Document ID: EPA-HQ-OPP-2007-1151-0007
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2008-01-16T05:00Z

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C. 20460

OFFICE OF PREVENTION, PESTICIDES

AND TOXIC SUBSTANCES

January 9, 2008

  SEQ CHAPTER \h \r 1 MEMORANDUM

SUBJECT:	Diiodomethyl p-tolyl sulfone: Hazard Assessment 

PC Code: 	101002

DP Barcode: 	D344852

	

FROM:	Jonathan Chen, Ph.D.	

	Senior Toxicologist, 

	Risk Assessment and Science Support Branch (RASSB)

Antimicrobial Division (7510P)

THROUGH:	Tim Mcmahon, Ph.D.	

	Senior Toxicologist, 

	Antimicrobial Division (7510P)

	Rick Petrie

Team Leader, Team Three

RASSB / AD

		

		And

Norm Cook

Chief

RASSB / AD

TO:	Avivah Jakob

	Team 36

	Regulatory Management Branch II / AD

In order to issue a Reregistration Eligibility Decision (RED) document
for Diiodomethyl p-tolyl sulfone, a complete risk assessment (RA) is
required to evaluate potential human and environmental hazards that may
result from exposure to this chemical.   Attached is the Hazard
Assessment (Toxicology Review) Section for the RED document. TABLE OF
CONTENTS

  TOC \o "1-3" \h \z \u    HYPERLINK \l "_Toc183247733"  0.0	BACKGROUND	
 PAGEREF _Toc183247733 \h  4  

  HYPERLINK \l "_Toc183247734"  1.0	HAZARD CHARACTERIZATION	  PAGEREF
_Toc183247734 \h  4  

  HYPERLINK \l "_Toc183247735"  2.0	AVAILABLE DATABASE	  PAGEREF
_Toc183247735 \h  5  

  HYPERLINK \l "_Toc183247736"  3.0	HAZARD ASSESSMENT	  PAGEREF
_Toc183247736 \h  6  

  HYPERLINK \l "_Toc183247737"  3.1	Acute Toxicity	  PAGEREF
_Toc183247737 \h  6  

  HYPERLINK \l "_Toc183247738"  3.2	Subchronic Toxicity	  PAGEREF
_Toc183247738 \h  7  

  HYPERLINK \l "_Toc183247740"  3.3	Chronic Toxicity	  PAGEREF
_Toc183247740 \h  8  

  HYPERLINK \l "_Toc183247741"  3.4	Developmental Toxicity	  PAGEREF
_Toc183247741 \h  8  

  HYPERLINK \l "_Toc183247742"  3.5	Reproductive toxicity	  PAGEREF
_Toc183247742 \h  10  

  HYPERLINK \l "_Toc183247743"  3.6	Neurotoxicity Toxicity	  PAGEREF
_Toc183247743 \h  14  

  HYPERLINK \l "_Toc183247744"  3.7	Mutagenicity and Carcinogenicity	 
PAGEREF _Toc183247744 \h  15  

  HYPERLINK \l "_Toc183247745"  4.0	HAZARD ENDPOINT SELECTION	  PAGEREF
_Toc183247745 \h  15  

  HYPERLINK \l "_Toc183247746"  4.1	Acute Reference Dose (RfD)	  PAGEREF
_Toc183247746 \h  15  

  HYPERLINK \l "_Toc183247747"  4.2	Chronic Reference Dose (RfD)	 
PAGEREF _Toc183247747 \h  15  

  HYPERLINK \l "_Toc183247748"  4.3	Occupational/Residential Exposure	 
PAGEREF _Toc183247748 \h  16  

  HYPERLINK \l "_Toc183247749"  4.3.1	Short-Term Incidental Oral
Exposure (1 – 30 days)	  PAGEREF _Toc183247749 \h  16  

  HYPERLINK \l "_Toc183247750"  4.3.2	Intermediate-Term Incidental Oral
Exposure (1 – 6 months)	  PAGEREF _Toc183247750 \h  17  

  HYPERLINK \l "_Toc183247751"  4.3.3	Relative Dermal Absorption Rate	 
PAGEREF _Toc183247751 \h  18  

  HYPERLINK \l "_Toc183247752"  4.3.4	Short-Term Dermal (1-30 days)
Exposure	  PAGEREF _Toc183247752 \h  19  

  HYPERLINK \l "_Toc183247753"  4.3.5	Intermediate-Term Dermal (7 Days
to Several Months) Exposure	  PAGEREF _Toc183247753 \h  20  

  HYPERLINK \l "_Toc183247754"  4.3.4	Long-Term Dermal (More than 6
Months to Life-Time) Exposure	  PAGEREF _Toc183247754 \h  20  

  HYPERLINK \l "_Toc183247755"  4.3.5.	Inhalation Exposure (All
Durations)	  PAGEREF _Toc183247755 \h  21  

  HYPERLINK \l "_Toc183247756"  4.3.6	Margins of Exposure for
Occupational/Residential Risk Assessments	  PAGEREF _Toc183247756 \h  21
 

  HYPERLINK \l "_Toc183247757"  4.4	Classification of Carcinogenic
Potential	  PAGEREF _Toc183247757 \h  22  

  HYPERLINK \l "_Toc183247758"  5.0	FQPA CONSIDERATION	  PAGEREF
_Toc183247758 \h  22  

  HYPERLINK \l "_Toc183247759"  6.0	Data Gaps	  PAGEREF _Toc183247759 \h
 22  

  HYPERLINK \l "_Toc183247760"  7.0	REFERENCE	  PAGEREF _Toc183247760 \h
 25  

 0.0	BACKGROUND tc \l1 "TABLE OF CONTENTS0.0	BACKGROUND	11.0	HAZARD
CHARACTERIZATION	22.0	AVAILABLE DATABASE	23.0	DATA GAP(S)	34.0	HAZARD
ASSESSMENT	44.1	Acute Toxicity	44.2	Subchronic Toxicity	44.3
Reproductive and Developmental Toxicity	64.4	Mutagenicity and
Carcinogenicity	74.7	Neurotoxicity	85.0	HAZARD ENDPOINT SELECTION	95.1
Acute Reference Dose (RfD) 	95.2	Chronic Dietary Reference Dose (RfD)
105.3	Occupational/Residential Exposure	105.3.1	Dermal Absorption
105.3.2	Short-Term Dermal - (1-7 Days)	115.3.3	Intermediate-Term Dermal
115.3.4	Long-Term Dermal	125.3.5	Inhalation Exposure 	125.3.6	MOEs	126.0
FQPA CONSIDERATIONS	147.0	REFERENCES	150.0	BACKGROUND 

Diiodomethyl p-tolyl sulfone is a fungicide, algaecide, bacteriostat,
insecticide, and/or miticide.  It is used in drains and/grease traps in
food handling/storage establishments premises and equipment.  It is used
as materials preservative in paints (in-can), coatings, fire retardant,
adhesives, caulks, sealants, slurries,
dispersions/emulsions/solutions/suspensions, rubber products,
plastic/pvc/vinyl products, hides/leathers/leather products, textiles,
papermaking, paper and paperboard, nitrocellulose, melamine formaldehyde
thermosetting resins. It is used in septic systems in industrial
processes and water systems.  Amical is also used as a general wood
preservative.  

Figure 1.  Chemical Structure of Diiodomethyl p-tolyl sulfone

1.0	HAZARD CHARACTERIZATION

Diiodomethyl p-tolyl sulfone is moderately acutely toxic and classified
as Toxicity Category II for inhalation route and Category IV for both
oral and dermal routes. It causes severe irritation to rabbit ocular
tissue and is classified as Category I for primary eye irritation. 
Diiodomethyl p-tolyl sulfone is not a dermal sensitizer.  It causes
minimum irritation to rabbit skin and is classified as Category IV for
primary skin irritation. 

