Document ID: EPA-HQ-OPP-2008-0453-0003
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2008-09-19T04:00Z

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C. 20460

 OFFICE OF

                                                                        
                                    PREVENTION, PESTICIDES AND 

         TOXIC SUBSTANCES

September 10, 2008

MEMORANDUM

SUBJECT:	Summary of Human Health Effects Data for the Biobor
Registration Review Decision Document.

	DP Barcode:	D351817		Case No.:  3029

			PC Codes:  012401 and 012402	CAS#’s:  2665-13-6, 

									    14697-50-8

FROM:		Nathan Mottl, Biologist 

			Team Two    

Risk Assessment and Science Support Branch (RASSB)

Antimicrobials Division (7510P)

TO:			K. Avivah Jakob, Chemical Review Manager

Regulatory Management Branch II

Antimicrobials Division (7510P)

THRU:	Nader Elkassabany, Ph.D.

	Team Leader

	Risk Assessment and Science Support Branch (RASSB)

Antimicrobials Division (7510P)

		

	Norm Cook, Branch Chief

	Risk Assessment and Science Support Branch (RASSB)

Antimicrobials Division (7510P)

Introduction

	The Agency has evaluated the status of the human health assessments for
biobor, which is an antimicrobial pesticide used as a bacteriocide, 
fungicide, and microbicide/microbiostat (slime forming bacteria and
fungi) for material preservative (e.g. fuels/oils) and wood preservative
(e.g. seasoned wood, non-pressure treatment) uses. The Agency looked at
the hazard and exposure databases for biobor and attempted to determine
whether changes in science policy or deficiencies in the databases
materially affected the overall risk picture.  Biobor was first
registered in 1965 as a fuel additive. A Reregistration Eligibility
Decision (RED) was conducted for biobor in June 1993.  

	Boric acid esters, including biobor, undergo rapid hydrolysis in the
presence of water, forming boric acid or borate ion and two organic
esters (esters of butylene glycol and ethylene glycol). Small amounts of
sodium borate and boron are naturally occurring in background levels in
the environment and in the human diet. Biobor is not registered on food,
feed or processed food, feed or processed commodities. The occupational
fuel preservative uses of biobor were assessed in the biobor RED.
However, recently registered wood preservative uses were not assessed in
the RED nor was a new use assessment conducted.  As a result both fuel
and wood preservative uses will be assessed in this registration review.

	The primary sources of information for this assessment were the most
recent health risk assessments is the biobor RED and supporting risk
assessments for boric acid and the esters of butylene glycol and
ethylene glycol (see section 9). No new toxicity data for biobor have
been submitted to the Agency since registration.  A comprehensive
listing of the documents considered is presented later in this document.
 The purpose of this screen is to determine whether sufficient data are
available to support registration review, whether new human health
assessments are needed to support registration review, and to report why
the Agency feels it may be appropriate to conduct new risk assessments
under the registration review process.  

	There is no proposed direct food or feed uses of biobor; therefore, the
EPA has not established tolerances or exemptions from tolerances in raw
agricultural commodities or processed food and feed products under the
Federal Food, Drug and Cosmetic Act (FFDCA).

Biobor has two primary labeled uses:

As a material preservative in fuels/oils and storage tanks; 

As a wood preservative in seasoned wood during non-pressure wood
treatment.

Section 1.  Chemical Identity

Table 1.1  Chemical Identity

Common Name	Biobor

Chemical Names	1,3,2-Dioxaborinane,
2,2'-((1-methyl-1,3-propanediyl)bis(oxy))bis(4-methyl-,

2,2'-(1-Methyltrimethylenedioxy)bis(4-methyl-1,3,2-dioxaborinane),

1,3,2-Dioxaborinane, 2,2'oxybis(4,4,6-trimethyl-,

2,2'-Oxybis(4,4,6-trimethyl-1,3,2-dioxaborinane)

PC Codes	012401 and 012402

CAS registry number	2665-13-6, 14697-50-8

Registration Review Case No.	3029

	Biobor is a liquid, which is a mixture of two borate compounds (PC Code
012401 and 012402) and miscible in organic solvents. Vapor pressure is
estimated to be 3E-4 mm Hg for PC Code 012401 and 5E-3 mm Hg for PC Code
012402. The density of the liquid of PC Code 012401 is 1.07 g/cm3 at
20°C and PC Code 012402 is 0.99 g/cm3 at 20°C. Boric acid esters,
including biobor, undergo rapid hydrolysis in the presence of water,
forming boric acid or borate ion. The half-lives of the two boric acid
esters in Biobor® JF in water were measured by the methods of Steinberg
and Hunter.  The half-life of 2,2’-(l-
methyltrimethylenedioxy)bis-(4-methyl-l,3,2-dioxaborinane) was too fast
to measure and the half-life of
2.2’-oxybis(4,4,6-trimethyl-l,3,2-dioxaborinane) was approximately 6
seconds. The intermediate products of hydrolysis are probably partial
esters of boric acid, mono-borates which also are hydrolytically
unstable, forming boric acid and the respective glycol on further
reaction with water (D351811).  

Section 2.  Toxicology

	This health assessment addresses the toxicity of biobor. When biobor
was initially registered, EPA required only a Tier I toxicity data set
which consisted mainly of acute toxicity data requirements and
developmental studies. Biobor was classified as toxicity category III
for acute oral toxicity (rats) and dermal toxicity (rabbits), and
toxicity category IV for inhalation. Biobor is a severe eye irritant
(rabbit) (toxicity category I), but was not irritating to skin (toxicity
category IV). Biobor was not a dermal sensitizer in guinea pigs. 

