Document ID: EPA-HQ-OPP-2007-0414-0009
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2007-06-13T04:00Z

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, DC 20460

OFFICE OF  PREVENTION, PESTICIDES,  AND TOXIC SUBSTANCES

 

March 5, 2007

MEMORANDUM:

Subject:		Evaluation of Toxicology Database for the Reregistration
Eligibility Decision Document Disciplinary Chapter

To:			K. Avivah Jacob, Chemical Review Manager,

			Regulatory Management Branch II

Antimicrobials Division (7510P)

From: 			Steven M. Malish, Ph.D.

Risk Assessment and Science Support Branch (RASSB)

Antimicrobials Division (7510P)

	And

Tim McMahon, Ph.D.

Antimicrobials Division (7510P)

Thru:			Norm Cook, Branch Chief

Risk Assessment and Science Support Branch (RASSB)

Antimicrobials Division (7510P)

DP Barcode: 		

Chemical Name:	2-n-Octyl-4-isothiazolin-3-one (Octhilinone or OIT)	

		

PC Code:		099901 

CAS Registry No. 	26530-20-1March 5, 2007 

Octhilinone

N-octylisothiazolone

PC Code: 099901

Evaluation of Toxicology Database for the Reregistration Eligibility
Decision Document Disciplinary Chapter

Steven L. Malish, Ph.D.

and

Tim McMahon, Ph.D.

		Table of Contents

            Page 

1.0 	Hazard Characterization
…………………………………………………………      
   3 

													

            1.1 Introduction
………………………………………………………………
……         3

2.0 	Toxicology Data Requirements  (Table 1)
…………………………………………       5

3.0 	Data Gaps
………………………………………………………………
……………      6

4.0 	Hazard Assessment
………………………………………………………………
…       6

            4.1 Acute Toxicity (Table 2, Table 3 See
Appendix)…………………………………      6

	4.2 Subchronic Toxicity (Table 4 See Appendix) 
……………………………………     6

	4.3 Developmental  Toxicity
……………………………………………………      .    
15	

	4.4 Reproductive Toxicity
…………………………………………………………      
 19

	4.5 Chronic Toxicity
………………………………………………………………
        19

	4.6 Carcinogenicity
………………………………………………………………
……   19

	4.7 Mutagenicity
………………………………………………………………
………   20

	4.8 Neurotoxicity
………………………………………………………………
………  21

	4.9 General Metabolism
………………………………………………………………
.  21

5.0 Hazard Endpoint Selection

	

	5.1 See Section 8.1, Summary of  Toxicology Doses and Endpoint
Selection

                  (Table 5 See Appendix)
………………………………………………………………
    21

	5.2 Dermal Absorption
………………………………………………………………
     21

	5.3 Classification of Carcinogenic Potential
………………………………………….    21

6.0 	FQPA Considerations

	6.1 Developmental Toxicity Study Conclusions
………………………………………  22

	6.2 Reproductive Toxicity Study Conclusions
………………………………………… 22

	6.3 Pre and/or Post-Natal Toxicity
…………………………………………………….. 22

		A. Determination of
Susceptibility…………………………………………   .   22

		B. Proposed Hazard based Special FQPA Safety Factor(s)
…………………     22

	6.4 Recommendation for a Developmental Neurotoxicity Endpoint
…………………   22

7.0 	References
………………………………………………………………
……………23

8.0 	Appendixes

8.1 Toxicology Profile Summary 

	8.11  Acute Toxicology Profile (Table 3)
……………………………………  26	8.12 Subchronic, Chronic
and other Toxicology Profile (Table 4) ……………27 	

	

	8.2 Summary of Toxicological Dose and Endpoints (Table 5)  
……………………39 

	

	

	

		

		

		

1.0	HAZARD CHARACTERIZATION

 		1.1 Introduction 

  Octhilinone  is used as an antimicrobial in high exposure scenarios,
such as metal working fluids, sap-stain prevention in wood preservation
etc. The exposure scenarios trigger the full set of toxicology studies
in Tier II. 

  Toxicology studies using the technical grade of Octhilinone (85% - 98%
a.i.),  were presented in this document, as per the Agency’s
guidelines. If studies containing the technical grade were not
available, studies employing the manufacturing use product (app. 50%
a.i.) were cited. 

The data base for the acute toxicity of Octhilinone is considered to be
incomplete. Three of the studies (acute inhalation, acute dermal
irritation and dermal sensitization) were Not-Acceptable. Additional
dermal sensitization studies were waived. The acute oral, acute dermal
and the primary eye study were acceptable. 

Octhilinone was found to be moderately orally toxic (Toxicity Category
III) in an acute oral toxicity study in rats, MRID 70456 [LD50 = 794
mg/kg (M); LD50= 681 mg/kg (F)].  Octhilinone was found to be moderately
toxic (Toxicity Category II) in an acute dermal toxicity study in
rabbits, MRID 70749 [LD50 = 1. 83 gm/kg (combined)] and moderately toxic
(Toxicity Category II) in an acute inhalation toxicity of  Octhilinone
in rats, MRID 70456 [LC50  > 200 mg/kg (nominal concentration,  combined
males and females).  In the primary eye irritation study in rabbits,
MRID 70456, Octhilinone was found to be a corrosive (Toxicity Category
I). In a primary dermal irritation test (MRID 63214), Octhilinone was
also found to be corrosive (Toxicity Category I). The test material was
considered a sensitizer, and subsequent studies were waived.  

The database for the subchronic toxicity of Octhilinone is considered to
be complete.  

For subchronic oral toxicity, the database includes three studies, an
acceptable non-guideline 14-day study in rats (MRID 43935707) and two
unacceptable 90-day oral toxicitiy studies, one in rats (MRID 00136524)
and another in dogs (MRID 00136525).  For subchronic dermal toxicity,
the database includes four studies: an acceptable 14-day dermal toxicity
study in rats (MRID 43935705); an unacceptable 28-day dermal toxicity
study in rabbits (MRID 00136526); and two 90-day dermal toxicity studies
in rats (MRID’s 42007301 and 43935706) that are classified as
acceptable and supplemental, respectively.  For subchronic inhalation
toxicity, the database includes an unacceptable non-guideline 10-day
inhalation toxicity study in rats (MRID 00136527) and an acceptable
90-day inhalation toxicity study in rats (MRID 41544701).

The database for the the developmental toxicity of Octhilinone is
considered to be complete.  

The database includes three developmental toxicity studies in rats and
two in rabbits.  The developmental toxicity studies in rats include two
acceptable studies (MRIDs 41482508 and 43944401) and one unacceptable
study (MRIDs 00046403).  For developmental toxicity in rabbits, the
database includes one acceptable study (MRID 41482509) and one
unacceptable study (MRIDs 00058029 and 00136528). The test material did
not cause a developmental effect at or below the maternally toxic doses
and there was no indication of an increased susceptibility of the
fetus/pups. 

The database for the reproductive toxicity of Octhilinone  is considered
incomplete.  A 2-generational reproductive toxicity study is required
for the non-food high exposure uses  of this chemical  in 1 species.

The database for the chronic toxicity of Octhilinone is considered
incomplete.  Chronic studies in the rat and mouse and required because
of the use of Octhilinone as a metalworking fluid and associated risks.

The database for the carcinogenicity of Octhilinone is considered
incomplete.  Carcinogenicity studies in the rat and mouse and required
because of the use of Octhilinone as a metalworking fluid and associated
risks.  An unacceptable carcinogenicity study in the mouse is available
in the database (TRID 470103024 and MRIDs 00139417, 00139419, and
00139484).  A carcinogenicity study in the rat is also required.

The database for mutagenicity of Octhilinone is considered to be
complete. In the Ames Salmonella test (MRID 43935708), octhilinone was
negative for reverse mutations in the absence or presence of microsomal
S9 in Salmonella strains TA98, TA100, TA102, TA1535, and TA1537.  In a
mammalian cell in culture gene mutation assay, L5178Y mouse lymphoma
cells cultured in vitro (MRID 43935709), the test substance was not
mutagenic in both the activated and non-activated conditions.  In a
mouse bone marrow chromosomal aberration test (MRID 43935710),
octhilinone (was negative in both the activated and non-activated
conditions.  In the unscheduled DNA synthesis assay (MRID 40647505), 
there was no evidence of a genotoxic effect. 

  SEQ CHAPTER \h \r 1 The database for neurotoxicity  studies is
considered incomplete. Neurotoxicity was evidenced by depression in
animals in both the acute oral and the acute dermal toxicity studies.
High dose level animals in the acute oral study showed histopathological
lesions. Neurotoxicity signs, however, were not seen at the more modest
dose levels used in the subchronic and developmental studies. 

The database for general metabolism studies is considered incomplete.
These studies are needed for additional information because of the lack
of carcinogenicity studies in the rat and mouse.2.0	TOXICOLOGY DATA
REQUIREMENTS

  SEQ CHAPTER \h \r 1 The Toxicology Data Requirements for Octhilinone
is listed in Table 1.

Table 1:  Toxicologic Data Requirements for Octhilonone.

Test 

	Technical

	MRID	Acceptable (Y/N)

870.1100	Acute Oral Toxicity (Rat)

 870.1100	Acute Oral Toxicity (Rat)

870.1200	Acute Dermal Toxicity (Rabbit)   

870.1300	Acute Inhalation (Rat) 

870.2400	Primary Eye Irritation (Rabbit)  

870.2500	Primary Dermal Irritation (Rabbit)  

870.2600	Dermal Sensitization (Guinea Pig)    	70456 

70456

70456 

70456 

70456 

63214 

4182505, 4182507 	yes

yes

yes

no

yes

no

no, waived

870.3050     14-Day Oral (Rat)

870.3100	Oral Subchronic (Rat)

870.3150     Oral Subchronic (Dog)

870.3200     14-Day Dermal (Rat)

870.3200      28-Day Dermal (Rabbit)

870.3250     90-Day Dermal (Rat)

870.3250     90-Day Dermal (Rat) 

870.4365     10-Day Inhalation (Rat)

870.3465     90-Day Inhalation (Rat)	43935707 

136524 

136525 

43935705 

136526 

42007301 

43935706 

136527 

41544701 	yes

no

no

yes

no

yes

no

no

yes

870.3700a	Developmental Toxicity (Rat)

870.3700b   Developmental Toxicity (Rabbit)

870.3700a   Developmental Toxicity (Rat)

870.3700a   Developmental Toxicity (Rat)

870.3700b   Developmental Toxicity (Rabbit)	46403 

136528 

41482508 

43944401

41482509 	no

no

yes

yes

yes

870.3800	Reproduction	NA	NA

870.4100a  Chronic Toxicity (Rat)

870.4100a  Chronic Toxicity (Mouse)	NA

NA	NA

NA

870.4200a   Carcinogenicity (Rat)

870.4200b  Carcinogenicity (Mouse)

	NA

470103024 

139484 

139419 

 	NA

no

870.5100	Mutagenicity – Bacterial Reverse Gene Mutation assay

870.5300	Mutagenicity – Forward Gene Mutation test (TK locus) 

870.5395	Mutagenicity – Mouse Erythrocyte Micronucleus test 

870.5550    Mutagenicity – Unscheduled DNA synthesis         	43935708
 

43935709  

43935710 

        40647505     	yes

yes

yes

              yes

 870.6200   Neurotoxicity Screening Battery	NA*	NA

 870.7845   General Metabolism 	NA	NA

* Required

 

3.0	DATA GAPS

Octhilinone data gaps

Acute Toxicity: Acute Inhalation/Rat and Dermal Irritation/Rabbit

Reproduction: 1 species

Chronic Toxicity: 2 species

Carcinogenicity: 2 species

Metabolism and Pharmacokinetics: 1 species

Neurotoxicity Screening Battery: 1 species 

 4.0	HAZARD ASSESSMENT

Acute Toxicity

Adequacy of database for Acute Toxicity:  The database for the acute
toxicity of Octilinone is considered incomplete.  An acceptable
inhalation study in the rat and primary dermal irritation study in the
rabbit are needed.   SEQ CHAPTER \h \r 1  The sensitization study was
considered not acceptable because of the lack of a positive control.
However, the material was a sensitizer; sensitization studies were
waived. See Table 2 below.

		Table 2. Acute Toxicity Data on Octhilinone

Guideline No.	Study Type	MRID	Results	Toxicity Category

870.1100	Acute Oral	00070456	LD50 = 794 mg/kg (M)

LD50= 681 mg/kg (F)	III

870.1200	Acute Dermal	00070456	LD50 = 1.83 gm/kg* (combined)	II

870.1300	Acute Inhalation	00070456	LC50 >200 mg/kg	III

870.2400	Primary Eye Irritation	00070456	Severely Irritating	I

870.2500	Primary Skin Irritation	00063214	Corrosive	I

870.2600	Skin Sensitization	41482505,

41482507, 010809	Sensitizer	…..