In short-term exposure condition, in the dog study, at dose level of 60
mg/kg/day of Diiodomethyl p-tolyl sulfone , 1-4 hours after dosing,
clinical signs included decreased activity, dehydration, mucoid eye
discharge, weakened condition and abnormal feces (mucoid and
occasionally blood-tinged) were noticed.  In rabbits, deaths and
abortions were noticed in dose level of 60 mg/kg/day or above; clinical
signs,  reduced body weight gain and food consumption were noticed in
the level of 15mg/kg/day and/or above.   For rat, however, at dose level
of 100 mg/kg/day, no toxicological significant effects were noticed in
maternal animal in the developmental study.

In sub chronic exposure condition, at dose level of 2 mg/kg/day and/or
above, female dogs shows signs of more than 20% decrease in body weight
gain in 90-day oral capsule study.  There are no toxicological
significant toxic effects in the 90-day rat oral study at level of 80
mg/kg/day.  

There are four developmental and two reproductive studies.  There are no
clear developmental and/or reproductive toxic effects.  Decreased mean
litter size, increased number of resorptions relative to the number of
implantation sites, reduced mean fetal body weight, increased incidences
of umbilical hernia and incomplete ossification of the supraoccipital
bones is noticed in rat developmental study but at the dose with
significant maternal toxic effects.  In rabbit developmental study,
there are no developmental effects at dose level of 2 mg/kg/day. In rat
reproductive studies, effects on the offspring including
post-implantation loss and decreased gestation survival, decreases in
litter size, neonatal survival and/or pup body weight at levels of 10
mg/kg/day or above.  All the effects were noticed at dosages with
significant maternal effects.

Thyroid is consider one the primary organ been affected.  Degeneration
of the thyroid gland is noticed in the 90-day dog study.  Increase
thyroid gland weight is noticed in rabbit and rat developmental studies.
 Histopathological changes (altered colloid staining, hypertrophy.
hyperplasia and/or follicular dilatation consistent were noticed in rat
reproductive studies.

There are no acceptable dermal and inhalation studies.  All mutagenicity
studies were negative suggest diiodomethyl p-tolyl sulfone is not
mutagenic.  There is no chronic and/or cancer studies.

2.0	AVAILABLE DATABASE 

The toxicology studies that have been submitted for Diiodomethyl p-tolyl
sulfone are shown in Table 1.

In this toxicology assessment chapter, the toxicology database of
Diiodomethyl p-tolyl sulfone is evaluated, and the toxicological
endpoints used for risk assessment are selected. In addition, the data
gaps in the database are also identified. 

Table 1. Toxicology Database for Diiodomethyl p-tolyl sulfone

Guideline

Number

	

Test 

	

Technical 

Required	

Satisfied	

MRID Number

870.3100	90-Day Feeding   -Rats	Y	Y	42054402

870.3150	90-Day Feeding - Dog	Y	Y	42054403

870.3200	21-Day Dermal – Rabbit	Y	N	00050924

870.3700a	Developmental Study – Rat	Y	Y	42054404 and 42054405

870.3700b	Developmental Study – Rabbit	Y	N	42243801

870.3000b	Developmental Study - Rabbit	Y	N	47242202

8703800	One-generation Reproductive Study - Rat	Y	N	46913302

870.3800	Two-generation Reproductive Study - Rat	Y	Y	46913301

8700.5100	Bacteria reverse Mutation Study	Y	Y	00054961

and

00054962

870.5300	In vitro Mammalian Gene Mutatyion Test (Mouse Lymphoma)	Y	Y
00160070

870.5300	In vitro Mammalian Gene Mutatyion Test (Mouse Lymphoma)	Y	Y
00054961

870.5375	In vitro Chrosome Aberration Test	Y	Y	43120601

870.5395	In vivo Mouse Ethrocyte Micronucleus Assay	Y	Y	001060071

870.5550	Unscheduled DNA Synthesis in Mammalian Cells in Culture	Y	Y
00160072

870.7485	Metabolism Study	Y	Y	47078801

Y - Yes;   N – no

3.0	HAZARD ASSESSMENT

Acute Toxicity

As summarized in Table 2, Diiodomethyl p-tolyl sulfone is moderately
acutely toxic and classified as Toxicity Category II for inhalation
route and Category IV for both oral and dermal routes. It causes severe
irritation to rabbit ocular tissue and is classified as Category I for
primary eye irritation.  Diiodomethyl p-tolyl sulfone is not a dermal
sensitizer.  It causes minimum irritation to rabbit skin and is
classified as Category IV for primary skin irritation. 

Table 2.  Acute Toxicity Decisions for Diiodomethyl p-tolyl sulfone

Guideline

 No.	

Study Type	

MRID #(S).	

Results	

Toxicity

 Category

870.1100

(81-1)	

Acute Oral	

41765401, 43008702, and 42586801	LD50  > 5000 mg/kg 

( for both male and female)

	

IV

870.1200

(81-2)	

Acute Dermal

(Rats)	

00123023	LD50 (Males) > 20000 mg/kg	

IV

870.1300

(81-3)	

Acute Inhalation	43660901

And

00087842	LC50 (combined)= 0.96 mg/L

LC50 (male) = 1.15 mg/L 

LC50 (female) = 0.77 mg/L	

II

870.2400

(81-4)	

Primary Eye Irritation	41765402 and 43008703

	

Severe irritant to ocular tissue of Rabbit	

I

870.2500

(81-5)	

Primary Skin Irritation	41765403, 43008704, and 00141066	

Minimum irritant to skin of Rabbit	

IV

870.2600

(81-6)	Dermal Sensitization	00230726

And

00054963	Not a Dermal Sensitizer

3.2	Subchronic Toxicity 

3.2.1	Subchronic oral Toxicity 

There are two subchronic oral studies (one 90-day rat feeding study, and
one 90-day dog oral capsule study) available in the toxicology database

90-day dog oral (capsule)  study (MRIDs 43246402 and 42054403)

In the 90-day dog oral capsule study, four groups, each consisting of 4
male and 4 female beagle dogs, were administered Diiodomethyl p-tolyl
sulfone at dosages-of either 0, 2, 10 or 60 mg/kg/day in gelatin
capsules for at least three months.  Clinical signs of toxicity, which
were observed 1-4 hours after dosing in the high dosage group, included
decreases activity, dehydration, mucoid eye discharge, weakened
condition and abnormal feces (mucoid and occasionally blood-tinged). Eye
discharge and abnormal feces in the intermediate dosage group were also
considered treatment related.  Female in all of the treated groups had
decreased in mean body weight gain from day 0 to 91 of at least 20% in
comparison to the control value.  Mean hematology evaluations of the
treated animals were not statistically significant from those of the
control animals, although the white blood cell count and neutrophil
counts of the males in the 60 mg/kg/day group were higher than the
control and other treated groups. The high dosage group males also had
significantly decreased mean calcium, albumin, a1bumin:globulin ratio
and total protein values on one of two evaluations during the treatment
period. On gross necropsy, the only findings were changes in the
gastrointestinal tract (patchy-red discoloration of the stomach and
mucoid appearance of the small intestines) in three males in the high
dosage group. Absolute and relative organ weight did not differ from the
control values, essentially. On histopatholoy, degeneration of the
thyroid gland was observed in males and females in the high and
intermediate dosage groups. Sialadenitis, gastritis, necrosis of the
small intestine and keratitis were also seen in the high dose group.  

The study is classified as Core-Minimum Data (Dobozy, 2004) and can be
used for hazard assessment.

90-day rat feeding  (MRIDs 43246401 and MRID 42054402)

In a 90-day rat oral toxicity study three groups, each containing 10
males and 10 females,  and an additional group containing 15 males and
15 females (high dose group) were treated with either 0, 5, 20 or 80
mg/kg/day of Diiodomethyl p-tolyl sulfone in their diet for 90 days. 
The only significant findings in the treated animals were statistically
significant elevations in mean phosphorus and cholesterol levels in the
high dose group males and squamous metaplasia of the salivary gland
ducts in three males in the high dose group.  No significant difference
in body weight and mean weight gains were found among treatment groups.
All the effects noticed in the treatment groups are not considered
toxicologically significant.  The highest dose does not reach the
maximum tolerated dose (MTD).   The study is classified as Core-Minimum
Data (Dobozy, 2004) and can be used for hazard assessment.