	A developmental study (MRID 41872402) for biobor using rats showed
reduced fetal weights, and reduced or incomplete ossification of parts
of the skeleton. The maternal LOAEL was 1000 mg/kg/day and the NOAEL was
300 mg/kg/day based on reduced mean weight of maternal dams and lower
gravid uterine weight of the maternal dams. The developmental LOAEL was
300 mg/kg/day based on significantly reduced mean fetal weights,
increased incidences of reduced incomplete ossification of the skeleton
including skull, vertebras. The NOAEL for developmental effects was 100
mg/kg/day.  This study was classified as an acceptable study. 

	A developmental study (MRID 41579701) for biobor was administered to
rabbits at dose levels of 0, 25, 75, and 225 mg/kg/day at gestation days
7-19 days. The highest dose tested 225 mg/kg/day was considered the
NOAEL. The developmental LOAEL was 75 mg/kg/day and the NOAEL was 25
mg/kg/day. At the 75 mg/kg/day, there were unossified or absent stern
brae, and higher doses produced a small or missing lung lobe, dilated
renal pelvis, and missing cervical rib. The study is currently
classified as core supplementary data. 

	In the 1993 biobor RED, the Agency did not require any additional
sub-chronic, chronic, or reproductive toxicity testing based on the
minimal exposure for closed metering pumps for fuel/oils and storage
tanks.  At the time of the Biobor RED, there were only registered uses
for fuel treatment and fuel oil treatment. However, since that time a
wood preservative use has been added and requires additional
assessments. However, as noted below, the Agency will rely on much of
the toxicological database from boric acid. 

Dissociation to Boric Acid, Borax, and Boron

	Boric acid esters, including biobor, undergo rapid hydrolysis in the
presence of water, to form boric acid or borate ion and glycol ethers.
Glycol ethers quickly degrade in the soil and water and their systemic
toxicity is low (USEPA, 2006). Therefore, the Agency will use the
database from boric acid to develop many of the key toxicological
endpoints for biobor to analyze exposure to biobor.

	The Agency reassessed the glycol ether inert tolerance exemptions in
2006 (USEPA, 2006).  According to the Agency review the glycol ethers
all biodegrade quickly in soil and water. Because the glycol ethers
biodegrade quickly, it is expected that the post-application exposure
would be to boric acid rather than the glycol ethers.

	As noted, the Agency reviewed the toxicity of many of the glycol ethers
in 2006. No systemic inhalation toxicity was noted in inhalation studies
with diethylene glycol monomethyl ether (DGME), diethylene glycol
monoethyl ether (DGEE). No toxicity after dermal exposure was reported
in DGBE reproductive and neurotoxicity studies. However, mild liver
changes were reported after dermal exposure to DGME in guinea pigs at
200 mg/kg/day. No treatment related neoplasms were found in a mouse
carcinogenicity study with ethylene glycol (EG). Bladder tumors, mostly
benign, occurred at 1,500 and 3,000 mg/kg/day in male rats treated with
DG; these tumors were associated with irritation from bladder stones
which occurred at those doses. Genetic toxicity studies with these
chemicals were negative, except for chromosomal damage which occurred in
a bone marrow assay with DG. EG underwent a comprehensive review by NTP
of potential human developmental and reproductive toxicity which
concluded that “there is negligible concern of adverse developmental
toxicity from EG at exposures below 125 mg/kg/day.” There was no
evidence of reproductive toxicity from EG in lab animals. DG caused
developmental toxicity in mice at 10,000 mg/kg/day and caused fetal-pup
mortality in a reproductive mouse study 6,125 mg/kg/day. DGME caused
decreased ossification at 600 mg/kg/day in a rat oral developmental
study (NOAEL = 200 mg/kg/day) and at 250 mg/kg/day in a rabbit dermal
developmental study (NOAEL = 50 mg/kg/day) (USEPA, 2006).

 

	The moiety of toxicological concern for boric acid and borate is boron.
 The toxicity database for boric acid and borate has already been
assessed in previous REDs and TREDs as adequate. The key endpoints for
boric acid are presented in the “Boric Acid/Sodium Borate Salts: HED
Chapter of the Tolerance Reassessment Eligibility Decision Document
(TRED)” dated June 26, 2006 (DP Barcode D320894). The toxicological
endpoints are presented in Table 1 and summarized below.

	A major target organ of boric acid/borate salts is the testes and males
appear somewhat more sensitive to boric acid/borate salts than females. 
The mechanism for testicular atrophy is not known at this time, but
seminiferous tubule degeneration, atrophy, reduction in sperm count and
reduced testicular weights are observed across species.  Dogs appear to
be more sensitive to this effect than rats or mice.  The ovaries are
also a target organ and a reduction in the number of corpora lutea were
observed in female rats in a reproductive toxicity study.  Crossover
matings in rat reproductive toxicity studies demonstrate that fertility
is lower in both treated males and females, but the effect on fertility
in females is considerably less severe than in males.  The red blood
cell may be a potential target at higher dose levels, based on slight
hematological changes reported in some studies in the rat and the dog.	 