*Octhilinone has a density of 1.03 gm/ml. =  LD50 = 1.83 gm/kg

Subchronic Toxicity

Adequacy of database for Subchronic Toxicity:    SEQ CHAPTER \h \r 1 The
database for subchronic toxicity of Octhilinone is considered complete. 

For subchronic oral toxicity, the database includes three studies, an
acceptable non-guideline 14-day study in rats (MRID 43935707) and two
unacceptable 90-day oral toxicitiy studies, one in rats (MRID 00136524)
and another in dogs (MRID 00136525).  For subchronic dermal toxicity,
the database includes four studies: an acceptable 14-day dermal toxicity
study in rats (MRID 43935705); an unacceptable 21-day dermal toxicity
study in rabbits (MRID 00136526); and two 90-day dermal toxicity studies
in rats (MRID’s 42007301 and 43935706) that are classified as
acceptable and supplemental, respectively.  For subchronic inhalation
toxicity, the database includes an unacceptable non-guideline 10-day
inhalation toxicity study in rats (MRID 00136527) and an acceptable
90-day inhalation toxicity study in rats (MRID 41544701).

The subchronic toxicity data are summarized in Table 4 in the Appendix.

Non-Guideline	14-Day Oral Toxicity (Rat)

In a repeated dose oral toxicity study (MRID 43935707),
N-octylisothiazolone (OIT 96%, Batch No. K1217) was administered by
intragastric intubation to eight female Sprague Dawley rats/dose at dose
levels of 0, 10, 60, or 120 mg/kg bw/day for 14 days.  The purpose of
this study was for selection of doses for a developmental toxicity study
in the rat.

Treatment-related gross pathology findings included a prominent lobular
pattern in the liver (≥10 mg/kg/day), and whitish-colored and
thickened fundus of the stomach (≥60 mg/kg/day).  Gastric hemorrhages
of the fundus were also noted in one 120-mg/kg/day rat. Body weight gain
and food consumption were reduced at ≥60 mg/kg/day.  However, body
weight gain was not statistically different from controls due to large
standard deviations, and food consumption was only significantly reduced
at the Day 1-3 treatment interval.   This study had numerous
deficiencies in meeting criteria for a repeat dose  oral toxicity study
in rodents.  However, because the purpose of this study was for dose
selection for a rat developmental toxicity study and not for fulfillment
of a specific guideline, the information contained in this study may be
scientifically useful for examining toxic effects from short-term oral
exposure   Based on the results of this study, doses of 5, 30, or 60
mg/kg/day were suggested for the rat developmental toxicity study.      

The LOAEL for N-octylisothiazolone (OIT) 96% is 10 mg/kg/day, based on
clinical signs of salivation and gross pathology in the liver.  A NOAEL
could not be defined for this study.

This 14-day repeated dose oral toxicity study is classified as
ACCEPTABLE NON- GUIDELINE and does not satisfy the Guideline
requirements (OPPTS 870.3050; OECD 407) for a 28-day oral toxicity study
in rodents.  Although there are major deficiencies in the guideline
requirements, the study is scientifically acceptable for the dose
range-finding purpose for which it was intended.

90-Day Oral Toxicity (Rat)

In a 90-day oral toxicity study (MRID 136524), RH-893 (octhilinone, %
a.i. not reported, lot no. SW 70/0293) was administered to 10 albino
rats/sex/dose in the diet at dose levels of 0, 100, 500, or 2000 ppm
(equivalent to 0, 7.0, 34.6, and 139.9 mg/kg bw/day, respectively).   

There was no effect on survival, feed efficiency, urinalysis, or gross
and microscopic pathology.  Body weight, body weight gain, and feed
consumption were low during the first week of treatment for high-dose
males and females, but were comparable to the respective control groups
for the remainder of the study. The results for hematology, clinical
chemistry, and organ weight were equivocal because of the high
variability, low number (5 rats/sex/treatment group for clinical
chemistry and hematology), inconsistency between the sexes, and lack of
a dose response.  The results, however, suggest a possible decrease in
hemoglobin and RBCs in all female treatment groups, which was
accompanied by an increase in serum carbon dioxide levels.  Similar
results were not observed in the males.  There was a decrease in total
WBC in the high-dose group at 13 weeks for both sexes and at 4 weeks in
females.  There also were some changes in the differential leukocyte
counts with an increase in the percent of segmented neutrophils
accompanied by a decrease in the percent of lymphocytes in all male (4
weeks only) and female (13 weeks only) treatment groups.  All treated
males and females also had increases in absolute and relative thyroid
weight.  

The deficiencies in this study were numerous with several being
sufficiently severe enough to compromise the overall integrity of the
study.  These deficiencies are mainly due to the age of the study,
having been performed prior to the implementation of Good Laboratory
Practices (GLP).  These deficiencies include high variability in the
data (which could be a result of the variability in the initial body
weight or an artifact of the strain); the lack of any analyses on the
dose formulation to indicate that homogeneity, stability, or adequate
concentrations were achieved and maintained throughout the study; an
inadequate number of animals (only 5 animals/sex/treatment) used for
hematology, clinical chemistry, and histopathology examinations; and the
lack of numerous measured parameters (e.g., neurological exams).  The
deficiencies in this study are such that neither a LOAEL nor NOAEL could
be determined.

This 90-day oral toxicity study in the rat is UNACCEPTABLE/NOT
UPGRADABLE and does not satisfy the guideline requirement for a 90-day
oral toxicity study (OPPTS 870.3100; OECD 408) in rodents.    There were
no analyses performed on the dose formulation to determine homogeneity,
stability, or concentration of the test compound.  In addition, only 5
of the 10 rats per sex and dose group were examined for hematology,
clinical chemistry, and histopathology endpoints.

90-Day Oral Toxicity (Dog)

In a 90-day oral toxicity study (MRID 136525), RH-893 (octhilinone, Lot
no. SW70/0293; purity assumed to be 100%) was administered to 4 Beagle
dogs/sex/dose in the diet at dose levels of 0, 100, 500, or 2000 ppm
(equivalent to 0, 3.5, 16.8, and 60.2 mg/kg bw/day, respectively, based
on the assumption that the dose formulation was homogeneous, stable, and
at the correct concentration). 

	

Data were highly variable, even at the initial measurement, making it
difficult to determine treatment-related effects.  The results indicate
the following as possibly related to the administration of RH-893:
reduced body weight gain in 500-ppm males and 2000-ppm males and
females, with reduced food efficiency in these groups; slightly reduced
hematocrit and hemoglobin and increased alkaline phosphatase in the
high-dose groups; decreased total protein in high-dose males and all
females, accompanied by some disruption in the protein electrophoresis;
increased relative liver weight (high-dose males only); increased
relative kidney weight (high-dose females only); and decreased relative
testis weight with an increase in slight to moderate epididymitis in
high-dose males.  The major deficiency in this study was the complete
lack of analyses on the dose formulation.  Because there was high
variability in the results, coupled with very little apparent affects,
this becomes a great deficiency.  The animals had such variability
initially in their body weights and the majority of the other measured
parameters that it cannot be determined if there is an inadequate
homogeneity, stability, or concentration in the dose formulation or if
there were just great variability in the animals.  Given the great
variability, the slight differences between the groups, and the lack of
information on the dose formulations, it cannot be determined what
effects are actually related to the treatment.  Although it is possible
that higher doses may have yielded more definitive results, this would
again largely depend on the homogeneity, stability, and accuracy of the
dose formulations.  The deficiencies in this study are so great that
neither a LOAEL nor NOAEL can be assigned.

This 90-day oral toxicity study in the dog is UNACCEPTABLE/NOT
UPGRADABLE and does not satisfy the guideline requirement for a 90-day
oral toxicity study (OPPTS 870.3150; OECD 409).  This study is
unacceptable because homogeneity, stability, and concentration of the
dose formulations were not measured.  Additionally, the animals were not
randomized and were possibly of different ages or older than 9 months
prior to dosing.  These and other numerous deficiencies discussed in
this review make the study not upgradable.

Non-Guideline	14-Day Dermal Toxicity (Rat)

In a 14-day dermal toxicity study (MRID 43935705), N-octylisothiazolone
(OIT) 96% was applied to the shaved skin of 5 Sprague Dawley
rats/sex/dose at dose levels of 0, 10, 100, or 1000 mg/kg bw/day for 6
hours/day during a 14-day period.

There were no treatment-related effects in mortality, clinical signs,
and food consumption.  Dermal irritation was observed at ≥100
mg/kg/day in both males and females at Weeks 1 and 2.  Slight to
moderate erythema, edema, atonia, and desquamation were observed in
100-mg/kg/day treated rats.  The severity of dermal irritation increased
to moderate to severe in the 1000-mg/kg/day treated rats.  Some 1000
mg/kg/day females also exhibited slight to moderate fissures at Week 1
(1/5) and Week 2 (3/5).  In addition to these observations, scabbing was
observed at ≥100 mg/kg/day at Weeks 1 and 2, and scabbing with
exfoliation was observed at 1000 mg/kg/day in males and females at Week
2.  There were no statistically-significant findings for body weight and
body weight gain data.  Body weight gain, however, was reduced in 1000
mg/kg/day males and females at Week 2 and in overall weight gain.  The
lowered weight gain was greater in males than in females.  Food
consumption data did not provide an explanation for the reductions
observed in body weight gain.  There were no statistically-significant
effects in mean food consumption in treated rats throughout the study. 
Macroscopic findings reported at necropsy were generally insignificant. 
A dermal-related finding of subcutaneous redness in the neck and
indurated skin in the treated area was observed in one 1000 mg/kg/day
male.

The lowest-observable-adverse-effect level (LOAEL) for
N-octylisothiazolone (OIT) 96% is 100 mg/kg/day based on dermal
irritation in both males and females.  A NOAEL of 10 mg/kg/day is
established based on no effects observed at this dose.

This 14-day subacute dermal toxicity study is ACCEPTABLE-NONGUIDELINE. 
Although    a number of deficiencies were noted for meeting the
guideline requirements for a 28-day dermal toxicity study (OPPTS
870.3200; OECD 410), the study is acceptable as a range-finding study. 

21-Day Dermal Toxicity (Rabbit)

In a 21-day dermal toxicity study (MRID 136526), RH-893-50% (purity
assumed to be 100.0% a.i. by study authors; however, the test
article’s name is RH-893-50%, lot and/or batch # not provided) was
applied to the shaved skin of 10 New Zealand White albino
rabbits/sex/dose at dose levels of 1 or 10%, 6 hours/day for 5 days/week
during a 21-day period at a dose volume of 1.0 mL/kg body weight/day;
sub-groups of 5/sex/dose were abraded or the skin was left intact.  The
vehicle controls 5/sex/dose were treated with 1% Tween 80/distilled
water solution, sub-groups were 3 males with abraded skin and 2 males
with intact shaved skin 2 females with abraded skin and 3 females with
intact shaved skin.  Dose volume for vehicle treated animals was 2.0
mL/kg body weight/day for the first 4 days of treatment, propylene
glycol for the fifth day and 1.0 mL/kg body weight/day of 1% Tween
80/distilled water solution for the rest of the study duration. 
Undiluted compound at a dosing volume of 0.25 mL/kg body weight/day was
applied for the first four days of Week 1; these animals were then given
a 10% dilution of RH-893-50% in a 1% Tween 80/distilled water solution
for the rest of the study duration.  The control and 1% animals’
vehicle was 1% Tween 80/distilled water solution except on the fifth day
of treatment when propylene glycol was applied to the rabbits; all
subsequent doses were in the 1% Tween 80/distilled water solution
vehicle.  

There were no treatment-related effects on mortality, appearance, and
behavior.  The 10% treatment effected dermal clinical findings, body
weight, body weight gain, hematological parameters (leukocytes,
segmented neutrophils, and lymphocytes) and histological findings of the
skin (acanthosis, hyperkeratosis, dermatitis, pseudoepithelial
hyperplasia, pustular epidermitis [males], ulcerations, folliculitis
[males]) with the abraded animals displaying a slightly more severe skin
lesions but with the small number of intact skin animals examined at
necropsy comparisons were difficult.  The 1% animals, displayed clinical
signs of dermal effects, decreases in body weight gains (males with a
greater effect noticed in males with abraded skin), and histological
findings of the skin (acanthosis, leukocyte infiltration,
hyperkeratosis, dermatitis, and pustular epidermitis) with the abraded
animals displaying a slightly more severe skin lesions but with the
small number of intact skin animals examined at necropsy comparisons
were difficult.   

In addition, a 10% dose-male, had severe hepatic necrosis and
inflammation and suppurative hepatitis; these changes cannot be fully
attributed to dosage due to the low number of control animals for
comparison but cannot be ruled at as incidental.    

The LOAEL is 1% based on dermal irritation (clinical findings and
microscopic findings) in both males and females.  A NOAEL cannot be
determined.

The systemic LOAEL is 10% in females (body weight gain) and 1% in males
(body weight gain).  A NOAEL is 1% in females and cannot be determined
in males.