3.3	Chronic Toxicity 

There is no chronic toxicity study in the toxicity database.

3.4	Developmental Toxicity 

There are four developmental toxicity studies in the toxicity database: 

Developmental Toxicity Study 1:

In a developmental toxicity study (MRIDs 42054404, 42054405, and
43246403), 90-day rat oral toxicity Crl:CD®(SD)BR albino rats from
Charles River Breeding Laboratories, Inc. received either 0, 100, 300,
or 1000 mg/kg/day 95% diiodomethyl-p-tolylsulfone a.i (Lot No.
66-207-CB) by oral gavage from gestation days 6 through 15.  In the
repeat study, only the 0 and 1000 mg/kg/day groups were included. 

Maternal toxicity was evident as reduced body weight gain and food
consumption in the mid and high dose groups and in the high dose group
as increased clinical signs of toxicity.  The Maternal Toxicity LOAEL is
300 mg/kg/day and the Maternal Toxicity NOAEL is 100 mg/kg/day based on
reduced body weight gain and reduced food consumption. 

Developmental toxicity was noted in the high dose group as slightly
decreased mean litter size, increased number of resorptions relative to
the number of implantation sites, reduced mean fetal body weight,
increased incidences of umbilical hernia and incomplete ossification of
the supraoccipital bones.  The Developmental Toxicity LOAEL is 1000
mg/kg/day and the Developmental Toxicity NOAEL is 300 mg/kg/day based on
decreased mean litter size, increased number of resorptions relative to
the number of implantation sites, reduced mean fetal body weight,
increased incidences of umbilical hernia and incomplete ossification of
the supraoccipital bones.

The study is classified as Core-Guideline data and satisfies the
guideline requirement (§83-3a), developmental toxicity (teratology)
study in rats.

Developmental Toxicity Study 2: 

Pregnant rats were given diiodomethyl p-tolyl sulfone at a dose of 0,
0.125, 0.25, 0.5 or 1.0% in the diet on days 6-15 of pregnancy. The
estimated daily intakes of Diiodomethyl p-tolyl sulfone were 0, 100,
182, 288, 411 mg/kg/day respectively.  Maternal body weight gain and
food consumption during the administration period were significantly
lowered in the 0.25, 0.5 and 1.0% groups. No significant changes induced
by diiodomethyl p-tolyl sulfone were detected in the number of
resorptions and dead fetuses, and body weight of live fetuses.
Morphological examinations of fetuses revealed no evidence of
teratogenesis. 

Developmental Toxicity Study 3: 

In the developmental toxicity study (MRIDs 42243801 and 43246404),
pregnant New Zealand White Rabbits from Hazleton Dutchland, Inc. (Denver
PA.) received either 0, 4, 15, or 60 mg/kg bw/day 95%
diiodomethyl-p-tolylsulfone a.i.(Lot No. 66-207-CB) by oral gavage from
gestation day 6 through 18, inclusive.

 

Maternal toxicity was noted as deaths and abortions primarily in the
high dose group, clinical signs in the mid and high dose group, reduced
body weight gain and food consumption in the mid and high dose groups.
The Maternal Toxicity LOAEL is 15 mg/kg/day and the Maternal Toxicity
NOAEL is 4 mg/kg/day, based on clinical signs, reduced body weight gain
and food consumption.

Developmental toxicity was noted in the mid and high dose in the form of
decreased mean litter size, increased number of resorptions relative to
the number of implantation sites as degenerating fetuses, and decreased
postnatal survival and reduced mean fetal body weight in the mid dose
(data only available for mid dose).  Also, developmental effects
occurred at the mid dose in the form of increased incidences of
hydrocephalus (which was also noted at a low incidence in the rat
developmental studies), the mid dose group also had a slight increase in
fetal and litter incidence of gnarled forepaw(s) and the low and mid
dose group of fetal and litter incidence of unossified olecranon and
unossified sternebrae. The Developmental Toxicity LOAEL is less than or
equal to 4 mg/kg/day and the Developmental Toxicity NOAEL is less than 4
mg/kg/day, based on the increased fetal and litter incidence of
unossified olecranon and unossified sternebrae.   

 

The study is classified as Core-Supplementary Data and does not satisfy
the guideline requirement (§83-3a), developmental toxicity (teratology)
study in rabbits; due to the lack of a NOAEL for Developmental Toxicity.
 In addition, in the study, the fetuses were incubated at approximately
34°C for approximately 24 hours. A record of survival was kept over
that period. Following incubation all fetuses in each litter were fixed
in alcohol and examined for internal abnormalities.  This is a procedure
different from the current guideline requirement (OPPTS 870.3700) for a
developmental toxicity (teratology) study in rabbits.  

However, even though there is a limitation in the developmental effects,
this study is considered an acceptable study for the maternal effects
and can be used for risk assessment purposes.

Developmental Toxicity 4.

In the developmental toxicity study (MRID 47242202), diiodomethyl
p-tolyl sulfone (97.7% ± 0.1% a.i., batch/lot PB1631LA01) was
administered to 26 rabbits/dose by gavage at dose levels of 0, 0.05,
0.5, or 2.0 mg/kg bw/day from days 7 through 27 of gestation. 

Maternal toxicity was observed at 2 mg/kg/day, and evidence of toxicity
included slightly increased absolute and relative thyroid weights and an
increased incidence of very slight thyroid follicular dilatation.  The
increased incidence of very slightly dilated follicles is also
consistent with iodine toxicity and, therefore, likely due to the high
iodine content (60% by weight) of diiodomethyl p-tolyl sulfone.  All the
maternal effects are not toxicologically significant.  The maternal
NOAEL is 2.0 mg/kg bw/day.

There were no signs of developmental toxicity observed at any dose
level.  Consequently, there is no developmental LOAEL.  The
developmental NOAEL is 2.0 mg/kg bw/day. 

The developmental toxicity study in the rabbit is classified Not
Acceptable, guideline and does not satisfy the guideline requirement for
a developmental toxicity study (OPPTS 870.3700) in rabbits.

3.5	Reproductive toxicity 

There are two reproductive studies:  

Rat One Generation Dietary Reproductive Toxicity Study (MRID46913302)

In the one-generation rat reproductive study (MRID 46913302),
diiodomethyl p-tolyl sulfone (97.4%; Lot # PB1631LA01) was administered
in the diet to 30 Sprague-Dawley (Crl:CD [SD] IGS BR) rats/sex/dose
group at dietary levels of 0, 20, 80, or 200 mg/kg/day (adjusted
time-weighted average of 0/0, 21.8/20.7, 86.1/82.0, and 213.9/204.0
mg/kg/day in males/females) for approximately ten weeks prior to mating
to produce the F1 litters.  This study was originally designed as a
two-generation reproductive toxicity study; however, due to unexpected
toxicity during the perinatal period of the F1 litters, the study was
terminated after one generation.

0 mg/kg/day and above males, body weights were decreased (p≤0.05;
except not significant [NS] at 20 mg/kg/day on Day 13) by 5-18% from Day
13 through termination, resulting in decreased (calculated by reviewers)
body weight gains during pre-mating (Days -2-69; decr 18-27%) and
throughout treatment (Days -2-104; decr 15-22%).  Food consumption was
also decreased (p≤0.05) by 5-20% at all intervals recorded. 
Additionally at this dose, red perinasal soiling was observed in 2/30
dams.

