St. John, Virgin Islands

2002 Regional Haze Base Year Modeling Inventory SIP

Technical Support Documentation

June 19, 2012

	PREFACE

This document is to support EPA's approval of a revision to the Virgin
Islands’ State Implementation Plan (SIP) which pertains to the
following:

Where applicable, 2002 modeling base year inventory annual emissions for
PM2.5, NOx and SO2 for St. John, Virgin Island (VI) area.  Among the
topics discussed below are the recent history and criteria for approval
and EPA’s final recommendations.

	BACKGROUND

On November 18, 2002, EPA designated the 2002 base year inventory as the
inventory for SIP planning process to address the pollutants for the
eight hour-ozone, PM2.5 and CO national ambient air quality standard.
Identifying the base year gives certainty to States, and the selection
of 2002 harmonized the date for EPA’s Consolidated Emissions Reporting
rule (See 67 FR 39602) dated June 10, 2002.) that requires submission of
the ozone, PM2.5 and CO emission inventories every three years; 2002 is
one of the required years for such updates.  These requirements allow
the EPA, based on the state’s progress in reducing emissions, to
periodically reassess its policies and air quality standards and revise
them as necessary.  Most important, the 2002 ozone, new PM2.5 and CO
inventories will be used to develop and assess new control strategies
that the states will need to submit in their attainment demonstration
SIPs for the new national ambient air quality standards for ozone, PM2.5
and CO.  The base year inventory may also serve as part of statewide
inventories for purposes of regional modeling in transport areas.  The
base year inventory plays an important role in modeling demonstrations
for areas classified as nonattainment and outside transport regions.
For the reasons stated above, ideally EPA would therefore emphasize the
importance and benefits of developing a comprehensive, current, and
accurate 2002 ozone and PM2.5 emission inventories.

	CRITERIA FOR APPROVAL

There are general and specific components of an acceptable emissions
inventory.  In general, the State must submit a revision to its SIP and
the emission inventory must meet the minimum requirements for reporting
by source category.  Specifically, the source requirements are detailed
below.

The Level I and II review process is used to determine that all
components of the base year inventory are present.  The review also
evaluates the level of supporting documentation provided by the State
and assesses whether the emissions were developed according to current
EPA or acceptable alternative guidance.  The data quality is also
evaluated.

The Level III review process is outlined here and consists of 9 points
that the inventory must adequately address.  For a base year emission
inventory to be acceptable it must pass all of the following acceptance
criteria:

Adequate documentation must be provided that enabled the reviewer to
determine the emission estimation procedures and the data sources used
to develop the inventory.

1.	Evidence that the inventory was quality assured by the state and its
implementation documented.

2.	The point source inventory must be complete.

3.	Point source emissions must have been prepared or calculated
according to the current EPA guidance.

4.	The area source inventory must be complete.

5.	The area source emissions must have been prepared or calculated
according to the current EPA guidance.

6.	Non-road mobile emissions were prepared according to current EPA
guidance for all of the source categories.

8.	The method (e.g., HPMS or a network transportation planning model)
used to develop VMT estimates must follow EPA guidance.  The VMT
development methods were adequately described and documented in the
inventory report.

9.	The MOBILE model must be correctly used to produce emission factors
for each of the vehicle classes.

	DETAILED ACTION AND EVALUATION

Drafts and final versions of the Emissions Inventory were provided to
Region 2 for the following documents and program area elements:

Where applicable, 2002 base year inventory annual PM2.5, NOx and SO2
emissions for the area.  See Tables 1-3 below.  This TSD contains a
detailed discussion and summary of the review conducted by EPA for,
where applicable, the 2002 base year inventory annual emissions for
PM2.5, NOx and SO2 the area.

	Details on How the Virgin Islands Satisfies Criteria 1 for the Quality
Assurance Plan

Quality Assurance Plan Implementation

The Quality Assurance (QA) plan was implemented for all portions of the
inventory.  The QA plan included a QA/Quality control (QC) program for
assessing data completeness and standard range checking.  Critical data
elements relative to the inventory sources were assessed for
completeness.  QA checks were performed relative to data collection and
analysis, and double counting of emissions from point, area and mobile
sources.  QA/QC checks were conducted to ensure accuracy of units, unit
conversions, transposition of figures, and calculations.

The reader is referred to Chapter II of Development of the 2002 Regional
Haze Area, Point, Nonroad Mobile and Onroad Mobile Source Emission
Inventories for St. John, Virgin Islands, dated June 2010.  The QA plan
for the inventory was performed in accordance with EPA Guidance.1,2,3

	Details on How the Virgin Islands Satisfies Criteria 2 and 3 for the
Point Source Inventory

Point Source Inventory

St. John, VI inventory includes point sources PM2.5, NOx and SO2
emissions for the area..  The inventory report describes how point
source activity levels and their associated parameters are developed,
and how the data are used to calculate emission estimates.  The report
references document for activity level and emission factors used and
provides sample actual activity data and emissions factors.  Information
on how control efficiencies are applied and the associated sample
calculations with numerical values are provided.  Where applicable,
annual PM2.5, NOx and SO2 point source emissions are presented for the
area.  Plant summary information on detailed plant levels is included in
the inventory.  The reader is referred to Chapter III of Development of
the 2002 Regional Haze Area, Point, Nonroad Mobile and Onroad Mobile
Source Emission Inventories for St. John, Virgin Islands, dated June
2010.  Thus, the point inventory was developed in accordance with
section 5.3 of EPA Guidance.1,2,3

	Details on How The Virgin Islands Satisfies Criteria 4 and 5 for the
Area Source Inventory

Area Source Inventory

The inventory lists the source categories that are included in the area
source inventory. Area source emissions are presented on a source
category, county basis.  Where applicable, annual emissions are provided
for PM2.5, SO2 and NOx for the area. Inventory documentation includes
emissions factors, activity levels and sample calculations.  Referenced
information for the input values to equations is included.  Point source
contributions have been correctly factored out of the area source
category totals where appropriate.  Control efficiency and rule
penetration are correctly applied for source categories. The reader is
referred to Chapter IV of Development of the 2002 Regional Haze Area,
Point, Nonroad Mobile and Onroad Mobile Source Emission Inventories for
St. John, Virgin Islands, dated June 2010.  Thus, the area source
inventory was developed in accordance with EPA Guidance.1,2,3

	Details on How The Virgin Islands Satisfies Criteria 6 for Non Road
Mobile Source Inventory

Commercial Marine Vessel Emissions

Commercial marine vessel (CMV) emissions for PM2.5, NOx, and SO2 and NH3
are prepared by EPA contractor.  The inventory report relied on actual
operational data and then used local activity parameters.  From this
information, emission estimates are prepared based on estimated activity
by mode, engine power by vessel, time in mode..etc.  Where applicable,
annual emissions are provided for PM2.5, NOx, and SO2 for total combined
nonroad mobile sources for the areas.  CMV source emissions are
presented on a source category basis.

The reader is referred to Chapter V of Development of the 2002 Regional
Haze Area, Point, Nonroad Mobile and Onroad Mobile Source Emission
Inventories for St. John, Virgin Islands, dated June 2010. CMV source
emissions was developed in accordance with EPA Guidance.1, 2, 3

.

	Details on How The Virgin Islands Satisfies Criteria 8 and 9  for the
Onroad  Source Inventory

Onroad Mobile Source Inventory

The Virgin Islands’  mobile source inventory was developed by using
2002 annual vehicle miles traveled (VMT) inventory from a surrogate area
of Kauai, Hawaii by using VMT data from Kauai and population data from
Kauai and St. Johns, VI to develop VMT estimates by county, geographic
component (urban, small urban and rural) and functional classes.

Mobile 6 model for PM2.5, NOx and SO2 was used to generate emission
factors for onroad vehicle emission estimates.  The report also explains
how Mobile 6 emission factors are used, in conjunction with VMT data, to
estimate mobile source emissions for the inventoried areas.  It provides
the sources for the key inputs into the Mobile model.  Key assumptions
are also included.  The methods used to determine on-road emission
estimates are explained in the EPA’s Documentation for the Onroad NEI
for Base Years 1970-2002, dated January 2004.  Where applicable, annual
emissions are provided for PM2.5, NOx and SO2 the area.  The breakdown
of annual emissions by highway vehicle classifications is included in
the inventory.  The inventory was developed in accordance with EPA
Guidance.1,2, 3

2018 Emissions Inventory

Unfortunately, not enough is known about possible growth on St. John to
use growth factors.

Growth of population and sources may be restricted, as a result of the
small size of the island and the large amount of land included in the
National Park.  There is not enough information available for the motor
vehicle fleet on St. John, and projections based on vehicle turnover may
be very different from reality in an isolated location such as St. John
and no interstate highways to bring outside traffic through.  Therefore,
no growth factors were applied to the area, nonroad mobile and onroad
mobile source inventories from base year 2002 to 2018.  See 2018
Modeling inventory below in Tables 1-3.

Table 1: Sulfur Oxides Emissions from Point, Area and Mobile Sources on
St. John, Virgin Islands (tons per year)

Source Sector	Baseline 2002	2018 (with measures for RPG)

Point	43.11	43.11

Area	0.05	0.05

Non-Road Mobile	17.89	17.89

On-Road Mobile	1.61	1.61

Marine Vessels	94.06	14.11

Total	  =SUM(ABOVE)  156.72 	  =SUM(above)  76.77

Table 2: Nitrogen Oxide Emissions from Point, Area and Mobile Sources on
St. John, Virgin Islands (tons per year)

Source Sector	Baseline 2002	2018 (with measures for RPG)

Point	477.66	477.66

Area	3.69	3.69

Non-Road Mobile	2.07	2.07

On-Road Mobile	25.03	25.03

Marine Vessels	318.23	63.65

Total	  =SUM(ABOVE)  826.68 	  =SUM(above)  572.1

Table 3: Direct Emissions of Particulate Matter from Point, Area and
Mobile Sources on St. John, Virgin Islands (tons per year)

Source Sector	Baseline 2002	2018 (with measures for RPG)

Point	34.33	34.33

Area	38.32	38.32

Non-Road Mobile	1.93	1.93

On-Road Mobile	0.73	0.73

Marine Vessels	8.57	1.28

Total	  =SUM(ABOVE)  83.88 	  =SUM(above)  76.59

Table 5: Emissions from HOVENSA (in tons per year)

	Sulfur Oxides	Nitrogen Oxides	Particulate Matter

HOVENSA Base 2002	12,778	26,362	2,207

HOVENSA Future 2018	9,318	21,331	2,192

Conclusion

Virgin Islands has a SIP that demonstrates the requirements for emission
inventory measures and reporting are adequately met.  To comply with the
emission inventory requirements, the State must submit a complete
inventory containing an implemented Quality Assurance Plan, point, area,
on-road, and non-road mobile source data, and accompanying support
documentation.