	The fetus is also affected by exposure to boric acid or sodium borate
salts. Developmental toxicity studies in the rat show increased fetal
susceptibility, with effects on skeletal development and pup weight
being the most sensitive and observed at doses that did not cause
maternal toxicity.  Skeletal abnormalities and reduced fetal weight were
also observed in mice at maternally toxic doses.  At higher dose levels
in the rat and rabbit, visceral abnormalities of the heart and/or great
vessels were observed and in the rat, enlarged lateral ventricles of the
brain were observed, with the fetal effects in rabbits observed at
maternally toxic doses.   Reduced survival was also reported in
developmental and reproductive toxicity studies at higher dose levels,
with all species tested (rat, rabbit, mouse) affected.

Although fetal toxicity is observed at doses below maternally toxic
levels in the rat, developmental toxicity has been well-characterized in
four developmental toxicity studies in three species.  Rabbits and mice
did not demonstrate clearly increased fetal sensitivity, although
developmental toxicity, including skeletal or visceral abnormalities and
reduced fetal survival, was observed.  Reproductive toxicity studies in
two species are also available.  The mechanism of testicular effects
(inhibited spermiation, testicular atrophy) has not been characterized,
but the lack of effects on male reproductive function in the rat and
mouse reproductive toxicity studies at doses greater than the endpoint
used for this risk assessment suggests that there is not increased
sensitivity of the developing testes.  At this time, there are no
residual uncertainties, based on sufficient data to characterize the
developmental effects.  The NOAEL used for risk assessments is lower
than the rat developmental toxicity NOAEL that is the most sensitive
developmental endpoint and is the most sensitive endpoint identified
from the available data.

	In addition it should be noted that boric acid/sodium borate salts are
not absorbed across intact skin and under the current Agency Cancer
Guidelines (D320894), boric acid/sodium salts are classified as “not
likely to be carcinogenic to humans.” 

  SEQ CHAPTER \h \r 1 Table 1.  Summary of Toxicological Endpoints Boron
from Boric Acid/Sodium Borate Salts TRED(D320894)

Exposure Scenario	

Factor Used in Risk Assessment	Study and Endpoint of Risk Assessment

Dietary Risk Assessment

Dietary (Acute and Chronic)- 

all populations

	NA	The contribution of boron residues from food/feed crop application
of boric acid/sodium borate salts to the total naturally occurring
background dietary boron intake from food and water is not considered to
be significant.  Endpoints for acute and chronic dietary exposure were
not selected for this risk assessment because it was determined that a
dietary risk assessment (food plus drinking water exposure) was not
necessary at the time.

Residential Risk Assessment (Adults and Toddlers)

Acute Oral Exposure (Toddlers)

Acute, Short-term and Intermediate-term 	

Level of Concern MOE= 100*	MRID no: 40692310

Chronic (2-year) toxicity (dogs)

NOAEL = 8.8 mg/kg/day

LOAEL was not determined

MRID no: 40692308

Chronic (38-week) toxicity (dogs)

NOAEL was not determined

LOAEL= 40 mg/kg/day males and 46 mg/kg/day females

Based on decreased body weight gain in males and females and testicular
atrophy in males.

MRID no 40692307

Subchronic (90-day) toxicity (dogs)

NOAEL= 4.1 mg/kg/day, males

LOAEL= 32 mg/kg/day, males based on testicular atrophy, anemia in
subchronic study.

Inhalation

Short-term and Intermediate-term	NA

	Dermal	NA	No evidence of absorption across intact skin.

Cancer	Not likely to be carcinogenic to humans

MOE = margin of exposure

LOC= level of concern

LOAEL=lowest observed adverse effect level

NOAEL= no observed adverse effect level

* LOC of 100 based on assigning a 10X for interspecies and 10 X for
intraspecies. The special FQPA SF has been reduced to 1x because there
are no residual uncertainties with regard to pre- and/or postnatal
toxicity.

	It should be noted that the Agency currently does not have
toxicological data to assess dermal, incidental oral and inhalation
exposure for biobor or boric acid. It is expected that applicators in
manufacturing settings and/or commercial settings may become exposed to
biobor/ borate mists from non-pressure dip treatments and residents may
become exposed to biobor from dermal and incidental oral (hand-to-mouth)
treatments.  

	It should also be noted that dermal absorption for boric acid is
negligible but the Agency does not have any dermal absorption data for
biobor. 

Section 3. Dietary and Drinking Water Assessment

	A dietary exposure risk assessment was not performed for biobor. There
is no direct food or feed uses of biobor. Therefore, EPA has not
established tolerances or exemptions from tolerances in raw agricultural
commodities or processed food and feed products under the Federal Food,
Drug and Cosmetic Act (FFDCA). Nor are there preservative uses that
would result in indirect food contact exposures.  Biobor would not
trigger a Tier I dietary screening-level assessment. 

	Biobor dissociates to boric acid.  Boric acid and borate salts are
registered for use on numerous food/feed crops. Boron is a naturally
occurring component of both food and water and is believed to be an
essential dietary trace nutrient, though a minimum daily requirement has
not been established.  The contribution of boron residues resulting from
the dissociation of treated products containing biobor is expected to be
considerably less than the naturally occurring background levels of
boron already existing in food and water.

Section 4.  Aggregate and Cumulative Exposure

	In examining aggregate exposure, EPA takes into account the available
and reliable information concerning exposures to pesticide residues in
food and drinking water, and non-occupational pesticide exposures.
Biobor has no food registrations and therefore, is not subject to FQPA
which requires the Agency to consider aggregate exposures.

	However, the contribution of boron residues resulting from the
dissociation of treated products containing biobor is expected to be
considerably less than the naturally occurring background levels of
boron already existing in food and water.  Therefore, an aggregate
assessment of biobor would not be required.