In the 80 mg/kg/day females, one dam was found dead on Test Day 99 (LD
1), and pale skin/mucus membranes and red perinasal soiling were each
observed in 2/30 dams.  During pre-mating, food consumption was
decreased (p≤0.05) by 4-10% at all intervals recorded.  During
gestation, body weights were decreased (p≤0.05; except NS on GD 0) by
4-7% throughout the period, resulting in decreased (p≤0.05) overall
(GD 0-21) gestational body weight gains (decr. 13%).  Additionally, food
consumption was decreased (p≤0.05) by 9-10% at all intervals recorded.
 During lactation, body weights were decreased (p≤0.05) by 6-9% on LD
1, 4, and 7, and food consumption was decreased (p≤0.05) by 10-23% on
LD 1-4, 4-7, and 7-11.

creased (p≤0.05) by 5-7% from Day 20-69, resulting in decreased
(calculated by reviewers) overall body weight gains (Days -2-69; decr.
14%), and food consumption was decreased (p≤0.05) by 6-13% at all
intervals recorded.  During gestation, body weights were decreased
(p≤0.05) by 8-14% throughout the period, resulting in decreased
(p≤0.05) overall (GD 0-21) gestational body weight gains (decr. 24%). 
Additionally, food consumption was decreased (p≤0.05) by 14-23% at all
intervals recorded.  During lactation, body weights were decreased
(p≤0.05) by 17% on LD 1.  This group was terminated shortly thereafter
due to high pup mortality.  Serum T3 (triiodothyronine) was decreased
(p≤0.05) by 26%, and TSH (thyroid stimulating hormone) was increased
(p≤0.05) by 98% compared to the surrogate controls.  Grossly, diffuse
roughened surface of the non-glandular mucosa of the stomach was
observed, and additional treatment-related, non-specific findings of
multifocal erosion/ulcer of the glandular mucosa of the stomach,
decreased amount of fat, and decreased ingesta were noted.  The
following microscopic findings were also: (i) very slight chromophobe
hypertrophy of the pars distalis of the pituitary gland; (ii) very
slight to slight multifocal metaplasia of the intralobular duct of the
salivary gland; (iii) very slight to slight diffuse hyperplasia of the
non-glandular mucosa of the stomach; (iv) very slight altered tinctorial
properties of the colloid of the thyroid gland; (v) very slight
dilatation of the follicle of the thyroid gland; and (vi) very slight
hypertrophy of the follicular cell of the thyroid gland.

The LOAEL for parental toxicity is 20 mg/kg/day (adjusted time-weighted
average of 21.8/20.7 mg/kg/day in males/females) based on decreased body
weights, body weight gains, and food consumption in the males and
clinical signs of toxicity (red perinasal soiling) in the females.  A
NOAEL was not established.

 (p≤0.05) in both sexes by 7-21% at 80 and 200 mg/kg/day on PND 1. 
Additionally, pup body weights were decreased (p≤0.05) in both sexes
at 80 mg/kg/day by 8-12% on PND 7 and 14.  Body weight gains for PND
1-14 were decreased by 11-14% in both sexes (calculated by reviewers).

The LOAEL for offspring toxicity is 80 mg/kg/day (adjusted time-weighted
average of 86.1/82.0 in males/females) based on decreased live birth and
survival indices, mean number of live born pups/litter, litter size, and
pup body weight and body weight gains, increased mean number of
stillborn pups, and increased incidence of clinical signs of toxicity as
described above.  The NOAEL is 20 mg/kg/day (adjusted time-weighted
average of 21.8/20.7 mg/kg/day in males/females).

Rat Two_Generation Dietary Reproductive Toxicity Study (MRID46913301)

In the two-generation rat reproductive study (MRID 46913301)
,diiodomethyl p-tolyl sulfone (97.4%; Lot # PB1631LA01) was administered
in the diet to 30 Sprague Dawley rats/sex/dose group at dietary levels
of 0, 2.5, 10, or 40 mg/kg/day for two successive generations.  The P
generation animals were fed the test diets for approximately 10 weeks
prior to mating to produce the F1 litters.  All litters were weaned on
PND 21, and one F1 weanling/sex/litter was randomly selected to be a
parent of the next generation, following the same procedures described
for the first generation.  

At 40 mg/kg/day, one P generation dam (#6068) was killed in extremis on
LD 0 due to dystocia.  In the F1 generation, one 40 mg/kg/day dam
(#1957) was euthanized in a moribund state on LD 2 and had excessive
blood loss and secondary uterine inflammation, most likely incurred
during parturition.  Because dystocia was observed previously with
exposure to the test material in the one-generation reproduction study
(MRID 46913302), these deaths were considered treatment-related.  There
were no other treatment-related deaths.  Aside from the clinical signs
associated with the death and moribundity mentioned above, there were no
treatment-related clinical observations.  Treatment-related effects on
body weights and food consumption during the pre-mating period were
observed at 10 and 40 mg/kg/day.  Body weights were decreased throughout
pre-mating in the P males, with the decreases attaining significance at
40 mg/kg/day from Days 27-62. In the F1 males, body weights were
decreased (p≤0.05) beginning on Day 27 at 10 mg/kg/day and throughout
the study at 40 mg/kg/day.  In the F1 females, body weights were
decreased (p≤0.05) on Day 13 at 10 mg/kg/day and on Days 1-34 at 40
mg/kg/day.  Food consumption in the P males was decreased (p≤0.05)
from Days 8-36 at 10 mg/kg/day and from Days 1-36 at 40 mg/kg/day.  In
the F1 males, food consumption was decreased throughout treatment at 10
and 40 mg/kg/day, with differences attaining significance beginning on
Day 22 at 10 mg/kg/day and throughout treatment at 40 mg/kg/day.

In the 40 mg/kg/day F1 females, body weights were decreased (p≤0.05)
on GD 21, and body weight gains were decreased throughout gestation
(p≤0.05, except NS for GD 7-14).  Food consumption was decreased
(p≤0.05) at 40 mg/kg/day in the P females for GD 14-21 and in the F1
females throughout gestation.  At 10 mg/kg/day in the F1 generation,
food consumption was decreased (p≤0.05) for GD 7-14.

In the F1 generation, body weights were decreased throughout lactation
at 10 mg/kg/day (p≤0.05 on LD 1, 4, and 21) and at 40 mg/kg/day
(p≤0.05 throughout lactation).  Food consumption in the P females was
decreased by 7-14% (p≤0.05) at 40 mg/kg/day for LD 4-7, 7-11, and
19-21.  In the F1 females, food consumption was decreased (p≤0.05) for
LD 4-7 at 10 mg/kg/day and throughout lactation at 40 mg/kg/day.

Absolute and relative thyroid weights were increased in the ≥2.5
mg/kg/day P males and in the ≥10 mg/kg/day P females and F1 males.  In
the thyroid, an increased incidence (# affected/30 vs 0 controls/30) of
altered staining of the colloid in the follicle was observed in the
≥2.5 mg/kg/day P males (30 each treated group), P females (19-28), F1
males (30 each treated group), and F1 females (26-29).  Although the
severity of this finding was Grade 1 and Grade 2 in all treated groups,
males were more affected than the females.

survival indices were decreased (p≤0.05) throughout the post-natal
period in both generations.  These decreases were significant (p≤0.05)
on PND 1 and 4 in the F1 litters and on PND 1, 4, and 7 in the F2
litters.  The mean number of pups born dead was increased in both
generations at this dose.  Additionally at 40 mg/kg/day, litter size was
decreased in both generations throughout the post-natal periods.  These
decreases were significant (p≤0.05) in the F1 litters at PND 4 prior
to culling and in the F2 litters throughout the post-natal period. 
Litter size remained decreased after culling in the F1 litters at this
dose; although these decreases were not significant.

At 40 mg/kg/day, pup weights were decreased in both sexes and both
generations.  These decreases were significantly different from the
controls at PND 1, 7, 14, and 21 in the P males, P females and F2
females.  In the F2 males, decreases were significant throughout the
post-natal period. 

The only findings at 10 mg/kg/day were slightly decreased (p≤0.05) pup
survival index in the F2 litters on PND 7 (95.3% vs 100% in controls)
and minor transient decreases of 6-7% in pup body weights in the F2
males (only) on PND 1 and 14.  Therefore, the reviewers disagree with
the investigators regarding the effects on the offspring at this dose
level.

The LOAEL for offspring toxicity is 40 mg/kg/day based on decreased live
birth index, post-natal pup survival, and pup body weights.  The NOAEL
is 10 mg/kg/day.

≤0.05) and live birth index was decreased (p≤0.05) in both
generations.

