  SEQ CHAPTER \h \r 1



UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

					WASHINGTON, D.C.  20460

																OFFICE OF PREVENTION PESTICIDES AND

                                                			TOXIC SUBSTANCES

TXR:		0054614

DATE: 	January 31, 2007

SUBJECT:	Mefluidide:   SEQ CHAPTER \h \r 1 Toxicology Section for the Reregistration Eligibility Decision Document (RED)

		  SEQ CHAPTER \h \r 1 Reregistration Case #: 2370

		PC Code: 114001

		DP Code D334513

FROM:	Abdallah Khasawinah, Ph.D.

		Reregistration Branch 4

		Health Effects Division (7509P)

THROUGH:	Susan Hummel

		Reregistration Branch 4

		Health Effects Division (7509P)

TO:		Yan Donovan

		Reregistration Branch 4

		Health Effects Division (7509P)

  SEQ CHAPTER \h \r 1   SEQ CHAPTER \h \r 1 Action Requested:

  SEQ CHAPTER \h \r 1 Prepare a toxicology section for mefluidide re-registration eligibility decision.

4.0	Hazard Characterization/Assessment

	4.1 Hazard characterization

Mefluidide has shown low acute toxicity by the oral, dermal and inhalation routes (Toxicity Category III and IV).  It was a weak eye or dermal irritant (Toxicity Category III and IV).  However, the precursor of mefluidide (S-15733) caused eye irritation (Toxicity Category II).  Mefluidide did not cause dermal sensitization in the guinea pig.  In rats and rabbits, critical effects of acute oral toxicity occurring at doses of 100 mg/kg/day and above were tremors, hunched posture, salivation, reduced body weight and body weight gain.

Mefluidide and its diethanolamine salt subchronic and chronic toxicity are manifested by decreased body weight and body weight gain in several species tested (rats, rabbits and dogs). Dogs are most sensitive to these effects, which occur at doses as low as 15 mg/kg/day in diets fed for one year. In addition, dogs fed mefluidide for one year exhibited chronic cortical nephrosis at doses of 150 mg/kg/day. Increased incidence of liver hyperplastic nodules in both sexes was observed in mice fed mefluidide at doses of 270 mg/kg/day and higher, but there was no oncogenic response in mice at doses as high as 900 mg/kg/day.  Rats fed mefluidide at doses up to 300 mg/kg/day did not exhibit any carcinogenic response either.  Based on lack of carcinogenic response in both rats and mice, mefluidide is considered as not likely to be carcinogenic to humans.

Mefluidide exhibited a negative response in various genotoxicity screening assays (bacterial reverse mutation, in vitro mouse lymphoma gene mutation, in vitro mammalian chromosome aberration, in vivo sister chromatid exchange, unscheduled DNA synthesis).

Mefluidide and its DEA salt were not dermally toxic when tested in rabbits at limit doses of 1000 mg/kg/day for 21 days. Effects were limited to slight erythema at the application site at the 1000 mg/kg/day dose.

Mefluidide or its DEA salt has not been tested for subacute or subchronic inhalation toxicity.  However, both of them are in category IV for acute inhalation toxicity.

Developmental effects of Mefluidide in rats included increased number of early resorptions and mean postimplantation loss.  These effects were observed at the same dose that caused maternal toxicity indicating there was no increased susceptibility to fetuses.  The maternal toxicity included tremors, decreased body weight, weight gain and mortality.  In rabbit, the LOAEL/NOAEL for developmental toxicity were above the highest dose tested (60 mg/kg/day).  In the 2-generation reproduction toxicity study, the offspring toxicity was characterized by decreased body weights in both sexes and both litters in all generations.  The reproductive LOAEL was not observed (NOAEL = 346/604 mg/kg bw/day).

The toxicology profile of mefluidide does not indicate a potential concern for estrogens, androgen and/or thyroid mediated toxicity.

Mefluidide was almost completely absorbed following oral ingestion (approximately 96%) and rapidly eliminated within 24 hours.  A majority of dose was eliminated in urine (86-89 %) and remainder in feces after a single oral dose in 24 hours. Residue consisted of mefluidide (97%) and 2 unidentified metabolites (1.2% and 0.5%) and unidentified polar material (0.7%).  Excretion of the radioactivity in expired air was not detected.  The chemical is unlikely to accumulate in body since it was excreted almost completely within 24 hrs and steadily declined thereafter.

The toxicology profile of mefluidide and its DEA salt is adequate for the purposes of hazard and dose response assessment.

4.2 Hazard considerations For Women and Children  tc \l1 "2.2	Food Quality Protection Act (FQPA) HAZARD CONSIDERATIONS

	4.2.1. Adequacy of the Toxicity Database

 tc \l2 "1. Adequacy of the Toxicity Database

The toxicology database for mefluidide is considered adequate.  The following acceptable studies are available:

- Developmental toxicity studies in rats

- Developmental toxicity studies in rabbits

- Two-generation reproduction study in rats

	4.2. tc \l2 "2.2.  2. Evidence of Neurotoxicity

Acute and subchronic neurotoxicity studies were not performed.  Clinical signs of neurotoxicity (such as tremors, ataxia, atonia, decreased limb tone, salivation) were seen in several studies (14-day oral in rabbit at or above 200 mg/kg/day, demyelination study in chickens at 1000 mg/kg/day and two developmental toxicity studies in rats at 115 mg/kg/day.  Edema and swelling with myelin loss in sciatic nerve was observed in a dermal toxicity study in rabbits at doses of 720 mg/kg and above. However, these effects were not seen in an additional dermal test of similar duration using a 58.2% mefluidide formulation or diethanolamine salt of mefluidide 28.8%.

	4.2.3. Developmental Toxicity Study Conclusions tc \l2 "2.2.3. Developmental Toxicity Study Conclusions

Developmental Toxicity Study - Rabbits:

In a developmental toxicity study (MRIDs 00047139 and 00047138), technical MBR 12325 (Lot #9) in 4% gum acacia was administered to 16-20 New Zealand White rabbits/dose group via gavage at dose levels of 0, 15, 30, or 60 mg/kg bw/day from gestation days (GD) 6-18.

There were no treatment-related effects on survival, clinical signs, body weight, food consumption, or cesarean parameters.

The maternal LOAEL was not observed.  The maternal NOAEL is 60 mg/kg bw/day (the highest dose tested).

There were no effects of treatment on the numbers of litters, live fetuses, dead fetuses, or resorptions, or on fetal body weights, sex ratio, or post-implantation loss.  There were no treatment-related external, visceral, or skeletal variations or malformations.

The developmental LOAEL was not observed.  The developmental NOAEL is 60 mg/kg bw/day (the highest dose tested).

This developmental toxicity study in rabbits has a number of deficiencies:  a LOAEL was not observed; test material purity was not provided; no information on dose formulation preparation or storage was provided; and no analyses of homogeneity, stability, or concentration were reported. However, when combined with the 14-day oral gavage study in rabbits (MRID 00047138), where a LOAEL of <100 mg/kg bw/day based on mortality and tremor was established, this developmental toxicity study is considered acceptable and satisfies the guideline for a developmental toxicity study (OPPTS 870.3700b; OECD 414) in rabbits.

Developmental Toxicity Study - Rats:

In a developmental toxicity study (MRID 42026102), Diethanolamine salt of Mefluidide (28.78% a.i. Lot # JB0624) in distilled water was administered to pregnant Sprague Dawley Crl:CD BR VAF/Plus (25/dose) by gavage at dose levels of 0, 50, 200 or 400 mg/kg bw/day (adjusted doses for 100 % purity were 0, 14, 58, or 115 mg/kg/day, respectively) from days 6 through 15 of gestation.

Animals were checked daily for clinical signs, mortality.  Body weights were measured on gestation day 0, 6, 9, 12, 16 and 20.  Unscheduled deaths, scheduled sacrifice and c-sections were subjected to gross necropsy examination. Each fetus was examined for external/visceral/skeletal anomalies, sexed and then weighed.

Evidence of maternal toxicity included transient clinical signs (tremors, dark material around the nose, few feces, urine stain and reddish vaginal discharge), decreased body weight gain (11-61%), decreased food consumption and mortality (2/25 females found dead on GD 11 and 16) observed at the 400 mg/kg/day levels.  At the 400 mg/kg dose, the clinical signs of toxicity appeared within 2 days after dosing in few animals, and after few days of dosing in some others and more than half of the animals at this dose were free from clinical signs of toxicity. No external malformations or developmental variations were observed associated with any fetus. Fetal toxicity was manifested by increase in the number of early resorptions which resulted in increase in mean postimplantation loss at 400 mg/kg/day dose.

