence of motor
vehicle accidents (MVAs) that occur because of drug-impaired driving is
a public health priority. This draft guidance recommends using a
systematic effort to identify drugs that increase the risk of MVAs as a
critical component of assessing drug risk and designing strategies to
reduce this risk.

DATES: Although you can comment on any guidance at any time (see 21 CFR
10.115(g)(5)), to ensure that the Agency considers your comment on this
draft guidance before it begins work on the final version of the
guidance, submit either electronic or written comments on the draft
guidance by March 17, 2015.

ADDRESSES: Submit written requests for single copies of the draft
guidance to the Division of Drug Information, Center for Drug
Evaluation and Research, Food and Drug Administration, 10001 New
Hampshire Ave., Hillandale Building, 4th Floor, Silver Spring, MD
20993. Send one self-addressed adhesive label to assist that office in
processing your requests. See the SUPPLEMENTARY INFORMATION section for
electronic access to the draft guidance document.
    Submit electronic comments on the draft guidance to http://www.regulations.gov. Submit written comments to the Division of Dockets
Management (HFA-305), Food and Drug Administration, 5630 Fishers Lane,
Rm. 1061, Rockville, MD 20852.

FOR FURTHER INFORMATION CONTACT: Aaron Sherman, Center for Drug
Evaluation and Research, Food and Drug Administration, 10903 New
Hampshire Ave., Bldg. 22, Rm. 4339, Silver Spring, MD 20993-0002, 240-
402-0493.

SUPPLEMENTARY INFORMATION:

I. Background

    FDA is announcing the availability of a draft guidance for industry
entitled ``Evaluating Drug Effects on the Ability to Operate a Motor
Vehicle.'' The purpose of this guidance is to assist sponsors in the
evaluation of the effects of psychoactive drugs on the ability to
operate a motor vehicle.
    Driving is a complex activity involving a wide range of cognitive,
perceptual, and motor activities that can be adversely affected by
therapeutic drugs. Reducing the incidence of MVAs that occur because of
drug-impaired driving is a public health priority.\1\
---------------------------------------------------------------------------

    \1\ See the Drugged Driving Web page on the Office of National
Drug Control Policy Web site at http://www.whitehouse.gov/ondcp/drugged-driving.
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    Drugs that impair driving ability may also impair the ability to
judge the extent of one's own impairment. This increases the need for
objective evaluation of the presence and degree of driving impairment,
with risk mitigation strategies based on that information. This
guidance recommends a systematic effort to identify drugs for which
evaluation of effects on driving abilities may be needed, and the types
of studies that such an evaluation entails.
    This draft guidance is being issued consistent with FDA's good
guidance practices regulation (21 CFR 10.115). The draft guidance, when
finalized, will represent the Agency's current thinking on evaluating
drug effects on the ability to operate a motor vehicle. It does not
create or confer any rights for or on any person and does not operate
to bind FDA or the public. An alternative approach may be used if such
approach satisfies the requirements of the applicable statutes and
regulations.

II. The Paperwork Reduction Act of 1995

    This guidance refers to previously approved collections of
information that are subject to review by the Office of Management and
Budget (OMB) under the Paperwork Reduction Act of 1995 (44 U.S.C. 3501-
3520). The collections of information in 21 CFR parts 312 and 314 have
been approved under OMB control numbers 0910-0014 and 0910-0001,
respectively. The collection of information for prescription drug
product labeling is approved under OMB control number 0910-0572.

III. Comments

    Interested persons may submit either electronic comments regarding
this document to http://www.regulations.gov or written comments to the
Division of Dockets Management (see ADDRESSES). It is only necessary to
send one set of comments. Identify comments with the docket number
found in brackets in the heading of this document. Received comments
may be seen in the Division of Dockets Management between 9 a.m. and 4
p.m., Monday through Friday, and will be posted to the docket at http://www.regulations.gov.

IV. Electronic Access

    Persons with access to the Internet may obtain the document at
either http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm or http://www.regulations.gov.

    Dated: January 12, 2015.
Leslie Kux,
Associate Commissioner for Policy.
[FR Doc. 2015-00596 Filed 1-15-15; 8:45 am]
BILLING CODE 4164-01-P


[Federal Register Volume 82, Number 46 (Friday, March 10, 2017)]
[Rules and Regulations]
[Pages 13251-13256]
[FR Doc No: 2017-04794]

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ENVIRONMENTAL PROTECTION AGENCY

40 CFR Part 180

[EPA-HQ-OPP-2016-0557; FRL-9958-75]

Flupyradifurone; Pesticide Tolerances for Emergency Exemptions

AGENCY: Environmental Protection Agency (EPA).

ACTION: Final rule.

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SUMMARY: This regulation establishes time-limited tolerances for
residues of flupyradifurone [4-[[(6-chloro-3-pyridinyl)methyl](2,2-
difluoroethyl)amino]-2(5H)-furanone] in or on sweet sorghum, forage and
sorghum, syrup resulting from use of flupyradifurone in accordance with
the terms of crisis exemptions issued under section 18 of the Federal
Insecticide, Fungicide, and Rodenticide Act (FIFRA). This action is in
response to the issuance of crisis emergency exemptions under FIFRA
section 18 authorizing use of the pesticide on sweet sorghum. This
regulation establishes maximum permissible levels for residues of
flupyradifurone in or on sweet sorghum forage and sorghum syrup. These
time-limited tolerances expire on December 31, 2019.