Recommendation

EPA is approving this SIP submittal because it meets the essential
reporting requirements for an Emissions Inventory.

 Emission Inventory Guidance Documents

1Emission Inventory Guidance for Implementation of ozone and Particulate
Matter NAAQS and Regional Haze Regulation, September 2005

2Example Documentation Report for 1990 Base Year Ozone and Carbon
Monoxide State Implementation Plan Emission Inventories, March 1992

3Guidance on the Use of Models and Other Analyses
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UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C.  20460

OFFICE OF

PREVENTION, PESTICIDES

  AND TOXIC SUBSTANCES

Date: September 30, 2007

MEMORANDUM

SUBJECT:	Revised Busan 77: Toxicology Chapter for Issuance of the
Reregistration Eligibility Decision (RED) Document.  PC Code:

FROM:	Timothy F. McMahon, Ph.D.

Senior Toxicologist/Risk Assessor

Antimicrobials Division (7510P)

TO:		ShaRon Carlisle, Chemical Review Manager

		Mark Hartman, Branch Chief

		Regulatory Management Branch II

		Antimicrobials Division (7510P)

	Attached is the Toxicology chapter for Busan 77 for the purpose of
issuance of the reregistration eligibility decision (RED).

TABLE OF CONTENTS

 TOC \f

1.0	HAZARD CHARACTERIZATION	3

2.0	TOXICOLOGY DATA	4

3.0	DATA GAP(S)	5

4.0	HAZARD ASSESSMENT	5

4.1	Acute Toxicity	5

4.2	Subchronic Toxicity	6

4.3	Developmental Toxicity	7

4.4	Reproductive Toxiciry	9

4.5	Chronic Toxicity	10

4.6	Carcinogenicity	11

4.7	Mutagenicity	12

4.8	Metabolism	13

4.9	Dermal Absorption	13

5.0	HAZARD ENDPOINT SELECTION	13

5.1	Summary of Toxicological Endpoint Selection 	14

5.2	Classification of Carcinogenic Potential	14

6.0	FQPA CONSIDERATIONS	16

6.1	Developmental Toxicity Conclusions	16

6.2	Reproductive Toxicity Conclusions	17

6.3	Determination of Susceptibility	17

6.4	Recommendation for Developmental Neurotoxicity
study………………18

7.0	Summary of Toxicological Doses and Endpoints	18

8.0	Toxicity Profile	20

9.0	References	29

            	                                13 1.0	  SEQ CHAPTER \h \r
1 HAZARD CHARACTERIZATION

The acute toxicity of Busan 77 is low for oral toxicity (Toxicity
Category III), dermal toxicity (Toxicity Category III), inhalation
toxicity (Toxicity Category III) and primary eye irritation (Toxicity
Category III); it is even lower for primary dermal irritation (Toxicity
Category IV).  It was not found to be a dermal sensitizer.

Subchronic toxicity studies (MRIDs 40170601 and 40025001) indicate that
the dermal route did not cause systemic effects when tested to the limit
dose (1,000 mg/kg/day).  However, signs of chronic
irritation/inflammation were noted in both males and females at the 100
and 1,000 mg/kg/day dose level (skin lesions included ulceration of the
epidermis, chronic inflammation of the edermis, acanthosis,
hyperkeratosis, parakeratosis, folliculitis, and epidermatitis).  The
oral route led toxic to effects at 1,000 mg/kg/day (mineralization of
renal tubules).

A chronic toxicity study in dogs (MRID 41234501) by the oral route
showed signs of toxicity in males (testicular hypoplasia,
atrophy/degeneration, aspermia, dysplasia and cellular debris of
testicular origin in  the epididymis at 500 mg/kg) at lower doses than
females (G-I disturbances, emaciation and nervous symptoms at 1,000
mg/kg).

Developmental toxicity studies (MRIDs 41423001 and 41248001) through the
oral route showed developmental effects occurred at greater than or
equal dose levels as maternal effects. A study conducted in rats had
maternal effects occurring at 350 mg/kg/day (decreased food consumption
and body weight gain, which were not statistically significant) and
became severe at 700 mg/kg/day (mortality, morbidity observed, including
lungs, brain, stomach, and intestines).  No developmental effects were
observed in the doses tested in this study.  In a study in rabbits,
maternal effects (increased incidence of abortions, clinical signs
including reduced defecations and emaciation, significantly reduced feed
consumption and body weight gain) were seen at the same dose, 45
mg/kg/day, as developmental effects (increased incidence of ribs and
unossified sternabrae).  There were no significant neurological effects
to warrant a neurotoxicity study.

A reproduction study (MRID 405578201) showed systemic effects (reduced
body weight, reduced absolute and relative liver weight, inflammation of
the choroid plexus in the brain, and tubular mineralization of the
kidney) at doses  of  600 mg/kg/day and above in parental animals.
There were no reproductive effects of Busan 77 at any dose level tested
in this study.

In a carcinogenicity study in mice (MRID 41494301),   there was a dose
related increase in  proteinaceous casts in males and pelvic and tubular
dilatation in males and females.  It could not be definitively
determined whether increased incidences of rough hair coat, bloody
crusts and red ears in males and convulsions in females occurred at the
low or high dose, 600 or 2400 mg/kg/day, respectivcely. Busan 77 in the
diet was determined to be non-carcinogenic in mice up to 2,400 mg/kgday.

In a combined chronic/carcinogernicity study (MRID 41809101),  rats
exposed to 0, 2000, 6000 and 18000 ppm ( 0, 100, 300 and 900 mg/kg/day,
in males and females) a chronic NOEL of 2000 and LOEL of 6000 ppm, was
based on reduced body weight gain (F), reduced albumin CM), reduced
total protein CM), reduced Pi (M & F) • increased urine pH (F) and a
dose-related increase in blood crusts(M).  In addition, at 18000 ppm,
hyperesthesia, bloody crusts, decreased body weight gain, decreased Pi,
globulin and total protein and increased brain-to-body weight ratio
associated with mineralization of the brain in the thalamic region, in
males and females; decreased albumin, glucose and cholesterol in males
and increased urine pH in females, were observed.  In the
carcinogenicity study, for females, there was a possible increased
incidence of thyroid C-cell adenomas in the 6000 and 18000 ppm groups
and a positive trend in males and females.

Busan 77 was not mutagenic in a reverse mutation assay in bacteria, in
the presence and absence of mammalian metabolic activation.  No increase
in sex-lined recessive lethal genes was found in flies.  Busan 77 did
not increase micronuclei in mice, nor did it increase unscheduled DNA
synthesis in primary rat hepatocytes.

Metabolism of Busan 77 showed no expired 14CO2. Under intravenous
injection, roughly half (52-55%) of the radioactivity was excreted after
7 days through urine (38-44%) and feces (11-14%), while tissues
contained 43-55% of the dose.  The major route of excretion after single
oral and repeated oral doses was feces (85-103%), urine was minor (3%).
Of the oral dose groups the highest residual radioactivity was found in
kidneys, liver and spleen.  Recoveries of doses in the tissues,
including carcass (≤0.14%) indicated a minimal potential for
bioaccumulation after oral dosing.

2.0	TOXICOLOGY DATA

Table 1. Busan 77

Test

Technical

MRID

Acceptable

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

41373401/93062009

41327101/93062010

41877501

41361701/93062011

41298601/93062012

40750301/93062013

yes

yes

yes

yes

yes

yes

870.3050    28-Day Oral (rodent)

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

40362601

40025001/93662014

none

none

40170661/93062015

none

Not reviewed

yes

waived

not required

yes

not required

870.3700a	Developmental Toxicity (rodent)

870.3700b	Developmental Toxicity (nonrodent)

870.3800	Reproduction

41423001/93062018

41248001/93062019

40578201/93062020	             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		41809101

41234501

41809101

41494301/93062017

41809101	yes

yes

yes

yes

yes

870.5100	Mutagenicity—Gene Mutation - bacterial

870.5275    Mutagenicity—Sex-linked recessive lethal test

870.5300	Mutagenicity—Gene Mutation - mammalian

870.5380	Mutagenicity—Spermatogonial chromosomal test

870.5550	Mutagenicity—UDS in mammalian cells in culture		41573701

00151205

none

none

 40978701/93062027	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		none

none

none

none

none	not required

not required

not required

      not required

      not required

870.7485	General Metabolism

870.7600	Dermal Penetration

40268607/93062024

40139201/93062025	yes

yes

Special Studies for Ocular Effects

Acute Oral (rat)

Subchronic Oral (rat)

Six-month Oral (dog)

3.0	DATA GAPS

4.0	HAZARD ASSESSMENT

4.1	Acute Toxicity

Adequacy of database for Acute Toxicity:  The acute toxicity database
for Busan 77 is complete.  Busan 77 tested at 61.6% (or other %) a.i.
has a moderate order of acute toxicity via the oral, dermal and
inhalation routes of exposure (Toxicity Category III).  For dermal
irritation, Busan 77   has a low order of acute toxicity (Toxicity
Cateogry IV).   Busan 77 is a slight eye irritant. Busan 77 is not a
dermal sensitizer. The acute toxicity data for Busan 77 is summarized
below in Table 2.

Table 2.  Acute Toxicity Profile for Busan 77

Guideline Number	Study Type/Test substance (% a.i.)	MRID Number/

Citation	Results	Toxicity Category

870.1100

(§81-1)	Acute Oral- Rat

purity 61.6% -Busan 77	41373401/

93062009	LD50 = 1951 (1727-2203) mg/kg (M); LD50 = 2587 (2059-3250)
mg/kg (F)	III

870.1200

(§81-2)	Acute Dermal- Rabbit

purity 61.6% – Busan 77	41327101/

93062010	LD50 > 2000 mg/kg	III

870.1300

(§81-3)	Acute Inhalation- Rabbit

Purity 60% - Busan 77	41877501	LC50 = 4.0 (2.3-7.1) mg/L (M); 2.4
(1.7-3.3) mg/L (F); 2.9 (2.3-3.7) mg/L (combined)	III

870.2400

(§81-4)	Primary Eye Irritation- Rabbit purity 61.6% -Busan 77	41361701/

93062011	Redness cleared on day 3	III

870.2500

(§81-5)	Primary Dermal Irritation- Rabbit

61.6% - Busan 77	41298601/

93062012	Slight Irritant	IV

870.2600

(§81-6)	Dermal Sensitization - Guinea pig

purity 60.1 % - Busan 77	40750301/

93062013	Not a sensitizer.	NA

4.2	Subchronic Toxicity

Adequacy of database for Subchronic Toxicity:  For Busan 77, there are
90-day oral and dermal toxicity studies in the rat and rabbit (MRIDs
40025001 and 40170601). These data are all considered acceptable by the
Agency and constitute an adequate database for evaluation of risks to
infants and children.