After adjusting to the pure active ingredient, the maternal NOAEL is 58 mg/kg/day and the LOAEL is 115 mg/kg/day based on clinical signs (tremors, dark material around the nose, urine stain and reddish vaginal discharge), decreased body weight gain, decreased food consumption and mortality (2/25 females).   The developmental toxicity NOAEL is also 58 mg/kg/day, the LOAEL is 115 mg/kg/day based on increase in the number of early resorptions and increase in mean postimplantation loss.

	This developmental toxicity study is classified acceptable/Guideline and it does satisfy the guideline requirement for a developmental toxicity study (OPPTS 870.3700; OECD 414) in the rat.

	4.2.4. Reproductive Toxicity Study

In a three-generation reproduction study (MRID 00082748), MBR 12325 (Mefluidide; 93% a.i., Lot #25) was administered in the diet to 20 male and 40 female Charles River CD® rats/dose group at dose levels of 0, 600, 1800, or 6000 ppm (equivalent to Males/Females - 0/0, 34/60, 102/183, and 346/604 mg/kg bw/day).  When approximately 100 days old, the P generation animals were mated (1 male: 2 females) for up to 15 days to produce the F1a litter.  Following weaning of the F1a litters, 50 F1a offspring/sex/dose were selected for a 2-year chronic feeding study, and the remaining F1a offspring were discarded.  The P generation was reduced to 10 males/20 females per dose group.  After a 10-day post-weaning rest period, these P animals were mated again to produce the F1b litter.  Upon weaning, 10 male and 20 female F1b offspring/dose group were selected to be parents of the F2 generation.  This study design was continued for three generations with 2 litters per generation.

There were no effects on food consumption, organ weights, gross pathology, or histopathology.

Numerous absolute and relative (to bw) organ weights in the 6000 ppm parents were significantly (p<0.05) different from the controls, however, none of these differences were corroborated by any macroscopic or microscopic findings indicating these decreases were most likely not related to treatment.  Thus, it is likely that they were attributable to decreased body weights at this dose.

The only deaths included one 6000 ppm F1 female, one 6000 ppm F2 male, and one 1800 ppm F2 female.  It was stated that macroscopic and microscopic findings in these animals were unremarkable.  Therefore, these deaths were considered incidental and were not treatment related.

At 6000 ppm, body weights were decreased by 1-8% in males and 1-12% in females throughout the study in the P generation, attaining significance (p<0.05) at Week 18 in the males and Weeks 8, 18, 19, and 27 in the females.  In the F1 generation at this dose, body weights were decreased throughout the study in the males (decr. 13-21%) and females (decr. 10-21%), attaining significance (p<0.01) at Weeks 27, 37, and 56 in both sexes.  Similarly in the F2 generation, body weights were decreased throughout the study in the 6000 ppm males (decr. 14-21%) and females (decr. 11-23%), attaining significance (p<0.01) at Weeks 57, 66, and 85 in both sexes.

At 1800 ppm, only minor and infrequent decreases in body weights were noted.  There were no treatment-related findings at 600 ppm.

The parental systemic LOAEL is 6000 ppm (346/604 mg/kg bw/day in males/females), based on decreased body weights in both sexes in all generations.  The parental systemic NOAEL is 1800 ppm (102/183 mg/kg bw/day in males/females).

There were no effects of treatment on post-natal survival (i.e., viability and lactation) indices in the pups at any dose.  There were no treatment-related findings at 600 or 1800 ppm.

At 6000 ppm, body weights were decreased by up to 27% compared to controls throughout the post-natal period in both litters in each generation (i.e., F1a, F1b, F2a, F2b, F3a, and F3b litters). These decreases attained significance in both sexes at PND 21.

The offspring LOAEL is 6000 ppm (346/604 mg/kg bw/day in males/females), based on decreased body weights in both sexes and both litters in all generations.  The offspring NOAEL is 1800 ppm (102/183 mg/kg bw/day in males/females).

There were no effects of treatment on male or female fertility indices or gestation survival index.

The reproductive LOAEL was not observed.  The reproductive NOAEL is 6000 ppm (346/604 mg/kg bw/day in males/females).

This study is acceptable/guideline and satisfies the guideline requirement for a three-generation reproductive study (OPPTS 870.3800; OECD 416) in rats.

	4.2.5. Additional Information from Literature sources

There was no published information on this subject.

	4.2.6. Pre-and/or Postnatal Toxicity tc \l2 "5. Pre-and/or Postnatal Toxicity

		<IP_ADDRESS>. Determination of Susceptibility:

There is no evidence of increased pre-natal susceptibility for mefluidide from in utero exposure in rats.  Developmental effects of mefluidide in rats included increased number of early resorptions and mean postimplantation loss. These effects were observed at the same dose that caused maternal toxicity indicating there was no increased susceptibility to the fetuses.  The maternal toxicity included tremors, decreased body weight, weight gain and mortality.  In rabbit, the NOAEL for developmental toxicity were above the highest dose tested (60 mg/kg/day).  In the 3-generation reproduction toxicity study, no treatment related reproductive effects were reported.  The offspring toxicity (decreased pup body weights) was observed at the highest dose tested (346 mg/kg/day) that also produced maternal toxicity indicating there was no increased post-natal susceptibility for the mefluidide.

		<IP_ADDRESS> Degree of Concern analysis and Residual Uncertainities for Pre- and 			/or Post –natal Susceptibility

There is no evidence of increased pre- or post-natal susceptibility in the developmental study or in the multi-generation reproduction study in rat.  Although the LOAEL/NOAEL for developmental toxicity in the rabbits were not established, the concern is low for the increased susceptibility to the rabbit fetuses since the developmental effects were not seen at the highest dose tested (60 mg/kg/day) which is above the developmental NOAEL in rat (58 mg/kg/day) and well above (40X) the dose that is used to establish chronic RfD (1.5 mg/kg/day).  Therefore, there is no residual uncertainty for pre- and/or post natal susceptibility.

4.3. Hazard Identification and Toxicity Endpoint Selection

 tc \l2 "2.4	Hazard Identification and Toxicity Endpoint Selection

4.3.1. Acute Reference Dose (aRfD)

Females age 13-49 : Acute dietary endpoint for child bearing females (females 13+ years old) was determined from the developmental toxicity study in rat (MRID 42026102).  A NOAEL of 58 mg/kg/day was derived based on developmental toxicity (increased number of early resorptions and mean post-implantation loss ) at a LOAEL of 115 mg/kg/day.  An UF of 100X (10-fold for inter-species extrapolation, 10-fold for intra-species variability) was applied to the NOAEL of 58 mg/kg/day to derive the aRfD.

Acute Reference Dose (aRfD) - General Population

The acute RfD for the general population including infants and children was determined from the developmental toxicity study in rat (MRID 42026102).  A NOAEL of 58 mg/kg/day was derived based on maternal toxicity (clinical signs: tremors)  at a LOAEL of 115 mg/kg/day.  An UF of 100X (10- fold for inter-species extrapolation, 10-fold for intra-species variability) was applied.  The selected endpoint of toxicity is appropriate for this exposure since clinical signs of toxicity occurred within two days of dosing.

4.3.2. Chronic Reference Dose (cRfD)

The cRfD of 0.015 mg/kg/day was determined on the basis of the Chronic Oral Feeding study in dogs (MRID 00132995).  A NOAEL of 1.5 mg/kg/day was selected based on chronic toxicity (decreased body weight (15%) and body weight gain (50%) in the males) occurring at a LOAEL of 15.0 mg/kg/day.  This was the most sensitive endpoint.  An UF of 100X (10-fold for interspecies extrapolation, 10-fold for intraspecies variability) was applied to the NOAEL of 1.5 mg/kg/day to derive the cRfD to give and RfD of 0.015 mg/kg/day.

	4.3.3. Incidental Oral Exposure (Short-and Intermediate-term durations: 1 day – 6 months)

Points of departure for these scenarios were based on the rat developmental study (MRID 42026102).  NOAEL = 58 mg/kg bw/day, LOAEL = 115 mg/kg bw/day based on mortality and clinical signs.  These data were also supported by the rabbit developmental study (NOAEL = 60 mg/kg bw/day) and rabbit 14 day oral study (LOAEL = 100 mg/kg bw/day based on mortality).  The level of concern for residential exposure is for MOEs = 100 and for occupational exposure is for MOEs =100.