This 21-day dermal toxicity study in the New Zealand White albino
rabbits is UNACCEPTABLE -NONGUIDELINE  and does not satisfy the
guideline requirement for a 21/28-day dermal toxicity study (OPPTS
870.3200; OECD 410) in rodents.  The experimental design of this study
appears to be one of range-finding, where dose volumes, vehicles, and
area of application were altered during the course of the study.   
Determining if a change was treatment related was difficult due to low
sample size, variability of the blood chemistry and hematology data, and
variation in experimental design during the study.    Several
hematological parameters, clinical chemistry, and several organs were
not examined.  These and other numerous deficiencies discussed in III.C
make the study not upgradable.

90-Day Dermal Toxicity (Rat)

In a dermal subchronic toxicity study (MRID 42007301), doses of 1 mL/kg
of RH-893 HQ Technical (99.1% a.i.) were applied to the shaved skin of
ten young adult Cr1:CDBR CD rats/sex/dose at dose levels of 0, 2.97,
5.95, or 14.87 mg/kg/day for 6 hours/day for 5 days/week for 13 weeks.

Skin irritation occurred in all treatment groups in a dose-related
manner.  The LOAEL for dermal irritation is 2.97 mg/kg/day and a NOAEL
could not be established.

No mortality or treatment-related signs of clinical toxicity were
observed during the study.  Treatment-related microscopic changes
observed in the treated area of the skin of male and female rats in
Groups 3, 4, and 5 and in male rats in Group 2 (vehicle control) include
hyperkeratosis, acanthosis, foci of necrosis, and eschar formations in
the epidermis and chronic inflammation and sebaceous gland hyperplasia
in the dermis.  No statistically significant effects on food consumption
or food efficiency were observed in Groups 2, 3, or 4 of either sec.  In
Group 5 males, food consumption and decreased body weights were
observed.  No changes in absolute organ weights or organ/body weight
ratios for males or females were considered to be treatment-related. 
The only treatment –related changes in hematology parameters observed
in the high-dose females, a slight but statistically-significant
decrease in red blood cell count, hematocrit, and hemoglobin were
observed; the biological significance of this effect is questioned
because of the low magnitude of the effect and because the effect was
only observed in females.  Likewise, statistically-significant
treatment-related changes in clinical chemistry patterns were observed
in the high dose animals, including decreases in albumin, glucose, and
total protein in females and an increase in alkaline phosphatase and a
decrease in triglycerides in males; the biological significance of these
effects is also questioned because of the low magnitude of the effects
and because they were not observed in both sexes.

The systemic NOAEL for this study is 5.95 mg/kg/day and the LOAEL is
14.87 mg/kg/day, based on decreases in HGB, HCT, RBC, albumin, glucose,
and total protein in females and a decrease in body weight and body
weight gain in males.

This dermal subchronic toxicity study is classified as Acceptable
because it satisfies the requirements for a repeated dose dermal
toxicity study (§82-3).  Minor deficiencies noted in the study report
include:  the test site was not occluded after dose administration, and
data for the differential leukocyte counts were not provided.

870.3250		90-Day Dermal Toxicity (Rat)

 scores ≤1) erythema, edema, and atonia; no lesions were observed. No
dermal irritation was observed in the 5 mg/kg treatment group during the
study.  Body weights of rats in the 5 and 25 mg/kg treatment groups were
similar to the controls.  For all treatment groups, food consumption was
similar to the controls. There were no treatment-related differences in
ophthalmology, hematology parameters, clinical blood chemistry, urine
chemistry and appearance, organ weights, or macroscopic or microscopic
organ morphology (with the exception of treated skin in the high dose
rats) between rats in the treated and the control groups.  No neoplastic
tissue was observed.  However, the investigator failed to
microscopically examine samples of tissue from the treatment sites in
the mid- and low-dose groups.  Damage to the treatment sites was not
assessed.  Therefore, the NOEL/LOEL cannot be determined.

This dermal subchronic toxicity study is classified
unacceptable/upgradable  and does not satisfy the guideline requirement
for a repeated dose dermal toxicity study (§82-3). The study may be
upgraded once microscopic examination of the treatment sites in the
lower dose groups is conducted.

Non-Guideline	10-Day Inhalation (Rat)

In a 10-day inhalation toxicity   study (MRID136527), RH-893-50%
(octhilinone, Lot and Batch no. not provided; purity assumed to be 50%),
was administered to 10 Sprague-Dawley albino rat/sex/dose, in an aerosol
under dynamic conditions at nominal concentrations of  0, 1%,  or 10%
with a target chamber concentrations of 2.0 mg/L for 1 hour per day, for
a total of 10 days. The vehicle was propylene glycol; the control
animals received the vehicle control as an aerosol.  All exposures were
whole body exposures.  After 10 days of exposure, 5 rats/sex/dose were
sacrificed in the 1% and 10% exposure groups and necropsied on Day 12. 
The rest of the surviving animals were sacrificed and necropsied on Day
26, after a 14th day recovery period.  

Animals in the 10% exposure group were found dead or sacrificed due to
moribundity 9/10 males and 7/10 females died as early as Day 3. 
Clinical signs of toxicity related to treatment were nose shuffling (1%
and 10%), dried red material around the eyes (10%), gasping (10%),
lacrimation (10%), red nasal exudate (10%), and coughing (10%);
preening, hypoactivity, wet hair, excessive water consumption, and
wheezing were exhibited in control and treated animals. Data were highly
variable, making it difficult to determine treatment-related effects.
Weight loss was observed in the 10%-RH-893-50% males and females;
however, only 1 male rat and 3 female rats survived to Day 8 so the body
weights on Days 8, 12, and 26 could not be statistically compared to
controls.  By the end of the recovery period the 10%-RH-893-50% group
had gained weight; however, the surviving 10%-treated male displayed a
weight gain of 69% of control, the 1% males a weight gain of 26% of
control, 10%-treated female displayed a weight gain of 86% of control;
the 1% females a weight gain of 91% of control. Blood was only taken on
Day 26 from the surviving animals and not on Day 12, after exposure
termination, it is difficult to determine treatment-related effects. 
Analysis of hematological data demonstrated a decrease in total white
blood cells (10% males and females; 1% females), an increase in
segmented neutrophils (1 and 10% males and females), and a decrease in
lymphocytes (10% males and females; 1% males), which may indicate an
irritation response.  However, without data from Day 12 this is
speculation. A significant decrease in glucose was observed in the
high-dose male.  Clinical pathology data does not correlate to this
change; therefore, it could be an incidental change.  Without data from
Day 12 when the treatment was terminated it is impossible to make a
conclusion as to the relevance of this finding.  An increase in
aspartate aminotransferase levels was observed in the 10% animals;
however due to data variability and the fact that only 1 male and 3
females remained after treatment, these values were not
statistically-significant.  These changes may have corresponded with
gross pathology findings of mottled liver; however, without clinical
chemistry data from Day 12 when the treatment was terminated it is
impossible to make a conclusion as to the relevance of this finding. 
Because there was high variability in the results, 

coupled with very little data from the day treatment was terminated,
this becomes a great deficiency.

Microscopic treatment related effects were limited to the respiratory
tract and included mild to moderate bronchiolitis in multiple 10%
RH-893-50% rats.  Additionally, four male rats from the 1%-RH-893-50%
group exhibited severe lung lesions, which were consistent with chronic
murine pneumonia that may have been exacerbated by inhalation treatment.
   

Based on the data in this study, neither a NOAEL or LOAEL can be
determined.  Analytical concentrations of test material in the breathing
zone of the rats were not determined.  Thus actual dose to the animals
cannot be determined. 

 

This 10-day inhalation toxicity   study in rats is UNACCEPTABLE/ NOT
UPGRADABLE   and does not satisfy the guideline requirement for a
subchronic inhalation study OPPTS 870.3465; OECD 413 in the rats. This
study is unacceptable because only two dose groups were used with 10
rats/sex/dose and satellite groups of 5 rats/sex/dose were kept for a
14-day recovery period. The animals were only exposed for 1 hour/day for
5 days a week for a total of 10 exposures where the guideline states
exposure for 6 hours/day, 5 days a week.     Homogeneity, stability, and
concentration of the dose formulations were not measured; test article
concentrations and analytical determination of the test article in the
exposure chamber were not provided.  Several toxicity testing parameters
were not measured.  These and other numerous deficiencies discussed in
section III.C make the study not upgradable.

870.3465		90-day inhalation (Rat)

In a subchronic aerosol inhalation (nose-only) toxicity study (MRID
41544701), eleven Crl:CD®BR rats/sex/exposure group were exposed by
inhalation (6 hours/day, 5 days/week) for 13 weeks to aerosolized
Skane® M-8 HQ Microbicide (octhilinone, a.i. 42%, Lot No. SW 85-0311)
at exposure concentrations of 0 (ambient air), 0 (propylene glycol, 123
mg/m3), 0.05, 0.64, and 6.39 mg of octhilinone/m3.  An additional eleven
rats/sex/exposure group were assigned to a forteen-week recovery period.

The mean mass diameter (MMD) and geometric mean (GM) were 2.5 µm and
9.2, respectively, for the propylene glycol exposure group and were 1.4
µm and 5.5, respectively, for all exposure groups of octhilinone. 
Three deaths occurred during the study but were not considered related
to the exposures.  No clinical signs were observed in the 0, 0 (PG),
0.05, and 0.64 mg/m3 groups.  Clinical signs in the 6.39 mg/m3 exposure
group included:  rales [males and females 5-22/22; weeks 1-13]; dyspnea
[females: 3/22: week 4; 3-9/22: weeks 7-10]; thriftless [(males: 3/22:
weeks 8 and 10) and (females: 9-22/22: weeks 7-10)]; and red staining of
the dropping sheet [(males: 11/22: week 2) and (females: 6/22: week 8)].
 There were statistically significant decreases (p < 0.05) in body
weights (3.3 to 8.8% for weeks 1, 7, and 13) and body weight gains (11.3
to 68.9% or weeks 1, 7, and 13) in male and female rats in the 6.39
mg/m3 group.  No clinical chemistry and organ weight changes and deaths
were related to the exposures.  There were no gross pathological
findings in exposed males and females.  Histopathological findings in
the male and/or females from the 6.39 mg/m3 group consisted of secretory
cell hyperplasia, squamous metaplasia, inflammation, and eosinophilic
droplets in the nasal cavity at the 13-week sacrifice.

During the recovery period, rales were present in the males and females
from the 6.39 mg/m3 group.

Based upon the clinical signs, the decreased body weights, fluid in the
uterus, and the pulmonary histopathological findings at the terminal
sacrifice for males and females in the 6.39 mg/m3 group, the LOAEL for
13-week inhalation exposure is 6.39 mg/m3.  The NOAEL is 0.64 mg/m3.

The study is classified as Acceptable, satisfying the requirements for a
subchronic inhalation toxicity study in the rats (§82-4).

4.3	Developmental Toxicity

Adequacy of database for Prenatal Developmental Toxicity:    SEQ CHAPTER
\h \r 1 The database for developmental toxicity of Octhilinone is
considered complete. The developmental toxicity data are summarized in
Table 4 in the Appendix.

The database includes three developmental toxicity studies in rats and
two in rabbits.  The developmental toxicity studies in rats include two
acceptable studies (MRIDs 41482508 and 43944401) and one unacceptable
study (MRIDs 00046403).  For developmental toxicity in rabbits, the
database includes one acceptable study (MRID 41482509) and one
unacceptable study (MRIDs 00058029 and 00136528).

The  prenatal developmental toxicity data are summarized below in Table
4 in the Appendix.

870.3700a	Prenatal Developmental Toxicity (Gavage) Study – Rat

	

Skane™ M-8 HQ (43% a.i., lot SW 86 6155) was administered to 25
Crl:CD® BR rats/dose by gavage at dose levels of 0, 1, 5, or 30 mg
active ingredient/kg bw/day from days 6 through 15 of gestation. 
Because Skane™ M-8 HQ contains about 50% propylene glycol; an
additional control group comprised of 25 rats was administered propylene
glycol at 30 mg/kg/day, a volume equal to that of the highest does
group.

Maternal toxicity was observed at 30 mg/kg/day.  Signs of toxicity at 30
mg/kg/day include: one death; salivation and decreased defecation;
decreased body weight and body weight gain; decreased corrected body
weight and body weight gain; and decreased food consumption.  The
investigator also concluded that there was a slight, treatment-related
increase in resorptions/dam and post-implantation loss at 30 mg/kg/day. 
Upon further inspection, however, the values appear comparable to
control values, as well as other treatment groups.  Additionally, these
changes did not reach statistical significance.  Although the
investigator concluded that maternal toxicity also was observed at 5
mg/kg/day, this determination does not seem reasonable.  Changes in body
weight, corrected body weight and body weight gain, and food consumption
observed at the mid-dose and deemed treatment-related by the
investigator were slight, and the values were not statistically
different in comparison to the control values.  The values actually
appear to be comparable to control values, especially when standard
deviations are taken into consideration.  The findings at the mid-dose
do not warrant being called a treatment-related effect.  Consequently,
the maternal LOAEL is 30 mg/kg bw/day, based on death, salivation and
decreased defecation, decreased body weight and body weight gain,
decreased corrected body weight and body weight gain, and decreased food
consumption.  The maternal NOAEL is 5 mg/kg bw/day.