870.3100	90-day Oral Toxicity - Rats

In a 90-day oral toxicity test (MRID 40020501) designed to determine the
subchronic toxicity effects of repeated oral exposure to Busan 77
(purity not reported) in Cr1:CD(SD)BR rats.  Rats were orally exposed to
0, 300, 1000, 3000 or 4000 mg/kg/day of Busan 77 for 13 weeks.  Animals
were observed twice daily for signs of mortality and toxicity.

There was a decrease in body weight and possibly absolute organ weights
were observed at 3000 and 4000 mg/kg/day.  An equivocal decrease in red
blood cell counts, elevated leukocyte counts and non-suppurative
inflammation in the choroid plexus of the brain as well as death was
also observed at the 3000 and 4000 mg/kg/day dose levels.

The NOAEL is (300 mg/kg/day) and the LOAEL is (1000 mg/kg/day), based on
mineralization of renal tubules.

This study is classified as Core-Minimum – Upgradeable.

870.3250	90-day Dermal Toxicity – Rabbits

  SEQ CHAPTER \h \r 1 In a 90-day dermal toxicity test (MRID
40170601/93062015) designed to determine the subchronic toxicity effects
of repeated dermal exposure to Busan 77 (>60% purity) in Hra: (NZW) SPF
rabbits.  The rabbits were dermally exposed to 0, 10, 100, or 1000
mg/kg/day of Busan 77 6 hours a day, 5 days a week for 13 weeks.
Animals were observed twice daily for signs of mortality and moribundity
and daily for signs of toxicity.    SEQ CHAPTER \h \r 1

No treatment-related toxicity/mortality was observed.  However, one
female given 100 mg/kg was sacrificed on Day 11 because of a large wound
in the anal region

The systemic toxicity NOAEL is (>1000 mg/kg/day, M/F).  The dermal
toxicity NOAEL is (10 mg/kg/day).  The dermal toxicity LOAEL is (100
mg/kg/day).

This study is classified as Core-Minimum - Guideline.

4.3	Prenatal Developmental Toxicity

Adequacy of database for Prenatal Developmental Toxicity:  For Busan 77,
there are developmental toxicity studies in the rat and rabbit (MRIDs
41223001 and 41248001/93062019) as well as a two-generation reproduction
study in the rat (MRID 40578201/93062020). The developmental toxicity
data is considered acceptable by the Agency and constitute an adequate
database for evaluation of risks to infants and children.  The
reproduction toxicity study remains a data gap, due to lack of purity
data and selection of doses such that NOAEL could be determined.

870.3700	Prenatal Developmental Toxicity– Rat

  SEQ CHAPTER \h \r 1 In a prenatal developmental toxicity study (MRID
41423001), Busan 77 (purity 61.21%) in deionized water, was administered
by gavage to 4 groups of 25 rats/dose at dose levels of 0, 70, 350, or
700 mg/kg/day, respectively, from gestation days (GD) 6 to 15.    As a
result of excessive mortality observed at 700 mg/kg/day, this dose group
was discarded and a 500 mg/kg/day dose group was added to the study
along with its own concurrent control.  The animals were checked daily
from gestation day 6 for indications of toxicity.  Body weights were
recorded daily from gestation days 6, 9, 12, 16 and 20.  Food and water
consumption were measured at 3 day intervals beginning on gestation day
6.  Examinations at sacrifice consisted of a determination of the number
and position of live, dead, and resorbed fetuses and staining of
apparent nonpregnant uteri along with liver weights.

The only observed clinical sign of maternal toxicity was hair loss of
the extremities, abdomen or lateral thoracic area, which were not
treatment related.   Busan 77 had no effect on food consumption in the
low dose group (77 mg/kg/day).  However, at 350 and 400 mg/kg/day food
consumption was reduced during the first three days of treatment when
compared with respective control groups.  At 500 mg/kg/day food
consumption was also decreased during GD 9 to 12.  Because of these
decreases, total food consumption measured statistically less than
corresponding controls for the entire treatment period (GD 6 to 15) in
the 350 and 500 mg/kg/day dose groups.  The only other effect of
biological concern was a statistically significant increase in
embryotfetal toxicity at 500 mg/kg/day when compared with it concurrent
control group.  There was no other evidence of developmental toxicity in
this study.  The maternal NOAEL is 70 mg/kg/day and the maternal LOAEL
is 350 mg/kg/day.  The developmental toxicity NOAEL was determined to be
500 mg/kg/day; a developmental toxicity LOAEL was not established.

This study is classified as Core-Minimum - Guideline.

870.3700	Prenatal Developmental Toxicity – Rabbit

  SEQ CHAPTER \h \r 1 In a prenatal developmental toxicity study (MRID
41248001/93062019), Busan 77 (purity 60.81%) in deionized water, was
administered by gavage to 4 groups of 20 New Zealand White rabbits/dose
at dose levels of 0, 15, 45, or 125 mg/kg/day, respectively, from
gestation days (GD) 6 to 18, inclusive.  The animals were checked daily
from gestation day 6 for indications of toxicity.  Body weights were
recorded daily from gestation days 6, 9, 12, 15, 19, 24 and 29.  Food
and water consumption were measured at 3 day intervals beginning on
gestation day 6.

Maternal toxicity showed an increase incidence in abortions as well as
reduced defecation and emaciation and significantly reduced feed
consumption and body weight gain during treatment. The observations of
the 13th rudimentary ribs and unossified 5th and 6th sternabrae at the
high dose are not considered treatment related, but statistical
anomalies based on the decreased number of litters at the high dose (125
mg/kg/day).  The effects reported are also just barely outside the
historical control range.  There is no evidence of developmental
toxicity in this study.

The maternal NOAEL is 45 mg/kg/day and the maternal LOAEL is 125
mg/kg/day.  The developmental toxicity NOAEL was determined to be 45
mg/kg/day and the developmental toxicity LOAEL is 125 mg/kg/day.

This study is classified as Core-Guideline.

4.4 Reproductive Toxicity

870.3800	Reproductive Toxicity - Rat

  SEQ CHAPTER \h \r 1 In a two-generation reproduction toxicity study
(MRID 40578201/93062020), Busan 77 (purity 60%) was administered in the
diet to groups of 25 Cr1:CD (SD)BR rats/dose at dose levels of 0, 300,
600 and 900 mg/kg/day, for two consecutive generations.  Body weights
were recorded weekly during the premating period, and at termination.
During gestation, females were weighed on presumed Days 0, 7, 14, and 20
of gestation. Dams that produced litters were weighed on Days 0, 4, 7,
14, and 21 of lactation.  Food consumption was measured weekly during
the premating period.  At least twice daily, all animals were observed
for moribundity, death, and obvious indications of a toxic effect. At
least once each week, animals were removed from their cages and
carefully examined for clinical signs of toxic or pharmacological
effects. Mated females were similarly observed during gestation and
lactation. During gestation, females were observed closely for signs of
abortion, excessive bleeding, premature delivery, or difficult and
prolonged parturition.

Dead animals were removed immediately and their tissues preserved
without delay; moribund animals were sacrificed and treated similarly.
Autolysis in dead animals was minimized by refrigerating them until
necropsy.

Maternal toxicity was observed at 300 mg/kg/day and above and consisted
of reduced body weight in F1 generation males, decreased liver weight in
F0 and F1 males and females. Chronic inflammation of the choroid plexus
and tubular mineralization of the kidney was also observed at the 600
and 900 mg/kg/day dose levels. Decreased numbers of live pups per litter
were observed for female pups on day 0 at the 600 and 900 mg/kg/day dose
levels, as was decreased pup weight on day 7 and 21 at the 900 mg/kg/day
dose level.  Sex ratio was significantly increased at 900 mg/kg/day (62%
vs. 42% in control).

Parental/systemic NOAEL = 300 mg/kg/day

Parental/systemic LOAEL = 600 mg/kg/day, based on significantly
decreased absolute and relative liver weight of male and female rats of
both generations as well as increased incidence of mineralization of
kidneys at the 600 mg/kg/day dose

Reproductive NOAEL = 900 mg/kg/day

Reproductive LOAEL > 900 mg/kg/day (HDT)

This study is classified as Core-Minimum/Guideline.

4.5 Chronic Toxicity

870.4100	Chronic toxicity

  SEQ CHAPTER \h \r 1 In a chronic study (MRID# 41234501) Beagle dogs
(4/sex/dose group) from Hazelton Laboratories, Cumberland, VA received
Busan 77 (purity  not provided; Lot# 6-14952-M) in the diet for 52 weeks
at dose levels of 0b 250, 500 and 1000 Mg/kg/day.

differences were significant (P≤ 0.05) for only the 1,000 mg/kg dose
group.  The decrease in pronounced in both sexes fed 1,000 mg/kg and in
males fed 250 mg/kg and 500 mg/kg, though the latter was not
significant. In the 500 mg/kg group, the mean body weight gain decreased
in males and females 17% and 6%, respectively, at 12 weeks when compared
to controls; and decreased in males and females 30 and 14 percent,
respectively, at termination (52 weeks) when compared to controls. In
the 1,000 mg/kg group, the mean cumulative body weight gain decreased in
males and females 39 and 42%, respectively, at 12 weeks when compared to
controls.

Mean food consumption was significantly lower throughout most of the
study for both sexes in 1,000 mg/kg dose group. Food consumption
significantly decreased 46% in males and 53% in females in the 1,000
mg/kg group at 12 weeks when compared to controls. Males in the 500
mg/kg group exhibited statistically significant increases of 52, 19, and
47%, respectively, in the body weight ratios of brain, kidney and liver,
when compared to controls. The actual change in the weights of brain,
kidney and liver were 1, -18 and -13%, respectively, when compared to
controls. Females exhibited significant increases of 4 and 47%,
respectively, in the body weight ratios of kidney and liver. A similar
pattern with higher magnitude was observed in the HTD group for these
organs; however statistical significance was not determined. Brain
weight decreased 12% (M & F) at 1,000 mg/kg.

The Systemic Toxicity NOAEL is 250 and 500 mg/kg for males and females,
respectively.  The Systemic Toxicity LOAEL is 500 mg/kg/day in males,
based on testicular hypoplasia, atrophy/degeneration, aspermia,
dysplasia and cellular debris of testicular origin in epididymis.  The
Systemic Toxicity LOAEL is 1,000 mg/kg/day in females, based on G-I
disturbances, weight loss and nervous symptoms (bloody stools,
emaciation and ataxia, respectively.

This study is classified as Core-Minimum.