DATES: This regulation is effective March 10, 2017. Objections and
requests for hearings must be received on or before May 9, 2017, and
must be filed in accordance with the instructions provided in 40 CFR
part 178 (see also Unit I.C. of the SUPPLEMENTARY INFORMATION).

ADDRESSES: The docket for this action, identified by docket
identification (ID) number EPA-HQ-OPP-2016-0557, is available at http://www.regulations.gov or at the Office of Pesticide Programs Regulatory
Public Docket (OPP Docket) in the Environmental Protection Agency
Docket Center (EPA/DC),West William Jefferson Clinton Bldg., Rm. 3334,
1301 Constitution Ave. NW., Washington, DC 20460-0001. The Public
Reading Room is open from 8:30 a.m. to 4:30 p.m., Monday through
Friday, excluding legal holidays. The telephone number for the Public
Reading Room is<PHONE_NUMBER>, and the telephone number for the OPP
Docket is<PHONE_NUMBER>. Please review

the visitor instructions and additional information about the docket
available at http://www.epa.gov/dockets.

FOR FURTHER INFORMATION CONTACT: Michael L. Goodis, Registration
Division (7505P), Office of Pesticide Programs, Environmental
Protection Agency, 1200 Pennsylvania Ave. NW., Washington, DC 20460-
0001; main telephone number:<PHONE_NUMBER>; email address:
<EMAIL_ADDRESS>
SUPPLEMENTARY INFORMATION:

I. General Information

A. Does this action apply to me?

    You may be potentially affected by this action if you are an
agricultural producer, food manufacturer, or pesticide manufacturer.
The following list of North American Industrial Classification System
(NAICS) codes is not intended to be exhaustive, but rather provides a
guide to help readers determine whether this document applies to them.
Potentially affected entities may include:
     Crop production (NAICS code 111).
     Animal production (NAICS code 112).
     Food manufacturing (NAICS code 311).
     Pesticide manufacturing (NAICS code 32532).

B. How can I get electronic access to other related information?

    You may access a frequently updated electronic version of 40 CFR
part 180 through the Government Printing Office's e-CFR site at http://www.ecfr.gov/cgi-bin/text-idx?&c=ecfr&tpl=/ecfrbrowse/Title40/40tab_02.tpl.

C. How can I file an objection or hearing request?

    Under section 408(g) of the Federal Food, Drug, and Cosmetic Act
(FFDCA), 21 U.S.C. 346a, any person may file an objection to any aspect
of this regulation and may also request a hearing on those objections.
You must file your objection or request a hearing on this regulation in
accordance with the instructions provided in 40 CFR part 178. To ensure
proper receipt by EPA, you must identify docket ID number EPA-HQ-OPP-
2016-0557 in the subject line on the first page of your submission. All
objections and requests for a hearing must be in writing, and must be
received by the Hearing Clerk on or before May 9, 2017. Addresses for
mail and hand delivery of objections and hearing requests are provided
in 40 CFR 178.25(b).
    In addition to filing an objection or hearing request with the
Hearing Clerk as described in 40 CFR part 178, please submit a copy of
the filing (excluding any Confidential Business Information (CBI)) for
inclusion in the public docket. Information not marked confidential
pursuant to 40 CFR part 2 may be disclosed publicly by EPA without
prior notice. Submit the non-CBI copy of your objection or hearing
request, identified by docket ID number EPA-HQ-OPP-2016-0557, by one of
the following methods:
     Federal eRulemaking Portal: http://www.regulations.gov.
Follow the online instructions for submitting comments. Do not submit
electronically any information you consider to be CBI or other
information whose disclosure is restricted by statute.
     Mail: OPP Docket, Environmental Protection Agency Docket
Center (EPA/DC), (28221T), 1200 Pennsylvania Ave. NW., Washington, DC
20460-0001.
     Hand Delivery: To make special arrangements for hand
delivery or delivery of boxed information, please follow the
instructions at http://www.epa.gov/dockets/contacts.html.
    Additional instructions on commenting or visiting the docket, along
with more information about dockets generally, is available at http://www.epa.gov/dockets.