Developmental toxicity was not observed at any dose level.  The
investigator concluded that developmental toxicity was observed at 30
mg/kg/day due to an increased percentage of litters and fetuses with any
type of malformation (external, visceral, or skeletal).  Malformations
occurred in only three fetuses from three litters at 30 mg/kg bw/day in
comparison to one control fetus from one control litter.  The difference
was not statistically significant, and the apparently high percentage
values (1.2% of fetuses and 17.6% of litters at 30 mg/kg/day; 0.4% of
fetuses and 5.3% of litters in the control; and 0.3% of fetuses and 4.3%
of litters in the historical control) are most likely an artifact of the
very small number of fetuses and litters available for evaluation.  In
addition, the malformations observed are known to occur spontaneously in
this strain of rats as demonstrated by the historical data. 
Consequently, the developmental NOAEL is 30 mg/kg bw/day.

This developmental toxicity study is classified ACCEPTABLE-GUIDELINE and
satisfies the guideline requirement for a developmental toxicity study
(OPPTS 870.3700; OECD 414) in rats. 

870.3700a	Prenatal Developmental Toxicity (Gavage) Study – Rat

 In a developmental toxicity study (MRID 43944401), N-octylisothiazolone
(octhilinone, 94% ai, Lot# K1217) was administered to 25 female Sprague
Dawley rats/dose in corn oil by gavage at dose levels, of 0, 5, 30, or
60 mg/kg/day from days 6 through 15 of gestation.

Maternal toxicity was demonstrated by reduced mean body weight gains on
days 6-9 of gestation (14%, compared to controls).  No other
treatment-related effects in mortality, clinical signs of toxicity, body
weight, food consumption, or cesarean parameters were noted at any dose
level.  The maternal LOEL is 60 mg/kg/day, based on reduced body weight
gains.  The maternal NOEL is 30 mg/kg/day. 

There were no treatment-related effects noted in the developmental
parameters.  A developmental LOEL was not observed.  The developmental
NOEL is 60 mg/kg/day.

This developmental toxicity study is classified ACCEPTABLE-GUIDELINE and
satisfies the guideline requirement for a developmental toxicity study
(OPPTS 870.3700; OECD 414) in rats. 

870.3700a	Prenatal Developmental Toxicity (Gavage) Study – Rat

In a developmental toxicity study (MRID 00046403), RH-893 (octhilinone,
lot no. SW 70/0293; purity assumed to be 100% active ingredient) was
administered to up to 18 female Charles River Caesarean-derived
rats/dose in the diet at dose levels of 0, 200, or 1000 ppm from days
6-15 of gestation.  All dams were sacrificed at gestation day (gd) 19.

There was no maternal toxicity observed at any dose level.  It should be
noted, however, that there may be treatment-related changes in maternal
body weight.  Mean maternal body weight values show a slight decrease in
body weight at the high dose that is difficult to interpret due to the
lack of individual data, standard deviations, and statistical analysis,
as well as the low number of animals.  The maternal NOAEL is 1000 ppm.

There were no developmental effects attributed to oral exposure to
RH-893 in the diet; therefore, the developmental NOAEL is 1000 ppm. 

This developmental toxicity study in the rat is UNACCEPTABLE/NOT
UPGRADABLE and does not satisfy the guideline requirement for a
developmental toxicity study (OPPTS 870.3700; OECD 414) in rats. 
Several major study reporting deficiencies including a lack of animal
data would not allow this study to be upgraded.

870.3700b	Prenatal Developmental Toxicity (Gavage) Study – Rabbit

In a developmental toxicity study (MRID 41482509), Skane™ M-8 HQ
Industrial Mildewcide (46.3% a.i., lot SW86-6155) was administered to 19
New Zealand White rabbits via gavage at dose levels of 0, 5, 20, or 80
mg active ingredient/kg bw/day from days 7 through 19 of gestation. 
Because Skane™ M-8 HQ Industrial Mildewcide contains about 50%
propylene glycol, an additional control group of 19 rabbits was
administered propylene glycol at 92.8 mg/kg/day, a volume equal to that
of the highest does group.

	

Maternal toxicity was observed at 80 mg/kg/day and included clinical
signs of toxicity (anorexia and scant, soft, or no feces), decreased
body weight and body weight gains, and increased number of abortions. 
The maternal LOAEL is 80 mg/kg bw/day, based on clinical signs of
toxicity, decreased body weight and body weight gains, and increased
number of abortions.  The maternal NOAEL is 20 mg/kg bw/day.

There was a significant treatment-related decrease in male fetal body
weight and total (male and female) fetal body weight at 80 mg/kg/day. 
There were no other treatment-related signs of developmental toxicity. 
The developmental LOAEL is 80 mg/kg bw/day, based on decreased male
fetal body weight and total (male and female) fetal body weight.  The
developmental NOAEL is 20 mg/kg bw/day. 

The developmental toxicity study in the rabbit is classified Acceptable
(Guideline) and satisfies the guideline requirement for a developmental
toxicity study (OPPTS 870.3700; OECD 414) in rabbits.  

870.3700b	Prenatal Developmental Toxicity (Gavage) Study – Rabbit

In a developmental toxicity study (MRIDs 00058029 and 00136528), RH-893
(100% a.i., lot SW 70/0293) was administered to 15 New Zealand White
rabbits/dose by gavage at dose levels of 0, 6, or 60 mg/kg bw/day.  Of
the 15 rabbits/group, 8/group were designated for Caesarean section and
7/group were designated for normal hutching. Doses were administered on
gestation days (gd) 6 through 18 (for females designated for Caesarean
section) or gd 6 through 16 (for females designated for normal
hutching).  Treatment was terminated two days earlier in dams designated
for normal hutching due to high mortality.  

The test material was toxic at both dose levels and resulted in high
maternal mortality rates.  Death occurred in 6 low-dose dams (3
designated for Caesarean section and 3 designated for normal hutching)
and 10 high-dose dams (6 designated for Caesarean section and 4
designated for normal hutching).  Changes in body weight and food
consumption appear treatment-related with those animals dying prior to
scheduled sacrifice exhibiting body weight losses and decreased food
consumption.  Animals that died prior to study termination also showed
gross pathology findings, with the predominate findings being dark, red
lungs or chest cavity anomalies.  There were no apparent
treatment-related changes in the number of implantation sites compared
to the number corpora lutea.  Additionally, there were no apparent
treatment-related changes in the number and placement of implantation
and resorption sites or in the number of live and dead fetuses/pups. 
The lack of a treatment-related response could be the result of too few
animals available for comparison.  Additional data are needed to fully
assess these endpoints.  The maternal LOAEL is 6 mg/kg/day based on
mortality, body weight loss, decreased food consumption, and gross
pathology findings. A Maternal NOAEL was not achieved.

There were no apparent developmental effects.  Fetal and pup body weight
and length in treated groups appeared to be comparable with the control
groups.  Skeletal changes occurred more frequently in high-dose fetuses;
however, these effects predominately occurred in one litter where one
out of five fetuses died.  There were only two high-dose litters to
examine.  Therefore, it is difficult to draw any meaningful conclusions
from these data.  A developmental NOAEL/ LOAEL could not be determined.

This developmental toxicity study is classified UNACCEPTABLE/NOT
UPGRADABLE and does not satisfy the guideline requirement for a
developmental toxicity study (OPPTS 870.3700; OECD 414) due to major
study deficiencies.  These include an inadequate number of dams per
group, high maternal mortality and abortion, and a lack of individual
animal data.  

4.4	Reproductive Toxicity

Adequacy of database for Reproductive:    SEQ CHAPTER \h \r 1 The
database for reproductive toxicity of Octhilinone  is considered
incomplete.  

A 2-generational reproductive toxicity study is required for the high
exposure non-food uses of this chemical.

Chronic Toxicity

Adequacy of database for Chronic Toxicity:   SEQ CHAPTER \h \r 1 The
database for chronic toxicity of Octhilinone is considered incomplete. 

Chronic studies in the rat and mouse are required because of the use of
Octhilinone as a metalworking fluid and the associated risks.

Carcinogenicity

Adequacy of database for Carcinogenicity:  The database for
carcinogenicity of Octhilinone is considered incomplete. The
carcinogenicity data are summarized in Table 4 in the Appendix.

Carcinogenicity studies in the rat and mouse are required because of the
use of Octhilinone as a metalworking fluid and the associated risks.  An
unacceptable carcinogenicity study in the mouse is available in the
database (TRID 470103024 and MRIDs 00139417, 00139419, and 00139484). A
carcinogenicity study in the rat is also required.

Carcinogenicity (Oral) – Mouse

In a carcinogenicity study (TRID 470103024 and MRIDs 00139417, 00139419,
and 00139484), RH-893 (octhilinone, purity not stated, Lot No. and Batch
No. not provided) was administered to 125 (C 57BL/6 x C3H/anf) F1
mice/sex/dose in diet at dose levels of 0, 500, or 1000 ppm (equivalent
mg/kg bw/day could not be determined because analytical measurement of
the feed were not performed and food consumption was not measured) for
78 weeks. Twenty-five mice/sex/dose were sacrificed at 6 months for
histopathologic examination.  Positive control mice were utilized to
compare two known carcinogens to the test article; 100 (C 57BL/6 x
C3H/anf) F1 mice/sex were fed diets containing 600 ppm
2-acetamidofluorene (AAF), 50 (C 57BL/6 x C3H/anf) F1 mice/sex/dose
received 4 mg/kg/day diethylnitrosamine (DEN), and 25 (C 57BL/6 x
C3H/anf) F1 mice/sex/dose received 6 mg/kg/day in the drinking water.  

There was no RH-893 treatment effect on mortality, but both positive
controls (i.e., DEN and AAF) caused an increase in mortality.  No
clinical findings were attributed to chronic feeding of octhilinone. 
High-dose RH-893 mice generally had reduced body weights in the
beginning of the study compared to the negative control group; however,
by Week 3 in males and Week 10 in females the high-dose RH-893 treated
mice had comparable or greater body weight and body weight gain than the
control group.  Body weight was depressed in the positive controls. 
There were no treatment-related effects on liver weight or microscopic
pathology in RH-893 treated mice.

Positive controls did exhibit an increase in lesions.  The DEN animals
were found with an increased incidence of carcinoma of the hepatocytes
in 6-mg/kg/day males and females at weeks 26 and 30; the 4-mg/kg/day
animals were not examined histopathologically.  The DEN 6-mg/kg/day
males and females were found with bronchitis or bronchiectasis.  The AAF
mice had increased incidence of hyperplasia of the bladder in the males,
urinary bladder carcinoma in both sexes and hepatocellular carcinomas in
both sexes.

Under the conditions of this 18-month feeding carcinogenicity study,
there was no apparent carcinogenic potential demonstrated for RH-893 in
either male or female (C 57BL/6 x C3H/anf) F1 mice exposed to 500 or
1000 ppm.  However, a number of study deficiencies precluded selection
of a LOAEL or NOAEL for this study.  

At the doses tested, there was no treatment-related increase in tumor
incidence when compared to controls; however, only 48 animals at the
high dose were examined histologically.  Therefore,   any carcinogenic
response would be potentially under-reported.  Dosing was not adequate
for this study, based on a lack of toxicity at the highest dose.  Even
considering the data from the preliminary 7-week study used to determine
appropriate doses for the carcinogenicity study, a dose of 1500 ppm or
one between 1000 and 1500 ppm may  have been a more appropriate high
dose for this 18-month carcinogenicity study.  In the preliminary 7-week
study a single male administered 1500 ppm died, which is why this dose
was neglected.    

This carcinogenicity study in mice is UNACCEPTABLE/NOT UPGRADABLE and
does not satisfy guideline requirement for a carcinogenicity study
[OPPTS 870.4200; OECD 451] in rodents.  There are several deficiencies,
but the lack an adequate top dose, lack of analysis of the dose
formulation,   and lack of microscopic examination of only half of the
high-dose RH-893 mice made this carcinogenicity study unacceptable and
not upgradeable.

Mutagenicity

Adequacy of database for Mutagenicity:  The database for carcinogenicity
of Octhilinone is considered complete. The mutagenicity data is
summarized below in Table 4 in the Appendix.

  SEQ CHAPTER \h \r 1 Octhilinone has been tested in the Ames Salmonella
assay (870.5100),  the mouse bone marrow chromosome aberration test
(870.5385), in an in-vitro mouse lymphoma cells (870.5300) and in an
in-vitro unscheduled DNA Synthesis assay (870. 5550). 