	4.3.4. Dermal Absorption Factor

A dermal penetration study is not available.  A dermal absorption factor is derived by extrapolation from the rabbit 21-day dermal (MRID 41972901) and rabbit 14 day oral (MRID 00082073) studies.  The dermal systemic NOAEL in the 21-day study is 1000 mg/kg/day based on minor increases in liver enzymes.   In the 14 day rabbit oral study(MRID 00047138), the LOAEL is less than 100 mg/kg/day based on mortality and clinical signs (tremors) and the NOAEL is <100 mg/kg/day, therefore, the calculated dermal absorption factor would at the most be (100/1000) x 100 = 10%.

	4.3.5. Dermal Exposure (Short and Intermediate:  (1-30 days and 30 d-180 days)

Three subacute (21-day) dermal toxicity studies were considered. Only one study (MRID 00082073) with 24% active ingredient showed toxic effects.  The other two more recent studies (MRID 42029601 and 41972901) showed no systemic effects at the limit dose.  These effects were not seen in additional GLP dermal tests of similar duration using a 58.2% mefluidide formulation (MRID 42029601) or diethanolamine salt of mefluidide 28.8% (MRID 41972901).  The risk assessment team determined that no quantitative dermal assessment is needed due to the following:

1) Two 21-day dermal toxicity studies with rabbits indicated no dermal systemic toxicity at 1000 mg/kg/day (the highest dose tested),

2) The rat developmental study indicated no developmental concern (developmental NAOEL equals to maternal NOAEL),

3) The acute dermal toxicity of mefluidide, where the acute dermal LD50 is >4000 mg/kg, it is not a skin irritant and is not a dermal sensitizer.

	4.3.6. Inhalation (Short- and Intermediate-Term)

Endpoint for this scenario was determined from the rat developmental study.  NOAEL = 58 mg/kg bw/day, LOAEL = 115 mg/kg bw/day based on mortality and clinical sings.  These data were also supported by the rabbit developmental study (NOAEL = 60 mg/kg bw/day) and rabbit 14 day oral study (LOAEL = 100 mg/kg bw/day based on mortality).  Since oral study was selected for inhalation exposure assessment an inhalation-absorption factor of 100% oral equivalent should be used.

 	4.3.7. Margins of Exposure

These are summarized in the following table:

Route

                                    	       Duration	Short-Term

(1-30 Days)	Intermediate-Term

(1 - 6 Months)

Occupational (Worker) Exposure

Dermal	NA	NA

Inhalation	100	100

Residential (Non-Dietary) Exposure

Oral	100	100

Dermal	NA	NA

Inhalation	100	100

4.3.8. Classification of Carcinogenic Potential

Mefluidide was negative for carcinogenicity in mouse (MRID 00082747) and rat (MRID 00061930 7 00082737) bioassays.  It was also evaluated for genotoxicity in several tests and found negative. It is unlikely that mefluidide will pose a cancer risk to humans.

Table 4.3.  Summary of Toxicological Dose and Endpoints for Mefluidide and its salt (114001, 114002, 114003) Used in Human Risk Assessment

Exposure

Scenario

Point of Departure

Uncertainty Factors

Level of Concern for Risk Assessment

Study and Toxicological Effects

Acute Dietary (general population)

NOAEL = 58 mg/kg/day

	UFA = 10X

UFH = 10X

Acute RfD =

Maternal NOAEL

UncertaintyFactor

= 0.58 mg/kg /day

MRID 42026102

Developmental toxicity - rat;

LOAEL= 115.0 mg/kg/day based on mortality(within 5 days of dosing) and clinical signs (within 2 days of dosing), and the NOAEL of 58 mg/kg/day.

Acute Dietary (Females 13+)

NOAEL = 58 mg/kg/day

	UFA = 10X

UFH = 10X

Acute RfD =

Develop. NOAEL

UncertaintyFactor

= 0.58 mg/kg

MRID 42026102

Developmental toxicity - rat;

LOAEL= 115.0 mg/kg/day based on increased number of early resorptions and mean postimplantation loss. NOAEL = 58 mg/kg/day

Chronic Dietary

(All populations)

NOAEL = 1.5 mg/kg/day

	UFA = 10X

UFH = 10X

Chronic RfD =

NOAEL__

Uncertainty Factor

= 0.015 mg/kg/day

MRID 00132995

Chronic Oral Feeding - dog;

LOAEL= 15.0 mg/kg/day based on decreased body weight (15%) and body weight gain (50%) in the males at 15 mg/kg/day.

Short-Term

Incidental Oral (1-30 days)

NOAEL = 58 mg/kg/day

	UFA = 10X

UFH = 10X

Residential LOC for MOE = 100

	MRID 42026102

Developmental toxicity - rat;

NOAEL = 58 mg/kg bw/day, LOAEL = 115 mg/kg bw/day based on mortality and clinical sings.  These data were also supported by the rabbit developmental study (MRID 00047139) (NOAEL = 60 mg/kg bw/day) and rabbit 14 day oral study (LOAEL = 100 mg/kg bw/day based on mortality).

Intermediate-Term

Incidental Oral (1- 6 months)

Short-Term Dermal (1 to 30 days)

Dermal  NOAEL = 1000 mg/kg/day

	UFA = 10X

UFH = 10X

No quantitative dermal assessment is needed.

Three subacute (21-day) dermal toxicity studies were considered. The risk assessment team determined that no quantitative dermal assessment is needed due to the following:

1) Two 21-day dermal toxicity studies with rabbits indicated no dermal systemic toxicity at 1000 mg/kg/day (the highest dose tested),

2) the rat developmental study indicated no developmental concern (developmental NOAEL = maternal NOAEL),

3) acute toxicity of mefluidide, where acute dermal LD50 is >4000 mg/kg, not a skin irritant and is not a dermal sensitizer.

Intermediate-Term

Dermal (1 to 6 months)

Short-Term Inhalation (1 to 30 days)

Oral NOAEL = 58 mg/kg/day

(inhalation- absorption rate = 100% oral equivalent)	UFA = 10X

UFH = 10X

Residential LOC for MOE = 100;

Occupational LOC for MOE = 100

MRID 42026102

Developmental toxicity - rat;

NOAEL = 58 mg/kg bw/day, LOAEL = 115 mg/kg bw/day based on mortality and clinical sings.  These data were also supported by the rabbit developmental study (NOAEL = 60 mg/kg bw/day) and rabbit 14 day oral study (LOAEL = 100 mg/kg bw/day based on mortality).

Intermediate-Term Inhalation (1 to 6 months)

Cancer	Mefluidide was negative for carcinogenicity in mouse (MRID 00082747) and rat (MRID 00061930 7 00082737) bioassays.  It was also evaluated for genotoxicity in several tests and found negative.

Point of Departure (POD) = a data point or an estimated point that is derived from observed dose-response data and used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human exposures.  UF = uncertainty factor, UFA = extrapolation from animal to human (intraspecies), UFH = potential variation in sensitivity among members of the human population (interspecies), NOAEL = no observed adverse effect level, LOAEL = lowest observed adverse effect level, RfD = reference dose (a = acute, c = chronic), MOE = margin of exposure, LOC = level of concern, NA = Not Applicable. Safety Factor = UF = 100.

4.4. Cumulative tc \l1 "9.0 Cumulative  Risk Characterization/Assessment

Unlike other pesticides for which EPA has followed a cumulative risk approach based on a common mechanism of toxicity, EPA has not made a common mechanism of toxicity finding as to Mefluidide and its salts.  Mefluidide does not appear to produce a toxic metabolite produced by other substances.  For the purposes of this action, therefore, EPA has not assumed that mefluidide has 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 the policy statements released by EPA’s Office of Pesticide Programs concerning common mechanism determinations and procedures for cumulating effects from substances found to have a common mechanism on EPA’s website at   HYPERLINK "http://www.epa.gov/pesticides/cumulative/"  http://www.epa.gov/pesticides/cumulative/ .

Appendix A:  Toxicology Assessment  TC \l1 "Appendix A:  Toxicology Assessment

A.1	Toxicology Data Requirements TC \l2 "A.1  Toxicology Data Requirements

The requirements (40 CFR 158.340) for food and non food use for Mefluidie are in Table 1. Use of the new guideline numbers does not imply that the new (1998) guideline protocols were used.