II. Background and Statutory Findings

    EPA, on its own initiative, in accordance with FFDCA sections
408(e) and 408(l)(6) of, 21 U.S.C. 346a(e) and 346a(1)(6), is
establishing time-limited tolerances for residues of flupyradifurone in
or on sweet sorghum, forage at 30.0 parts per million (ppm) and
sorghum, syrup at 90.0 ppm. There are no Canadian or Codex MRLs for
residues of flupyradifurone in or on sweet sorghum, forage or sorghum,
syrup at this time, so international harmonization is not an issue for
these time-limited tolerances. These time-limited tolerances expire on
December 31, 2019.
    Section 408(l)(6) of FFDCA requires EPA to establish a time-limited
tolerance or exemption from the requirement of a tolerance for
pesticide chemical residues in food that will result from the use of a
pesticide under crisis exemptions issued under FIFRA section 18. Such
tolerances can be established without providing notice or period for
public comment. EPA does not intend for its actions on FIFRA section 18
related time-limited tolerances to set binding precedents for the
application of FFDCA section 408 and the safety standard to other
tolerances and exemptions. Section 408(e) of FFDCA allows EPA to
establish a tolerance or an exemption from the requirement of a
tolerance on its own initiative, i.e., without having received any
petition from an outside party.
    Section 408(b)(2)(A)(i) of FFDCA allows EPA to establish a
tolerance (the legal limit for a pesticide chemical residue in or on a
food) only if EPA determines that the tolerance is ``safe.'' Section
408(b)(2)(A)(ii) of FFDCA defines ``safe'' to mean that ``there is a
reasonable certainty that no harm will result from aggregate exposure
to the pesticide chemical residue, including all anticipated dietary
exposures and all other exposures for which there is reliable
information.'' This includes exposure through drinking water and in
residential settings, but does not include occupational exposure.
Section 408(b)(2)(C) of FFDCA requires EPA to give special
consideration to exposure of infants and children to the pesticide
chemical residue in establishing a tolerance and to ``ensure that there
is a reasonable certainty that no harm will result to infants and
children from aggregate exposure to the pesticide chemical residue. . .
.''
    Section 18 of FIFRA authorizes EPA to exempt any Federal or State
agency from any provision of FIFRA, if EPA determines that ``emergency
conditions exist which require such exemption.'' EPA has established
regulations governing such emergency exemptions in 40 CFR part 166.

III. Emergency Exemptions for Flupyradifurone on Sweet Sorghum and
FFDCA Tolerances

    Crisis exemptions for use of flupyradifurone on sweet sorghum to
control sugarcane aphids were issued to the Arkansas, Kentucky,
Mississippi, North Carolina, and Tennessee Departments of Agriculture.
Sweet sorghum growers in these states experienced severe and damaging
infestations of sugarcane aphids.
    The state agencies asserted that emergency conditions existed in
accordance with the criteria for approval of an emergency exemption,
and declared crisis exemptions under 40 CFR part 166, subpart C, to
allow the use of flupyradifurone on sweet sorghum for control of
sugarcane aphids. After having reviewed the emergency actions, EPA
concurred on the crisis exemptions on July 21, 2016 in order to meet
the needs of sweet sorghum growers in Arkansas, Kentucky, Mississippi,
North Carolina, and Tennessee who faced significant economic loss
resulting from sugarcane aphid damage. These crisis exemption programs
expired on November 15, 2016.

    As part of its evaluation of the proposed crisis exemptions, EPA
assessed the potential risks presented by residues of flupyradifurone
in or on sweet sorghum. In doing so, EPA considered the safety standard
in FFDCA section 408(b)(2), and EPA decided that the necessary time-
limited tolerances under FFDCA section 408(l)(6) would be consistent
with the safety standard and with FIFRA section 18. Consistent with the
need to move quickly on these emergency exemptions in order to address
an urgent non-routine situation and to ensure that the resulting food
is safe and lawful, EPA is issuing these time-limited tolerances
without notice and opportunity for public comment as provided in FFDCA
section 408(l)(6). Although these time-limited tolerances expire on
December 31, 2019 under FFDCA section 408(l)(5), residues of the
pesticide not in excess of the amounts specified in the tolerances
remaining in or on sweet sorghum, forage and sorghum, syrup after that
date will not be unlawful, provided the pesticide was applied in a
manner that was lawful under FIFRA, and the residues do not exceed a
level that was authorized by these time-limited tolerances at the time
of that application. EPA will take action to revoke these time-limited
tolerances earlier if any experience with scientific data or other
relevant information on this pesticide indicate that the residues are
not safe.
    Because these time-limited tolerances are being approved under
emergency conditions, EPA has not made any decisions about whether
flupyradifurone meets FIFRA's registration requirements for use on
sweet sorghum or whether permanent tolerances for this use would be
appropriate. Under these circumstances, EPA does not believe that these
time-limited tolerance decisions serve as a basis for registration of
flupyradifurone by a State for special local needs under FIFRA section
24(c), nor do these time-limited tolerances by themselves serve as the
authority for persons in any State other than Arkansas, Kentucky,
Mississippi, North Carolina, and Tennessee to use this pesticide on
sweet sorghum under FIFRA section 18 absent the issuance of an
emergency exemption applicable within that State. For additional
information regarding the emergency exemptions for flupyradifurone,
contact the Agency's Registration Division at the address provided
under FOR FURTHER INFORMATION CONTACT.

IV. Aggregate Risk Assessment and Determination of Safety

    Section 408(b)(2)(A)(i) of FFDCA allows EPA to establish a
tolerance (the legal limit for a pesticide chemical residue in or on a
food) only if EPA determines that the tolerance is ``safe.'' Section
408(b)(2)(A)(ii) of FFDCA defines ``safe'' to mean that ``there is a
reasonable certainty that no harm will result from aggregate exposure
to the pesticide chemical residue, including all anticipated dietary
exposures and all other exposures for which there is reliable
information.'' This includes exposure through drinking water and in
residential settings, but does not include occupational exposure.
Section 408(b)(2)(C) of FFDCA requires EPA to give special
consideration to exposure of infants and children to the pesticide
chemical residue in establishing a tolerance and to ``ensure that there
is a reasonable certainty that no harm will result to infants and
children from aggregate exposure to the pesticide chemical residue. . .
.''
    Consistent with the factors specified in FFDCA section
408(b)(2)(D), EPA has reviewed the available scientific data and other
relevant information in support of this action. EPA has sufficient data
to assess the hazards of and to make a determination on aggregate
exposure expected as a result of these emergency exemption requests and
the time-limited tolerances for residues of flupyradifurone on sweet
sorghum, forage and sorghum, syrup at 30.0 and 90.0 parts per million
(ppm) respectively. EPA's assessment of exposures and risks associated
with establishing these time-limited tolerances follows.