4.6    Carcinogenicity

870.4200	Carcinogenicity - Mice

  SEQ CHAPTER \h \r 1 In a carcinogenicity study (MRID#
41494301/93062017) Cr1:CD-1 (ICR) BR mice (50/sex/dose group) from
Charles River Laboratory, Portage, MI received Busan 77 (60.8% a.i.;
Lot# 8806-14952-M) in the diet for 18 months at dose levels of 0, 600,
1200 and 2400 mg/kg/day.  A satellite group of five animals/sex/dose
group were sacrificed at 12 months.

Animals were inspected once daily for signs of toxicity and twice daily
for mortality.  Systemic toxicity was noted at the 1200 mg/kg/day dose
and above; for example, convulsions (M and F), urine stains (M and F),
rough hair coat (F), bloody crusts (F), swollen abdomen (M and F),
swollen anus (M), red tails (M and F), red ears (F), reduced body weight
gains (M and F), diffuse rough kidneys (M and F), large kidney pelvis (M
and F), relative kidney weights (high-dose males, and mid and high-dose
females), proteinaceous casts (F), cortical fibrosis/scarring (F) and
cysts (F) were observed.   The Systemic Toxicity NOAEL was not
established and the Systemic Toxicity LOAEL was less than 600 mg/kg/day
based on large kidney pelvis and diffuse rough kidney in females; and
histologically in kidneys, a dose related increase in the proteinaceous
casts in males and pelvic and tubular dilatation in males and females,
was observed.

This study is classified as Core-Minimum Guideline.

870.4300	Combined Chronic Toxicity/Carcinogenicity - Rat

  SEQ CHAPTER \h \r 1 In a combined chronic toxicity /carcinogenicity
study (MRID 41809101) Cr1:CD rats received Busan 77 (60% a.i.; Batch #
5-12070-M and 6-14952-M) in the diet for 24 months at dose levels of 0,
2000, 6000 and 18000 ppm in males and females (0, 100, 300 and 900
mg/kg/day).  Interim sacrifice high dose groups of ten animals/sex were
sacrificed at 12 months.  Systemic toxicity was noted as decreased
significantly in males and females high dose groups (900 mg/kg/day).  In
males, the mean body weight gain decreased generally from 11 to 78% by
week 80.  In the mid dose/low dose male the body weight gain was reduced
20 to 59/1 or 14% during weeks 12 to 80 weeks of treatment. At 900
mg/kg/day, the mean body weight gain of females decreased approximately
11, 18, 78, 65 and 45%.  Food consumption was significantly decreased in
males (~11%) and in females (~13%) in the 900 mg/kg/day dose group.  In
females there was a possible increased incidence of thyroid C-cell
adenomas in the 300 and 900 mg/kg/day groups and a positive trend in
male and females.  Based on the results of this study, the Systemic
Toxicity NOEL is equal to 2000 ppm (100 mg/kg/day for males and females
and the Systemic Toxicity LOEL is equal to 6000 ppm (300 mg/kg/day for
males and females) based on decreased body weight gain (F), reduced
albumin (M), reduced total protein (M), reduced Pi (M & F) and increased
urine pH (F).

This study is classified as Core-Minimum – Guideline.

4.7	Mutagenicity

Adequacy of database for Mutagenicity Toxicity:  The database for
mutagenicity toxicity is considered complete.

870.5100	Bacterial Reverse Mutation Assay Test - Ames

In a gene mutation assays, MRID 41573701, Busan 77 (purity not given),
at concentrations of 0, 66.7, 100, 333, 667, 1000, and 3330 ug/ml was
evaluated for mutagenic potential in the S. typhimurium strains TA1535,
TA1537, TA1538m TA98 and TA100.  No adverse effect.  There was not an
increase in the number of histidine revertants either in  the presence
or absence of S9 system.

This study is classified as Acceptable – Guideline.

870.5275	Sex-linked recessive lethal test in Drosophila melanogaster -
Flies

In a sex-linked lethal assay, MRID 00151205, Busan 77 (purity 60%), at
concentrations of 0.08, 0.3 and 0.8 mg/ml was evaluated for mutagenic
potential in flies.  A dose-related increase in sterility was observed
in the mated P1 males to increasing concentration of the test material
when compared to the solvent control values.  The Agency concluded that
this Busan 77 is non-mutagenic in the drosophila test system.

This study is classified as Acceptable – Guideline.

870.5395	Mammalian Micronucleus Test - Mice

In a micronucleus assay test submitted to the Agency, (MRID 00151206,
Busan 77, at concentrations of 200, 600, 1000 and 2000 mg/kg was
administered once via gavage to 15 CD-1 mice/sex/dose. It was reported
that the number and severity of abnormal observations )e.g., depressed
activity, tremors, rough coat) increased with increasing dose.  Mice
administered higher dose levels (660, 100 and 2000 mg/kg) showed larger
decreases in body weight.  Busan did not induce a significant increase
of the PCE containing micronuclei, which indicated the sensitivity of
the assay system (p<0.0001).   Busan 77 is non-mutagenic in the
micronucleus assay.

This study is classified as Acceptable – Guideline.

Unscheduled DNA synthesis in mammalian cells in culture

In a Unscheduled DNA Synthesis  (UDS) study submitted to the Agency,
(MRID 40978701/93062022), Busan 77, at concentrations of 0, 188, 375,
750 and 1,500 mg/kg was evaluated in the unscheduled DNA synthesis test
using rat primary hepatocytes and autoradiography.  The mean number of
net nuclear grains did not increase significantly at any dose level over
the solvent control.  It was concluded, therefore, that Busan 77 was
tested over an appropriate range of concentrations and failed to induce
a genotoxic response.

This study is classified as Acceptable – Guideline.

4.8	Metabolism

870.7485	Metabolism and Pharmacokinetics - Rat

In a metabolism study, MRID 40268601/93062024, 14C-labeled Busan 77
(Purity 60%), at concentrations of 10 or 1000 mg/kg were administered
orally or intravenously to (5 CD rats/sex/dose).  Expired CO2 was not
detected. In the intravenous dose group, the major routes of excretion
of radioactivity were via urine and feces. Over a 7-day period,
approximately 52-55% of the test material administered was excreted in
the urine (38-44%) and feces ( 11-14%); 43-55% were found in the
tissues. In a single or repeated oral dosed groups 88-106% of the test
compound administered was excreted in the urine (3%) and feces (55
-105%); kidneys, liver, and spleen had a higher residue level. In these
groups, tissue residue levels were low in all tissues, except kidneys.
Not more than 0.14% of the administered dose was recovered in tissue.
Potential for bioaccumulation at the single or repeated oral is minimal.
At the highest oral dose, 85% of the administered dose was recovered in
urine (14- 17%) and feces (68-71%).

This study is classified as Acceptable – Guideline.

4.9 Dermal Absorption

870.7485	Dermal Penetration – Rat

  SEQ CHAPTER \h \r 1 In a dermal penetration study (MRID
40139201/93062025), 14C-Busan 77 (purity 60%), was administered dermally
to male CRL:CD BR rats(24/group) at single dose levels of 0,  2, 20 or
300 mg/rat, (0.16, 1.59 or 15.97 mg/cm2, respectively).   Less than 0.2%
of the 14C-Busan 77 was absorbed. Mean % recovery of radioactive dose
ranged from 74.5 - 92.7%. Majority of the dose was recovered in the skin
rinse (65.5% - 88.6%) and at the skin site (0.4% - 13.7%).

This study is classified as Acceptable-Guideline.

 5.0	TOXICITY ENDPOINT SELECTION

5.1	See Section 7.1, Summary of Toxicological Doses and Endpoint
Selection, Table 2.

5.2	Classification of Carcinogenic Potential

1. Combined Chronic Toxicity/Carcinogenic Study in Rats

	MRID No.: 41809101

Conclusions: Doses: 0, 2000, 6000, and 18000 ppm (~ 0, 100, 300, and 900
mg/kg/day, in males and females) in Crl:CD (SD) BR rats.

Chronic: The NOEL of 2000 and LOEL of 6000 ppm, was based on reduced
body weight gain (F), reduced albumin (M), reduced total protein (M),
reduced Pi (M and F), increased urine pH (F), and a dose-related
increase in blood crusts (M) .

In addition, at 18,000 ppm, hyperesthesia, bloody crusts, decreased body
weight gain, decreased Pi, globulin and total protein and increased
brain-to-body weight ratio associated with mineralization of the brain
in the thalamic region, in males and females; decreased albumin, glucose
and cholesterol in males and increased urine pH in females, were
observed.

Carcinogenicity: Females - there was a possible increased incidence of
thyroid C-cell adenomas in the 6,000 and 18,000 ppm groups and a
positive trend in males and females.  This will be considered by the HED
Cancer Peer Review Committee.

Classification: Core - Minimum for Chronic and Oncogenicity Studies.
The Study satisfies the requirements of subdivision F Guideline, 83-5
for the combined Chronic/Oncogenicity Study in the rat.

Discussion of Tumor Data: There was an increased incidence of thyroid
C-cell adenomas in females at the mid- and high-dose levels and in males
at the high dose level.  The increase in the overall incidence of
thyroid C-cell adenomas in males did not attain a statistically
significant level when compared with the concurrent controls.  However,
there was a statistically significant positive dose-related trend in
males and females for this type of tumor.  The incidence of C-cell
adenomas in females was outside the range and higher than the mean of
historical control incidences.  Historical control incidences for this
type of tumor in this strain of rat were as follows: a) in females, the
range was 0- 14% with a mean value of 4.5%, b) in males, the range was
1.7-11% with a mean value of 5.8%.  Only one C-cell carcinoma (1/24;
4.1%) was observed in the middle-dose males.  The (HED) Committee
thought that the increase in tumor incidences might have been due to
alteration of the normal metabolic pathways, biotransformation and/or
elimination of the chemical as a result of compromised liver and kidney
failure.

Adequacy of the Dose Levels Tested: Dose levels tested were considered
adequate for this type of study.

2. Carcinogenicity Study in Mice

MRID No.: 41494301 / 93062017

Conclusion: Doses: 0, 4000, 8000, and 16000 ppm (~ 0, 600, 1200, and
2400 mg/kg/day, in males and females) in Crl:CD-1 (ICR) BR mice (doses
based on technical not % a.i.).

Systemic: Systemic NOEL can not be established and LOEL < 4,000 ppm was
based on large kidney pelvis and diffuse rough kidney in females; and
histologically in kidneys, a dose-related increase in the proteinaceous
casts in males and pelvic and tubular dilation in males and females, was
observed.  It could not be definitively determined whether increase
incidence of rough hair coat, bloody crusts and red ears in males and
convulsions in females had a LOEL of 4,000 or 16,000 ppm.