In the F1 generation, total epididymal sperm count was decreased in all
treated groups compared to controls, although the number of sperm/g
tissue at the high dose was comparable to controls.  Similarly,
testicular sperm count in this generation was decreased at 40 mg/kg/day,
and although sperm count/g tissue was increased at 10 mg/kg/day, it was
comparable to controls at 40 mg/kg/day.  There were no treatment-related
effects on epididymal or testicular sperm counts or organ weights in the
P generation.

There were no effects of treatment on sperm motility, progressive
motility, or on the proportion of abnormal sperm in either generation. 
Furthermore, there were no treatment-related effects on mating,
conception, fertility, or gestation indices or on sex ratio, pre-coital
interval, or gestation duration in either generation.  Given the lack of
an effect of the reproductive indices, the minor decreases in total
sperm count in the F1 males were likely due to the decreased terminal
body weights and were not considered adverse.  Finally, there were no
effects of treatment on estrous cycle duration or periodicity.

The LOAEL for reproductive toxicity is 40 mg/kg/day based on
embryo-lethality as evidenced by increased post-implantation loss and
decreased gestation survival (live birth) index.  The NOAEL is 10
mg/kg/day.

The release of the iodine from the diiodomethyl p-tolyl sulfone is
considered to result in dystocia and changes in the thyroid and
pituitary in the parents and in decreased survival and pup weights in
the offspring.

3.6	Neurotoxicity Toxicity 

There are no neurotoxicity studies available in the toxicity database.
In the 90 day Dog and Rat study

(MRIDs 42054403/43246402 and 42054402/43246401) neural tissues (both
central and

peripheral) were examined; no neurotoxicological effects were observed

3.7	Mutagenicity and Carcinogenicity  

There is a battery of negative mutagenicity studies.  Diiodomethyl
p-tolyl sulfone is not mutagenic.

4.0	HAZARD ENDPOINT SELECTION

The doses and endpoints for short-term, intermediate-term and long-term
occupational or residential exposure have been selected  by the Agency
for diiodomethyl p-tolyl sulfone.  Table 4 summarizes the toxicological
dose and endpoints for diiodomethyl p-tolyl sulfone for use in human
risk assessments.

4.1	Acute Reference Dose (RfD)	

No appropriate end-point can be selected for Acute RfD.  Although in the
90-day dog study (MRID42054403 and 43246402) clinical signs of toxicity,
which were observed (including decreased activity, dehydration, mucoid
eye discharge, weaken condition and abnormal feces) were noticed after
single dose of exposure, it only happened at high dose tested (60 mg/kg
bw).  It is not considered to be a valid end-point to be selected for
regulatory purpose.

4.2	Chronic Reference Dose (RfD)

Proposed Study: 90-day Oral  (Dog)					§ Number 870.3150

MRID No.: 42054403 and 43246402

Executive Summary: 

Four groups, each consisting of 4 males and 4 females beagles, were
administered Diiodomethyl p-tolyl sulfone at dosages of either 0, 2, 10
or 60 mg/kg/day in gelatin capsules for at least three months.  Clinical
signs of toxicity, which were observed 1-4 hours after dosing in the
high dosage group, included decreased activity, dehydration, mucoid eye
discharge, weaken condition and abnormal feces (mucoid and occasionally
blood-tinged), Eye discharge and abnormal feces in the intermediate
dosage group were also considered treatment related. Females in all of
the treated groups had decreases in mean body weight gain from Day 0 to
91 of at least 20% in comparison to the control value.

Mean hematology evaluations of the treated animals were not
statistically significant from those of the control animals, although
the white blood cell counts and neutrophil counts of the males in the 60
mg/kg/day group were higher than the control and other treated groups. 
The high dosage group males also had significantly decreased mean
calcium, albumin, albumin: globulin ratio and total protein values on
one or two evaluations during the treatment period.  On gross necropsy,
the only findings were changes in the gastrointestinal tract (patchy-red
discoloration of the stomach and mucoid appearance of the small
intestines) in three males in the high dosage group.  Absolute and
relative organ weight did not differ from the control values,
essentially.  On histopathology, degeneration of the thyroid gland was
observed in males and females in the high and intermediate dosage
groups.  Sialadenitis, gastritis, necrosis of the small intestine and
keratitis were also seen in the high dose group.  The clinical and
pathologic findings were considered to be a result of iodine toxicity
induced by the iodine moiety of Diiodomethyl p-tolyl sulfone.

In this study, the NOAEL and LOAEL for males and females are as follows:

Males:

NAOAEL = 2 mg/kg/day and LOAEL= 10 mg/kg/day based on decreased
activity, dehydration, mucoid ocular discharge, weakened appearance,
abnormal feces, and degeneration of the thyroid.

Females 

NOAEL < 2.0 mg/kg/day and LOAEL = 2 mg/kg/day based on decreased body
weight gain.

Dose and Endpoint for Risk Assessment:

LOAEL = 2 mg/kg/day (based on decreased body weight gain)

Proposed Uncertainty Factor(s): 

1000 [10x for inter-species, 10x for intra-species, 3X for database
uncertainty (missing chronic and cancer studies) and 3 for using LOAEL]

 

Comments about Study/Endpoint

In the study, females in all of the treated groups had decreases in mean
body weight gain from Day 0 to 91 of at least 20% in comparison to the
control value. 

4.3	Occupational/Residential Exposure

Short-Term Incidental Oral Exposure (1 – 30 days)

Proposed Study:  Developmental Toxicity - Rabbit		§ Number  870.3700a

MRID No.: MRIDs 42243801 and 43246404

Executive Summary: 

In a developmental toxicity study (MRIDs 42243801 and 43246404),
pregnant New Zealand White Rabbits from Hazleton Dutchland, Inc. (Denver
PA.) received either 0, 4, 15, or 60 mg/kg/day 95%
diiodomethyl-p-tolylsulfone a.i.(Lot No. 66-207-CB) by oral gavage from
gestation day 6 through 18, inclusive.

 

Maternal toxicity was noted as deaths and abortions primarily in the
high dose group, clinical signs in the mid and high dose group, reduced
body weight gain and food consumption in the mid and high dose groups.
The Maternal Toxicity LOAEL is 15 mg/kg/day and the Maternal Toxicity
NOAEL is 4 mg/kg/day, based on clinical signs, reduced body weight gain
and food consumption.

Dose and Endpoint for Risk Assessment:

Maternal NOAEL of 4 mg/kg day (100% a.i) based on based on clinical
signs, reduced body weight gain and food consumption.

Proposed Uncertainty Factor(s): 

100 (10x for inter-species variation and 10x for intra-species
variation).

Comments about Study/Endpoint

The appropriateness of using the rabbit developmental maternal effects
of 4 mg/kg/day in the study (MRIDs 42243801 and 43246404) as end-point
is confirmed by the second rabbit developmental study (MRID 47242202).
At the highest dose tested in the second developmental study (2 mg/kg
bw/day) no toxicologically and/or developmental effects were seen in
both maternal animal and fetus.   

4.3.2	Intermediate-Term Incidental Oral Exposure (1 – 6 months)

Proposed Study: 90-day Oral (Dog)					§ Number 870.3150

MRID No.: 42054403 and 43246402

Executive Summary: 

Four groups, each consisting of 4 males and 4 females beagles, were
administered diiodomethyl p-tolyl sulfone at dosages of either 0, 2, 10
or 60 mg/kg/day in gelatin capsules for at least three months.  Clinical
signs of toxicity, which were observed 1-4 hours after dosing in the
high dosage group, included decreased activity, dehydration, mucoid eye
discharge, weaken condition and abnormal feces (mucoid and occasionally
blood-tinged), Eye discharge and abnormal feces in the intermediate
dosage group were also considered treatment related. Females in all of
the treated groups had decreases in mean body weight gain from Day 0 to
91 of at least 20% in comparison to the control value.