A. Toxicological Points of Departure/Levels of Concern

    Once a pesticide's toxicological profile is determined, EPA
identifies toxicological points of departure (POD) and levels of
concern to use in evaluating the risk posed by human exposure to the
pesticide. For hazards that have a threshold below which there is no
appreciable risk, the toxicological POD is used as the basis for
derivation of reference values for risk assessment. PODs are developed
based on a careful analysis of the doses in each toxicological study to
determine the dose at which no adverse effects are observed (the no
observed adverse effect level or NOAEL) and the lowest dose at which
adverse effects of concern are identified (the lowest observed adverse
effect level or LOAEL). Uncertainty/safety factors are used in
conjunction with the POD to calculate a safe exposure level--generally
referred to as a population-adjusted dose (PAD) or a reference dose
(RfD)--and a safe margin of exposure (MOE). For non-threshold risks,
the Agency assumes that any amount of exposure will lead to some degree
of risk. Thus, the Agency estimates risk in terms of the probability of
an occurrence of the adverse effect expected in a lifetime. For more
information on the general principles EPA uses in risk characterization
and a complete description of the risk assessment process, see http://www.epa.gov/pesticides/factsheets/riskassess.htm.
    A summary of the toxicological endpoints for flupyradifurone used
for human risk assessment is discussed in Table 1 of Unit III B. of the
final rule published in the Federal Register of January 23, 2015 (80 FR
3483) (FRL-9914-77).

B. Exposure Assessment

    1. Dietary exposure from food and feed uses. In evaluating dietary
exposure to flupyradifurone, EPA considered exposure under the time-
limited tolerances established by this action as well as all existing
flupyradifurone tolerances in 40 CFR 180.679. EPA assessed dietary
exposures from flupyradifurone in food as follows:
    i. Acute exposure. Quantitative acute dietary exposure and risk
assessments are performed for a food-use pesticide, if a toxicological
study has indicated the possibility of an effect of concern occurring
as a result of a 1-day or single exposure. Such effects were identified
for flupyradifurone. In estimating acute dietary exposure, EPA used
food consumption data from the United States Department of
Agriculture's (USDA's) National Health and Nutrition Examination
Survey, What We Eat in America (NHANES/WWEIA; 2003-2008), which it
should be noted did not identify any individuals as consuming sweet
sorghum. The flupyradifurone acute dietary exposure assessment was
conducted using the Dietary Exposure Evaluation Model (DEEM, ver.
3.16). An unrefined acute dietary exposure analysis was performed for
the established and requested uses of flupyradifurone that incorporated
recommended tolerance-level residues, default and empirical processing
factors, and assumed that 100% of the crops were treated.
    ii. Chronic exposure. In conducting the chronic dietary (food and
drinking water) exposure and risk assessment EPA used the food
consumption data from the USDA's NHANES/WWEIA; 2003-2008, which did not
identify any

individuals as consuming sweet sorghum. The flupyradifurone chronic
dietary exposure assessment was conducted using the Dietary Exposure
Evaluation Model (DEEM, ver. 3.16). An unrefined chronic dietary
exposure analysis was performed for the established and requested uses
of flupyradifurone that incorporated recommended tolerance-level
residues, default and empirical processing factors, and assumed that
100% of the crops were treated.
    iii. Cancer. Based on the data summarized in Table 1 of Unit III B.
of the final rule published in the Federal Register of January 23, 2015
(80 FR 3483) (FRL-9914-77), EPA has concluded that flupyradifurone does
not pose a cancer risk to humans. Therefore, a dietary exposure
assessment for the purpose of assessing cancer risk is unnecessary.
    iv. Anticipated residue and percent crop treated (PCT) information.
EPA did not use anticipated residue and/or PCT information in the
dietary assessment for flupyradifurone. Tolerance level residues and
100% CT were assumed for all food commodities.
    2. Dietary exposure from drinking water. The Agency used screening
level water exposure models in the dietary exposure analysis and risk
assessment for flupyradifurone in drinking water. These simulation
models take into account data on the physical, chemical, and fate/
transport characteristics of flupyradifurone. Further information
regarding EPA drinking water models used in pesticide exposure
assessment can be found at http://www.epa.gov/oppefed1/models/water/index.htm.
    Based on the Pesticide Root Zone Model/Exposure Analysis Modeling
System (PRZM/EXAMS), Tier 1 Rice Model and Pesticide Root Zone Model
Ground Water (PRZM GW) model, the estimated drinking water
concentrations (EDWCs) of flupyradifurone for acute exposures are
estimated to be 112 parts per billion (ppb) for surface water and 352
ppb for ground water, and for chronic exposures are estimated to be 112
ppb for surface water and 307 ppb for ground water.
    Modeled estimates of drinking water concentrations were directly
entered into the dietary exposure model. For the acute dietary risk
assessment, the water concentration value of 352 ppb was used to assess
the contribution to drinking water. For the chronic dietary risk
assessment, the water concentration value of 307 ppb was used to assess
the contribution to drinking water.
    3. From non-dietary exposure. The term ``residential exposure'' is
used in this document to refer to non-occupational, non-dietary
exposure (e.g., for lawn and garden pest control, indoor pest control,
termiticides, and flea and tick control on pets).
    Flupyradifurone is not registered for any specific use patterns
that would result in residential exposure. Residential exposure is not
anticipated from the proposed section 18 use on sweet sorghum.
    Further information regarding EPA standard assumptions and generic
inputs for residential exposures may be found at: http://www.epa.gov/pesticides/trac/science/trac6a05.pdf.
    4. Cumulative effects from substances with a common mechanism of
toxicity. Section 408(b)(2)(D)(v) of FFDCA requires that, when
considering whether to establish, modify, or revoke a tolerance, the
Agency consider ``available information'' concerning the cumulative
effects of a particular pesticide's residues and ``other substances
that have a common mechanism of toxicity.''
    EPA has not found flupyradifurone to share a common mechanism of
toxicity with any other substances, and flupyradifurone does not appear
to produce a toxic metabolite produced by other substances. For the
purposes of this time-limited tolerance action, therefore, EPA has
assumed that flupyradifurone does not have a common mechanism of
toxicity with other substances. For information regarding EPA's efforts
to determine which chemicals have a common mechanism of toxicity and to
evaluate the cumulative effects of such chemicals, see EPA's Web site
at http://www.epa.gov/pesticides/cumulative.