Test

	Technical

	Required	Satisfied

870.1100    Acute Oral Toxicity

870.1200    Acute Dermal Toxicity

870.1300    Acute Inhalation Toxicity

870.2400    Primary Eye Irritation

870.2500    Primary Dermal Irritation

870.2600    Dermal Sensitization		yes

yes

yes

yes

yes

yes	yes

yes

yes

yes

yes

no

870.3100    Oral Subchronic (rodent)

870.3150    Oral Subchronic (nonrodent)

870.3200    21-Day Dermal

870.3250    90-Day Dermal

870.3465    90-Day Inhalation		yes

yes

yes

-

-	yes

yes

yes

-

-

870.3700a  Developmental Toxicity (rodent)

870.3700b  Developmental Toxicity (nonrodent)

870.3800    Reproduction		yes

yes

yes	yes

yes

yes

870.4100a  Chronic Toxicity (rodent)

870.4100b  Chronic Toxicity (nonrodent)

870.4200a  Oncogenicity (rat)

870.4200b  Oncogenicity (mouse)

870.4300    Chronic/Oncogenicity		yes

yes

yes

yes

yes	yes

yes

yes

yes

yes

870.5100    Mutagenicity—Gene Mutation - bacterial

870.5300    Mutagenicity—Gene Mutation - mammalian

870.5375    Mutagenicity—Structural Chromosomal Aberrations

870.5550    Mutagenicity—Unscheduled DNA synthesis		yes

yes

yes

yes	yes

yes

yes

yes

870.6100a  Acute Delayed Neurotox. (hen)

870.6100b  90-Day Neurotoxicity (hen)

870.6200a  Acute Neurotox. Screening Battery (rat)

870.6200b  90-Day Neuro. Screening Battery (rat)

870.6300    Develop. Neuro		no

no

no

no

no	-

-

-

-

-

870.7485    General Metabolism

870.7600    Dermal Penetration		yes

-	yes*

Special Studies for Ocular Effects

Acute Oral (rat)

Subchronic Oral (rat)

Six-month Oral (dog)

no

no

no

-

-

-

* Non-guideline studyA.2. Toxicology Profile

Table A.2.1.  Acute Toxicity of Mefluidide and its salts (114001, 114002, 114003)

Guideline

 No.

Study Type

MRID	Results (LD50/LC50)

Toxicity Category

870.1100

(81-1)	Acute Oral (female rat)

Mefluidide tech	>4000 mg/kg

MRID 00047118

III

870.1100

(81-1)	Acute Oral (mouse) Mefluidide tech	1920.2 mg/kg

MRID 00047117

III

870.1100

(81-1)	Acute Oral (mouse) Mefluidide tech	829.8 mg/kg

MRID 00047116

III

870.1100

(81-1)	Acute Oral (dog)

Mefluidide tech	Not established

MRID 00049627;  emesis precluded evaluation at 100, 500, 2000 mg/kg doses

III

870.1200

(81-2)	Acute Dermal (female rabbit)

Mefluidide tech	>4000 mg/kg

MRID 00047122 & 00049628 & 00083817

IV

870.1300

(81-3)	Acute inhalation – rat

DEA salt of Mefluidide       	>5.2 mg/L

MRID 41888801	IV

870.1300

(81-3)	Acute inhalation – rat

Mefluidide tech.  	>5.4 mg/L

MRID 41964601	IV

870.2400

(81-4)	Primary Eye Irritation (rabbit) Mefluidide tech	minimal irritation

MRID 00047126, 00049630

III

870.2400

(81-4)	Primary Eye Irritation (rabbit) DEA Mefluidide	minimal irritation

MRID43481203	III

870.2500

(81-5 )

Primary Skin Irritation (rabbit), Mefluidide tech

Not a dermal irritant

MRID 00047124, 00049629, 00083819

IV

87.2600

(81-6)	Dermal Sensitization (guinea pig), Mefluidide 	Not a dermal sensitizer

MRID 41887701

N/A

87.2600

(81-6)	Dermal Sensitization (guinea pig), Mefluidide 	Not a dermal sensitizer

MRID 00082076

N/A

Table A.2.2.  Toxicity Profile of Mefluidide and its salts (114001, 114002, 114003)

Guideline No./ Study type

MRID No.(year)/Doses/ classification

Results

Non-guideline

21-day Oral - dog	00047137, (1975)

0, 1000, 3000, 10000 ppm Vistar tech, 93% a.i./d (0, 25, 75, 250 mg/kg/d)

One dog/sex/dose

range finding

Acceptable/non-guideline

	LOAEL = not established.

NOAEL > 250 mg/kg/d,

Non-guideline

5-week - mouse	00082072, (1976)

0, 1800, 6000 ppm Vistar tech, 93% a.i./d (0, 270, 900 mg/kg/d)

(Dietary 5/sex/dose)

range finding

Acceptable/non-guideline	LOAEL = not established

NOAEL  = 900 mg/kg/d,

None-guideline

28-Day oral dietary [rat]	00047135, (1973),

0, 1000, 3000 or 10000 ppm Vistar tech, 93% a.i. (0, 100, 300, 1000 mg/kg/d)

 (Dietary 5 rats/sex/dose)

range finding

Acceptable/non-guideline

	LOAEL = not established.

NOAEL > 1000 mg/kg/d,

870.3100

(82-1a)

90-Day oral dietary [rat]	00047136, (1975),

0, 300, 1000 or 6000 ppm Vistar tech, 93% a.i. (0, 15, 50, 300 mg/kg/d) (10 rats/sex/dose)

00047140 (1975)

0, 300, 1000, 3000 ppm (0, 15, 50, 150 mg/kg/day). (10 females/dose)

Acceptable/Guideline

LOAEL = 300 mg/kg/d, based on decreased body weight, body weight gain and food consumption in the females.

NOAEL = 150 mg/kg/d (in conjunction with MRID # 00047140),

870.3150

82-1(b)

90-Day oral dietary [dog]	00047141, (IBT Study, 1977),

0, 300, 1000 or 6000 ppm Vistar tech, 93% a.i. (0, 7.5, 25, 150 mg/kg/d)

(4/sex/dose)

Unacceptable/guideline (LOAEL was not observed)

	LOAEL = not established.

NOAEL = 150 mg/kg/d.

870.3200

82-2

21-Day  Dermal toxicity - rabbit	00082073, (1977)

0, 1, 3, 10 ml of 2S formulation/kg/day (Formulation containing 24% a.i., equivalent to  0, 240, 720, or 2400 mg mefluidide/kg/day)

(4 rabbits/sex/dose)

Acceptable/Non-guideline

(NOAEL was not observed)

	Dermal LOAEL = 240 mg/kg/day, based on irritation, inflammation and necrosis at test sites.

Systemic LOAEL = 240 mg/kg/day, based on clinical chemistry (increased alkaline phosphatase and alanine aminotransferase) and organ weights (decreased spleen weight in females and increased liver weights in males).  Edema and swelling with myelin loss in sciatic nerve was seen in 720 and 2400 mg/kg/day dose group. Dehydration observed at 2400 mg/kg/day dose.

Dermal and systemic NOAELs were not established.

870.3200

82-2

21-Day  Dermal toxicity - rabbit	42029601 (1991)

0, 100, 500 or 1000 mg a.i./kg/d

Mefluidide 58.2% a.i.

(5/rabbits/sex/dose)

Acceptable/guideline

	Dermal toxicity LOAEL = 1000 mg/kg/day based on erythema at the test site.

Dermal toxicity NOAEL = 500 mg/kg/day

Systemic toxicity LOAEL was not established.  Minor hematological and clinical chemistry findings at 1000 mg/kg/day dose reported, that were within normal biological variation and did not correlate to histopathological findings.

Systemic toxicity NOAEL = 1000 mg/kg/day

870.3200

82-2

21-Day  Dermal toxicity - rabbit	41972901 (1991)

0, 100, 500 or 1000 mg a.i./kg/d

Mefluidide DEA salt 28.78% a.i.

(5/rabbits/sex/dose)

Acceptable/ guideline

	Dermal and systemic toxicity LOAEL was not established.  Minor incidences of erythema at 500 mg and 1000 mg/kg/day dose. Increased liver weight (absolute and relative) noted at 1000 mg/kg dose but no correlating histopathological findings. Minor statistical increases in liver enzymes AST and ALT.

Dermal and systemic NOAEL = 1000 mg/kg/day

Non-guideline

1-year feeding (Rat)	00132993, (1981)

0, 60, 200, 600 ppm Vistar tech, 93% a.i. (0, 3, 10, 30 mg/kg/d)

(20 rats/sex/dose)

Addendum to 2-year feeding study.