At the 8,000 ppm dose and above, all of the above findings and including
convulsions (M and F), urine stains (M and F), rough hair coat (F),
bloody crusts (F), swollen abdomen (M and F), swollen anus (M), red
tails (M and F), red ears (F), reduced body weight gains (M and F),
diffuse rough kidneys (M and F), large kidney pelvis (M and F), relative
kidney weights (high-dose males, and mid and high-dose females),
proteinaceous casts (F), cortical fibrosis/scarring (F) and cysts (F)
were observed.

Carcinogenicity: Not carcinogenic in Crl:CD-1 (ICR) BR mice up to 16,000
ppm (2,400 mg/kg/day) Busan 77 in diet.

Classification: Core - Minimum for oncogenicity study. The study
satisfies the requirements of Subdivision F, Guideline 83-2 for the
Oncogenicity Study in mice.

Discussion of Tumor Data: Not found to induce tumors

Adequacy of the Dose Levels Tested: Dose levels tested were appropriate
for carcinogenicity testing.

3. Classification of Carcinogenic Potential: Classified as a “Group
D” carcinogen.  An Ad Hoc Group (on October 5, 1994) determined that
the chemical be referred to the HED- CPRC for weight of evidence
evaluation.

6.0	FQPA CONSIDERATIONS

Adequacy of the Toxicity Database

For Busan 77, there are developmental toxicity studies in the rat and
rabbit (MRIDs 41423001 and 41248001) as well as a two-generation
reproduction study in the rat (MRID 40578201).  These data are all
considered acceptable by the Agency and constitute an adequate database
for evaluation of risks to infants and children.

6.1	Developmental Toxicity Study Conclusions

There were two developmental toxicity studies for Busan 77.  Both
studies used the gavage route of exposure for Busan 77.  In the rabbit
study (MRID 41248001), groups of timed-pregnant New Zealand White
rabbits (20/dose) received the test material Busan 77 (60.8% a.i.) by
gavage in deionized water at doses of 0, 15, 45, or 125 mg/kg/day from
days 6 through 18 of gestation, inclusive.  Based on the results of this
study, the maternal NOAEL was determined to be 45 mg/kg/day, based on
increased abortions, clinical signs of toxicity, and reduced body weight
gain and food consumption.  The developmental toxicity NOAEL was
determined to be 45 mg/kg/day, based on increased incidence of 13th
rudimentary rib and unossified sternebrae #5 and #6 at 125 mg/kg/day.

The ADTC concluded that the observations of 13th rudimentary ribs and
unossified 5th and 6th sternebrae at the high dose are not considered
treatment related, but statistical anomalies based on the decreased
number of litters at the high dose.  The effects reported are also just
barely outside the historical control range.  There is no evidence of
developmental toxicity in this study.

In the rat study (MRID 41423001), Crl:CD BR SD rats (25/dose)
impregnated naturally were administered the test substance Busan 77
(61.21% a.i.) in deionized water at doses of 0, 70, 350, and 700
mg/kg/day on gestation days 6 through 15 inclusive.  As a result of
excessive mortality observed at 700 mg/kg/day, this dose group was
discarded and a 500 mg/kg/day dose group was added to the study along
with its own concurrent control.

The maternal NOAEL was determined to be 70 mg/kg/day, and the maternal
LOAEL was determined to be 350 mg/kg/day based on decreased food
consumption and body weight gain.  The developmental toxicity NOAEL is
500 mg/kg/day; a developmental toxicity LOAEL was not established.

There was no evidence of developmental toxicity in this study

6.2	Reproductive Toxicity Study Conclusions

In a two-generation reproduction toxicity study (MRID 4058201), groups
of Crl:Cd (SD)BR rats (25 males and 25 females per dose level) were
administered diets containing Busan 77 (purity not stated) at doses of
0, 300, 600, and 900 mg/kg/day for two consecutive generations.
Maternal toxicity was observed at 300 mg/kg/day and above and consisted
of reduced body weight in F1 generation males, decreased liver weight in
F0 and F1 males and females. Chronic inflammation of the choroid plexus
and tubular mineralization of the kidney was also observed at the 600
and 900 mg/kg/day dose levels. Decreased numbers of live pups per litter
were observed for female pups on day 0 at the 600 and 900 mg/kg/day dose
levels, as was decreased pup weight on day 7 and 21 at the 900 mg/kg/day
dose level.  Sex ratio was significantly increased at 900 mg/kg/day (62%
vs. 42% in control).

Parental/systemic NOAEL = 300 mg/kg/day

Parental/systemic LOAEL = 600 mg/kg/day, based on   significantly
decreased absolute and relative liver weight of male and female rats of
both generations as well as increased incidence of mineralization of
kidneys at the 600 mg/kg/day dose

Reproductive NOAEL = 900 mg/kg/day

Reproductive LOAEL > 900 mg/kg/day (HDT)

In the rat reproduction toxicity study, the ADTC concluded that the
report of decreased number of live pups on day 0 of the study was based
in part on the inclusion into this calculation of maternal animals that
did not deliver any litters.  The observation is also inconsistent with
the lack of effect on viability index and the lack of effect on number
of live pups on day 21 post- natal.

The committee recommended that the reproductive NOAEL/LOAEL should be
re-stated as 900 and > 900 mg/kg/day, respectively.  There are no
reproductive effects of Busan 77 in this study.  The parental/systemic
NOAEL/LOAEL should be re-stated as 300 mg/kg/day and 600 mg/kg/day,
based on significantly decreased absolute and relative liver weight of
male and female rats of both generations as well as increased incidence
of mineralization of kidneys at the 600 mg/kg/day dose.

6.3	Determination of Susceptibility

There is an adequate database for determining potential sensitivity of
Busan 77 to offspring.  Two developmental toxicity studies conducted
with rats and rabbits demonstrated developmental toxicity effect levels
that were at the same or higher dose levels than those doses causing
maternal toxicity.  In the rat, a developmental toxicity LOAEL was not
established; the NOAEL was 500 mg/kg/day.  The maternal LOAEL of 350
mg/kg/day was based on decreased body weight gain and food consumption.
In rabbits, the maternal and developmental toxicity LOAELs were the
same, 45 mg/kg/day.  Maternal effects consisted of increased abortions,
reduced defecation and emaciation, reduced food consumption, and
decreased weight gain.  Offspring effects at this dose consisted of
increased incidence of 13th rudimentary ribs and unossified sternebrae
#5 and #6.  In the two-generation reproduction toxicity study, the
reproductive LOAEL was >900 mg/kg/day, whereas the parental LOAEL was
600 mg/kg/day.

The weight of the evidence from these data indicates no increased
sensitivity of the offspring in either the developmental or reproductive
toxicity studies to the adverse effects of Busan 77.  This conclusion is
supported by the previous conclusion of the HED RfD/Peer Review
Committee in 1994

B. Degree of Concern Analysis and Residual Uncertainties

None.

C.  Proposed Hazard-based Special FQPA Safety Factor(s):

The ADTC recommended that the special hazard-based FQPA safety factor
for Busan 77 be removed.  This conclusion is based upon the availability
of acceptable developmental and reproductive toxicity studies with Busan
77 that adequately characterize the dose-response of this compound and
the lack of evidence for any sensitivity of offspring to the adverse
effects of Busan 77.

6.4	Recommendation for a Developmental Neurotoxicity Study

The ADTC concluded that a developmental neurotoxicity study for Busan 77
is not warranted.

7.0	SUMMARY OF TOXICOLOGICAL DOSES AND ENDPOINTS FOR BUSAN 77 FOR USE IN
HUMAN RISK ASSESSMENT

7.1	Summary Table of Toxicological Dose and Endpoint Selection (Table 4)

Exposure Scenario

Dose (mg/kg/day) UF / MOE

Hazard Based Special FQPA Safety Factor

Study and Toxicological Effects

Dietary Risk Assessments

Acute Dietary

(gen pop)

This risk assessment is not required.

Acute Dietary

(females 13+)

This risk assessment is not required.

Chronic Dietary

NOAEL = 100 mg/kg/day

UF = 100

Chronic RfD = 1.0 mg/kg/day

1x

Chronic toxicity in rats

LOAEL = 300 mg/kg/day based on clinical alterations and reduced body
weight gain

Incidental Oral

Short-Term

(1 - 30 Days)

NOAEL = 500 mg/kg/day

MOE = 100

Developmental Toxicity - Rat

LOAEL = 700 mg/kg/day (increased mortality)

Incidental Oral

Intermediate-Term

(1 - 6 Months)

NOAEL = 221 mg/kg/day

MOE = 100

Subchronic toxicity in Rats

LOAEL = 752 mg/kg/day

Based on renal tubular mineralization

Non-Dietary Risk Assessments

Dermal

Short-Term

NOAEL = 10 mg/kg/day

(125 µg/cm2)a

MOE = 100

 90-day dermal toxicity study in rats

MRID 40170601

LOAEL = 100 mg/kg/day, based on dermal irritation.

Dermal

Intermediate and Long-Term

No endpoint identified in the database.

Inhalation

Short-Term

(1 - 30 Days)

MOE = 1000

See short-term incidental oral endpoint

Inhalation

Intermediate-Term

(1 - 6 Months)

MOE = 1000

See intermediate-term incidental oral endpoint

Inhalation

Long-Term

(> 6 Months)

MOE = 1000

See chronic RfD endpoint

Cancer

Group “D” based on increased thyroid C-cell adenomas by ad hoc
committee.  Referred to the full HED CARC for evaluation of carcinogenic
potential.

aTGAI based dermal endpoint = (10 mg/kg  x  0.2kg rat x  1000 µg/mg) /
16 cm2 = 125 µg/cm2

8.0	TOXICITY PROFILE TABLES

8.1	Acute Toxicity Profile Table - (See Section 4.1, Acute Toxicity,
Table 1).

8.2	Subchronic, Chronic and Other Toxicity Profiles Table (Tables 5a and
5b)

Table 5: Subchronic, Chronic, and other Toxicity Profiles for Busan 77

Guideline Number/

Study Type

Test Substance (% a.i.)	MRID Number (Year) /Citation/

Classification/ Doses	Results

870.3050

28-day oral (mice)

Purity:  not reported	MRID 40362601

Kehoe, D.F. (1987). Four-Week Toxicity Study with Busan 77 in Mice.
Buckman Labs, Inc., Memphis, TN. Study #: 6176-108

Not reviewed

Busan 77 administered orally in the diet at 0, 2500, 5000, 10000, 20000
ppm for 28 days

5  rats/sex/dose

NOAEL = 10, 000 ppm

Body weights, food consumptions, and antemortem observations were
recorded at initiation and then weekly for at least 4 weeks. At the end
of the study, all surviving mice were bled for hematology and clinical
chemistry tests. The mice were then anesthetized, exsanguinated, and
necropsied. A female mouse that died on test was also necropsied and
representative tissues were collected. At the scheduled necropsies,
macroscopic observations were recorded, selected organs were weighed,
and representative tissues were collected as required by the protocol.
Specified tissues from mice given  0 or 20,000 ppm were examined
microscopically. Representative samples of gross lesions and rectums
were also examined microscopically from all groups.