C. Safety Factor for Infants and Children

    1. In general. Section 408(b)(2)(C) of FFDCA provides that EPA
shall apply an additional tenfold (10X) margin of safety for infants
and children in the case of threshold effects to account for prenatal
and postnatal toxicity and the completeness of the database on toxicity
and exposure unless EPA determines based on reliable data that a
different margin of safety will be safe for infants and children. This
additional margin of safety is commonly referred to as the Food Quality
Protection Act (FQPA) Safety Factor (SF). In applying this provision,
EPA either retains the default value of 10X, or uses a different
additional SF when reliable data available to EPA support the choice of
a different factor.
    2. Prenatal and postnatal sensitivity. There is no evidence in the
rat developmental study that developing animals have increased
susceptibility to flupyradifurone. There is quantitative increase in
susceptibility in the rabbit developmental and rat reproduction
studies. In the rabbit developmental study, no maternal effect was seen
at the highest tested dose (80 milligram/kilogram/day (mg/kg/day)),
while there was an increase in fetal death and decrease fetal body
weight at the same dose level. In the rat reproduction study, decreases
in maternal body weight were seen at 137 mg/kg/day, whereas decreases
in pup body weight were seen at the next lower dose, 38.7 mg/kg/day.
However, the PODs selected for risk assessment are protective of the
quantitative susceptibility seen in the rabbit fetuses and rat pups.
    3. Conclusion. EPA has determined that reliable data show that the
safety of infants and children would be adequately protected if the
FQPA SF were reduced to 1x. That decision is based on the following
findings:
    i. The toxicity database for flupyradifurone is complete.
    ii. Although there is evidence that flupyradifurone has neurotoxic
effects, EPA has a complete set of neurotoxicity studies (acute,
subchronic, and developmental). The effects of those studies are well-
characterized and indicate neurotoxic effects that occur at levels
above the chronic POD that was selected for risk assessment. The NOAEL
for the acute neurotoxicity study is being used for the acute POD.
Therefore, there is no need to retain the 10X FQPA SF to account for
any uncertainty concerning these effects.
    iii. There is no evidence that flupyradifurone produces increased
susceptibility in the prenatal developmental study in rats, but there
is increased quantitative susceptibility in rabbit fetuses and in the
rat pups. However, the PODs selected for risk assessment are protective
of the quantitative susceptibility seen in the fetuses and rat pups.
    iv. There are no residual uncertainties identified in the exposure
databases. The dietary food exposure assessments were performed based
on 100 PCT and tolerance-level residues. EPA made conservative
(protective) assumptions in the ground and surface water modeling used
to assess exposure to flupyradifurone in drinking water. EPA used
similarly conservative assumptions to assess post-application exposure
of children. These assessments will not underestimate the exposure and
risks posed by flupyradifurone.
    EPA made conservative (protective) assumptions in the ground and
surface water modeling used to assess exposure to flupyradifurone in
drinking water. These assessments will not

underestimate the exposure and risks posed by flupyradifurone.