In the Ames Salmonella test (MRID 43935708), Octhilinone was negative
for reverse mutations in the absence or presence of microsomal S9 in
Salmonella strains TA98, TA100, TA102, TA1535, and TA1537.  In a mouse
bone marrow chromosomal aberration test (MRID 43935710), octhilinone
(96% a.i.) was negative. In a mammalian cell in culture gene mutation
assay, L5178Y mouse lymphoma cells cultured in vitro (MRID 43935709),
the test substance (96% a.i.) was not mutagenic in both the activated
and non-activated conditions. The unscheduled DNA Synthesis assay was
negative.

4.8	Neurotoxicity

Adequacy of database for the neurotoxicity of Octhilinone: The database
for the neurotoxicity of Octhilinone is considered incomplete.  

A neurotoxicity screening battery is needed in at least 1 species. The
study is needed because 

depression was seen >24 hours post dose at the lower dose levels in both
the acute oral and the acute dermal toxicity studies. Moreover, in the
high dose level oral toxicity study, at necropsy, poor differentiation
was seen between the cortex and medulla with the cut surfaces appearing
very dark red. 

	4.9	General Metabolism 

  SEQ CHAPTER \h \r 1   SEQ CHAPTER \h \r 1 A General Metabolism study
in rats (870.7485) is needed to help assess and add to the data base
because of the lack of carcinogenicity studies in two species. 

Dermal Absorption studies (870.7600) were done in both the rat and
rabbit and can be found in the subchronic toxicity section (4.2). 

5.0 	Hazard Endpoint Selection

	5.1	See Section 8.1, Summary of Toxicology Doses and Endpoint Selection

		Table 5.

 

Dermal Absorption 

		Dermal Absorption Factor:    SEQ CHAPTER \h \r 1 Since a dermal
endpoint was selected from a dermal 			toxicity study, a dermal
absorption factor is not needed for Octhilinone.

Classification of Carcinogenic Potential

	

	No carcinogenicity studies were done, the carcinogenicity potential,
therefore, 		cannot 	be assessed. 

FQPA Considerations

	

	FQPA is not a consideration since this substance is not used in food.

  SEQ CHAPTER \h \r 1  

Developmental Toxicity Study Conclusions

There is no evidence that the test material is a teratogen in either the
rat or the rabbit.

	6.2	Reproductive Toxicity Study Conclusions

	Reproductive studies were not performed and, therefore, no conclusions
can be drawn.

	6.3	Pre-and/or Postnatal Toxicity

	A. Determination of Susceptibility:   SEQ CHAPTER \h \r 1  Although, no
neurotoxicity signs were seen in 	any of the other studies, a
Neurotoxicity Screening Battery is needed in at least 	1 species. The
study is needed because depression was seen >24 hours post 	dose at the
lower dose levels in both the acute oral and the acute dermal 	toxicity
studies. Moreover, in the high dose level oral toxicity study, at
necropsy, 	poor differentiation was seen between the cortex and medulla
with the cut 	surfaces appearing very dark red. 

		B.  Proposed Hazard-based Special FQPA Safety Factor:   SEQ CHAPTER \h
\r 1   SEQ CHAPTER \h \r 1  Not a food use and 			no FQPA Safety factor
is needed. 

 

6.4	Recommendation for a Developmental Neurotoxicity Study

Not recommended because of the lack of a developmental toxicity
potential.

8.0	REFERENCES

70456 (MRID) Powers, M.B. (1970) Final Report [for Octhininone]: Acute
Oral - Rats; Acute Dermal - Rabbits; Acute Eye Irritation - Rabbits;
Acute Inhalation Exposure - Rats: Projects No. 417-306, No. 417-307, No.
417-308, and No. 417-310 and 417-310. (Unpublished study, received April
4, 1978 under 707-143 prepared by TRW, Inc. submitted by Rohm & Haas
Co., Philadelphia, Pa; CDL:233428-B). 

63214 (MRID) Powers, M.B. (1970) Final Report [for Octhininone]: Acute
Oral - Rats; Draize Eye Irritation - Rabbits; Primary Skin Irritation -
Rabbits; Skin Sensitization - Guinea Pigs; Acute Inhalation Exposure -
Rats: Projects No. 417-323, No. 417-324, No. 417-325, and No. 417-326,
417-327. (Unpublished study, received Jul 18, 1978 under 707-127;
prepared by Hazleton Laboratories, Inc., Philadelphia, Pa.; CDL:
234400-C). 

41482505 (MRID) Murphy, M. Chen, P. (1983) RH-893-A Study of the
Concentrated Dependent  Delayed Contact Hypersensitivity study in Guinea
Pigs; Lab Project Number: 83R-143. Unpublished study prepared by Rohm
and Haas Co. 48 p. 

41482507 (MRID) Bonin, R; Murphy, M. (1983) RH-893 Process Variation  A
Study of the Concentrated-Dependent  Delayed Contact Hypersensitivity
study in Guinea Pigs; Lab Project Number: 83R-025. Unpublished study
prepared by Rohm and Haas Co. 36 p. 

010890 (Tox ID No.): Copley, M. (1994) Octhilinone, Waiver Request for a
Dermal of Sensitization Study; Unpublished study prepared by the U.S.
EPA, ID 099901-000707, Apr. 8, 1994.

43935707 (MRID) Fuchs, A. (1995) N-Octylisothiazolone (OIT) 96%: 14-Day
Oral (Gavage) Dose Range-Finding Study in the Female Rat: Final Report:
Lab Project Number: 1248-1154-050: 1154-050. Unpublished study prepared
by Hazleton Deutschland GmbH. 108 p.

00136524 (MRID) Powers, M.; Kundzin, M.; Ferrell, J. (1970) Three-month
Dietary Ad- ministration-Rats: RH-893 (Technical): Project No. 417-320.
Final report (Unpublished study received Feb 9, 1971 under 707- 100;
prepared by Hazleton Laboratories, Inc., submitted by Rohm & Haas Co.,
Philadelphia, PA; CDL:004372-H).

00136525 (MRID) Powers, M.; Ferrell, J. (1970) Three-month Dietary
Administration- Dogs: RH-893 (Technical): Project No. 417-334. Final
report (Unpublished study received Feb 9, 1971 under 707-100; prepared
by Hazleton Laboratories, Inc., submitted by Rohm & Haas Co.,
Philadelphia, PA; CDL:004372-I).

43935705 (MRID) Zuehlke, U. (1995) N-Octylisothiazolone (OIT) 96%:
14-Day Dermal Subacute Toxicity Study in the Rat: Final Report: Lab
Project Number: 1247-1154-052: 1154-052. Unpublished study prepared by
Hazleton Deutschland GmbH. 145 p.

00136526 (MRID) Powers, M.; Kwapien, R. (1970) Three-week Dermal
Application-Rabbits: RH-893-50%: Project No. 417-321. Final report
(Unpublished study received Feb 9, 1971 under 707-100; prepared by
Hazleton Laboratories, Inc., submitted by Rohm & Haas Co., Philadelphia,
PA; CDL:004372-J).

42007301 (MRID) Bernacki, H.; Hamilton, J. (1991) RH-893 HQ Technical:
Three-Month Dermal Toxicity Study in Rats: Lab Project Number: 90P-031:
90R- 031. Unpublished study prepared by Rohm and Haas Co. 374 p.

43935706 (MRID) Zuehlke, U. (1995) N-Octylisothiazolone (OIT) 94 +/- 3%
90-Day Dermal Subchronic Toxicity Study in the Rat: Final Report: Lab
Project Number: 1282-1154-051: 1154-051. Unpublished study prepared by
Corning Hazleton GmbH. 403 p.

00136527 (MRID) Hiddemen, J.; Ferrell, J. (1971) Subacute Inhalation
Study-Rats: RH-893-50%: Project No. 417-345. Final report (Unpublished
study received Feb 9, 1971 under 707-100; prepared by Hazleton
Laboratories, Inc., submitted by Rohm & Haas Co., Philadelphia, PA;
CDL:004372-K).

41544701 (MRID) Hagan, J.; Kulwich, B.; Fisher, J. (1989) Skane M-8 HQ
Microbicide: Thirteen-Week Inhalation Toxicity Study in Rats: Protocol
No. 86P-196: Report No. 87R-013: Lab Project Number: 87R-013: 86P- 196.
Unpublished study prepared by Rohm and Haas Co. 521 p.

41482508 (MRID) Powers, M. (1970) Teratology Study: Rabbits: RH-893
(Technical): Project No. 417-346. Final report (Unpublished study
received Feb 9, 1971 under 707-100; prepared by Hazleton Laboratories,
Inc., submitted by Rohm & Haas Co., Philadelphia, PA; CDL: 004372-L).

43944401 (MRID) Fuchs, A. (1995) N-Octylisothiazolone (OIT) 94+/-3%:
Oral (Gavage) Teratogenicity Study in the Rat: Final Report: Lab Project
Number: 1272-1154-049: 1154-049. Unpublished study prepared by Hazleton
Europe GmbH. 189 p.

00046403 (MRID) Powers, M.B. (1971) Final Report: Teratology Study-Rats:
Project No. 417-349. (Unpublished study received May 25, 1971 under
unknown admin. no.; prepared by Hazleton Laboratories, submitted by Rohm
& Haas Co., Philadelphia, Pa.; CDL:107967-A).

41482509 (MRID) Solomon, H.; Lutz, M. (1987) Skane M-8 HQ Industrial
Mildewcide: Oral (Gavage) Developmental Toxicity Study in Rabbits: Lab
Project Number: 87R-019: 86P-504. Unpublished study prepared by Rohm and
Haas Co. 178 p.

00136528 (MRID) Powers, M. (1970) Teratology Study: Rabbits: RH-893
(Technical): Project No. 417-346. Final report (Unpublished study
received Feb 9, 1971 under 707-100; prepared by Hazleton Laboratories,
Inc., submitted by Rohm & Haas Co., Philadelphia, PA; CDL: 004372-L).

00058029 (MRID) Powers, M.B. (1970) Final Report: Teratology
Study-Rabbits: Project No. 417-346. (Unpublished study received Feb 3,
1977 under 984-67; prepared by Hazleton Laboratories, Inc., submitted by
Whitmoyer Laboratories, Inc., Myerstown, Pa.; CDL:229345-A).

00139417 (MRID) Piccirillo, V.J.; Smith, J.M.; Larson, P.S.; et al.
(1975) Eighteen Month Study on the Carcinogenic Potential of RH-893 in
Mice. (Unpublished study received Jun 4, 1975 under 5F1632; prepared by
Medical College of Virginia, Health Sciences Center, Dept. of
Pharmacology and Medical Univ. of South Carolina, Dept. of Pathology,
submitted by Rohm & Haas Co., Philadelphia, Pa.; CDL: 094944-B).

00139419 (MRID) Hennigar, G.R.; Larson, P.S. (1974) Eighteen-Month Study
in Which RH-893 Is Being Added to the Diet of Mice: Monthly Reports.
(Unpublished study received Jun 4, 1975 under 5F1632; prepared by
Medical Univ. of South Carolina, Dept. of Pathology and Medical College
of Virginia, Health Sciences Center, Dept. of Pharmacology, submitted by
Rohm & Haas Co., Philadelphia, Pa.; CDL: 094944-D).

00139484 (MRID) Piccirillo, V.J.; Smith, J.M. (1975) Eighteen Month
Study on the Carcinogenic Potential of RH-893 in Mice. (Unpublished
study received Feb 3, 1977 under 984-67; prepared by Medical College of
Virginia, Toxicology Research Dept., submitted by Whitmoyer
Laboratories, Inc., Myerstown, Pa.; CDL:229346-A).

43935708 (MRID) Ballantyne, M. (1995) N-Octylisothiazolone (OIT) 94 +/-
3%: Reverse Mutation in 5 Histidine-Requiring Strains of Salmonella
typhimurium: Final Report: Lab Project Number: 1154/53. Unpublished
study prepared by Hazleton Europe Ltd. 49 p.

43935709 (MRID) Clements, J. (1995) N-Octylisothiazolone (OIT) 94 +/-
3%: Mutation at the Thymidine Kinase (TK) Locus of Mouse Lymphoma L5178Y
Cells Using the Microtitre Fluctuation Technique: Final Report: Lab
Project Number: 1154/54. Unpublished study prepared by Corning Hazleton
(Europe). 44 p.

43935710 (MRID) Riley, S. (1995) N-Octylisothiazolone (OIT) 94 +/- 3%:
Induction of Micronuclei in the Bone Marrow of Treated Mice: Final
Report: Lab Project Number: 1154/55. Unpublished study prepared by
Corning Hazleton (Europe). 36 p.

40647505 (MRID) Muller, G. (1986) Skane M-8 HQ Microbiocide in vitro
Unscheduled DNA Synthesis Assay: Report 86R-0018. Unpublished study
prepared by Rohm and Haas Co. 29 p.