No treatment-related antemortem observations were seen in animals fed
Busan 77; and no treatment-related changes occurred in body weight or
food consumption the cumulative body weight gains were significantly
lower during Week 1, 2 and 4 in males fed 20,000 ppm Busan 77. Although
females fed 20,000 ppm had a lower body weight when compared with the
control group, there were no statistically significant differences.

There were no treatment-related effects on the clinical pathology data,
organ weight data, or microscopic observations. The only microscopic
lesions that may have been treatment related were small foci of
neutrophils at the anorectal junction of mice given 20,000 ppm Busan 77.

870.3100

90-day oral (rat)

Purity:  not reported

	MRID 40025001/93662014

Tisdel, Merrill (1986). Thirteen Week Subchronic Toxicity Study With
Busan 77 in Rats. Buckman Labs, Inc. Memphis, TN. Study #: 6176-106.

Core-Minimum

Busan 77 administered orally in the diet at 0, 3000, 10,000, 30,000 and
40,000ppm (0, 300 1000, 3000, and 4000 mg/kg ) for 13 weeks

10  rats/sex/dose

NOAEL = 3,000 ppm(2000 mg/kg)

LOAEL  = 10,000 ppm (752 mg/kg)

Mineralization of renal tubules. At 30,000 ppm and 40,000 ppm (approx.
2554 and 3685 mg/kg/d, resp.) the following were observed: decreases in
body weights and possibly absolute organ weights (heart, liver, kidney
and gonads); an equivocal decrease in red blood cell counts; elevated
leukocyte counts; non-supportive inflammation in the choroid plexus of
the brain; death.

The occurrence of increased kidney weight and mineralization at 10,000
ppm and above suggests a treatment—related response. Severity of
mineralization was not discussed. Chronic inflammation of the choroid
plexus was observed at the two highest dose levels only, suggesting a
treatment—related response in this parameter. The decrease in actual
numbers of animals affected at the highest dose level (40,000 ppm) is a
function of the mortality that was observed at that level (8 males, 2
females).

870.3250

90-day dermal (rabbit)

Purity:60%	MRID 40170601/93062015

Spindler, M. (1987).  13-Week Dermal Toxicity Study with Busan 77 in
Rabbits. Buckman Laboratories, Inc. Memphis, TN.

Study #: 6176-118

Acceptable

Guideline

Busan 77 applied dermally at 0, 10, 100, 1000 mg/kg for 13 weeks

10 rabbits/sex/dose

Systemic Toxicity

NOAEL > 1000 mg/kg/day (HDT)

Dermal Toxicity

NOAEL = 10 mg/kg/day

LOAEL = 100 mg/kg/day, Based on treatment related dermatological changes
consistent with chronic irritation/inflammation. The skin lesions
consisted of one or more combinations of ulceration of the epidermis,
chronic inflammation of the dermis, acanthosis, hyperkeratosis,
parakeratosis, folliculitis and epidermatitis.

Following the dermal application of Busan 77 to male and female rabbits
at dose levels of 0, 10, 100 and 1,000 mg/kg/day, 6 hours/day, 5
days/week for 13 weeks, there were no treatment-related changes in the
body weights, food consumption, hematology, clinical chemistry, organ
weights and organ—to-body weight ratios and gross and/or
histopathological changes of internal organs of males and females.
However, there was treatment related dermatological changes consistent
with chronic irritation/inflammation were seen in males and females
receiving 100 and 1,000 mg/kg/day. The skin lesions consisted of one or
more combinations of ulceration of the epidermis, chronic inflammation
of the dermis, acanthosis, hyperkeratosis, parakeratosis, folliculitis
and

epidermatitis. The doses tested did not establish the MTD, however, the
highest dose tested reached Limit Dose.

870.3700a

Developmental Toxicity – oral gavage (rat)

Purity:  61.2%

	MRID 41423001/93062018

Nemec, Marc D. (1987). A Teratology Study in Rats with Busan 77. Buckman
Laboratories, Inc. Study #: WIL-94020.

Core-Minimum

Guideline

Busan 77 administered orally at 0, 70, 350 500 mg/kg/day on GD 6-15

25 rats/dose group

Maternal Toxicity

NOAEL = 70 mg/kg/day

LOAEL = 350 mg/kg/day, based on decreased food consumption and body
weight gain.  Mortality observed at 700 mg/kg/day

Developmental Toxicity

NOAEL = 500 mg/kg/day LOAEL > 500 mg/kg/day (HDT)

Busan 77 was toxic to rat dams, causing decreases in food consumption
and (non-statistically significant) decreases in body weight gains at
350 mg/kg/d and 500 mg/kg/d, and death and morbidity at 700 mg/kg/d. The
dose response curve appears to be inordinately steep, since 1) none of
the toxicity (convulsions, lethargy and pathological changes in lung,
brain, stomach and intestines) observed at 700 mg/kg/d was observed at
500 mg/kg/d, which is only of a log dose lower; and 2) the profile of
other adverse effects such as decrease food consumption (Table 2)
suggests a more gradual slope. However, absence of effects at lower dose
levels cannot be adequately verified from the data submitted with this
study (see Deficiencies Section above). It is also remarkable that liver
and/or kidney effects were not reported as being observed, even at
levels that killed 25% of the dams.

Busan 77 appears to cause a dose-related increase in embryonal death, as
manifested by a statistically significant increase in early resorptions,
at 500 mg/kg/d.

870.3700b

Developmental Toxicity – oral gavage (rabbit)

Purity:  60.8%	MRID 41248001/93062019

Rodwell, Dean E. (1989). Teratology Study in Rabbits with Busan 77.
Buckman Laboratories, Inc. Study #: 3138.29

Core

Guideline

Busan 77 administered via gavage at 0, 15, 45 and 125 mg/kg on GD 6-18
inclusive

20 rabbits/dose group

Maternal Toxicity

NOAEL = 45 mg/kg/day

LOAEL = 125 mg/kg/day, based upon increased incidence of abortions,
clinical signs including reduced defecation and emaciation,
significantly reduced feed consumption and body weight gain during
treatment.

Developmental Toxicity

NOAEL = 45 mg/kg/day

LOAEL = 125 mg/kg/day

based upon increased incidence of 13th rudimentary ribs and unossified
sternebrae #5 and #6.

The data reporting was thorough and the summary means that were
validated were supported by the individual animal data, except for minor
discrepancy in reporting the mean body weight gain of 80 instead of 183
for the high dose dams during gestation Day 24 - 29 (Report summary
Table 4). The error had been factored in, in the calculation of body
weight gain of dams and will not alter the conclusions of the study.

It was reported that the doses were selected based upon a range finding
study, but no details were provided. While this information should have
been included in the report, the deficiency is not a factor since
results of current study indicate maternal toxicity at 125 mg/kg/day.

a. Maternal Toxicity: At 125 mg/kg/day, increased incidence of
abortions, clinical signs including reduced defecation and emaciation,
significantly reduced feed consumption and body weight gain occurred
during treatment.

b. Developmental Toxicity: At 125 mg/kg/day, the incidence of 13th
rudimentary ribs and unossified sternebrae #5 and #6 was increased
significantly (P 0.05). The litter incidences for 13th rudimentary rib
(93.3 vs. 89.5 of historical controls) and unossified sternebrae #5
and/or #6 (40.0 vs. 36.8 of historical controls) are slightly above the
corresponding historical controls values. Although, the incidence lacked
a trend or dose- relationship and occurred at a maternally toxic dose,
the increases are considered treatment-related.

870.3800

Reproduction and fertility effects (rat)

Purity: not reported	MRID 40578201/93062020

MacKenzie, K.M. (1988). Two-Generation Reproduction Study with Busan 77
in Rats (One Litter per Generation).  Buckman Laboratories, Inc.,
Memphis, TN.  Study #: HLA 6176-104.

Core-Minimum

Guideline

Busan 77 administered in the diet at 0, 6000, 12000 and 18000 (0, 300,
600 and 900 mg/kg/day) for two generations

25 rats/sex/dose

Maternal Toxicity

NOAEL: not established

LOAEL: 300 mg/kg/day, based on decr. Body weight, inflammation of
choroid plexus, tubular mineralization of the kidney.

Reproductive Toxicity:

NOAEL = 600 mg/kg/day

LOAEL = 900 mg/kg/day, based on decreased live pups.

870.4100

Chronic Toxicity (dog)

Purity: not reported	MRID 41234501/93062016

Kehoe, Daniel F. (1989). One-Year Chronic Toxicity Study with Busan 77
in Dogs.  Buckman Laboratories, Inc. Memphis, TN. Study #: HLA 6176-111

Supplementary

Busan 77 administered  orally at 0, 10000, 20000 and 40000 ppm (0, 250,
500, 1000 mg/kg)for 52 weeks

4 dogs/sex/dose

NOAEL: 250 mg/kg/day (M); 500 mg/kg/day (F)

LOAEL = 500 mg/kg/day (M), based on testicular hypoplasia,
atrophy/degeneration, aspermia, dysplasia and cellular debris of
testicular origin in epididymis.

LOAEL = 1,000 mg/kg/day (F), based on G-I disturbances, weight loss and
nervous symptoms (bloody stools, emaciation and ataxia, respectively).

Administration of Busan 77 in the feed for up to 52 weeks had no affect
on mortality. However, an increased incidence of vomits and abnormal
stools (soft and bloody) was observed with increasing dose. In the KTD
group, all males and females exhibited bloody stools at 12 (1) and 26
(2) weeks, respectively. Probably this is related to treatment. At
necropsy, thickened wall of duodenum (3 males and 2 females), jejunum (2
males) and ileum (1 male) were observed in the 40,000 ppm group.
Microscopic examination of these tissues did not reveal any changes
associated with the treatment and is probably of no toxicological
significance. In addition, microscopic examination of rectum or colon of
all HDT males revealed changes associated with chronic inflammatory
processes and was probably treatment related. Body weight gain of males
and females in the 40,000 ppm group decreased significantly when
compared to controls. Body weight gain of males and females was reduced
by 39 and 42%, respectively, at 12 weeks when compared to controls. In
the 20,000 ppm group, the mean body weight gain decreased
non-significantly in males and females 17 and 6%, respectively, at 12
weeks when compared to controls; and decreased in males and females 30
and 14%, respectively, at termination (52 weeks) when compared to
controls and it may not be related to treatment. Food consumption was
significantly decreased in the males and females in the 40,000 ppm group
at several intervals. At week 13, food consumption of males and females
in the 40,000 ppm group decreased 46 and 53%, respectively, when
compared to controls.