	EPA has not yet determined whether biobor has a common mechanism with
other compounds, consequently a cumulative assessment will not be
performed.  If biobor is found to have a common mechanism with other
compounds, a cumulative assessment would be conducted.

Section 5.  Occupational/Residential Exposure

	

	The Agency must conduct risk assessments to ensure that biobor salts
meet the safety standards established by FFDCA, as amended by FQPA.  In
June 1993, the Agency conducted an occupational assessment for the
registered fuel preservative uses.  The Agency concluded that there
would be minimal occupational exposure to adding fuel preservative to
fuel tanks.  Biobor was delivered in three different size containers 1
quart, 5-gallon and 55-gallon containers.  Most of the activities would
involve using a closed metering pump to deliver the product from
55-gallon tanks containing the preservative to large storage tanks to
preserve the fuel.  It is anticipated that the smaller containers the
handlers are open poured.

	A dermal assessment has not been conducted for biobor.  The Agency
currently needs a hydrolysis study (GLN 835.2120). This study will
determine if a dermal assessment for the parent compound, biobor, will
be needed.  If the parent compound, biobor, completely and rapidly
degrades to boric acid, a dermal assessment will not be needed because
it was determined in the “Boric Acid/Sodium Borate Salts: HED Chapter
of the Tolerance Reassessment Eligibility Decision Document (TRED) (DP
Barcode D320894),” dated June 26, 2006, that dermal absorption is
negligible for boron/boric acid salts and that boron/boric acid salts
are not absorbed across intact skin.  

If the Agency determines that biobor is not completely and rapidly
degraded to boric acid, a dermal assessment will be needed.  A dermal
toxicity study (GLN 870.2500), dermal outdoor exposure study (GLN
875.1100), dermal indoor exposure study (GLN 875.1200), and an indoor
surface residue dissipation study (GLN 875.2300) will be required to
conduct occupational and residential dermal assessments.  However, it
should be noted that the indoor surface residue dissipation study (GLN
875.2300) will be needed even if it is determined that a dermal
assessment is not needed, because this data is also required to
determine residential oral exposure from possible hand to mouth contact
with treated wood decks. 

	There is also the potential for inhalation exposure during open pouring
smaller containers of the product to diesel engine fuel tanks.  The
Agency anticipates that inhalation occupational assessments may be
needed to assess exposure to biobor from pouring small containers
(1-quart and 5-gallon containers).

 

	According to the Biobor JF label (EPA Reg 65217-1), biobor is used as a
wood preservative booster additive. Biobor additive is used for water
repellant wood preservatives. The label states that Biobor is used in
the following labels: Woodlife® F, Milltreat® F, Woodtreat ®MB, and
Woodlife ® 111. These labels have since changed to Woodlife® F Clear,
Woodlife® Milltreat ® Type F VM&P water repellent wood preservative,
and Wolman® F&P. According to the label, biobor is added to treating
solution only through metering pumps. 

	For wood preservative treatment uses, there are a variety of
occupational worker functions that lead to occupational handler and
post-application exposure.  The Agency commonly assesses exposure based
on individual occupational worker exposure, such as worker functions for
non-pressure wood treatment (i.e., chemical operators, diptank
operators, blender/spray operators, graders, trimsaw operators, and
cleanup crews).  The Agency expects that dermal and inhalation
occupational assessment would be required for this use and additional
occupational monitoring data may be needed as well as toxicological data
to support these uses.  A residential risk assessment is required since
the label does not specifically prohibit the use of biobor for pressure
treated wood and the supplemental labels (Woodlife® F, Milltreat® F,
Woodtreat ®MB, and Woodlife ® 111) link Biobor JF with the application
of biobor for non-pressure wood preservation of decks. In order to
develop these assessments the Agency will need additional data (see
Appendix B for data justifications).

Section 6.  Anticipated Data Needs

The Antimicrobial Division (AD) will need the following studies for
registration review to assess occupational and residential exposures:

Toxicity

(GDLN 870.2500) 90-day dermal toxicity in rats.

(GDLN 870.3465) 90-day inhalation toxicity in rats.

(GDLN 870.3100) 90-day oral toxicity study – rodent

(GDLN 870.3150) 90-day oral toxicity study- non-rodent

(GDLN 870.3700) Rabbit developmental study

(GDLN 870.3800) Reproduction and Fertility Effects- rodent

(GDLN 870.4200) Carcinogenicity rat/(GDLN 870.4300) Combined Chronic
Toxicity/Carcinogenicity Study

(GDLN 870.4200) Carcinogenicity mouse or

	 

Occupational and Residential Exposure Data Needs

(GDLN 875.1100) Dermal Outdoor Exposure

(GDLN 875.1200) Dermal Indoor Exposure

(GDLN 875.1300) Inhalation Outdoor Exposure

(GDLN 875.1400) Inhalation Indoor Exposure

(GDLN 875.1600) Data Reporting and Calculations

(GDLN 875.1700) Product Use Information

(GDLN 875.2300) Indoor Surface Residue Dissipation

(GDLN 870.2700) Product Use Information

(GDLN 875.2900) Data Reporting and Calculations

(GDLN 875.3000) Non-Dietary Ingestion Exposure

Appendix A and B provide detailed justifications why these studies are
required.

Section 7.  Tolerances

There are no tolerances for biobor. In 2006, the Agency reassessed the
exemptions from the requirement of a tolerance established for residues
of boric acid, sodium metaborate, and sodium tetraborate in/on raw
agricultural commodities under 40 CFR 180.920 and 180.1121. The Agency
considered the exemptions as safe under section 408(q) of the FFDCA.