D. Aggregate Risks and Determination of Safety

    EPA determines whether acute and chronic dietary pesticide
exposures are safe by comparing aggregate exposure estimates to the
acute PAD (aPAD) and chronic PAD (cPAD). For linear cancer risks, EPA
calculates the lifetime probability of acquiring cancer given the
estimated aggregate exposure. Short-, intermediate-, and chronic-term
risks are evaluated by comparing the estimated aggregate food, water,
and residential exposure to the appropriate PODs to ensure that an
adequate MOE exists.
    1. Acute risk. Using the exposure assumptions discussed in this
unit for acute exposure, the acute dietary exposure from food and water
to flupyradifurone will occupy 37% of the aPAD for children 1-2 years
old, the population group receiving the greatest exposure.
    2. Chronic risk. Using the exposure assumptions described in this
unit for chronic exposure, EPA has concluded that chronic exposure to
flupyradifurone from food and water will utilize 86% of the cPAD for
(children 1-2 years old) the population group receiving the greatest
exposure. There are no residential uses for flupyradifurone and
residential uses are not anticipated from the proposed section 18 on
sweet sorghum.
    3. Short-term risk. Short-term aggregate exposure takes into
account short-term residential exposure plus chronic exposure to food
and water (considered to be a background exposure level).
    As there are no residential uses of flupyradifurone,
flupyradifurone does not pose a short-term aggregate risk that differs
from the chronic dietary risk addressed in Unit IV.D.2. Chronic dietary
risks do not exceed the Agency's level for the U.S. population or any
other population subgroups.
    4. Intermediate-term risk. Intermediate-term aggregate exposure
takes into account intermediate-term non-dietary, non-occupational
exposure plus chronic exposure to food and water (considered to be a
background exposure level).
    As there are no residential uses of flupyradifurone,
flupyradifurone does not pose an intermediate-term aggregate risk that
differs from the chronic dietary risk addressed in Unit IV.D.2. Chronic
dietary risks do not exceed the Agency's level for the U.S. population
or any other population subgroups.
    5. Aggregate cancer risk for U.S. population. Based on the lack of
evidence of carcinogenicity in two adequate rodent carcinogenicity
studies, flupyradifurone is not expected to pose a cancer risk to
humans.
    6. Determination of safety. Based on these risk assessments, EPA
concludes that there is a reasonable certainty that no harm will result
to the general population, or to infants and children, from aggregate
exposure to flupyradifurone residues.

V. Other Considerations

A. Analytical Enforcement Methodology

    An adequate analytical method (Method RV-001-P10-03), which uses
high-performance liquid chromatography with tandem mass spectrometry
(HPLC/MS/MS) to quantitate residues of flupyradifurone and
difluoroacetic acid (DFA) in various crops, is available for
enforcement.
    The method may be requested from: Chief, Analytical Chemistry
Branch, Environmental Science Center, 701 Mapes Rd., Ft. Meade, MD
20755-5350; telephone number:<PHONE_NUMBER>; email address:
<EMAIL_ADDRESS>
B. International Residue Limits

    In making its tolerance decisions, EPA seeks to harmonize U.S.
tolerances with international standards whenever possible, consistent
with U.S. food safety standards and agricultural practices. EPA
considers the international maximum residue limits (MRLs) established
by the Codex Alimentarius Commission (Codex), as required by FFDCA
section 408(b)(4). The Codex Alimentarius is a joint United Nations
Food and Agriculture Organization/World Health Organization food
standards program, and it is recognized as an international food safety
standards-setting organization in trade agreements to which the United
States is a party. EPA may establish a tolerance that is different from
a Codex MRL; however, FFDCA section 408(b)(4) requires that EPA explain
the reasons for departing from the Codex level.
    There are currently no established Codex or Canadian MRLs for
flupyradifurone residues in sweet sorghum commodities.

VI. Conclusion

    Therefore, time-limited tolerances are established for residues of
flupyradifurone, [4-[[(6-chloro-3-pyridinyl)methyl](2,2-
difluoroethyl)amino]-2(5H)-furanone] in or on sweet sorghum, forage at
30.0 and sorghum, syrup at 90.0 parts per million (ppm).

VII. Statutory and Executive Order Reviews

    This action establishes tolerances under FFDCA sections 408(e) and
408(l)(6). The Office of Management and Budget (OMB) has exempted these
types of actions from review under Executive Order 12866, entitled
``Regulatory Planning and Review'' (58 FR 51735, October 4, 1993).
Because this action has been exempted from review under Executive Order
12866, this action is not subject to Executive Order 13211, entitled
``Actions Concerning Regulations That Significantly Affect Energy
Supply, Distribution, or Use'' (66 FR 28355, May 22, 2001) or Executive
Order 13045, entitled ``Protection of Children from Environmental
Health Risks and Safety Risks'' (62 FR 19885, April 23, 1997). This
action does not contain any information collections subject to OMB
approval under the Paperwork Reduction Act (PRA), 44 U.S.C. 3501 et
seq., nor does it require any special considerations under Executive
Order 12898, entitled ``Federal Actions to Address Environmental
Justice in Minority Populations and Low-Income Populations'' (59 FR
7629, February 16, 1994).
    Since tolerances and exemptions that are established in accordance
with FFDCA sections 408(e) and 408(l)(6), such as the tolerances in
this final rule, do not require the issuance of a proposed rule, the
requirements of the Regulatory Flexibility Act (RFA) (5 U.S.C. 601 et
seq.) do not apply.
    This action directly regulates growers, food processors, food
handlers, and food retailers, not States or tribes, nor does this
action alter the relationships or distribution of power and
responsibilities established by Congress in the preemption provisions
of FFDCA section 408(n)(4). As such, the Agency has determined that
this action will not have a substantial direct effect on States or
tribal governments, on the relationship between the national government
and the States or tribal governments, or on the distribution of power
and responsibilities among the various levels of government or between
the Federal Government and Indian tribes. Thus, the Agency has
determined that Executive Order 13132, entitled ``Federalism'' (64 FR
43255, August 10, 1999) and Executive Order 13175, entitled
``Consultation and Coordination with Indian Tribal Governments'' (65 FR
67249, November 9, 2000) do not apply to this action. In addition, this
action does not impose any enforceable duty or