Acceptable/non-guideline

	LOAEL = not established

NOAEL = 30 mg/kg/d,

870.4100b

83-1b

Chronic Oral Feeding [dog]	00132995, (1982)

0, 60, 600, 6000 ppm Vistar tech, 93% a.i. (0, 1.5, 15, 150 mg/kg/d)

(6 dogs/sex/dose)

Acceptable/guideline

	LOAEL = 15 mg/kg/d, based on decreased body weight (15%) and body weight gain (50%) in the males. Chronic cortical nephrosis was observed at 150 mg/kg/day dose.

NOAEL = 1.5 mg/kg/d,

870.4100b

83-2b

 Carcinogenicity Dietary [mouse]	00082747, (1979)

0, 600, 1800, 6000 ppm Vistar tech, 93% a.i. (0, 90, 270, 900 mg/kg/d)

(60 mice/sex/dose)

Acceptable/guideline

	LOAEL = 270 mg/kg/day, based on increased incidence of liver hyperplastic nodules in both sexes.

NOAEL = 90 mg/kg/day.

No oncogenicity up to and including the highest dose tested.

870.4300

83-5

 2-year feeding/carcinogenicity [rat]	00061930, 00082737 (1979)

0, 600, 1800, 6000 ppm Vistar tech, 93% a.i. (0, 30, 90, 300 mg/kg/d)

(50 rats/sex/dose)

Acceptable/guideline

	LOAEL = 30 mg/kg/d, based on body weight loss.

NOAEL < 30 mg/kg/d,

No oncogenicity up to and including the highest dose tested.

870.3700a

83-3(a)

Developmental Toxicity, gavage [rat]

00132992, (1981)

0, 15, 30, 60 mg/kg/d

Unacceptable/guideline

(LOAEL was not observed)

Maternal LOAEL = not established.

Maternal NOAEL > 60 mg/kg/day,

Developmental NOAEL > 60 mg/kg/day, Developmental LOAEL = not established.

Non-guideline

Range Finding Developmental Toxicity , gavage[rat]	42026101, (1991)

0, 100, 200, 400, 600or 800 mg diethanolamine salt of mefluidide (28.78%)/kg/day

Doses adjusted for 100 % purity were 0, 29, 58, 115, 173, 230 mg/kg/day

(6 female rats/dose)

Acceptable/non-guideline

	Maternal LOAEL: 115 mg a.i./kg/day based on clinical signs (tremors, hunched posture, and salivation), maternal body weight gain and food consumption.

Maternal NOAEL: 58 mg a.i./kg/day;

Developmental LOAEL: 230 mg a.i. /kg/day based on significantly decreased fetal body weight.

Developmental NOAEL: 173 mg a.i. /kg/day,

The dosage levels of 0, 50, 200 and 400 mg of the 28.78% formulation/kg/day were selected for the definitive developmental study.

870.3700a

83-3(a)

Developmental Toxicity, gavage [rat]	42026102, (1991)

0, 50, 200 400 mg diethanolamine salt of mefluidide (28.78%)/kg/d

(25 females/dose)

Doses adjusted for 100 % purity were 0, 14, 58, or 115 mg/kg/day.

Acceptable/guideline	Maternal LOAEL = 115 mg a.i./kg/day based on mortality, clinical signs (tremors, stained nose, urine and vaginal discharge), decreased body weight and weight gain.

Maternal NOAEL = 58 mg a.i./kg/day,

Developmental LOAEL = 115 mg a.i./kg/day based on increased number of early resorptions and mean post-implantation loss.

Developmental NOAEL: 58mg a.i./kg/day

Non-guideline

14-Day Oral gavage [rabbit]	00047138, (1975)

0, 100, 200, 400, 800 mg/kg/d Vistar tech, 93% a.i.

4 females/dose

range finding

Acceptable/non-guideline	LOAEL = < 100 mg/kg/day (females), based on mortality (1/3 deaths) at 100 mg/kg/d.  Tremors and 100% mortality were noted at the levels of 200 mg/kg/d and above. Histopathology not reported.

NOAEL: not established,

870.3700b

83-3(b) Developmental Toxicity, gavage [rabbit]

	00047139, (1975)

0, 15, 30, 60 mg technical MBR 12325/kg/d (purity not reported).

Unacceptable by itself, however, if combined with the 14-day oral study (00047138), it is acceptable.	Maternal LOAEL = not established.

Maternal NOAEL = 60 mg/kg/day,

Developmental LOAEL = not established.

Developmental NOAEL = 60 mg/kg/day,

870.3800

(83-4 )

3-generation reproduction [rat]

00082748, (1979)

0, 600, 1800, 6000 ppm, 93% a.i. (M/F: 0/0, 34/60, 102/183, 346/604 mg/kg/d)

Acceptable/guideline

The parental systemic LOAEL = 346/604 mg/kg bw/day (M/F), based on decreased body weights.

The parental systemic NOAEL = 102/183 mg/kg bw/day in males/females.

The offspring LOAEL = 346/604 mg/kg bw/day in males/females, based on decreased body weights in both sexes and both litters in all generations.  The offspring NOAEL = 102/183 mg/kg bw/day in males/females.

The reproductive LOAEL was not observed.

The reproductive NOAEL = 346/604 mg/kg bw/day in males/females.

870.5100

84-2

Bacterial reverse mutation 	00132996, (1983)

EL-565 (Lily compound 151065: mefluidide technical) tested at 0.1 – 1000 µg/ml

Acceptable/Guideline	No reverse mutations were noted in any of 8 tester strains of Salmonella typhimurium and two tryptophan autotrophs of E. coli with or without metabolic activation

870.5100

84-2

Bacterial reverse mutation 	41888804, (1991)

0, 100, 333, 667, 1000, 3330, or 5000 µg/plate diethanolamine salt of mefluidide (28.78%)/

Acceptable/guideline	DEA mefluidide did not increase the number of histidine revertants per plate in any of the tester strains with or without metabolic activation.

870.5300

84-2

In-vitro Mouse lymphoma - gene mutation 	00132996, (1983)

EL-565 (Lily compound 151065: mefluidide technical)0, 1, 25, 50, 100, 250, 500, 750 or 1000 µg/ml

Acceptable/guideline	There was no evidence of mutation in the presence or absence of metabolic activation.

870.5375

84-2

In-vitro mammalian chromosome aberration test	41888803, (1991)

Diethanolamine salt of mefluidide (28.8%)

500,- 5010 µg a.i. /ml (without S9 mix) or 500, - 5000 (with S9 mix)

Acceptable/guideline 	No significant increase in structural chromosomal aberration with or without metabolic activation was seen, however, the results were considered equivocal.

(84-2 In-vitro mammalian chromosome aberration test	(1992)

concentrations of 1250 to 5000 µg/ml (w S9 mix) or 200-1600 µg/ml (wt S9 mix)

	Not mutagenic in Chinese Hamster Ovary cells

870.5550

84-2

Unscheduled DNA Synthesis	41888802, (1991)

Diethanolamine salt of mefluidide (28.8%)

Concentrations of 100, 250, 500, 1000, 2000, 3000 µg/ml in trial 1; 1000, 1500, 2000, 3000, 3500 µg/ml in trial 2.

Acceptable/guideline	No unscheduled DNA synthesis response in the absence of moderate to severe cytotoxicity.

870.5550

84-2

Unscheduled DNA Synthesis	00132996, (1983)

EL-565 (Lily compound 151065: mefluidide technical)

Tested at 0.5 to 1000 nmoles/mL	No indication of DNA repair synthesis was observed in cultured rat heapatocytes treated with the test material (EL-565 (Lily compound 151065: mefluidide technical))

870.5915

84-2

In-vivo Sister Chromatid Exchange	00132996, (1983)

EL-565 (Lily compound 151065: mefluidide technical)

(0, 12.5, 25, 50, or 100 mg/kg.

Acceptable/Guideline	Negative in sister chromatid exchange in in-vivo bone marrow of Chinese hamster assay.

870.5915

85-1

Metabolism- male rat

MRID is not known: Steifer, LJ (1978). 3M Company Report Number 852 (1-26-78)

Dose: 1 or 10 mg/kg of C-14, labeled mefluidide

Acceptable/None-Guideline

By 24 hrs of post-treatment, 86-89% of the dose was found in urine with the remainder in the feces.  Residue consisted of mefluidide (97%) and 2 unidentified metabolites (1.2% and 0.5%) and unidentified polar material (0.7%).