9.0 	Appendices

	9.1 Acute Toxicology Profile

Table 3.  Acute Toxicity Profile for Octhilinone

Guideline No./ 

Study Type/ Test Substance (% a.i.)	MRID No. /

Classification/ Doses	Results

870.1100 (§81-1)	

Acute Oral Toxicity (gavage) – Rat

Technical (85 - 95% a.i.)	MRID 00070456 

Rats (5/sex/dose)

0, 100, 215, 464, 1000, or 2150 mg/kg 	Toxicity Category III

LD50 = 794 mg/kg (males)

        = 681 mg/kg (females)

Toxic effects included depression (3 highest doses), labored
respiration, red crust around nose, diarrhea, and unkempt fur. At the
high dose level, poor differentiation between cortex and medulla with
the cut surfaces very dark red. White pinpoint markings on the outer
surface. 

870.1200	

Acute Dermal Toxicity – Rabbit

Technical material l(85 - 95% a.i.)	MRID 00070456

Rabbits (4/sex/dose)

Single 24-hours dermal applications made to clipped intact and abraded
skin at doses of 0, 0.316, 1.0, 3.16, 10, or 10 mL/kg 

Acceptable - Guideline	Toxicity Category II

LD50 = 1.83 gm/kg *

Dermal: Toxic effects included greenish colored areas, blanching, slight
to severe erythema, slight to severe edema, necrotic areas and
coriaceous areas.

Systemic: Depression was seen at  the two lower doses  from 24 hours
thru  day 4 to 6.

Acute Inhalation Toxicity – Mouse

Technical material (95% a.i.)	MRID 00070456

Total body exposure to  a nominal concentration 200 mg/L of 0.5%
solution for 1 hour

10 mice/ sex/ group 

Not Acceptable/Not guideline	Toxicity Category III

LC50 > 200 mg/L (nominal concentration)

There were no deaths.  Increased activity was the only clinical sign
exhibited by the rats exposed to the aerosol.

Not Acceptable/Not guideline because of the 1 hour duration of the
study.

870.2400	

Primary eye irritation – Rabbit

Technical material l(95% a.i.)	MRID 00070456

6 rabbits, 0.1 mL of undiluted test material applied to conjunctival sac
of left eye; eye was held closed for 1 second following application;
eyes were not rinsed

Acceptable - Guideline	Toxicity Category I (Corrosive)

Moderate to severe corneal opacity, iritis, chemosis, discharge marked
conjunctival redness or blanching.

870.2500 

Primary Skin irritation – Rabbit

(50% a.i.)	MRID 00063214

24 hour  Contact

Not Acceptable/Not guideline	Toxicity Category I (Corrosive)

Study not acceptable, because of the 24 hour duration of exposure 

Not Acceptable/Not guideline because of the 14 hour duration of
exposure. 

870.2600

Dermal Sensitization – Guinea Pig

	MRID 41482505, 41482507 

Not Acceptable/Not guideline	Sensitizer

 Not Acceptable/Not guideline because of the lack of a positive control.
Waiver was subsequently granted. 

*Octhilinone has a density of 1.03 gm/ml.  The acute dermal LD50 was
cited in ml/kg (1.78 mg/kg) in the MRID.

	9.1	Subchronic, Chronic and Other Toxicity Profiles Table (Table 4)

Table 4.  Subchronic, Chronic and Other Toxicity Profiles for
Octhilinone

Guideline Number/

Study Type/

Test Substance (% a.i.)	MRID Number Classification/ Doses	Results

Non-Guideline

14-day intragastric intubation - Rat

Purity 96% a.i.

Batch K1217	MRID 43935707

Acceptable -Nonguideline

Octhilinone administered orally at 0, 100, 500 and 2000 ppm (equivalent
to 0, 7.0, 34.6, or 139.9 mg/kg/day)

Rats (10/sex/dose)	Clinical observations and gross pathology findings
indicated dose-related signs of toxicity in all treatment groups. 
Observations of salivation and abnormal position increased in incidence
and frequency of occurrence with increasing dose level.  Piloerection,
soft feces, and excessive urination were also noted in the 120-mg/kg/day
animals.  Treatment-related gross pathology findings included a
prominent lobular pattern in the liver (≥10 mg/kg/day), and
whitish-colored and thickened fundus of the stomach (≥60 mg/kg/day). 
Gastric hemorrhages of the fundus were also noted in one 120-mg/kg/day
rat. Body weight gain and food consumption were reduced at ≥60
mg/kg/day.  However, body weight gain was not statistically different
from controls due to large standard deviations, and food consumption was
only significantly reduced at the Day 1-3 treatment interval.   This
study had numerous deficiencies in meeting criteria for a repeat dose 
oral toxicity study in rodents.  However, because the purpose of this
study was for dose selection for a rat developmental toxicity study and
not for fulfillment of a specific guideline, the information contained
in this study may be scientifically useful for examining toxic effects
from short-term oral exposure   Based on the results of this study,
doses of 5, 30, or 60 mg/kg/day were suggested for the rat developmental
toxicity study.      

The LOAEL for N-octylisothiazolone (OIT) 96% is 10 mg/kg/day, based on
clinical signs of salivation and gross pathology in the liver.  A NOAEL
could not be defined for this study.

This 14-day repeated dose oral toxicity study is classified as
ACCEPTABLE NONGUIDELINE and does not satisfy the Guideline requirements
(OPPTS 870.3050; OECD 407) for a 28-day oral toxicity study in rodents. 
Although there are major deficiencies in the guideline requirements, the
study is scientifically acceptable for the dose range-finding purpose
for which it was intended.  

870.3100 

90-day oral - Rat

Purity not reported

Lot SW 70/0293	MRID 00136524

Unacceptable – Not upgradeable

Octhilinone administered orally at 0, 100, 500 and 2000 ppm (equivalent
to 0, 7.0, 34.6, or 139.9 mg/kg/day)

Rats (10/sex/dose)	Subchronic Toxicity:

NOAEL, LOAEL not determined.

There was no effect on survival, feed efficiency, urinalysis, or gross
and microscopic pathology.  Body weight, body weight gain, and feed
consumption were low during the first week of treatment for high-dose
males and females, but were comparable to the respective control groups
for the remainder of the study. The results for hematology, clinical
chemistry, and organ weight were equivocal because of the high
variability, low number (5 rats/sex/treatment group for clinical
chemistry and hematology), inconsistency between the sexes, and lack of
a dose response.  The results, however, suggest a possible decrease in
hemoglobin and RBCs in all female treatment groups, which was
accompanied by an increase in serum carbon dioxide levels.  Similar
results were not observed in the males.  There was a decrease in total
WBC in the high-dose group at 13 weeks for both sexes and at 4 weeks in
females.  There also were some changes in the differential leukocyte
counts with an increase in the percent of segmented neutrophils
accompanied by a decrease in the percent of lymphocytes in all male (4
weeks only) and female (13 weeks only) treatment groups.  All treated
males and females also had increases in absolute and relative thyroid
weight.  

The deficiencies in this study were numerous with several being
sufficiently severe enough to compromise the overall integrity of the
study.  These deficiencies are mainly due to the age of the study,
having been performed prior to the implementation of Good Laboratory
Practices (GLP).  These deficiencies include high variability in the
data (which could be a result of the variability in the initial body
weight or an artifact of the strain); the lack of any analyses on the
dose formulation to indicate that homogeneity, stability, or adequate
concentrations were achieved and maintained throughout the study; an
inadequate number of animals (only 5 animals/sex/treatment) used for
hematology, clinical chemistry, and histopathology examinations; and the
lack of numerous measured parameters (e.g., neurological exams).  The
deficiencies in this study are such that neither a LOAEL nor NOAEL could
be determined.

This 90-day oral toxicity study in the rat is UNACCEPTABLE/NOT
UPGRADABLE and does not satisfy the guideline requirement for a 90-day
oral toxicity study (OPPTS 870.3100; OECD 408) in rodents.    There were
no analyses performed on the dose formulation to determine homogeneity,
stability, or concentration of the test compound.  In addition, only 5
of the 10 rats per sex and dose group were examined for hematology,
clinical chemistry, and histopathology endpoints.

870.3150 

90-day oral - Dog

Purity 100%

Lot SW 70/0293	MRID 00136525

Unacceptable – Not Upgradeable

Dogs (4/sex/dose)

0, 100, 500 or 2000 ppm	Subchronic Toxicity:

NOAEL, LOAEL not established.

Data were highly variable, even at the initial measurement, making it
difficult to determine treatment-related effects.  The results indicate
the following as possibly related to the administration of RH-893:
reduced body weight gain in 500-ppm males and 2000-ppm males and
females, with reduced food efficiency in these groups; slightly reduced
hematocrit and hemoglobin and increased alkaline phosphatase in the
high-dose groups; decreased total protein in high-dose males and all
females, accompanied by some disruption in the protein electrophoresis;
increased relative liver weight (high-dose males only); increased
relative kidney weight (high-dose females only); and decreased relative
testis weight with an increase in slight to moderate epididymitis in
high-dose males.  The major deficiency in this study was the complete
lack of analyses on the dose formulation.  Because there was high
variability in the results, coupled with very little apparent affects,
this becomes a great deficiency.  The animals had such variability
initially in their body weights and the majority of the other measured
parameters that it cannot be determined if there is an inadequate
homogeneity, stability, or concentration in the dose formulation or if
there were just great variability in the animals.  Given the great
variability, the slight differences between the groups, and the lack of
information on the dose formulations, it cannot be determined what
effects are actually related to the treatment.  Although it is possible
that higher doses may have yielded more definitive results, this would
again largely depend on the homogeneity, stability, and accuracy of the
dose formulations.  The deficiencies in this study are so great that
neither a LOAEL nor NOAEL can be assigned.

This 90-day oral toxicity study in the dog is UNACCEPTABLE/NOT
UPGRADEABLE and does not satisfy the guideline requirement for a 90-day
oral toxicity study (OPPTS 870.3150; OECD 409).  This study is
unacceptable because homogeneity, stability, and concentration of the
dose formulations were not measured.  Additionally, the animals were not
randomized and were possibly of different ages or older than 9 months
prior to dosing.  These and other numerous deficiencies discussed in
this review make the study not Upgradeable.

14-day dermal - Rat

Purity 96%

Batch K 1217	MRID 43935705

Acceptable – Non-Guideline

5 rats/sex/dose

0, 10, 100, 1000 mg/kg/day for 14 days	Dermal Irritation

NOAEL = 10 mg/kg/day

LOAEL = 100 mg/kg/day,
base⁤湯搠牥慭⁬物楲慴楴湯椠⁮潢桴洠污獥愠摮映浥
污獥മ

ition to these observations, scabbing was observed at ≥ 100 mg/kg/day
at Weeks 1 and 2, and scabbing with exfoliation was observed at 1000
mg/kg/day in males and females at Week 2.  There were no
statistically-significant findings for body weight and body weight gain
data.  Body weight gain, however, was reduced in 1000 mg/kg/day males
and females at Week 2 and in overall weight gain.  The lowered weight
gain was greater in males than in females.  Food consumption data did
not provide an explanation for the reductions observed in body weight
gain.  There were no statistically-significant effects in mean food
consumption in treated rats throughout the study.  Macroscopic findings
reported at necropsy were generally insignificant.  A dermal-related
finding of subcutaneous redness in the neck and indurated skin in the
treated area was observed in one 1000 mg/kg/day male.

The 14-day subacute dermal toxicity study is ACCEPTABLE –
NONGUIDELINE.  Although a number of deficiencies were noted for meeting
the guideline requirements for a 28-day dermal toxicity study (OPPTS
870.3200; OECD 410), the study is acceptable as a range-finding study.

870.3200 

21-day dermal - Rabbit

Purity 50%	MRID 00136526

Unacceptable – Not upgradeable

Rabbits (10sex/dose)

0, 1% or 10%, for 6 hours/day, 5 days/week, for 3 weeks.  Half of the
animals were abraded, half intact.

Vehicle control:  1% Tween 80/distilled water solution	Dermal
irritation:

NOAEL not established.

LOAEL = 1% based on dermal irritation (clinical findings and microscopic
findings) in both males and females.

Systemic Toxicity:

NOAEL not determined (males).

NOAEL = 1% (females).

LOAEL = 1% (males) based on body weight gain.

LOAEL = 10% (females) based on body weight gain.

There were no treatment-related effects on mortality, appearance, and
behavior.  The 10% treatment affected dermal clinical findings, body
weight, body weight gain, hematological parameters (leukocytes,
segmented neutrophils, and lymphocytes) and histological findings of the
skin (acanthosis, hyperkeratosis, dermatitis, pseudoepithelial
hyperplasia, pustular epidermitis [males], ulcerations, folliculitis
[males]) with the abraded animals displaying a slightly more severe skin
lesions but with the small number of intact skin animals examined at
necropsy comparisons were difficult.  The 1% animals, displayed clinical
signs of dermal effects, decreases in body weight gains (males with a
greater effect noticed in males with abraded skin), and histological
findings of the skin (acanthosis, leukocyte infiltration,
hyperkeratosis, dermatitis, and pustular epidermitis) with the abraded
animals displaying a slightly more severe skin lesions but with the
small number of intact skin animals examined at necropsy comparisons
were difficult.   