Section 8.  Overall Conclusions

	The Agency reviewed the hazard and exposure databases for biobor and
anticipates that additional toxicity and exposure data will be needed
(see section 6 for specific studies) for registration review.  In
addition, the EPA anticipates that an occupational handler assessment
will need to be conducted for occupational inhalation and dermal
exposures to non-pressure treatment (e.g. immersion, vacuum, flood
spray, etc.). In addition it is anticipated that a residential
post-application assessment for dermal and incidental ingestion exposure
to treated wood decks will be needed.  The Agency feels that they need
to conduct risk assessments to ensure that the biobor registration
review case meets the safety standards established by FFDCA, as amended
by FQPA. 

Section 9.  Reference Memoranda

The memoranda listed in Table 2 were considered in the development of
this document.

Table 2. Memoranda Relevant to Registration Review

Author	Barcode	Date	Title

Hansen, L

	D320894	6/26/06	Boric Acid/Sodium Borate Salts: HED Chapter of the
Tolerance Reassessment Eligibility Decision Document (TRED).  

Farwell, K.

(USEPA, 2006)	none	6/29/06	Reassessment of 3 Tolerance Exemptions for
Ethylene Glycol, Diethylene Glycol, and the Combination of Diethylene
Glycol Monomethyl Ether, Diethylene Glycol Monoethyl Ether, and
Diethylene Glycol Monobutyl Ether

Gowda, S.

	D351811	7/31/08	Summary of Product Chemistry, Environmental Fate, and
Ecotoxicity Data for the Biobor Registration Review Decision Document.



Appendix A. Toxicity Guideline Study Justifications

Guideline	Study Title	Practical Utility of the Data

870.3100	90-day oral toxicity study – rodent	1)  What is the value of
the study?

The Agency does not have a full picture of the potential effects which
could occur as a result of exposure via the oral route.  The needed
study will provide insight into concerns regarding toxicity via the oral
route.  It may also provide a toxicity endpoint applicable to risk
assessment.

2)  How would the data be used?

The study would form the foundation for hazard characterization and
toxicity endpoints selection for risk assessment through all exposure
routes (oral, inhalation, and dermal).  The data would allow the Agency
to conclude more definitively whether or not there would be any concerns
for oral toxicity in the rat.  This would provide a more complete hazard
characterization of biobor in regards to the potential risks to the U.S.
general population including infants and children as needed by the FQPA.

3)  How could the data affect the risk assessment?

The study would form the foundation for hazard characterization and
toxicity endpoints selection for risk assessment through all exposure
routes (oral, inhalation, and dermal).  It is possible that the database
uncertainty factor be reduced or removed, resulting in different
magnitude of the value of the endpoint used for regulation.

4)  What is triggering the need for this data?

The difficulty of predicting real world human oral exposure (as well as
inhalation and/or dermal) with limited data and no repeated-dose
toxicity data or other alternative information, such as SAR
(structure-activity-relationship), surrogate data, and/or
weight-of-evidence to the Agency triggered the need for a 90-day
(guideline) oral toxicity study, in order to adequately evaluate real
world human exposure to biobor based on how it is used (e.g., use on
outdoor decks).

870.3150	90-day oral toxicity study – non-rodent	1)  What is the value
of the study?

The Agency does not have a full picture of the potential effects which
could occur as a result of exposure via the oral route.  The needed
study would provide insight into concerns regarding toxicity via the
oral route.  It may also provide a toxicity endpoint applicable to risk
assessment.

2)  How would the data be used?

The study would form the foundation for hazard characterization and
toxicity endpoints selection for risk assessment through all exposure
routes (oral, inhalation, and dermal).  The data would allow the Agency
to conclude more definitively whether or not there would be any concerns
for oral toxicity in a non-rodent species.  This would provide a more
complete hazard characterization of biobor in regards to the potential
risks to the U.S. general population including infants and children as
needed by the FQPA.

3)  How could the data affect the risk assessment?

The study would form the foundation for hazard characterization and
toxicity endpoints selection for risk assessment through all exposure
routes (oral, inhalation, and dermal).  It is possible that the database
uncertainty factor be reduced or removed, resulting in different
magnitude of the value of the endpoint used for regulation.

4)  What is triggering the need for this data?

The difficulty of predicting real world human oral exposure (as well as
inhalation and/or dermal) with limited data and no repeated-dose
toxicity data or other alternative information, such as SAR
(structure-activity-relationship), surrogate data, and/or
weight-of-evidence to the Agency triggered the need for a 90-day
(guideline) oral toxicity study, in order to adequately evaluate real
world human exposure to biobor based on how it is used.

870.3250	90-Day Dermal Toxicity Study (Rat)	1)  What is the value of the
study?

The Agency does not have adequate data to assess the potential effects
for biobor which could occur as a result of exposure via the dermal
route.  The needed study would provide conclusive data on the potential
toxicities via repeat dermal exposures to biobor.  It may also provide a
toxicity endpoint applicable to risk assessment.

2)  How would the data be used?

The results of the study change how risks are quantified.  The data
would allow the Agency to conclude more definitively whether or not
there would be any concerns for dermal toxicity in the rat.  This would
provide a more complete hazard characterization of biobor in regards to
the potential risks to the U.S. general population.

3)  How could the data affect the risk assessment? 