870.6200

81-8

 Demyelination study – Female Chicken

00082075 (1977)

S-12325-2S  formulation

Single doses at 1000, 3000, 5000, 10,000 and 20,000 mg/kg/day.

TOCP as positive control

5-10 hens/dose

Non-Acceptable/Non-Guideline

LD50 was 8500 mg/kg

At 1000 mg/kg/day: clinical signs (hypoactivity, ataxia, tremors, lethargy and dyspnea) that were subsided by 48 hrs following dosing.

The test material did not induce delayed neurotoxicity in hens

M = Males; F = Females

 PAGE

Page   PAGE  17  of   NUMPAGES  17

Acute RfD (general population)  =      58 mg/kg (NOAEL)   = 0.58 mg/kg

		    	100 (UF)

Acute RfD (Females 13-50 years old)  =      58 mg/kg (NOAEL)   = 0.58 mg/kg

		    	         100 (UF)


          Responses to Comments - SO2 Data Requirement Rule Modeling
              (Source: Emails between Rick Gillam, EPA Region 4,
                     and Tom Anderson, NCDENR, June 2017)

Duke Energy Marshall Steam Station

1)      Marshall Source Parameters
-          *Actual SO2 emissions were used in the impact assessment.  Information on the quality and completeness of these data should be provided as well as the procedures used to replace/substitute missing actual emissions.
SO2 emissions were obtained from Duke Energy staff.
Duke Response: The SO2 emissions data were obtained from the data reported by our CEMS, using the same data base that is reported to the EPA Clean Air Markets Division (CAMD).  All substituted values are as reported to CAMD in accordance with Part 75 requirements.  SO2 data availability was 98.9% or greater for all stacks during this period.
-          *Varying stack exit parameters were indicated used in the modeling.  Information on the quality and completeness of these data should be provided as well as the procedures used to replace/substitute missing actual values.
Hourly varying stack parameters were obtained from Duke Energy staff.
Duke Response:  The hourly stack exit velocity was calculated using Part 75 CEMS data.  CEMS monitor data availability for flow measurement was 99.5% or greater for all stacks during this period.  The hourly exit velocity was calculated from the hourly flow and stack temperature data  using the following equation.

      V msec=A STD ft3hr x hr60 min x min60 sec x B+480528 x PI x D22x 0.3048 m3ft3

      Where:
      V is the stack exist velocity in meter/sec
      A is the Part 75 stack flow rate in standard cubic feet per hour
      B is the stack gas temperature in degree F
      D is the stack diameter in feet

2)      Other Nearby SO2 Emission Sources
-          *The emission inventory of all nearby emissions sources considered should be provided.  The sources eliminated should be identified along with the basis for their elimination.  This information is needed to evaluate the appropriateness of the procedures used.
A file including all SO2 sources within 50 km is attached to this message (filename: Duke SO2 Inventories_Actuals.xls).  Section 9, page 8, of the modeling report describes how nearby sources were evaluated for inclusion in the analysis.

Duke Energy Allen Steam Station

1)      Other Nearby SO2 Emission Sources
-          *The emission inventory of all nearby emissions sources considered should be provided.  The sources eliminated should be identified along with the basis for their elimination.  This information is needed to evaluate the appropriateness of the procedures used.
A file including all SO2 sources within 50 km is attached to this message (filename: Duke SO2 Inventories_Actuals.xls).  Section 9, page 9, of the modeling report describes how nearby sources were evaluated for inclusion in the analysis.

Duke Energy Mayo Electric Generating Plant

1)      Modeled Emissions
-          *The Mayo facility was indicated to operate two coal-fired boilers each vented to individual stacks.  Figure 3 is indicated to provide the location of buildings, stacks, and the facility fence line.  Based on Figures 3 & 4 and the modeling files, there is only one stack.  These differences should be explained.
The text in Section 7, page 4, of the modeling report that indicates that the two boilers vent to individual stacks is an error.  The statement was simply an inadvertent carryover from another report that was used as a template and the two boilers do indeed vent from only a single stack.

2)      Other Nearby SO2 Emission Sources
-          *The basis for the hourly emission rates developed for the Duke-Roxboro Units 1-4 and CPI-Roxboro Units 1A, 1B, and 1C should be provided/ explained (e.g., actual emission from CEM data for period 2013-2015, etc.).  Additionally, the hourly emissions files used in the modeling should be provided for review.
A file including all SO2 sources within 50 km is attached to this message (filename: Duke SO2 Inventories_Actuals.xls).  Section 9, page 6, of the modeling report describes how nearby sources were evaluated for inclusion in the analysis.

The hourly emission rates for both the Duke  -  Roxboro units and the CPI units were obtained from actual CEM data for the period 2013-2015 and were obtained from EPA's Clean Air Markets Database (https://ampd.epa.gov/ampd/).

The hourly emissions file used in the modeling is attached to this message (filename: mayo_hourly emissions SO2.txt)

Duke Energy Belew Creek Generating Station

1)      Modeled Emissions
-          * Missing CEMS stack temperatures were replaced with an average stack temperature determined from the CEMS data (i.e., 120 degrees F). If the data record has many missing values, use of the recorded actual stack temperatures about the missing value(s) to developed replacements would be more appropriate.
Duke Response:  Use of "before and after" temperatures might be appropriate for short periods of missing data where the operating conditions are similar during the missing period, but for longer periods of missing data, an average temperature is a more appropriate representation since the operating conditions (minimum to maximum generating load and heat input) may vary significantly over time .  Also, due to the continuous operation of the wet scrubbers, there is a relatively small range of temperature variation ( average 121 °F with standard deviation of 3.5 °F) and there should be little impact on the modeling whether using the average temperature or a temperature based on the period before and after.

-          *These Auxiliary Boilers were modeled using the EPA Clarifications Memorandum guidance on intermittent sources that annualizes the emissions for the full year, to obtain an annual average hourly value used for each hour of the year.  These boilers were indicated to only operate when the coal-fired Utility Boilers are not operating or just starting up (i.e., no simultaneous operations).  If simultaneous operations are not possible and the coal-fired boilers have much larger SO2 hourly emissions than fuel oil-fired boilers, the operation of Auxiliary Boilers (ES-3 and ES-4) should not be controlling.  A comparison of the maximum SO2 emission rates for these boilers should be provided.  Because of the lower stack height for ES-3/4 boilers, the maximum impacts of the oil-fired and coal-fired boilers may be needed to demonstrate the appropriateness of treating the Auxiliary Boilers as intermittent sources.
Duke Response:  The two auxiliary boilers combust fuel oil that is exclusively the ULSD fuel oil supply that is commercially available in the region. The maximum emissions rate for these boilers is 0.27 lb/hr each.  The emissions rate for the Belews Creek Units 1 and 2 EGU boilers operating at maximum averages approximately 1,200 lb/hr, with a typical range (95% of data) between 600 to 2000 lb/hr.

2)      Other Nearby SO2 Emission Sources
-          *The emission inventory of all nearby emissions sources considered should be provided.  The sources eliminated should be identified along with the reason/basis for their elimination to support the appropriateness of the procedures used.
Duke Response:  A file including all SO2 sources within 50 km is attached to this message (filename: BCInventory010517.xlsx).  Section 13, pages 22-25, of the modeling report describes how nearby sources were evaluated for inclusion in the analysis.

-          *Documentation on the 2015 permit removal of the 4 coal-fired boilers at Millers Coors Brewery should be provided to support this source's exclusion from the modeling assessment..
Attached are two files to support the exclusion of the boilers from the modeling  -  1) a 2015 Permit Review in which removal of the boilers is discussed and, 2) the latest 2017 Compliance Inspection Report that shows all permitted sources at the facility.
-          *Section 13.1 indicates maximum annual emissions over the 2013-2015 period were used in the modeling of nearby emission sources.  This does not appear to agree with Section 13.0 indication that actual emissions were used.  The report should clearly indicate the basis of the emissions for each nearby source used in the screening process and in the impact modeling assessment. Also, the following information is needed:
         o   The reason the assumption of 8,760 hours of operation for years 2013 -2015 is appropriate.
 The reason permit estimated emission rates for the melt, casting, and arc furnaces emitted from roof vents are appropriate for permit application and not actuals during the 2013-2015 period.
Duke Response: The modeled emissions rate was estimated by dividing the reported annual emissions over the period from 2013 to 2015  by 8760 hour/year. The inventory did not provide information on the hours of operation,  therefore  8,760 hours of operation was used to estimate the lbs/hr emissions rate used in the modeling .