In addition, a 10% dose-male, had severe hepatic necrosis and
inflammation and suppurative hepatitis; these changes cannot be fully
attributed to dosage due to the low number of control animals for
comparison but cannot be ruled at as incidental.    

This 21-day dermal toxicity study in the New Zealand White albino
rabbits is UNACCETABLE/NOT UPGRADABLE and does not satisfy the guideline
requirement for a 21/28-day dermal toxicity study (OPPTS 870.3200; OECD
410) in rodents.  The experimental design of this study appears to be
one of range-finding, where dose volumes, vehicles, and area of
application were altered during the course of the study.    Determining
if a change was treatment related was difficult due to low sample size, 
variability of the blood chemistry and hematology data, and variation in
experimental design during the study.    Several hematological
parameters, clinical chemistry, and several organs were not examined. 
These and other numerous deficiencies discussed in III.C make the study
not upgradable.

870.3250 

90-day dermal - Rat

Purity 99.1%	MRID 42007301

Acceptable - Guideline

Rats (10/sex/dose)

0, 2.97, 5.95 and 14.87 mg/kg/day (0, 0.3%, 0.6% and 1.5%), 5 days/week
for 13 weeks

	Dermal Toxicity:

NOAEL: <2.97 (0.3%) mg/kg/day

LOAEL: =2.97 (0.3%) mg/kg/day, based on skin irritation: hyperkeratosis,
acanthosis, foci of necrosis, eschar formation, sebacious gland
hyperplasia and chronic inflammation

Systetmic Toxicity:

NOAEL: 5.95 (0.6%) mg/kg/day

LOAEL: 14.87 (1.5%) mg/kg/day, based on decreases in HGB, HCT, RBC,
albumin, glucose and total protein in females and a decrease in body
weight gain in males)

870.3250 

90-day dermal - Rat

Purity 99.1%	MRID 43935706

Supplemental

Rats (10/sex/dose)

0, 5, 25 or 125 mg/kg/day for 6 hours/day for 90 days

	NOAEL not established.

LOAEL not established.

Male and female rats in the 125 mg/kg treatment groups exhibited slight
to moderate (mean score <=2.1 on a scale of 0 to 3) erythema, edema,
atonia, desquamation, and fissures, and lesions described as squamous
cell hyperplasia, sebaceous cell hyperplasia, folliculitis, dermatitis,
and hemorrhages at the site of treatment.  Body weight gains of male
rats in the 125 mg/kg treatment group were 21% less than rats in the
control group after 90 days of treatment; the depressed weights were
first noted at 22 days.  The body weight and body weight gains of female
rats in the 125 mg/kg treatment group were unaffected.  Male and female
rats in the 25 mg/kg treatment groups were found to have minimal (mean
scores <=1) erythema, edema, and atonia; no lesions were observed. No
dermal irritation was observed in the 5 mg/kg treatment group during the
study.  Body weights of rats in the 5 and 25 mg/kg treatment groups were
similar to the controls.  For all treatment groups, food consumption was
similar to the controls.  There were no treatment-related differences in
ophthalmology, hematology parameters, clinical blood chemistry, urine
chemistry and appearance, organ weights, or macroscopic or microscopic
organ morphology (with the exception of treated skin in the high dose
rats) between rats in the treated and the control groups.  No neoplastic
tissue was observed.  However, the investigator failed to
microscopically examine samples of tissue from the treatment sites was
not assessed.

Therefore, the NOAEL/LOAEL can not be determined.

Non-Guideline

10-day inhalation - Rat

Purity 50%	MRID 00136527

Unacceptable – Not upgradeable

Whole-body inhalation exposure to 2 mg/L of  0, 1% or 10% solution, 1
hour per day, for 10 days

5 rats from each treatment group were sacrificed and necropsied at Day
12; rest of animals sacrificed and necropsied Day 26.

10 Rats/sex/exposure

Vehicle:  propylene glycol

Purity: 50%	NOAEL and LOAEL could not be determined.

Animals in the 10% exposure group were found dead or sacrificed due to
moribundity 9/10 males and 7/10 females died as early as Day 3. 
Clinical signs of toxicity related to treatment were nose shuffling (1%
and 10%), dried red material around the eyes (10%), gasping (10%),
lacrimation (10%), red nasal exudate (10%), and coughing (10%);
preening, hypoactivity, wet hair, excessive water consumption, and
wheezing were exhibited in control and treated animals. Data were highly
variable, making it difficult to determine treatment-related effects.
Weight loss was observed in the 10%-RH-893-50% males and females;
however, only 1 male rat and 3 female rats survived to Day 8 so the body
weights on Days 8, 12, and 26 could not be statistically compared to
controls.  By the end of the recovery period the 10%-RH-893-50% group
had gained weight; however, the surviving 10%-treated male displayed a
weight gain of 69% of control, the 1% males a weight gain of 26% of
control, 10%-treated female displayed a weight gain of 86% of control;
the 1% females a weight gain of 91% of control. Blood was only taken on
Day 26 from the surviving animals and not on Day 12, after exposure
termination, it is difficult to determine treatment-related effects. 
Analysis of hematological data demonstrated a decrease in total white
blood cells (10% males and females; 1% females), an increase in
segmented neutrophils (1 and 10% males and females), and a decrease in
lymphocytes (10% males and females; 1% males), which may indicate an
irritation response.  However, without data from Day 12 this is
speculation. A significant decrease in glucose was observed in the
high-dose male.  Clinical pathology data does not correlate to this
change; therefore, it could be an incidental change.  Without data from
Day 12 when the treatment was terminated it is impossible to make a
conclusion as to the relevance of this finding.  An increase in
aspartate aminotransferase levels was observed in the 10% animals;
however due to data variability and the fact that only 1 male and 3
females remained after treatment, these values were not
statistically-significant.  These changes may have corresponded with
gross pathology findings of mottled liver; however, without clinical
chemistry data from Day 12 when the treatment was terminated it is
impossible to make a conclusion as to the relevance of this finding. 
Because there was high variability in the results, coupled with very
little data from the day treatment was terminated, this becomes a great
deficiency.

Microscopic treatment related effects were limited to the respiratory
tract and included mild to moderate bronchiolitis in multiple 10%
RH-893-50% rats.  Additionally, four male rats from the 1%-RH-893-50%
group exhibited severe lung lesions, which were consistent with chronic
murine pneumonia that may have been exacerbated by inhalation treatment.
   

This 10-day inhalation toxicity   study in rats is UNACCEPTABLE/ NOT
UPGRADEABLE   and does not satisfy the guideline requirement for a
subchronic inhalation study OPPTS 870.3465; OECD 413 in the rats. This
study is unacceptable because only two dose groups were used with 10
rats/sex/dose and satellite groups of 5 rats/sex/dose were kept for a
14-day recovery period. The animals were only exposed for 1 hour/day for
5 days a week for a total of 10 exposures where the guideline states
exposure for 6 hours/day, 5 days a week.     Homogeneity, stability, and
concentration of the dose formulations were not measured; test article
concentrations and analytical determination of the test article in the
exposure chamber were not provided.  Several toxicity testing parameters
were not measured.  These and other numerous deficiencies discussed in
section III.C make the study not Upgradeable.

870. 3465 

90-day inhalation - Rat

Purity 42%	MRID 41544701

Acceptable -Guideline

11 Rats/sex/exposure

 0.05, 0.64 and 6.39 mg/m3	NOAEL: 0.64 mg/m3 

LOAEL: 6.39 mg/m3, based on decreased body weights, fluid in the uterus,
 and the pulmonary histopathological findings at the terminal sacrifice
for males and females in the 6.39 mg/m3 group.

Clinical signs in the 6.39 mg/m3 exposure group included: rales [males
and females: 5-22/22: weeks 1-13];

dyspnea [females: 3/22: wee 4; 3-9/22, weeks 7-10]

thriftless [(males: 3/22: week 8 and 10) (females: 9-22/22; weeks 7-10)]

Red staining of the drop sheet [(males: 11/22: week 2) and (females:
6/22: week 8)].

There were significantly decreases in body weights (3.3 to 8.8% for
weeks 1, 7, and 13) and body weight gains (11.3 to 68.9% for weeks1, 7,
and 13) in male and female rats in the 6.39 mg/m3 group.

870.3700

Developmental (gavage) - Rat

Purity 43%

	MRID 41482508

Acceptable - Guideline

Female rats (25/dose)

0, 1, 5 or 30 mg/kg administered orally, gestation days 6-15, inclusive.
Maternal Toxicity:

NOAEL = 5 mg/kg/day

LOAEL = 30 mg/kg/day, based on death, salivation and decreased
defecation, decreased body weight and body weight gain, decreased
corrected body weight and body weight gain, and decreased food
consumption.

Developmental Toxicity:

NOAEL = 30 mg/kg/day (highest dose tested)

LOAEL not established.

Maternal toxicity was observed at 30 mg/kg/day.  Signs of toxicity at 30
mg/kg/day include: one death; salivation and decreased defecation;
decreased body weight and body weight gain; decreased corrected body
weight and body weight gain; and decreased food consumption.  The
investigator also concluded that there was a slight, treatment-related
increase in resorptions/dam and post-implantation loss at 30 mg/kg/day. 
Upon further inspection, however, the values appear comparable to
control values, as well as other treatment groups.  Additionally, these
changes did not reach statistical significance.  Although the
investigator concluded that maternal toxicity also was observed at 5
mg/kg/day, this determination does not seem reasonable.  Changes in body
weight, corrected body weight and body weight gain, and food consumption
observed at the mid-dose and deemed treatment-related by the
investigator were slight, and the values were not statistically
different in comparison to the control values.  The values actually
appear to be comparable to control values, especially when standard
deviations are taken into consideration.  The findings at the mid-dose
do not warrant being called a treatment-related effect.  

Developmental toxicity was not observed at any dose level.  The
investigator concluded that developmental toxicity was observed at 30
mg/kg/day due to an increased percentage of litters and fetuses with any
type of malformation (external, visceral, or skeletal).  Malformations
occurred in only three fetuses from three litters at 30 mg/kg bw/day in
comparison to one control fetus from one control litter.  The difference
was not statistically significant, and the apparently high percentage
values (1.2% of fetuses and 17.6% of litters at 30 mg/kg/day; 0.4% of
fetuses and 5.3% of litters in the control; and 0.3% of fetuses and 4.3%
of litters in the historical control) are most likely an artifact of the
very small number of fetuses and litters available for evaluation.  In
addition, the malformations observed are known to occur spontaneously in
this strain of rats as demonstrated by the historical data.  

870.3700a 

Developmental (gavage) - Rat

Purity 94 ± 3%	MRID 43944401

Acceptable – Guideline

Female Rats (25/dose)

0, 5, 30, or 60 mg/kg administered orally, gestation days 6-15,
inclusive.	Maternal Toxicity:

NOAEL = 30 mg/kg/day

LOAEL = 60 mg/kg/day, based on reduced body weight gains

Developmental Toxicity

NOAEL >= 60 mg/kg/day, highest dose tested.

LOAEL not established.

Maternal toxicity was demonstrated by reduced mean body weight gains on
days 6-9 of gestation (14%, compared to controls).  No other
treatment-related effects in mortality, clinical signs of toxicity, body
weigh, food consumption, or cesarean parameters were noted at any dose
level.

870.3700

Developmental (gavage) - Rat

Purity 96%

	MRID 00046403

Unacceptable – Not upgradeable

Females rats (18/dose)

0, 200 or 1000 ppm administered orally, gestation days 6-15, inclusive.

	Maternal Toxicity:

NOAEL = 1000 ppm (highest dose tested)

LOAEL - not established.

Developmental Toxicity:

NOAEL = 1000 ppm (highest dose tested)

LOAEL - not established.

There was no maternal toxicity observed at any dose level.  It should be
noted, however, that there may be treatment-related changes in maternal
body weight.  Mean maternal body weight values show a slight decrease in
body weight at the high dose that is difficult to interpret due to the
lack of individual data, standard deviations, and statistical analysis,
as well as the low number of animals.  The maternal NOAEL is 1000 ppm.

There were no developmental effects attributed to oral exposure to
RH-893 in the diet; therefore, the developmental NOAEL is 1000 ppm. 

This developmental toxicity study in the rat is UNACCEPTABLE/NOT
UPGRADEABLE and does not satisfy the guideline requirement for a
developmental toxicity study (OPPTS 870.3700; OECD 414) in rats. 
Several major study reporting deficiencies including a lack of animal
data would not allow this study to be upgraded.