The results of the study may change how risks are quantified.  It is
possible that the database uncertainty factor could be reduced or
removed, resulting in different magnitude of the value of the endpoint
used for pesticide regulation.

4)  What is triggering the need for this data?

The difficulty of predicting real world human exposure via dermal routes
with limited data or other alternative information, such as SAR
(structure-activity-relationship), surrogate data, and/or
weight-of-evidence to the Agency triggered the requirement for a 90-day
dermal (guideline) toxicity study, in order to adequately evaluate real
world human exposure to biobor preservatives from treated wood decks are
triggering the need for toxicological data in order to conduct a risk
assessment for biobor. 

870.3465	90-Day Inhalation Toxicity Study

(Rat)	1)  What is the value of the study?

The Agency does not have a full picture of the potential effects which
biobor could occur as a result of exposure via the inhalation route. 
The needed study would provide insight into concerns regarding toxicity
via the inhalation route.  It may also provide a toxicity endpoint
applicable to risk assessment.

2)  How would the data be used?

The study may result in a change in how risks are quantified.  The data
would allow the Agency to conclude more definitively whether or not
there would be any concerns for inhalation toxicity in the rat.  This
would provide a more complete hazard characterization of biobor in
regards to the potential risks to the U.S. general population.

3)  How could the data affect the risk assessment?

The study may result in a change in how risks are quantified.  It is
possible that the database uncertainty factor be reduced or removed,
resulting in different magnitude of the value of the endpoint used for
regulation.

4)  What is triggering the need for this data?

The difficulty of predicting real world human inhalation exposure with
limited data and no inhalation data or other alternative information,
such as SAR (structure-activity-relationship), surrogate data, and/or
weight-of-evidence to the Agency triggered the need for a 90-day
(guideline) Inhalation toxicity study, in order to adequately evaluate
real world human exposure to biobor particles based on how it is used
(The OPPTS Guidelines require an MMAD of 1-3 (m in inhalation toxicity
studies of aerosols so that a portion of the test article will reach the
lungs). The exposures to mists and sprays from non-pressure wood
treatment are triggering the need for toxicological data in order to
conduct a risk assessment. 

870.3700	Rabbit Developmental Study	1)  What is the value of the study?

The needed study would provide insight into concerns regarding pre-
and/or postnatal toxicity as needed by FQPA.  It may also provide a
toxicity endpoint applicable to risk assessment.

2)  How would the data be used?

The study may result in a change in how risks are quantified.  The data
would allow the Agency to conclude more definitively whether or not
there are any concerns for pre- and/or postnatal toxicity in the rabbit.
 This would provide a more complete hazard characterization of biobor in
regards to the potential risk of developmental toxicity.

3)  How could the data affect the risk assessment?

The study may result in a change in how risks are quantified.  It is
possible that the database uncertainty factor may be reduced or removed,
resulting in different magnitude of the value of the endpoint used for
regulation.

4)  What is triggering the need for this data?

The difficulty of predicting real world human exposure via oral route
with limited data and no developmental toxicity data in rabbit or other
alternative information, such as SAR (structure-activity-relationship),
surrogate data, and/or weight-of-evidence to the Agency triggered the
need for a developmental (guideline) toxicity study in the rabbit, in
order to adequately evaluate real world human exposure to biobor,
particularly women in the 15-49 years of age and infants and children,
based on how it used.

870.3800	Reproduction and Fertility Effects - rodent	1)  What is the
value of the study?

The needed study would provide insight into concerns regarding the
potential risks of reproductive toxicity in the rat as well as potential
neurotoxicity in developing offspring.  It may also provide a toxicity
endpoint applicable to the risk assessment.

2)  How would the data be used?

The data would allow the Agency to conclude more definitively whether or
not there are any concerns for potential reproductive toxicity in the
rat.  Since the reproductive toxicity would also include neurotoxicity
evaluations, it would also provide some information regarding potential
neurotoxicity in developing offspring exposed to biobor.

3)  How could the data affect the risk assessment?

The study may result in a change in how risks are quantified.  The
needed study may provide a toxicity endpoint applicable to the risk
assessment.  It is possible that the database uncertainty factor be
reduced or removed, resulting in a different magnitude of the value of
the endpoint used for regulation.

4)  What is triggering the need for this data?

The difficulty of predicting real world human exposure via oral route
with limited data and no reproductive toxicity in rat or other
alternative information, such as SAR (structure
–activity-relationship), surrogate data, and/or weight-of-evidence to
the Agency triggered the need for a reproductive (guideline) toxicity
study in the rat, in order to adequately evaluate real world human
exposure to biobor, particularly women in the 15-49 years of age and
infants and children, based on how it is used.

870.4200	Carcinogenicity Rat	1)  What is the value of the study?

The Agency does not have a full picture of the potential effects which
could occur as a result of long-term exposure.  The needed study would
provide insight into concerns regarding carcinogenicity through
long-term exposure.  It may also provide a toxicity endpoint applicable
to the risk assessment.

2)  How would the data be used?

The study may result in a change in how risks are quantified.  The data
would allow the Agency to conclude more definitively whether or not
there would be any concerns for carcinogenicity in the rat.  This would
provide a more complete hazard characterization of biobor in regards to
the potential risks to the U.S. general population including infants and
children as needed by the FQPA.

3)  How could the data affect the risk assessment?

The study may result in a change in how risks are quantified.  It is
possible that the database uncertainty factor be reduced or removed,
resulting in different magnitude of the value of the endpoint used for
regulation.

4)  What is triggering the need for this data?