Mean hematology evaluations of the treated animals were not
statistically significant from those of the control animals, although
the white blood cell counts and neutrophil counts of the males in the 60
mg/kg/day group were higher than the control and other treated groups. 
The high dosage group males also had significantly decreased mean
calcium, albumin, albumin:globulin ratio and total protein values on one
or two evaluations during the treatment period.  On gross necropsy, the
only findings were changes in the gastrointestinal tract (patchy-red
discoloration of the stomach and mucoid appearance of the small
intestines) in three males in the high dosage group.  Absolute and
relative organ weight did not differ from the control values,
essentially.  On histopathology, degeneration of the thyroid gland was
observed in males and females in the high and intermediate dosage
groups.  Sialadenitis, gastritis, necrosis of the small intestine and
keratitis were also seen in the high dose group.  The clinical and
pathologic findings were considered to be a result of iodine toxicity
induced by the iodine moiety of diiodomethyl p-tolyl sulfone.

In this study, the NOAEL and LOAEL for males and females are as follows:

Males:

NAOAEL = 2 mg/kg/day and LOAEL= 10 mg/kg/day based on decreased
activity, dehydration, mucoid ocular discharge, weakened appearance,
abnormal feces, and degeneration of the thyroid.

Females 

NOAEL < 2.0 mg/kg/day and LOAEL = 2 mg/kg/day based on decreased body
weight gain. 

Dose and Endpoint for Risk Assessment

LOAEL = 2 mg/kg/day and NOAEL of < 2 mg/kg/day based on decreased body
weight gain.

Comments about Study/Endpoint/Margins of Exposure: 

Dog is consider a more sensitive species.  Magrin of Exposure of 300 is
proposed [10x for interspecies extrapolation and 10x for intra species
variations and 3 for using LOAEL].

4.3.3	Relative Dermal Absorption Rate

There is no guideline acceptable dermal penetration study.  There is
some dermal absorption information in the newly available
pharmacokinetic and metabolism study (MRID 47076601).

In the study, Fischer 344 rats (4 males and 4 females) were dosed
dermally by applying C14-Diiodomethyl p-tolyl sulfone on the shaved back
(between scapula) and covering the site with mesh, the site was washed 6
hours after application. Dose suspension for the dermal application was
prepared at the target concentration of ~ 8.8 mg/ml and applied at a
dose volume of 10 µl/cm2 to 12 cm2, which resulted in a dose of ~ 5
mg/kg.  Absorption of the dermally applied diiodomethyl p-tolyl sulfone
antifungal agent was 7-12% of the dose . Between 5 and 7% of the applied
dose was excreted in urine, fecal elimination was negligible (~0.3%).
The level of radioactivity and free iodide in the plasma of the dermally
dosed animals remained <LOQ throughout the study. The dermally applied
dose was slowly absorbed from the site of application and rapidly
eliminated in urine accounting for 23-30% and 38-45% of the absorbed
dose within 24 hours and 48 hours, respectively. The total amount of
iodide found in the urine of the dermally dosed rats was 10-40% higher
than the total radioactivity, which was opposite to what was observed in
the orally dosed animals, indicating higher metabolism/liberation of one
or both of the iodide from the parent molecule. Elimination of
radioactivity and iodide in urine continued during the analysis period
due to slow continuous absorption of 14C- diiodomethyl p-tolyl sulfone
antifungal agent from the application site.

Because only 6 hour of exposure, only one dosage concentration group
studies, and the slowly absorption from the site of application and
rapidly eliminated in urine, it is very possible that more absorption
can happened in longer-term exposure conditions.  Therefore, as
summarized in Table 5, the Agency considers all the unabsorbed portion
in the skin should also consider to be absorbable.  The appropriate
dermal absorption factor to be risk in risk assessment should be around
12%.

	Table 1.  Disposition and Recovery of c14-Diiodomethyl p-tolyl sulfone
From Fischer 344 rats after a single Dermal Application of
C14-Diiodomethyl p-tolyl sulfone

	Single Dermal (~5mg/kg) Application

	Male	Female

	Mean	SD	Mean	SD

Tissues	0.33	0.34	0.31	0.24

Urine	7.09	2.44	4.72	0.65

Feces	0.26	0.15	0.05	-

Final Cage Wash	0.24	0.21	0.48	0.36

Application Site Skin	2.39	0.47	1.05	0.38

Skin wash	79.52	8.52	90.45	12.37

Tape Striping	0.18	0.07	0.11	0.10

Total	89.95	10.78	97.11	12.82

Absorbed Dose (w/ Tape Striping)	10.49

6.72

	Absorbed Dose (w/O Tape Striping)	10.31

6.61

	% of Absorption (W/ Tape Striping)	11.66%

6.92%

	% of Absorption (W/O Tape Striping)	11.46%

6.81%

		Note: Calculated from table 5 of the study report (MRID 47076601)

	

4.3.4	Short-Term Dermal (1-30 days) Exposure

Proposed Study: Developmental Study (Rabbit)	       		§ MRID No.:
42243801

Executive Summary: 

In a developmental toxicity study (MRID # 42243801), pregnant New
Zealand White Rabbits from Hazleton Dutchland, Inc. (Denver PA.)
received either 0, 4, 15, or 60 mg/kg/day 95%
diiodomethyl-p-tolylsulfone a.i.(Lot No. 66-207-CB) by oral gavage from
gestation day 6 through 18, inclusive.

 

Maternal toxicity was noted as deaths and abortions primarily in the
high dose group, clinical signs in the mid and high dose group, reduced
body weight gain and food consumption in the mid and high dose groups.
The Maternal Toxicity LOAEL is 15 mg/kg/day and the Maternal Toxicity
NOAEL is 4 mg/kg/day, based on clinical signs, reduced body weight gain
and food consumption.

Proposed Dose and Endpoint for Risk Assessment: 

NOAEL = 4 mg/kg/day (based on maternal toxic effects on clinical signs,
reduced body weight gain and food consumption.).

Comments about Study/Endpoint/Margins of Exposure:

It is based appropriated exposure period and dog is consider a more
sensitive species. Magrin of Exposure (MOE) = 100 (10x for interspecies,
10x for intraspecies)

4.3.5	Intermediate-Term Dermal (7 Days to Several Months) Exposure

Proposed Study: 90-day Oral (Dog)					§ Number 870.3150

MRID No.: 42054403 and 43246402

Executive Summary: 

See Above

Dose and Endpoint for Risk Assessment

LOAEL = 2 mg/kg/day and NOAEL of < 2 mg/kg/day (based on decreased body
weight gain.).

Comments about Study/Endpoint/Margins of Exposure: 

It is based appropriated exposure period and dog is consider a more
sensitive species.  Margin of Exposure of 300 is proposed[10x for
interspecies extrapolation and 10x for intra species variations and 3
for using LOAEL].

4.3.4	Long-Term Dermal (More than 6 Months to Life-Time) Exposure

Proposed Study: 90-day Oral (Dog)					§ Number 870.3150

MRID No.: 42054403 and 43246402

Executive Summary: 

See Above

Proposed Dose and Endpoint for Risk Assessment

LOAEL = 2 mg/kg/day and NOAEL of < 2 mg/kg/day (based on female based on
decreased activity, dehydration, mucoid ocular discharge, weakened
appearance, abnormal feces, and degeneration of the thyroid).

Comments about Study/Endpoint/Margins of Exposure: 

It is based appropriated exposure period and dog is consider a more
sensitive species.  Margin of Exposure of 1000 is proposed[10x for
interspecies extrapolation and 10x for intra species variations, 3 for
database uncertainty factor and 3X for using LOAEL].

4.3.5.	Inhalation Exposure (All Durations)	

Proposed Study: 90-day Oral (Dog)					§ Number 870.3150

MRID No.: 42054403 and 43246402

Executive Summary: 

See above

Proposed Dose and Endpoint for Risk Assessment

LOAEL = 2 mg/kg/day and NOAEL of < 2 mg/kg/day day based on decreased
body weight gain in female.

Comments about Study/Endpoint/Margins of Exposure: 

There is no appropriate inhalation study.  A target MOE of 300 is
selected (10x for intrapecies variation, 10X for inter species
variation, and 10X for using LOAEL) and if a MOE of 3000 is not achieved
a route-specific inhalation toxicity study will be needed (hence the
extra 10x).  The 90-day inhalation is considered as the primary data gap
for inhalation exposure scenarios.