[Federal Register Volume 84, Number 246 (Monday, December 23, 2019)]
[Rules and Regulations]
[Pages 70423-70424]
[FR Doc No: 2019-27529]

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

DEPARTMENT OF TRANSPORTATION

Federal Aviation Administration

14 CFR Part 97

[Docket No. 31287; Amdt. No. 3883]

Standard Instrument Approach Procedures, and Takeoff Minimums and
Obstacle Departure Procedures; Miscellaneous Amendments

AGENCY: Federal Aviation Administration (FAA), DOT.

ACTION: Final rule.

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

SUMMARY: This rule establishes, amends, suspends, or removes Standard
Instrument Approach Procedures (SIAPs) and associated Takeoff Minimums
and Obstacle Departure Procedures (ODPs) for operations at certain
airports. These regulatory actions are needed because of the adoption
of new or revised criteria, or because of changes occurring in the
National Airspace System, such as the commissioning of new navigational
facilities, adding new obstacles, or changing air traffic requirements.
These changes are designed to provide safe and efficient use of the
navigable airspace and to promote safe flight operations under
instrument flight rules at the affected airports.

DATES: This rule is effective December 23, 2019. The compliance date
for each SIAP, associated Takeoff Minimums, and ODP is specified in the
amendatory provisions.
    The incorporation by reference of certain publications listed in
the regulations is approved by the Director of the Federal Register as
of December 23, 2019.

ADDRESSES: Availability of matters incorporated by reference in the
amendment is as follows:

For Examination

    1. U.S. Department of Transportation, Docket Ops-M30, 1200 New
Jersey Avenue SE, West Bldg., Ground Floor, Washington, DC 20590-0001.
    2. The FAA Air Traffic Organization Service Area in which the
affected airport is located;
    3. The office of Aeronautical Navigation Products, 6500 South
MacArthur Blvd., Oklahoma City, OK 73169 or,
    4. The National Archives and Records Administration (NARA). For
information on the availability of this material at NARA, email
<EMAIL_ADDRESS>or go to: https://www.archives.gov/federal-register/cfr/ibr-locations.html.

Availability

    All SIAPs and Takeoff Minimums and ODPs are available online free
of charge. Visit the National Flight Data Center at nfdc.faa.gov to
register. Additionally, individual SIAP and Takeoff Minimums and ODP
copies may be obtained from the FAA Air Traffic Organization Service
Area in which the affected airport is located.

FOR FURTHER INFORMATION CONTACT: Thomas J. Nichols, Flight Procedures
and Airspace Group, Flight Technologies and Procedures Division, Flight
Standards Service, Federal Aviation Administration. Mailing Address:
FAA Mike Monroney Aeronautical Center, Flight Procedures and Airspace
Group, 6500 South MacArthur Blvd., Registry Bldg. 29, Room 104,
Oklahoma City, OK 73169. Telephone:<PHONE_NUMBER>.

SUPPLEMENTARY INFORMATION: This rule amends Title 14 of the Code of
Federal Regulations, Part 97 (14 CFR part 97), by establishing,
amending, suspending, or removes SIAPS, Takeoff Minimums and/or ODPS.
The complete regulatory description of each SIAP and its associated
Takeoff Minimums or ODP for an identified airport is listed on FAA form
documents which are incorporated by reference in this amendment under 5
U.S.C. 552(a), 1 CFR part 51, and 14 CFR part 97.20. The applicable FAA
forms are FAA Forms 8260-3, 8260-4, 8260-5, 8260-15A, and 8260-15B when
required by an entry on 8260-15A.
    The large number of SIAPs, Takeoff Minimums and ODPs, their complex
nature, and the need for a special format make publication in the
Federal Register expensive and impractical. Further, airmen do not use
the regulatory text of the SIAPs, Takeoff Minimums or ODPs, but instead
refer to their graphic depiction on charts printed by publishers of
aeronautical materials. Thus, the advantages of incorporation by
reference are realized and publication of the complete description of
each SIAP, Takeoff Minimums and ODP listed on FAA form documents is
unnecessary. This amendment provides the affected CFR sections and
specifies the types of SIAPs, Takeoff Minimums and ODPs with their
applicable effective dates. This amendment also identifies the airport
and its location, the procedure, and the amendment number.

Availability and Summary of Material Incorporated by Reference

    The material incorporated by reference is publicly available as
listed in the ADDRESSES section.
    The material incorporated by reference describes SIAPS, Takeoff
Minimums and/or ODPS as identified in the amendatory language for part
97 of this final rule.

The Rule

    This amendment to 14 CFR part 97 is effective upon publication of
each separate SIAP, Takeoff Minimums and ODP as Amended in the
transmittal. Some SIAP and Takeoff Minimums and textual ODP amendments
may have been issued previously by the FAA in a Flight Data Center
(FDC) Notice to Airmen (NOTAM) as an emergency action of immediate
flight safety relating directly to published aeronautical charts.
    The circumstances that created the need for some SIAP and Takeoff
Minimums and ODP amendments may require making them effective in less
than 30 days. For the remaining SIAPs and Takeoff Minimums and ODPs, an
effective date at least 30 days after publication is provided.
    Further, the SIAPs and Takeoff Minimums and ODPs contained in this
amendment are based on the criteria contained in the U.S. Standard for
Terminal Instrument Procedures (TERPS). In developing these SIAPs and
Takeoff Minimums and ODPs, the TERPS criteria were applied to the
conditions existing or anticipated at the affected airports. Because of
the close and immediate relationship between these SIAPs, Takeoff
Minimums and ODPs, and safety in air commerce, I find that notice and
public procedure under 5 U.S.C. 553(b) are impracticable and contrary
to the public interest and, where applicable, under 5 U.S.C. 553(d),
good cause exists for making some SIAPs effective in less than 30 days.
    The FAA has determined that this regulation only involves an
established body of technical regulations for which frequent and
routine amendments are necessary to keep them operationally current.
It, therefore--(1) is not a ``significant regulatory action'' under
Executive Order 12866; (2) is not a ``significant rule'' under DOT
Regulatory Policies and Procedures (44 FR 11034; February 26, 1979);
and (3) does not warrant preparation of a regulatory evaluation as the
anticipated impact is so minimal. For the same reason, the FAA
certifies that this amendment will not have a significant economic
impact on a substantial number of small entities under the criteria of
the Regulatory Flexibility Act.

List of Subjects in 14 CFR Part 97

    Air traffic control, Airports, Incorporation by reference,
Navigation (Air).

    Issued in Washington, DC, on December 13, 2019.
Rick Domingo,
Executive Director, Flight Standards Service.

Adoption of the Amendment

    Accordingly, pursuant to the authority delegated to me, Title 14,
Code of Federal Regulations, Part 97 (14 CFR part 97) is amended by
establishing, amending, suspending, or removing Standard Instrument
Approach Procedures and/or Takeoff Minimums and Obstacle Departure
Procedures effective at 0901 UTC on the dates specified, as follows:

PART 97--STANDARD INSTRUMENT APPROACH PROCEDURES

0
1. The authority citation for part 97 continues to read as follows:

    Authority: 49 U.S.C. 106(f), 106(g), 40103, 40106, 40113, 40114,
40120, 44502, 44514, 44701, 44719, 44721-44722.