At 26 weeks, males and females in the 40,000 ppm group had a significant
increase in Hct, MCV, MCH and platelets, and in females a significant
increase in Hb was observed. Also, a significant decrease in RBC was
seen in males and females at the 26 week time interval. The low RBC and
increased MCV may signal mild anemia; however, histopathology of bone
marrow smears and bone sections did not correspond to morphological
changes. These changes in the HTD group may be in part/whole related to
mild anemia, emaciation and dehydration. Significant increases in MCV in
the 10,000 and 20,000 groups in males/females are of questionable
biological significance because of the sporadic nature of occurrence.

Total protein, albumin and creatinine were significantly decreased in
males and females in the 40,000 ppm group at 26 weeks, probably due to
anemia and emaciation and may be treatment related. Also, a significant
decrease in K, glucose in males and P(inorganic), Na and Cl in females
were also observed at this interval. This is probably due to
dehydration, associated with vomition/diarrhea. Changes noticed in the
10,000 ppm group and in the 20,000 ppm group for K, and P(i) at 26
weeks, are of sporadic nature and have no toxicological significance.
The significant (slight) increase of SGPT in males at 26 weeks, in the
40,000 ppm group and of SCOT at 52 weeks, in the 10,000 and in the
20,000 ppm groups at 52 weeks, is probably of no toxicological
significance, since the histopathology revealed no treatment related
affects. At 52 weeks, males and females had significantly reduced
cholesterol in the 20,000 ppm group; the toxicological significance of
this is uncertain.

urine pH in males was significantly reduced in the 40,000 ppm group at
26 weeks and in the 10,000 and in the 20,000 ppm groups at 52 weeks.
Also, higher urinary blood pigment was noticed in the 40,000 ppm group.
The significance of low urine pH and higher urinary blood pigment on the
urinary tract is of questionable values, since there was no
corresponding histopathological changes.

Organ to body weight ratios for brain, liver and kidney increased
(significantly) 52, 19 and 47%, respectively for males in the 20,000 ppm
group at termination, when compared to controls. The actual weights of
the brain, liver, and kidney in males were 1, -18 and -13 %,
respectively, when compared to controls. Females exhibited significant
increases of 4 and 47 %, respectively, in the body weight ratio of
kidney and liver. The apparent increase in the organ to body weight
ratios, and actual decrease in the absolute organ weights without
corresponding histopathological changes, suggest that the changes seen
grossly may be due to in part/whole to body weight loss, especially
water loss from vomition and diarrhea. In addition, testes relative
organ weights were not affected, where as actual weights decreased 27,
20 and 58 % in the LTD, MTD, and NW, respectively, when compared to
controls. Reduced testicular weights corresponded to testicular
hypoplasia on histopathology, evidenced by atrophy/degeneration,
aspermia, dysplasia and presence of cellular debris of testicular origin
in the epididymis of all males in the 40,000 ppm group and 2 males in
the 20,000 ppm group.

870.4200

Carcinogenicity (mice)

Purity: 60.8%	MRID 41494301/93062017

Kehoe, Daniel F. (1989). One-Year Chronic Toxicity Study with Busan 77
in Dogs.  Buckman Laboratories, Inc. Memphis, TN. Study #: HLA 6176-111

Core-Minimum

Guideline

Busan 77 administered  orally at 0, 4000, 8000 and 16000 ppm (0, 600,
1200, and 2400 mg/kg)for 18 months

50 mice/sex/dose

NOAEL= not established

LOAEL <600 mg/kg/day, based on enlarged kidney pelvis, diffuse rough
kidney I females; dose-related increase in proteinaceous casts in males,
and pelvic and tubular dilation in males and females.

It could not be definitively determined whether increase incidence of
rough hair coat, bloody crusts and red ears in males and convulsions in
females had a LEL of 4,000 or 16,000 ppm.

At the 8000 and above, all of the above findings and including
convulsions (M & F), urine scams (M & F), rough hair coat (F), bloody
crusts (F) swollen abdomen (M & F), swollen anus (M), red tails (H & F),
red ears (F), reduced body weight gains (H & F), diffuse rough kidneys
(H & F), large kidney pelvis (H & F), relative kidney weights (high dose
males, and mid and high dose females), proteinaceous casts (F), cortical
fibrosis/scarring (F) and cysts (F), were observed.

870.4300

Combined chronic toxicity/carcinogenicity (rat)

Purity: 60%	MRID 41809101/41561301

Kehoe, Daniel F. (1991). Combined Chronic Toxicity Study and
Carcinogenicity Study with Busan 77.  Buckman Laboratories, Inc.
Memphis, TN. Study #: HLA 6176-107.

Core-Minimum

Guideline

Busan 77 administered orally at 0, 2000, 6000 and 18,000 ppm (0, 100,
300 and 900 mg/kg./day)

50 rats/sex/dose

Chronic:

NOAEL = 100 mg/kg/day

LOAEL = 300 mg/kg/day, based on reduced body weight gain (F), reduced
albumin (M), reduced total protein (M), reduced Pi (M&F), increased
urine pH(F) and a dose related-related increase. In blood crusts.

Carcinogenicity:

I females, possible increased incidence of thyroid C-cell adenoma at 300
and 900 mg/kg/day, and positive trend for this tumor in both sexes.

RfD comm.. considered the data in this study; classified Busan Group D.

Mutagenicity

870.5100

Reverse mutation assay – salmonella typh.

Purity: not reported	MRID 41573701

Lawler, T.L. and  DaCosta, K. (1990). Mutagenicity Test on Busan 77 in
the Salmonella/Mammalian-Microsome Reverse Mutation Assay with
Confirmatory Assay. Buckman Laboratories, Inc. Study #: 12144-0-401R.

Acceptable

Guideline

Busan 77 doses of 66.7, 100, 333, 667, 1000 and  3330µg/plate

Strains: salmonella (TA1535, TA1537, TA1538, TA98 and TA100

Negative

In the initial mutagenic assay (Table 3), using strains TA1535, TA1537,
TA1538, TA100 and TA98 in the presence and absence of S9 activating
system, at doses of 66.7, 100, 333, 667, 1,000 and 3,330 mg/plate, did
not increase in the number of histidine revertants were observed, either
in the presence or absence of S9 system. The experiment was repeated and
all data were acceptable except for strain TA9B for which the means were
outside the acceptable range both in the presence and absence of S9. The
TA98 strain was retested both in the presence/absence of activation
system and the results were acceptable (Table 4). Revertants frequencies
for all doses of Busan 77 in all strains approximated or were less than
those observed in the concurrent negative controls (Tables 1 and 2). All
positive controls produced positive responses expected of the chemicals.

Based on the results of the Salmonella Reverse Mutation Assay the test
article Busan 77 did not cause a positive increase in the number of
histidine revertants per plate.

870.5275

Sex-linked recessive lethal test

Purity: 100%	MRID 00151205

McCarroll, N. (1985). Drosophila Sex-linked Recessive Lethal Assay [with
WSCP (Busan 77)]: Hazelton Laboratories, Inc. Project #: 197-183.
Unpublished

Acceptable

Busan 77 administered at 0.08, 0.3 and 0.8 mg/ml

Test strain: Flies

Negative

A dose-related increase in sterility was observed in the mated P1 males
to increasing concentration of the test material when compared to the
solvent control.

870.5300

In vivo micronucleus assay (mice)

Purity: 100%

	MRID 00151206/93062021

Drake, K. (1990) Buckman Labs Inc Phase 3 Summary of MRID 00151206.
Busan 77- in Vivo Mouse Micronucleus Assay: Laboratory ID 197-182.
Prepared by Hazleton Biotechnologies Corporation. 8 p.

Acceptable

Guideline

Busan 77 administered via gavage at 0.08, 0.3 and 0.8 mg/ml

15 mice/sex/dose

Negative

The test compound WSCP (Busan 77) is considered non-mutagenic in mice
under the condition of this assay.

The test compound WSCP (Busan 77) did not induce a significant increase
of the PCE containing micronuclei in the treated mice when compared to
that of the vehicle control value.

The positive control compound cyclophosphamide induced a significant
increase of the PCE containing micronuclei, which indicated the
sensitivity of the assay system

(p < 0.0001).

870.5550

Unscheduled DNA synthesis in mammalian cells in culture (rat)

Purity: not reported

	MRID 40978701/93062022

Cifone, M. (1989) Mutagenicity Test on Busan 77 in the in vivo/in vitro
Rat Primary Hepatocyte Unscheduled DNA Synthesis Assay: Project ID: HLA
Study No. 10280-0-494. Unpublished study pre- pared by Hazleton
Laboratories America, Inc. 26 p.

Acceptable

Guideline

Busan 77 administered at 188, 375, 750 and 1500 mg/kg

3 rats/group

Negative

Hepatocyte viability/attachment efficiency ranged from 85.4 to
95.2%/66.2 to 81.5%. Busan at a concentration of 188, 375, 750 and 1,500
mg/kg resulted in hepatocyte viability (attached cells) of  93.9, 93.2,
94.9 and 93.3%, respectively; i.e., no toxicity (see Appendix 2).  None
of the treatments with Busan resulted in a significant increase in
nuclear labeling, when compared to the controls and did not meet the
minimum criteria for UDS assay for mean net nuclear grain count
exceeding 6, or at least 10% of the nuclei containing 6 or more grains,
or at least 2% of the nuclei containing 20 or more grains, to conclude a
positive response (see Appendix 1). Furthermore, there was no
dose-related trend observed. Positive control treated cultures exhibited
greatly exceeded all three criteria used to indicate UDS.

870.7485

Metabolism and pharmacokinetics (rat)

Purity: 60%	MRID 40268601/93062024

Puhl, R. (1987) Metabolism Study with Busan 77 (WSCP) in Rats: Final
Report: Laboratory Project ID: HLA 6176-115. Unpublished study prepared
by Hazleton Laboratories America, Inc. 98 p.

Acceptable

14C-labeled Busan 77 administered oral and i.v. single of 10 mg/kg;
single oral dose of 1000 mg/kg; repeated oral dose of 10 mg/kg

5 rats/sex/dose

Intravenous excretion at 10 mg/kg; urine, 38-44% feces, 11-14%.  Tissue
contained 43-55% of the dose.  Single and repeated oral dose excretion:
urine, 3% of dose, feces 85-105% of dose.  Tissue levels low in these
groups (0.14% highest levels in any tissue)

Oral 1000 mg/kg dose: urine, 14-17%; feces 68-71% of dose.