The inconclusive results of the mutagenicity data, difficulty of
predicting real world human exposure via oral routes with limited data
and no carcinogenicity data or other alternative information, such as
SAR (structure-activity-relationship), surrogate data, and/or
weight-of-evidence to the Agency triggered the need for a
carcinogenicity (guideline) study, in order to adequately evaluate real
world human exposure to biobor based on how it is used, particularly
used as wood preservatives.

870.4200	Carcinogenicity

Mouse	1)  What is the value of the study?

The Agency does not have a full picture of the potential effects which
could occur as a result of long-term exposure.  The needed study would
provide insight into concerns regarding carcinogenicity through
long-term exposure.  It may also provide a toxicity endpoint applicable
to risk assessment.

2)  How would the data be used?

The study may result in a change in how risks are quantified.  The data
would allow the Agency to conclude more definitively whether or not
there would be any concerns for carcinogenicity in the mouse.  This
would provide a more complete hazard characterization of biobor in
regards to the potential risks to the U.S. general population including
infants and children as needed by the FQPA.

3)  How could the data affect the risk assessment?

The study may result in a change in how risks are quantified.  It is
possible that the database uncertainty factor be reduced or removed,
resulting in different magnitude of the value of the endpoint used for
regulation.

4)  What is triggering the need for this data?

The inconclusive results of the mutagenicity data, difficulty of
predicting real world human exposure via oral routes with limited data
and no carcinogenicity data or other alternative information, such as
SAR (structure-activity-relationship), surrogate data, and/or
weight-of-evidence to the Agency triggered the need for a
carcinogenicity (guideline) study, in order to adequately evaluate real
world human exposure to biobor based on how it is used, particularly
used as wood preservative.

870.4300	Chronic Toxicity Rodent/

Carcinogenicity	1)  What is the value of the study?

The Agency does not have a full picture of the potential effects which
could occur as a result of long-term exposure.  The needed study would
provide insight into concerns regarding toxicity through long-term
exposure.  It may also provide a toxicity endpoint applicable to risk
assessment.

2)  How would the data be used?

The study may result in a change in how risks are quantified.  The data
would allow the Agency to conclude more definitively whether or not
there would be any concerns for chronic toxicity in the rat.  This would
provide a more complete hazard characterization of biobor in regards to
the potential risks to the U.S. general population including infants and
children as needed by the FQPA.

3)  How could the data affect the risk assessment?

The study may result in a change in how risks are quantified.  It is
possible that the database uncertainty factor be reduced or removed,
resulting in different magnitude of the value of the endpoint used for
regulation.

4)  What is triggering the need for this data?

The difficulty of predicting real world human exposure via all routes
(oral, inhalation or dermal) with limited data and no chronic data or
other alternative information, such as SAR
(structure-activity-relationship), surrogate data, and/or
weight-of-evidence to the Agency triggered the need for a chronic
(guideline) toxicity study, in order to adequately evaluate real world
human exposure to biobor based on how it is used, particularly used as a
wood preservative.



Appendix B: Exposure Guideline Study Justifications 

Guideline	Study Title	Practical Utility of the Data

875.1100 and 875.1200

(Applicator)

	Dermal Outdoor Exposure and Dermal Indoor Exposure	Note:  Dermal
exposure data are needed for both residential and occupational uses. 
The selection of an outdoor versus an indoor site is based on the high
end exposure scenario.  In almost all cases, repeating an exposure study
for the same scenario outdoors and indoors is not necessary.

1)  What is the value of the study?

The potential for dermal exposure is very likely for exposure scenarios
non-pressure treatment for wood structures .  The existing CMA data base
and PHED for these scenarios are limited in scope for QA/QC and number
of monitoring units.  EPA presented the need for additional handler
exposure data to the January 2007 Science Advisory Panel (SAP) as well
as to the April 2007 Human Studies Review Board (HSRB) and both groups
agreed that additional data are warranted. 

2)  How will the data be used?

The dermal exposure data will be used to assess dermal exposures to
non-pressure treatment facilities.  For occupational uses, the dermal
exposure data will be used to assess the short-, intermediate- and
chronic exposures.

3)  How could the data affect the risk assessment?

The dermal exposure data will be used to determine the accuracy of the
dermal risks to both residence and occupational workers.  If risks
warrant mitigation, the dermal exposure data will provide the types of
mitigation necessary such as chemical resistant gloves or closed systems
for commercial uses, or potential removal of uses from the label.

4)  What is triggering the need for this data?

The criteria for the dermal exposure data are based on the potential for
dermal exposure from the labeled uses (e.g., occupational workers at
non-pressure treatment facilities) and evidence of toxicity.  If the
toxicological endpoints from biobor are used to assess the risks, there
is an endpoint selected for the dermal route.  

875.1300 and

875.1400

(Applicator)	Inhalation Outdoor Exposure and Inhalation Indoor Exposure
Note:  Inhalation exposure data are needed for both residential and
occupational uses.  The selection of an outdoor versus an indoor site is
based on the high end exposure scenario (for inhalation the selection is
typically indoors).  In almost all cases, repeating an exposure study
for the same scenario outdoors and indoors is not necessary.

1) What is the value of the study?