0
2. Part 97 is amended to read as follows:

Effective 30 January 2020

Klawock, AK, Klawock, RNAV (GPS) RWY 20, Orig
Klawock, AK, Klawock, RNAV (GPS) Y RWY 2, Amdt 1
Riverside, CA, Riverside Muni, RIVERSIDE ONE, Graphic DP
Riverside, CA, Riverside Muni, Takeoff Minimums and Obstacle DP, Amdt
11
Denver, CO, Colorado Air and Space Port, Takeoff Minimums and Obstacle
DP, Amdt 3A
Washington, DC, Ronald Reagan Washington National, Takeoff Minimums and
Obstacle DP, Amdt 8B
Georgetown, DE, Delaware Coastal, RNAV (GPS) RWY 22, Amdt 2D
Jacksonville, FL, Cecil, ILS OR LOC RWY 36R, Amdt 4
Jacksonville, FL, Cecil, VOR RWY 9R, Amdt 1A, CANCELLED
Jacksonville, FL, Cecil, VOR RWY 27L, Orig
Miami, FL, Miami Intl, LOC RWY 8L, Orig-C
Atlanta, GA, Fulton County Airport--Brown Field, ILS OR LOC RWY 8, Amdt
18
Atlanta, GA, Fulton County Airport--Brown Field, RNAV (GPS) Y RWY 8,
Amdt 2
Atlanta, GA, Fulton County Airport--Brown Field, RNAV (RNP) Z RWY 8,
Amdt 2
Tifton, GA, Henry Tift Myers, ILS OR LOC RWY 34, Amdt 3
Honolulu, HI, Daniel K Inouye Intl, ILS Y RWY 4R, Amdt 2
Honolulu, HI, Daniel K Inouye Intl, ILS Z RWY 4R, Amdt 2
Mc Call, ID, Mc Call Muni, RNAV (GPS) RWY 34, Amdt 1A
Warsaw, IN, Warsaw Muni, Takeoff Minimums and Obstacle DP, Amdt 3
Washington, KS, Washington County Veteran's Memorial, RNAV (GPS) RWY
35, Amdt 1A
Washington, KS, Washington County Veteran's Memorial, Takeoff Minimums
and Obstacle DP, Amdt 1
Pittsfield, MA, Pittsfield Muni, LOC RWY 26, Amdt 10
Pittsfield, MA, Pittsfield Muni, RNAV (GPS) RWY 26, Amdt 2
Grand Rapids, MI, Gerald R Ford Intl, ILS OR LOC RWY 35, ILS RWY 35 (SA
CAT I), ILS RWY 35 (SA CAT II), Amdt 2B
Grand Rapids, MI, Gerald R Ford Intl, RNAV (GPS) RWY 8L, Amdt 1B
New Bern, NC, Coastal Carolina Regional, ILS OR LOC RWY 4, Amdt 2
Minot, ND, Minot Intl, RNAV (GPS) RWY 31, Amdt 1C
Toledo, OH, Toledo Express, ILS Z OR LOC Z RWY 25, Amdt 9
Perkasie, PA, Pennridge, Takeoff Minimums and Obstacle DP, Amdt 1
Galveston, TX, Scholes Intl at Galveston, RNAV (GPS) RWY 18, Amdt 2B
Houston, TX, George Bush Intercontinental/Houston, RNAV (GPS) RWY 15R,
Amdt 2C
Kerrville, TX, Kerrville Muni/Louis Schreiner Field, RNAV (GPS) RWY 12,
Amdt 1B
Kerrville, TX, Kerrville Muni/Louis Schreiner Field, RNAV (GPS) RWY 30,
Orig-B
San Angelo, TX, San Angelo Rgnl/Mathis Field, ILS Y OR LOC Y RWY 3,
Amdt 22A
Wheatland, WY, Phifer Airfield, SLATR ONE, Graphic DP
Wheatland, WY, Phifer Airfield, Takeoff Minimums and Obstacle DP, Amdt
1

    Rescinded: On November 29, 2019 (84 FR 65673), the FAA published an
Amendment in Docket No. 31283, Amdt No. 3879, to Part 97 of the Federal
Aviation Regulations under sections 97.37. The following entry for
Shreveport, LA effective January 30, 2019, is hereby rescinded in its
entirety:

Shreveport, LA, Shreveport Downtown, Takeoff Minimums and Obstacle DP,
Amdt 4

[FR Doc. 2019-27529 Filed 12-20-19; 8:45 am]
 BILLING CODE 4910-13-P


[Federal Register: March 31, 2008 (Volume 73, Number 62)]
[Notices]
[Page 16861-16862]
[DOCID:fr31mr08-73]

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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. FDA-2008-D-0143] (formerly Docket No. 2006D-0056)

Compliance Policy Guide Sec. 500.500 Guidance Levels for 3-MCPD
(3-chloro-1, 2-propanediol) in Acid-Hydrolyzed Protein and Asian-Style
Sauces; Availability

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice.

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

SUMMARY: The Food and Drug Administration (FDA) is announcing the
availability of compliance policy guide (CPG) Sec. 500.500 Guidance
Levels for 3-MCPD (3-chloro-1, 2-propanediol) in Acid-Hydrolyzed
Protein and Asian-Style Sauces. The CPG provides regulatory action
guidance for FDA staff regarding 3-MCPD in acid-hydrolyzed

protein (acid-HP) and Asian-style sauces.

DATES: Submit written or electronic comments regarding the CPG at any
time.

ADDRESSES: Submit written comments on the CPG to the Division of
Dockets Management (HFA-305), Food and Drug Administration, 5630
Fishers Lane, rm. 1061, Rockville, MD 20852. Submit electronic comments
to: http://www.regulations.gov.
    Submit written requests for single copies of CPG Sec. 500.500
Guidance Levels for 3-MCPD (3-chloro-1,2-propanediol) in Acid-
Hydrolyzed Protein and Asian-Style Sauces to the Division of Compliance
Policy (HFC-230), Office of Enforcement, Food and Drug Administration,
5600 Fishers Lane, Rockville, MD 20857,<PHONE_NUMBER>. Send two self-
addressed adhesive labels to assist that office in processing your
request, or fax your request to<PHONE_NUMBER>. See the SUPPLEMENTARY
INFORMATION section for electronic access to the document.

FOR FURTHER INFORMATION CONTACT: Judith L. Kidwell, Office of Food
Additive Safety, Center for Food Safety and Applied Nutrition (HFS-
265), Food and Drug Administration, 5100 Paint Branch Pkwy., College
Park, MD, 20740-3835,<PHONE_NUMBER>.

SUPPLEMENTARY INFORMATION:

I. Background

    In the Federal Register of May 23, 2006 (71 FR 29651), FDA
announced the availability of draft CPG Sec. 500.500 Guidance Levels
for 3-MCPD (3-chloro-1,2-propanediol) in Acid-Hydrolyzed Protein and
Asian-Style Sauces. FDA received one comment on the draft CPG. The
International Hydrolyzed Protein Council (IHPC) offered clarification
for the following sentence found in the BACKGROUND section of the draft
CPG: ``Since 1996, many countries * * * have recommended or required
that industry take steps to ensure that 3-MCPD is not detectable in
acid-HP or Asian-style sauces at levels ranging from 0.01 parts per
million (ppm) to 1 ppm.'' IHPC suggested that we revise the sentence as
follows: ``Since 1996, many countries * * * have recommended or
required that industry take steps to ensure that 3-MCPD in acid-HP or
Asian-style sauces does not exceed levels ranging from 0.01 parts per
million (ppm) to 1 ppm.'' IHPC explained that using the phrase ``not
detectable'' and then listing allowable levels is confusing. We concur
with the comment and have revised the final CPG accordingly. FDA also
revised the SPECIMEN CHARGES section in the final CPG to provide
operational guidance regarding reference to the United States Code
(U.S.C.) when citing the violation charged in a domestic seizure and
reference to the Federal Food, Drug, and Cosmetic Act when citing the
violation charged in an import detention. We also have made other
editorial changes to the CPG for clarification.
    This CPG is being issued as level 1 guidance consistent with FDA's
good guidance practices regulations (21 CFR 10.115). The CPG represents
the agency's current thinking on 3-MCPD in acid-HP and Asian-style
sauces. It does not create or confer any rights for or on any person
and does not operate to bind FDA or the public. An alternate approach
may be used if such approach satisfies the requirements of the
applicable statutes and regulations.

II. Comments

    Interested persons may submit to the Division of Dockets Management
(see ADDRESSES) written or electronic comments on the CPG at any time.
Submit a single copy of electronic comments or two paper copies of any
mailed comments, except that individuals may submit one paper copy.
Comments are to be identified with the docket number found in brackets
in the heading of this document. The CPG and received comments may be
seen in the Division of Dockets Management between 9 a.m. and 4 p.m.,
Monday through Friday.
    Please note that on January 15, 2008, the FDA Division of Dockets
Management Web site transitioned to the Federal Dockets Management
System (FDMS). FDMS is a Government-wide, electronic docket management
system. Electronic comments or submissions will be accepted by FDA
through FDMS only.

III. Electronic Access

    Persons with access to the Internet may obtain the CPG from the
Office of Regulatory Affairs home page at http://www.fda.gov/ora under
``Compliance Reference.''

    Dated: March 14, 2008.
Margaret O'K. Glavin,
Associate Commissioner for Regulatory Affairs.
[FR Doc. E8-6504 Filed 3-28-08; 8:45 am]

BILLING CODE 4160-01-S