Expired CO2 was not detected. In the intravenous dose group, the major
routes of excretion of radioactivity were via urine and feces. Over a
7-day period, approximately 52-55% of the test material administered was
excreted in the urine (38-44%) and feces (11-14%); 43-55% was, found in
the tissues. In a single repeated oral dosed groups 88-106% of the test
compound administered was excreted in the urine (3%) and feces
(85-105%); kidneys, liver, and spleen had a highest residue level. In
these

groups, tissue residue levels were low in all tissues, except kidneys.
Not more than 0.14% of the administered dose was recovered in tissues.
Potential for bioaccumulation at the single or repeated oral is minimal.
At the highest oral dose, 85% of the administered dose was recovered in
urine (14-17%) and feces (68-71%).  The information provided by the
sponsor explains that almost the entire administered dose was excreted
in the feces unchanged and remaining 40% of the composition of the
technical or radiolabeled material was water.

870.7600

Dermal penetration (rat)

Purity: 60%	MRID 40139201/93062025

Bosch, A. (1987) Dermal Absorption of [Carbon 14]-Busan 77 (WSCP) in
Male Rats: HLA Study No. 6176-117: Final Report. Unpublished study
prepared by Hazleton Laboratories America, Inc. 52 p.

Acceptable

Guideline

single dermal administration to male rats at 2, 20, or 200 mg/rat (0.16,
1.59, or 15.97 mg/cm2, respectively)

24 rats/group

The total amount of Busan 77 absorbed (expressed as percent of 14C-dose)
from rats at various times following dermal administration of 14C-Busan
77 at 2, 20 or 200 mg/animal is negligible (less than 0.2% of the dose).
Also, no radioactivity was found in carcass and blood of all treated
animals indicating no dermal absorption of Busan 77.

Only less than 0.2% of the Busan  77was absorbed. Mean % recovery of
radioactive dose ranged from 74.5 - 92.7%. Majority of the dose was
recovered in the skin rinse (65.5% - 88.6%) and at the skin site (0.4% -
13.7%).

9.0	REFERENCES

00151205	McCarroll, N. (1985) Drosophila Sex-linked Recessive Lethal
Assay [with WSCP (Busan 77)]: Final Report: Project No. 197-183.
Unpublished study prepared by Hazleton Laboratories. 20 p.

00151206	Cortina, T. (1984) In vivo Micronucleus Assay in Mice: WSCP:
Final Report: Project No. 197-182. Unpublished study prepared by
Hazleton Laboratories America, Inc. 38 p.

40025001	Tisdel, M. (1986) Busan 77-Thirteen-week Subchronic Toxicity
Study in Rats: Project ID: Study No. 6176-106. Unpublished study
prepared by Hazleton Laboratories of America, Inc. 285 p.

40139201	Bosch, A. (1987) Dermal Absorption of [Carbon 14]-Busan 77
(WSCP) in Male Rats: HLA Study No. 6176-117: Final Report. Unpublished
study prepared by Hazleton Laboratories America, Inc. 52 p.

40170601	Spindler, M. (1987) 13-Week Dermal Toxicity Study with Busan 77
in Rabbits: Laboratory Project ID: HLA 6176-118. Unpublished study
prepared by Hazleton Laboratories America, Inc. 290 p.

40268601	Puhl, R. (1987) Metabolism Study with Busan 77 (WSCP) in Rats:
Final Report: Laboratory Project ID: HLA 6176-115. Unpublished study
prepared by Hazleton Laboratories America, Inc. 98 p.

40578201	MacKenzie, K. (1988) Two-Generation Reproduction Study with
Busan 77 in Rats (One Litter per Generation): Project ID: HLA 6176-104.
Unpublished study prepared by Hazleton Laboratories America, Inc. 952 p.

40750301	Glaza, S. (1987) Dermal Sensitization Study in Guinea Pigs with
WSCP: Proj. ID 70303995. Unpublished study prepared by Hazleton
Laboratories America, Inc. 30 p.

40978701	Cifone, M. (1989) Mutagenicity Test on Busan 77 in the in
vivo/in vitro Rat Primary Hepatocyte Unscheduled DNA Synthesis Assay:
Project ID: HLA Study No. 10280-0-494. Unpublished study prepared by
Hazleton Laboratories America, Inc. 26 p.

41234501	Kehoe, D. (1989) One-Year Chronic Toxicity Study with Busan 77
in Dogs: Laboratory Project ID: HLA 6176-111. Unpublished study prepared
by Hazleton Laboratories America, Inc. 301 p.

41248001	Rodwell, D. (1989) Teratology Study in rabbits with Buan 77:
SLS Study No. 3138.29. Unpublished study prepared by Springborn Life
Sciences, Inc. 229 p

41298601	Rush, R. (1989) Primary Skin Irritation Study in Rabbits with
Busan 77: SLS Study No. 3138.49. Unpublished study prepared by
Springborn Laboratories, Inc. 19 p.

41327101	Rush, R. (1989) Acute Dermal Toxicity Study in Rabbits with
Busan 77: Lab Project Number: 3138.50. Unpublished study prepared by
Springborn Laboratories, Inc. 26 p.

41361701	Rush, R. (1989) Primary Eye Irritation Study in Rabbits with
Busan 77 (EPA-FIFRA): Lab Project Number: 3138/52. Unpublished study
prepared by Springborn Laboratories, Inc. 25 p.

41373401	Rush, R. (1990) Acute Oral Toxicity Study in Rats with Busan
77: SLS Study No. 3138.51. Unpublished study prepared by Springborn
Laboratories, Inc. 65 p.

41423001	Nemec, M. (1987) A Teratology Study in Rats with Busan 77:
Final Report: Lab Project Number: WIL-94020. Unpublished study prepared
by WIL Research Laboratories, Inc. 281 p.

41494301	Kehoe, D. (1990) 18-Month Study with Busan 77 in Mice: Lab
Project Number: HLA 6176-109. Unpublished study prepared by Hazleton
Labs America, Inc. 924 p.

41561301	Kehoe, D. (1990) Combined Chronic Toxicity and Carcinogenicity
Study with Busan 77 in Rats: Draft Report: Lab Project Number: HLA
6176-107. Unpublished study prepared by Hazleton Laboratories America,
Inc. 1511 p.

41573701	Lawlor, T.; DaCosta, K. (1990) Mutagenicity Test on Busan 77 in
the Salmonella/Mammalian-Microsome Reverse Mutation Assay (Ames Test)
with Confirmatory Assay: Lab Project Number: 12144-0-401R. Unpublished
study prepared by Hazleton Laboratories America, Inc. 33 p.

41809101	Kehoe, D. (1991) Combined Chronic Toxicity and Carcinogenicity
Study with Busan 77 in Rats: Final Report (Supplement to MRID 41561301):
Lab Project Number 6176-107. Unpublished study prepared by Hazleton Labs
America, Inc. 1511 p.

41877501	Hoffman, G. (1991) An Acute Inhalation Toxicity Study of Busan
77 in the Rat: Lab Project Number: 90-8305. Unpublished study prepared
by Bio/dynamics, Inc. 105 p.

93062009	Drake, K. (1990) Buckman Labs Inc Phase 3 Summary of MRID
41373401. Busan 77- Acute Oral Toxicity Study in Rats: Laboratory ID:
313851. Prepared by Springborn Laboratories, Inc. 9 p.

93062010	Drake, K. (1990) Buckman Labs Inc Phase 3 Summary of MRID
41327101. Busan 77- Acute Dermal Toxicity Study in Rabbits: Laboratory
ID: 313850. Prepared by Springborn Laboratories, Inc. 6 p.

93062011	Drake, K. (1990) Buckman Labs Inc Phase 3 Summary of MRID
41361701. Busan 77- Primary Eye Irritation in the Rabbit: Laboratory ID:
313852. Prepared by Springborn Laboratories, Inc. 7 p.

93062012	Drake, K. (1990) Buckman Labs Inc Phase 3 Summary of MRID
41298601. Busan 77- Primary Dermal Irritation in the Rabbit: Laboratory
ID: 313849. Prepared by Springborn Laboratories, Inc. 6 p.

93062013	Drake, K. (1990) Buckman Labs Inc Phase 3 Summary of MRID
40750301. Busan 77- Dermal Sensitization in the Guinea Pig (Closed Patch
Technique) Laboratory ID: 70303995. Prepared by Hazleton Laboratories
America, Inc. 6 p.

93062014	Drake, K. (1990) Buckman Labs Inc Phase 3 Summary of MRID
40025001. Busan 77- Thirteen Week Subchronic Toxicity Study in Rats
Laboratory ID: HLA 6176-106. Prepared by Hazleton Laboratories America,
Inc. 12 p.

93062015	Drake, K. (1990) Buckman Labs Inc Phase 3 Summary of MRID
40170601. Busan 77- 13 Week Dermal Toxicity Study in Rabbits: Laboratory
ID: 6176-118. Prepared by Hazleton Laboratories America, Inc. 6 p.

93062016	Drake, K. (1990) Buckman Labs Inc Phase 3 Summary of MRID
41234501. Busan 77- One Year Chronic Toxicity Study in Dogs: Laboratory
ID: HLA 6176-111. Prepared by Hazleton Laboratories America, Inc. 8 p.

93062017	Drake, K. (1990) Buckman Labs Inc Phase 3 Summary of MRID
41494301. Busan 77- 18 Month Study in Mice: Laboratory ID: HLA 6176-109.
Prepared by Hazleton Laboratories America, Inc. 10 p.

93062019	Drake, K. (1990) Buckman Labs Inc Phase 3 Summary of MRID
41248001. Busan 77- Teratology Study in Rabbits: Laboratory ID: SLS
Study No. 3138-29. Prepared by Springborn Laboratories, Inc. 9 p.

93062020	Drake, K. (1990) Buckman Labs Inc Phase 3 Summary of MRID
40578201. Busan 77- Two Generation Reproduction Study in Rats:
Laboratory ID: HLA 6176-104. Prepared by Hazleton Laboratories America,
Inc. 9 p.

93062021	Drake, K. (1990) Buckman Labs Inc Phase 3 Summary of MRID
00151206. Busan 77- in Vivo Mouse Micronucleus Assay: Laboratory ID:
197-182. Prepared by Hazleton Biotechnologies Corporation. 8 p.

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Unscheduled DNA Synthesis Assay: Laboratory ID: 10280-0-494. Prepared by
Hazleton Laboratories America, Inc. 8 p.

93062024	Drake, K. (1990) Buckman Labs Inc Phase 3 Summary of MRID
40268601. Busan 77- Metabolism Study in Rats: Laboratory ID: HLA
6176-115. Prepared by Hazleton Laboratories America, Inc. 17 p.

93062025	Drake, K. (1990) Buckman Labs Inc Phase 3 Summary of MRID
40139201. Busan 77- Dermal Absorption: Laboratory ID: HLA 6176-117.
Prepared by Hazleton Laboratories America, Inc. 11 p.

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