870.3700

Developmental (gavage) - Rat

Purity 96%	MRID 43935707

Acceptable – Non-Guideline

Female Rats (8/dose)

0, 10, 60, or 120 mg/kg administered orally, for 14 days.	Short-term
toxicity:

NOAEL - not established.

LOAEL = 10 mg/kg/day, based on clinical signs of salivation and gross
pathology in the liver.

Treatment-related gross pathology findings included a prominent lobular
pattern in the liver (≥10 mg/kg/day), and whitish-colored and
thickened fundus of the stomach (≥60 mg/kg/day).  Gastric hemorrhages
of the fundus were also noted in one 120-mg/kg/day rat. Body weight gain
and food consumption were reduced at ≥60 mg/kg/day.  However, body
weight gain was not statistically different from controls due to large
standard deviations, and food consumption was only significantly reduced
at the Day 1-3 treatment interval.   This study had numerous
deficiencies in meeting criteria for a repeat dose oral toxicity study
in rodents.  However, because the purpose of this study was for dose
selection for a rat developmental toxicity study and not for fulfillment
of a specific guideline, the information contained in this study may be
scientifically useful for examining toxic effects from short-term oral
exposure   Based on the results of this study, doses of 5, 30, or 60
mg/kg/day were suggested for the rat developmental toxicity study.      

870.3700

Developmental (gavage) - Rabbit

Purity 46.3%	MRID 41482509

Acceptable - Guideline

Female rabbits (19/dose)

0, 5, 20 or 80 mg/kg administered orally, gestation days 7-19,
inclusive.

	Maternal Toxicity:

NOAEL = 20 mg/kg/day

LOAEL = 80 mg/kg/day, based on clinical signs of toxicity, decreased
body weight and body weight gains, and increased number of abortions.

Developmental Toxicity:

NOAEL = 20 mg/kg/day

LOAEL = 80 mg/kg/day, based on decreased male fetal body weight and
total (male and female) fetal body weight.

Maternal toxicity was observed at 80 mg/kg/day and included clinical
signs of toxicity (anorexia and scant, soft, or no feces), decreased
body weight and body weight gains, and increased number of abortions.

There was a significant treatment-related decrease in male fetal body
weight and total (male and female) fetal body weight at 80 mg/kg/day. 
There were no other treatment-related signs of developmental toxicity. 

870.3700

Developmental (gavage) - Rabbit

Purity 96%

Lot SW 70/0293	MRIDs 00136528 and 00058029

Unacceptable – Not upgradeable

Females rabbits (15/dose)

0, 6 or 60 mg/kg administered orally, gestation days 6-18, inclusive.
Maternal toxicity:

NOAEL-  not established

LOAEL = 6 mg/kg/day based on mortality, body weight loss, decreased food
consumption, and gross pathology findings.

Developmental toxicity:

NOAEL and LOAEL not determined.

The test material was toxic at both dose levels and resulted in high
maternal mortality rates.  Death occurred in 6 low-dose dams (3
designated for Caesarean section and 3 designated for normal hutching)
and 10 high-dose dams (6 designated for Caesarean section and 4
designated for normal hutching).  Changes in body weight and food
consumption appear treatment-related with those animals dying prior to
scheduled sacrifice exhibiting body weight losses and decreased food
consumption.  Animals that died prior to study termination also showed
gross pathology findings, with the predominate findings being dark, red
lungs or chest cavity anomalies.  There were no apparent
treatment-related changes in the number of implantation sites compared
to the number corpora lutea.  Additionally, there were no apparent
treatment-related changes in the number and placement of implantation
and resorption sites or in the number of live and dead fetuses/pups. 
The lack of a treatment-related response could be the result of too few
animals available for comparison.  Additional data are needed to fully
assess these endpoints.  The maternal LOAEL is 6 mg/kg/day based on
mortality, body weight loss, decreased food consumption, and gross
pathology findings. A Maternal NOAEL was not achieved.

There were no apparent developmental effects.  Fetal and pup body weight
and length in treated groups appeared to be comparable with the control
groups.  Skeletal changes occurred more frequently in high-dose fetuses;
however, these effects predominately occurred in one litter where one
out of five fetuses died.  There were only two high-dose litters to
examine.  Therefore, it is difficult to draw any meaningful conclusions
from these data.  A developmental NOAEL/LOAEL could not be determined.

This developmental toxicity study is classified UNACCEPTABLE/NOT
UPGRADABLE and does not satisfy the guideline requirement for a
developmental toxicity study (OPPTS 870.3700; OECD 414) due to major
study deficiencies.  These include an inadequate number of dams per
group, high maternal mortality and abortion, and a lack of individual
animal data.  

870.4200

Carcinogenicity (gavage) - Mouse

Purity:  Not reported

	TRID 470103024

MRIDs 00139417, 00139419 and 00139484

Unacceptable – not upgradeable

Mice (125/sex/dose)

0, 500 or 1000 ppm for 18 months	There was no RH-893 treatment effect on
mortality, but both positive controls (i.e., DEN and AAF) caused an
increase in mortality.  No clinical findings were attributed to chronic
feeding of octhilinone.  High-dose RH-893 mice generally had reduced
body weights in the beginning of the study compared to the negative
control group; however, by Week 3 in males and Week 10 in females the
high-dose RH-893 treated mice had comparable or greater body weight and
body weight gain than the control group.  Body weight was depressed in
the positive controls.  There were no treatment-related effects on liver
weight or microscopic pathology in RH-893 treated mice.

Positive controls did exhibit an increase in lesions.  The DEN animals
were found with an increased incidence of carcinoma of the hepatocytes
in 6-mg/kg/day males and females at weeks 26 and 30; the 4-mg/kg/day
animals were not examined histopathologically.  The DEN 6-mg/kg/day
males and females were found with bronchitis or bronchiectasis.  The AAF
mice had increased incidence of hyperplasia of the bladder in the males,
urinary bladder carcinoma in both sexes and hepatocellular carcinomas in
both sexes.

Under the conditions of this 18-month feeding carcinogenicity study,
there was no apparent carcinogenic potential demonstrated for RH-893 in
either male or female (C 57BL/6 x C3H/anf) F1 mice exposed to 500 or
1000 ppm.  However, a number of study deficiencies precluded selection
of a LOAEL or NOAEL for this study.  

At the doses tested, there was no treatment-related increase in tumor
incidence when compared to controls; however, only 48  animals at the
high dose were examined histologically.  Therefore,   any carcinogenic
response would be potentially under-reported.  Dosing was not adequate
for this study, based on a lack of toxicity at the highest dose.  Even
considering the data from the preliminary 7-week study used to determine
appropriate doses for the carcinogenicity study, a dose of 1500 ppm or
one between 1000 and 1500 ppm may  have been a more appropriate high
dose for this 18-month carcinogenicity study.  In the preliminary 7-week
study a single male administered 1500 ppm died, which is why this dose
was neglected.    

This carcinogenicity study in mice is UNACCEPTABLE/NOT UPGRADABLE and
does not satisfy guideline requirement for a carcinogenicity study
[OPPTS 870.4200; OECD 451] in rodents.  There are several deficiencies, 
but the lack an adequate top dose, lack of analysis of the dose
formulation,   and lack of microscopic examination of only half of the
high-dose RH-893 mice made this carcinogenicity study unacceptable and
not upgradeable.

870.5100 

Bacterial reverse mutation test

Purity 96%	MRID 43935708 OK

Acceptable - Guideline

Strain: TA98, TA100, TA102, TA1535, and TA 1537 of S. typh. at 0.064,
0.32, 1.6, 1.875, 3.75, 7.5, 8, 15, 30, or 40 ug/plate (+/-S9)	Negative

There was no evidence of induced mutant colonies over background at any
concentration in repeat experiments.

N-octylisothiazolone (96%) was tested up to cytotoxic concentrations and
the limit concentration, 5000 ug/plate.  The positive controls induced
the appropriate responses in the corresponding strains.

870.5300 

Mammalian cell forward gene mutation 

Purity 96%	MRID 43935709 OK

Acceptable - Guideline

Test Cells: Mouse lymphoma L5178Y cells 

Octhilinone administered in the mutation assays as follows:

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Initial:  Doses: 0.156,  0.313, 0.625 (without activation) and 0.156,
0.313, 0.625 or 1.25 ug/ml (with S9 activation)

Repeat: Doses: 0.25, 0.50, 0.75, 1, or 1.25 ug/ml (without activation); 
0.50, 1, 1.5, 2, or 2.5 ug/ml (with S9 activ.)	Negative

N-Octylisothiazolone was tested up to toxic concentrations and the limit
of solubility.  Mutation frequencies were determined for concentrations
selected on the basis of relative survival.  In the initial mutation
assay, concentrations selected were 0.156, 0.313, or 0.625 ug/ml
nonactivated, and 0.156, 0.313, 0.625, or 1.25 ug/ml activated.  In a
repeat assay, concentrations selected were 0.25, .0.5, .0.75, 1, or 1.25
ug/ml nonactivated and 0.5, 1, 1.5, 2, or 2.5 ug/ml activated.  For
these concentrations, percent relative survival ranged from 27.4 to
100.7 without activation and from 15.4 to 120.3 with activation in the
initial assay; and from 11.2 to 82.9 without activation and from 14.6 to
64.7 with activation in the repeat assay.

No statistically significant increase in mutant frequency was observed
at any dose level tested in the absence of S9 activation.  A linear
trend was observed in the absence of S9 in both assays and in the
presence of S9 in one assay.  However, the linear trends did not reflect
a true dose-relationship in all cases and were not considered to be
biologically significant.  Therefore, it was determined that the test
material was not mutagenic under both nonactivated and activated
conditions in this in vitro assay.  In both the nonactivated and
activated conditions, the positive controls induced the appropriate
responses.

870.5385 

Mouse Micronucleus Test

Purity 96%	MRID 43935710 OK

Acceptable - Guideline

CD-1 Mice (5/sex/dose)

Octhilinone administered orally at 163, 325, or 650 mg/kg/day	Negative

There was no significant increase in the frequency of MPCEs in bone
marrow after any OIT treatment time; therefore, the test article is
considered negative in this micronucleus assay

870.5385 

In vitro Unscheduled DNA Assay

46.7% a.i.

	MRID 406475-05

Acceptable-Guideline	Negative

No increase in unscheduled DNA synthesis in rat hepatocytes up to toxic
concentrations Positive controls gave the appropriate response. 

8  SEQ CHAPTER \h \r 1 .0	Toxicity Endpoint Selection

	8.1	Summary Table of Toxicological Dose and Endpoint Selection (Table
5)

Table 5. Summary of Toxicological Dose and Endpoints for Octhilinone for
Use in Risk Assessment

Exposure  Scenario

	

Dose (mg/kg/day)

	

   Endpoint	

   Study

[Comments]

Acute Dietary	

Will  not be  used  on food, therefore,  acute RfD not required

Chronic Dietary	

Will  not be  used  on food, therefore, chronic RfD not required 

Occupational /Residential Exposure	

	

	

1. Incidental Oral 

Short Term;

Intermediate Term

MRID 41482508

	Systemic: 

NOAEL: 5 mg/kg/day

MOE = 100 for Short-term

MOE = 300 for Intermediate Term	Systemic: Mortality, decreased body
weight and body weight gain, decreased food consumption 	Developmental
Study 

Acceptable/Guideline

2. Short-term  (Dermal) [1 Day to 30 Days]

MRID 43935705

[5 x 7 cm application area]	

Dermal Irritation: 

NOAEL: 10 mg/kg/day

(0.0674 mg/cm2)

MOE = 10+ 

Systemic: NOAEL: >1000 mg/kg/day

MOE = 100	

Dermal: dermal irritation in both sexes 

Systemic: No systemic effects

	

14 Day Dermal Study

Acceptable/Non-guideline

4. Intermediate-term (Dermal)* 

[30 Days to 6 Months]

MRID 42007301

[4 x 5 cm application area]	

Systemic: NOAEL: 5.95 mg/kg/day

MOE = 100

	

Systemic: 

Decreases in HGB, HCT, RBC, albumin, and total protein and a decrease in
body weight gain in the male	

90 Day Dermal Study

Acceptable/Guideline

5. Long-term (Dermal)

(>6 Months)	

Not Selected	

Not Selected	

Not Selected

6. Inhalation** 

(short/intermediate-term [0 to 30 Days]/[30 Days to 6 Months]

MRID 415447-01	

NOAEL: 0.64 mg/m3

MOE:100	

Clinical signs (rales, dyspnea) decreases in body weight gain, fluid in
uterus and pulmonary and nasal cavity pathology	

90 Day Inhalation Toxicity

Acceptable-Guideline

* Assumed to be 100% absorbed.

**Assumed to be 100% absorbed.

+ Currently the dermal irritation endpoint is applied only for the short
short-term exposure scenario. Although the standard margin of exposure
(MOE) of 100 is normally applied, a semi-occlusive dressing used in the
study is considered more conservative than
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