4.3.6	Margins of Exposure for Occupational/Residential Risk Assessments

A MOE of 100 is selected for short oral and dermal risk assessment (10x
for inter species variation, and 10X for intraspecies variation)  

A MOE of 300 is selected for intermediate term oral and dermal exposure
risk assessments (10x for inter species variation, and 10X for
intraspecies variation, and 3X for using LOAEL)  

A MOE of 1000 is selected for long  term dermal exposure  risk
assessments (10x for inter species variation, and 10X for intraspecies
variation, 3x for missing chronic/cancer studies and 3X for using
LOAEL);

A MOE of 300 is selected for all term inhalation dermal exposure risk
assessments (10x for inter species variation, and 10X for intraspecies
variation, and 3X for using LOAEL).  However, and if a MOE of 3000 is
not achieved a route-specific inhalation toxicity study will be needed
(hence the extra 10x).  

4.4	Classification of Carcinogenic Potential

There are no chronic and/or cancer studies.  Because there are high
exposure scenarios (e.g. wood preservative), chronic studies and cancer
studies (two species) are considered as data gaps.

5.0	FQPA CONSIDERATION

	No food use was involved in this registration, therefore, no FQPA
concern.

Data Gaps

Following studies are suggested as data gaps:

(1). 90-day inhalation study

(2). Rat chronic study; and

(3). Cancer studies (2 species rat and mice)

Table 4 	Summary of Toxicological Dose and Endpoints for Diiodomethyl
p-tolyl sulfone

Exposure

Scenario	

Dose Used in Risk Assessment, UF 	

Special FQPA SF* and Level of Concern for Risk Assessment	

Study and Toxicological Effects

Acute Dietary

 (All populations)	No appropriate end-point can be selected for Acute
RfD.

Chronic Dietary

(All populations)	Oral LOAEL =2 mg/kg/day

UF = 1000 

[10x for interspecies, 10x for intraspecies, 3X for database uncertainty
(missing chronic/cancer  and reproductive studies) and 3 for using
LOAEL]	

NA	90-day Oral  (Dog)

MRID 42054403 and 43246402

based on decreased body weight gain, decreased activity, dehydration,
mucoid ocular discharge, weakened appearance, abnormal feces, and
degeneration of the thyroid.

 

Short-Term Incidental Oral (1-30 days)

	

Oral Maternal NOAEL =4 mg/kg/day 

UF = 100

(10x for interspecies, 10x for intraspecies)

	

N/A	

Rabbit Developmental Toxicity – 

(MRID  42243801 and 43246404)

based on clinical signs, reduced body weight gain and food consumption.

 

Intermediate-Term Oral (1- 6 months)

	

Oral LOAEL =2 mg/kg/day

MOE = 300 

[10x for interspecies, 10x for intraspecies, and 3X for using LOAEL]	

N/A	

90-day Oral  (Dog)

MRID 42054403 and 43246402

based on decreased body weight gain, decreased activity, dehydration,
mucoid ocular discharge, weakened appearance, abnormal feces, and
degeneration of the thyroid.

Dermal Ad. Factor

	

12% [based on the Rat Pharmacokinetics and Metabolism (MRID 47076641]

Dermal (System, Short-Term)	Oral Maternal NOAEL =4 mg/kg/day 

MOE = 100

(10x for interspecies, 10x for intraspecies)

	NA	Rabbit Developmental Toxicity – 

(MRID  42243801 and 43246404.)

based on clinical signs, reduced body weight gain and food consumption.

Dermal (Inter-term)	

Oral LOAEL =2 mg/kg/day

MOE = 300 

[10x for interspecies, 10x for intraspecies, 3X for using LOAEL]	

N/A	90-day Oral  (Dog)

MRID 42054403 and 43246402

based on decreased body weight gain, decreased activity, dehydration,
mucoid ocular discharge, weakened appearance, abnormal feces, and
degeneration of the thyroid.

Dermal (long-term)	

Oral LOAEL =2 mg/kg/day

MOE= 1000 

[10x for interspecies, 10x for intraspecies, 3X for database uncertainty
(missing chronic/cancer  and reproductive studies) and 3X for using
LOAEL]	

NA

	

 90-day Oral  (Dog)

MRID 42054403 and 43246402

based on decreased body weight gain, decreased activity, dehydration,
mucoid ocular discharge, weakened appearance, abnormal feces, and
degeneration of the thyroid.based on lymphocytic infiltration in females
and erosion of gastric mucosa and prominence of limiting ridge of the
stomach in males

Inhalation (All Exposure Terms)	

Oral LOAEL =2 mg/kg/day

MOE = 3000 

[10x for interspecies, 10x for intraspecies, 10X for route-to-route
extrapolation  and 3X for using LOAEL]	

NA

	

 90-day Oral  (Dog)

MRID 42054403 and 43246402

based on decreased body weight gain, decreased activity, dehydration,
mucoid ocular discharge, weakened appearance, abnormal feces, and
degeneration of the thyroid.based on lymphocytic infiltration in females
and erosion of gastric mucosa and prominence of limiting ridge of the
stomach in males

Cancer (oral, dermal, inhalation)	

	

	

no cancer data available

UF = uncertainty factor, FQPA SF = Special FQPA safety factor, NOAEL =
no observed adverse effect level, LOAEL = lowest observed adverse effect
level, PAD = population adjusted dose (a = acute, c = chronic) RfD =
reference dose, MOE = margin of exposure, LOC = level of concern, NA =
Not Applicable

 

 REFERENCE

Æ

@

œ

¦

Ø

Ù

Ú

Û

ì

í

î

摧⼆/

摧⁻z

Ú

í

f

»

ሇഀࣆȀπ┺਀ᄇഀࣆȀː┺਀ဇഀࣆȀː┺਀

	



,

-

-

.

/

2

3

D

E

F

`

a

b

c

d

e

f

g

h

„

…

†

‡

Š

‹

™

š

›

µ

µ

¶

·

¸

¹

º

»

¼

½

Ù

Ú

Û

Ü

ß

à

ó

ô

õ

j¸

j;

j¬

j/

j

̤̀옍

̤̀옍

̤̀옍

옍

 ̀Ĥ옍

摧盝é ̀Ĥ옍

 ̀Ĥ옍

Æ

$̀Ĥ옍)

摧盝é$̀Ĥ옍)

摧盝é$̀Ĥ옍)

$̀Ĥ옍)

㐀ۖĀ̊脃昀Ĵ$̀Ĥ옍)

$̀Ĥ옍)

愀Ĥ摧慙'$̀Ĥ옍)

摧盝é$̀Ĥ옍)

$̀Ĥ옍)

㐀ۖĀ̊脃昀Ĵ$̀Ĥ옍)

$̀Ĥ옍)

愀Ĥ摧慙'$̀Ĥ옍)

摧盝é$̀Ĥ옍)

$̀Ĥ옍)

㐀ۖĀ̊脃昀Ĵ$̀Ĥ옍)

$̀Ĥ옍)

愀Ĥ摧慙'$̀Ĥ옍)

摧໎>$̀Ĥ옍)

$̀Ĥ옍)

㐀ۖĀ̊脃昀Ĵ'̀Ĥ옍)

'̀Ĥ옍)

愀Ĥ摧慙'$̀Ĥ옍)

摧啔ó$̀Ĥ옍)

$̀Ĥ옍)

㐀ۖĀ̊脃昀Ĵ'̀Ĥ옍)

'̀Ĥ옍)

愀Ĥ摧慙'$̀Ĥ옍)

摧໎>$̀Ĥ옍)

$̀Ĥ옍)

㐀ۖĀ̊脃昀Ĵ'̀Ĥ옍)

'̀Ĥ옍)

愀Ĥ摧慙'$̀Ĥ옍)

摧啔ó$̀Ĥ옍)

$̀Ĥ옍)

㐀ۖĀ̊脃昀Ĵ'̀Ĥ옍)

'̀Ĥ옍)

愀Ĥ摧慙'$̀Ĥ옍)

'̤̀옍)

̤̀옍)

♀愁̤摧ޠÔ'̤̀옍)

$

@

~

@

@

~

~

~

@

h

@

@

@

h

h

hª

@

@

@

„Ð^„Ðgd

@

 h

h

h

h

 h

 h

 h

 h

 h

 h

 hi

 hi

 h

 h

 h

 h

 h

 h

 h

 h

 h

@

 h

 h

 h

 hi

 hi

 h

 h

 h

 hi

 hi

 h

 h

h

 h

 h

 h

@

hçF

hçF

h

愀Ĥ摧吁Ì

摧吁Ì

愀Ĥ摧吁Ì

摧吁Ì

B*

愀Ĥ摧吁Ì

愀Ĥ摧吁Ì

B*

愀Ĥ摧吁Ì

㓿ۖĀ̊x砃昀Ĵ

rusick, D.J. (1977) Mutagenicity Evaluation of A-47685 50/50 Mixture
with Dipropylene glycol: LBI Project No. 2683.. Final rept., rev. 11 p.
MRID 00054962.  Unpublished.