contain any unfunded mandate as described under Title II of the
Unfunded Mandates Reform Act (UMRA) (2 U.S.C. 1501 et seq.).
    This action does not involve any technical standards that would
require Agency consideration of voluntary consensus standards pursuant
to section 12(d) of the National Technology Transfer and Advancement
Act (NTTAA) (15 U.S.C. 272 note).

VIII. Congressional Review Act

    Pursuant to the Congressional Review Act (5 U.S.C. 801 et seq.),
EPA submitted a report containing a draft of this rule and other
required information to the U.S. Senate, the U.S. House of
Representatives, and the Comptroller General of the United States prior
to publication of the rule in the Federal Register. This action is not
a ``major rule'' as defined by 5 U.S.C. 804(2).

List of Subjects in 40 CFR Part 180

    Environmental protection, Administrative practice and procedure,
Agricultural commodities, Pesticides and pests, Reporting and
recordkeeping requirements.

    Dated: February 13, 2017.
Michael Goodis,
Director, Registration Division, Office of Pesticide Programs.
    Therefore, 40 CFR chapter I is amended as follows:

PART 180--[AMENDED]

0
 1. The authority citation for part 180 continues to read as follows:

     Authority: 21 U.S.C. 321(q), 346a and 371.

0
2. In Sec.  180.679, revise paragraph (b) to read as follows:

Sec.  180.679  Flupyradifurone; tolerances for residues.

* * * * *
    (b) Section 18 emergency exemptions. Time-limited tolerances are
established for residues of flupyradifurone, including its metabolites
and degradates in or on the specified commodities listed in the table
below, resulting from use of the pesticide under section 18 emergency
exemptions granted by EPA. The time-limited tolerances expire and are
revoked on the date specified in the table. Compliance with the
tolerance levels specified in the following table is to be determined
by measuring only flupyradifurone, 4-[[(6-chloro-3-
pyridinyl)methyl](2,2-difluoroethyl)amino]-2(5H)-furanone in or on the
commodity.

------------------------------------------------------------------------
                                 Parts per
          Commodity            million (ppm)        Expiration date
------------------------------------------------------------------------
sorghum, syrup..............            90.0  December 31, 2019.
sweet sorghum, forage.......            30.0  December 31, 2019.
------------------------------------------------------------------------

* * * * *
[FR Doc. 2017-04794 Filed 3-9-17; 8:45 am]
 BILLING CODE 6560-50-P


[Federal Register Volume 84, Number 139 (Friday, July 19, 2019)]
[Notices]
[Pages 34910-34911]
[FR Doc No: 2019-15337]

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

DEPARTMENT OF HOMELAND SECURITY

Federal Emergency Management Agency

[Docket ID FEMA-2019-0002; Internal Agency Docket No. FEMA-B-1940]

Proposed Flood Hazard Determinations

AGENCY: Federal Emergency Management Agency, DHS.

ACTION: Notice.

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

SUMMARY: Comments are requested on proposed flood hazard
determinations, which may include additions or modifications of any
Base Flood Elevation (BFE), base flood depth, Special Flood Hazard Area
(SFHA) boundary or zone designation, or regulatory floodway on the
Flood Insurance Rate Maps (FIRMs), and where applicable, in the
supporting Flood Insurance Study (FIS) reports for the communities
listed in the table below. The purpose of this notice is to seek
general information and comment regarding the preliminary FIRM, and
where applicable, the FIS report that the Federal Emergency Management
Agency (FEMA) has provided to the affected communities. The FIRM and
FIS report are the basis of the floodplain management measures that the
community is required either to adopt or to show evidence of having in
effect in order to qualify or remain qualified for participation in the
National Flood Insurance Program (NFIP). In addition, the FIRM and FIS
report, once effective, will be used by insurance agents and others to
calculate appropriate flood insurance premium rates for new buildings
and the contents of those buildings.

DATES: Comments are to be submitted on or before October 17, 2019.

ADDRESSES: The Preliminary FIRM, and where applicable, the FIS report
for each community are available for inspection at both the online
location https://www.fema.gov/preliminaryfloodhazarddata and the
respective Community Map Repository address listed in the tables below.
Additionally, the current effective FIRM and FIS report for each
community are accessible online through the FEMA Map Service Center at
https://msc.fema.gov for comparison.
    You may submit comments, identified by Docket No. FEMA-B-1940, to
Rick Sacbibit, Chief, Engineering Services Branch, Federal Insurance
and Mitigation Administration, FEMA, 400 C Street SW, Washington, DC
20472,<PHONE_NUMBER>, or (email<EMAIL_ADDRESS>
FOR FURTHER INFORMATION CONTACT: Rick Sacbibit, Chief, Engineering
Services Branch, Federal Insurance and Mitigation Administration, FEMA,
400 C Street SW, Washington, DC 20472,<PHONE_NUMBER>, or (email)
<EMAIL_ADDRESS>or visit the FEMA Map Information
eXchange (FMIX) online at https://www.floodmaps.fema.gov/fhm/fmx_main.html.