The inhalation exposure route is very important for exposure scenarios
such as non-pressure treatment of wood where aerosols would be
generated.  In addition, inhalation exposures from liquid pouring are
evident in exposure studies in the Pesticide Handlers Exposure Database
(PHED).  The significance of these exposures is directly affected by the
severity of the inhalation toxicological endpoint of concern.  At this
point in time, no toxicological data are available to assess the
inhalation risk. The existing Chemical Manufacturer Association (CMA)
data base and PHED for these scenarios are limited in scope for QA/QC
and number of monitoring units.  EPA presented the need for additional
handler exposure data to the January 2007 Science Advisory Panel (SAP)
as well as to the April 2007 Human Studies Review Board (HSRB) and both
groups agreed that additional data are warranted. 

2) How would the data be used?

The inhalation exposure data would be used to assess the occupational
exposure from non-pressure treatment facilities. 

3) How could the data affect the risk assessment?

The inhalation exposure data would be used to determine the accuracy of
the inhalation risks to both residence and occupational workers.  If
risks warrant mitigation, the inhalation exposure data would provide the
types of mitigation necessary such as respiratory protection from
respirators or closed systems for commercial uses to potential removal
of uses from the label.

What is triggering the need for this data?

The criteria for the inhalation exposure data are based on the potential
for respiratory exposure from the labeled uses (e.g., exposure to biobor
powders) and evidence of toxicity.  If no toxicological endpoints of
concern were identified, then the inhalation exposure data would not be
needed.

875.1600

(Applicator)	Data Reporting and Calculations 	1) What is the value of
the study?

For all exposure studies this data need is needed to facilitate the
review of the data.

2) How would the data be used?

The study report and all raw data/calculations would be reviewed for the
adequacy of the data.

3) How could the data affect the risk assessment?

The data are needed to interpret the inhalation exposure data collected.

4) What is triggering the need for this data?

This data need is triggered if an exposure study is conducted.

875.1700

(Applicator)	Product Use Information	1) What is the value of the study?

Product use information is a description of how the product is actually
applied; it is not a field study.  A description of how this product is
used would provide for a comprehensive realistic assessment of its
potential applications.

2) How would the data be used?

The description of the application techniques would be used to define
the exposure scenarios to be assessed in the risk assessment.

3) How could the data affect the risk assessment?

A complete description of product use would ensure that the risk
assessment is inclusive of the types of exposures occurring during
occupational use.

What is triggering the need for this data?

The need for a risk assessment as needed under Registration Review would
require that the risk assessor understands how the product is applied.

875.2300

(Post Application)

	Indoor Surface Residue Dissipation	1) What is the value of the study?

No data are currently available to determine the residues available for
incidental oral exposure from treated wood decks. As a first tier to the
risk assessment 100% residue transfer is assumed.  If no risk concerns
are evident, this study will not be required.  If risks of concern are
indicated at 100% residue transfer, then this study is needed to refine
the assessment.

2) How will the data be used?

This product is used as a wood preservative.  The available residues
from decks will be used to determine the magnitude of children’s
incidental exposure from hand-to-mouth exposure from decks.

3) How could the data affect the risk assessment?

The data are needed to refine the risk estimates if risks of concern are
identified assuming 100% residue transfer from treated decks. 

What is triggering the need for this data?

The specific biobor use triggering the criteria for the surface residue
data is the potential for incidental oral exposure from the wood
preservative uses.  If no toxicological endpoints of concern were
identified for the oral route, then the surface residue data would not
be needed.  Moreover, if risks of concern are not identified when 100%
residue transfer is assumed, the data are not needed.

875.2700

(Post Application)	Product Use Information	1) What is the value of the
study?

Product use information for the post application data need is a
description of what types of consumer products are treated; it is not a
field study.  A description of what types of consumer products are
treated, specifically what the wood preservative uses, would provide for
a comprehensive realistic assessment of potential post application
exposures.

2) How would the data be used?

The listing of the end use consumer products would be used to define the
exposure scenarios to be assessed in the risk assessment.  For example,
the product use must describe the scenario of use (treatment for wood
decks).

 

3) How could the data affect the risk assessment?

A complete description of consumer products treated would ensure that
the risk assessment is inclusive of the types of exposures occurring
during residential use.

4) What is triggering the need for this data?

The need for a risk assessment as needed under Registration Review would
require that the risk assessor understands how the product is applied.

875.2900

(Post Application)	Data  Reporting and Calculations	1) What is the value
of the study?

For all exposure studies this data requirement is required to facilitate
the review of the data.

2) How will the data be used?

The study report and all raw data/calculations will be reviewed for the
adequacy of the data.

3) How could the data affect the risk assessment?

The data are needed to interpret the residue data collected.

4) What is triggering the need for this data?

The data reporting requirement is triggered if a residue study is
conducted.

875.3000

(Post Application)	Non-dietary Ingestion Exposure

	1) What is the value of the study?

The design of the non dietary ingestion exposure study can be combined
with the Indoor Surface Residue Dissipation study (875.2300) to
determine the available residue leaching from a child mouthing treated
wood play sets and decks.

2) How will the data be used?

This product is used as a wood preservative in play sets and decks.  The
available residues from treated play sets and decks will be used to
determine the magnitude of children’s incidental exposure.

3) How could the data affect the risk assessment?

The data are needed to refine the risk estimates if risks of concern are
identified assuming 5% residue transfer from treated wood play sets and
decks 

4) What is triggering the need for this data?

The criteria for the surface residue data are the potential for
incidental oral exposure from pressure treated wood play set and decks
and evidence of toxicity.  If no toxicological endpoints of concern are
identified for the oral route, then the non-dietary ingestion exposure
data would not be needed.  Moreover, if there are no risks of concern
when 5% residue transfer is assumed, the data are not needed.

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