Brusick, D.J. (1977) Mutagenicity Evaluation of A-47685: LBI Project No.
2683. Final rept., rev. (Unpublished study received Jun 15, 1977 under
275-33; prepared by Litton Bionetics, Inc., MRID 00054961 submitted by
Abbott Laboratories, North Chicago, Ill.; CDL: 230726-E)

Carney, E. W., Zablotny, C. L., and Johnson, K. A. (2006) Amical 48: 
one-generation dietary reproduction toxicity study in CD rats. 
Toxicology & Environmental Research and Consulting, The Dow Chemical
Company, Midland, MI.  Laboratory Project Study ID.:  031007, April 28,
2006.  MRID 46913302.  Unpublished.

(2007) AMICAL™ 48, antifungal agent: oral gavage developmental
toxicity study in New Zealand white rabbits. The Dow Chemical Company.
Laboratory Project Study ID 061146, August 29, 2007. MRID 47242202.
Unpublished.

Carney, E.W., C.L. Zablotny, J.F. Quast, and K.A. Johnson (2006) Amical
48: two-generation dietary reproductive toxicity study in CD rats. 
Toxicology & Environmental Research and Consulting, The Dow Chemical
Company, Midland, MI.  Laboratory Project Study ID.:  031007, May 15,
2006.  MRID 46913301.  Unpublished.

Cifone, M. (1985) Evaluation of A-9248 in the Rat Primary Hepatocyte
Unscheduled DNA Synthesis Assay: LBI Project No. 20991: Final Report.
MRID 00160072 

Cifone, M. (1985) Mutagenicity of A-9248 in a Mouse Lymphoma Mutation
Assay: LBI Project No. 20989: Final Report. MRID 00160070 Unpublished
study prepared by Litton Bionetics, Inc. 17 p.

Creighton, J. (1986) Three-Month Toxicity Study of Amical 48
Administered Orally to Dogs: Lab Project Number: TB85-158. Abbot labs. 
MRID 42054403.  Unpublished

Creighton, J.; Bollmeier, A. (1986) Three-Month Toxicity Study of AMICAL
48 Administered Orally to Dogs: Supplemental Data: Lab Project Number:
TB85/158. Abbott Labs. 22 p. MRID 43246402. Unpublished.

Davis, J. and Erhardt, S.  (2005) Amical 48 antifungal agent: 
Pharmacokinetics and metabolism in Fisher 344 rats. The Dow Chemical
Company, Midland, Michigan. Laboratory report number not reported,
January 18, 2007. MRID 47076601. Unpublished. 

Dudley, R. (1986) Three-Month Toxicity Study of Amical 48 Administered
Via the Diet to Rats: Lab Project Number: TA85-096. Abbot Laboratories. 
MRID010504. Unpublished 

Ema M, Itami T, Kawasaki H. (1992).Teratological assessment of
diiodomethyl p-tolyl sulfone in rats. Toxicol Lett. 62(1):45-52.

FitzGerald, G. (1992) Acute Oral Limit Study: Amical WP: Lab Project
Number: 92G-1490. Toxikon Corp. MRID 42586801. Unpublished.

Ivett, J. (1986) Clastogenic Evaluation of A-9248...in the in vivo Mouse
Micronucleus Assay: HB Project No. 20996: Final Report. MRID
00160071Unpublished study prepared by Hazleton Biotechnologies. 20 p.

Kesterson, J.; Majors, K.; Moore, L.; et al. (1976) Acute Dermal
Toxicity of Amical 48 (Dry Powder) and an Amical 48 Dispersion in
Rabbits: Study Nos. 76-245 and 76-246. (Unpublished study received Jun
16, 1976 under 275-30; submitted by Abbott Labora- tories, North
Chicago, IL; CDL:225439-A.  MRID 00123023.  Unpublished.

Kesterson, J.; Majors, K.; Moore, L.; et al. (1976) Acute Dermal
Toxicity of Amical 48 (Dry Powder) and an Amical 48 Dispersion in
Rabbits: Study Nos. 76-245 and 76-246. submitted by Abbott Laboratories,
North Chicago, IL; CDL:225439-A.  MRID 00123023. Unpublished.

Kreuzmann, J. (1990) Acute Oral Toxicity in Rats--Limit Test of AMICAL
48: Supplemental Information: Lab Project Number: 90/4015/21/A. Hill Top
Biolabs, Inc. MRID 43008702.  Unpublished. 

Kreuzmann, J. (1990) Acute Oral Toxicity in Rats-Limit Test: Amical 48:
Lab Project Number: 90-4015-21 Hill Top Biolabs, Inc. MRID 41765401
Unpublished. 

Lehrer , SB (1985). Evaluation of the Effects of Orally Administered
AMICAL® 48 on the Embryonic and Fetal Development of the Rat - Segment
II, TFR Abbott Laboratories, North Chicago, IL MRID 42054404. 
Unpublished.

Lehrer , SB (1986). Evaluation of the Effects of Orally Administered
AMICAL® 48 on the Embryonic and Fetal Development of the Rat - Segment
II, TFR Supplement to Study TA85-022. Abbott Laboratories, North
Chicago, IL MRID 42054405.  Unpublished.

Lehrer, S. (1985) Evaluation of the Effects of Orally Administered
Amical 48 on the Embryonic and Fetal Development of the Rat: Segment II,
TFR: Lab Project Number: TE85-022. MRID 42054404  Unpublished study
prepared by Abbott Labs. 56 p.

Lehrer, S. (1985) Evaluation of the Effects of Orally Administered
AMICAL 48 on the Embryonic and Fetal Development of the Rabbit--Segment
II, TFR: Lab Project Number: TE85-054. MRID 42243801 Unpublished study
prepared by Abbott Labs. 64 p. 

Lehrer, S. (1986) Evaluation of the Effects of Orally Administered
Amical 48 on the Embryonic and Fetal Development of the Rat: Segment II,
TFR: Supplement to Study TA85-022: Lab Project Numb- er TE85-230. MRID
42054405.Unpublished 

Lehrer, S.; Bollmeier, A. (1985) Evaluation of the Effects of Orally
Administered AMICAL 48 on the Embryonic and Fetal Development of the
Rabbit--Segment II, TFR: Supplement: Lab Project Number: TE85/054.
Abbott Labs. 179 p. MRID 43246404 Unpublished.

Putman, D.; Curry, P.; Schadly, E. (1994) Chromosome Aberrations in
Chinese Hamster Ovary (CHO) Cells (Amical 48 Preservative): Final
Report: Lab Project Number: TD585/337. MRID 43120601. Unpublished study
prepared by Microbiological Associates, Inc. 30 p.

harmacokinetics and metabolism in Fisher 344 rats. The Dow Chemical
Company, Midland, Michigan. Laboratory report number not reported,
January 18, 2007. MRID 47076601. Unpublished. 

Page   PAGE  23  of 24

	

Page   PAGE  26  of 24