SUPPLEMENTARY INFORMATION: FEMA proposes to make flood hazard
determinations for each community listed below, in accordance with
section 110 of the Flood Disaster Protection Act of 1973, 42 U.S.C.
4104, and 44 CFR 67.4(a).
    These proposed flood hazard determinations, together with the
floodplain management criteria required by 44 CFR 60.3, are the minimum
that are required. They should not be construed to mean that the
community must change any existing ordinances that are more stringent
in their floodplain management requirements. The community may at any
time enact stricter requirements of its own or pursuant to policies
established by other Federal, State, or regional entities. These flood
hazard determinations are used to meet the floodplain management
requirements of the NFIP and are used to calculate the appropriate
flood insurance premium rates for new buildings built after the FIRM
and FIS report become effective.
    The communities affected by the flood hazard determinations are
provided in the tables below. Any request for reconsideration of the
revised flood hazard information shown on the Preliminary FIRM and FIS
report that satisfies the data requirements outlined in 44 CFR 67.6(b)
is considered an appeal. Comments unrelated to the flood hazard
determinations also will be considered before the FIRM and FIS report
become effective.
    Use of a Scientific Resolution Panel (SRP) is available to
communities in support of the appeal resolution process. SRPs are
independent panels of experts in hydrology, hydraulics, and other
pertinent sciences established to review conflicting scientific and
technical data and provide recommendations for resolution. Use of the
SRP only may be exercised after FEMA and local communities have been
engaged in a collaborative consultation process for at least 60 days
without a mutually acceptable resolution of an appeal. Additional
information regarding the SRP process can be found

online at https://www.floodsrp.org/pdfs/srp_overview.pdf.
    The watersheds and/or communities affected are listed in the tables
below. The Preliminary FIRM, and where applicable, FIS report for each
community are available for inspection at both the online location
https://www.fema.gov/preliminaryfloodhazarddata and the respective
Community Map Repository address listed in the tables. For communities
with multiple ongoing Preliminary studies, the studies can be
identified by the unique project number and Preliminary FIRM date
listed in the tables. Additionally, the current effective FIRM and FIS
report for each community are accessible online through the FEMA Map
Service Center at https://msc.fema.gov for comparison.

(Catalog of Federal Domestic Assistance No. 97.022, ``Flood
Insurance.'')

Michael M. Grimm,
Assistant Administrator for Risk Management, Department of Homeland
Security, Federal Emergency Management Agency.

------------------------------------------------------------------------
                                             Community map repository
               Community                             address
------------------------------------------------------------------------
                  Fairbanks North Star Borough, Alaska
        Project: 17-10-0011S Preliminary Date: February 15, 2019
------------------------------------------------------------------------
Fairbanks North Star Borough...........  Department of Community
                                          Planning, Borough
                                          Administrative Center, 809
                                          Pioneer Road, Fairbanks, AK
                                          99701.
------------------------------------------------------------------------
                Story County, Iowa and Incorporated Areas
        Project: 17-07-0055S Preliminary Date: November 15, 2018
------------------------------------------------------------------------
City of Ames...........................  City Hall, 515 Clark Avenue,
                                          Ames, IA 50010.
City of Cambridge......................  City Hall, 225 Water Street,
                                          Cambridge, IA 50046.
City of Collins........................  City Hall, 212 Main Street,
                                          Collins, IA 50055.
City of Gilbert........................  City Hall, 105 Southeast 2nd
                                          Street, Gilbert, IA 50105.
City of Huxley.........................  City Hall, 515 North Main
                                          Avenue, Huxley, IA 50124.
City of Maxwell........................  City Hall, 107 Main Street,
                                          Maxwell, IA 50161.
City of McCallsburg....................  City Hall, 425 Main Street,
                                          McCallsburg, IA 50154.
City of Nevada.........................  City Hall, 1209 6th Street,
                                          Nevada, IA 50201.
City of Roland.........................  City Hall, 208 North Main
                                          Street, Roland, IA 50236.
City of Slater.........................  City Hall, 101 Story Street,
                                          Slater, IA 50244.
City of Story City.....................  City Hall, 504 Broad Street,
                                          Story City, IA 50248.
City of Zearing........................  City Hall, 105 West Main
                                          Street, Zearing, IA 50278.
Unincorporated Areas of Story County...  Story County Administration
                                          Building, 900 6th Street,
                                          Nevada, IA 50201.
------------------------------------------------------------------------
              Clark County, Missouri and Incorporated Areas
        Project: 17-07-1396S Preliminary Date: February 15, 2019
------------------------------------------------------------------------
City of Alexandria.....................  City Hall, 109 Market Street,
                                          Alexandria, MO 63430.
Unincorporated Areas of Clark County...  Clark County Circuit Clerk's
                                          Office, 288 East Main Street,
                                          Kahoka, MO 63445.
------------------------------------------------------------------------

[FR Doc. 2019-15337 Filed 7-18-19; 8:45 am]
 BILLING CODE 9110-12-P