**UNITED STATES ENVIRONMENTAL PROTECTION AGENCY**

**WASHINGTON, DC 20460**

OFFICE OF PREVENTION, PESTICIDES, AND TOXIC SUBSTANCES

![](media/image1.png)

> October 31, 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

**October 31, 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]{.underline}**

**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 **s**tudies 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 \[LD~50~ = 794
mg/kg (M); LD~50~= 681 mg/kg (F)\]. Octhilinone was found to be
moderately toxic (Toxicity Category II) in an acute dermal toxicity
study in rabbits, MRID 70749 \[LD~50~ = 1. 83 gm/kg (combined)\] and
moderately toxic (Toxicity Category II) in an acute inhalation toxicity
of Octhilinone in rats, MRID 70456 \[LC~50~ \> 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]{.underline} (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*]{.underline} (MRID
43935709), the test substance was not mutagenic in both the activated
and non-activated conditions. In a [mouse bone marrow chromosomal
aberration test]{.underline} (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.

**[Number range CHAPTER]{.underline}**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**

Number range CHAPTERThe 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)       | 70456       | yes         |
|                                          |             |             |
| 870.1100 Acute Oral Toxicity (Rat)       | 70456       | yes         |
|                                          |             |             |
| 870.1200 Acute Dermal Toxicity (Rabbit)  | 70456       | yes         |
|                                          |             |             |
| 870.1300 Acute Inhalation (Rat)          | 70456       | no          |
|                                          |             |             |
| 870.2400 Primary Eye Irritation (Rabbit) | 70456       | yes         |
|                                          |             |             |
| 870.2500 Primary Dermal Irritation       | 63214       | no          |
| (Rabbit)                                 |             |             |
|                                          | 4182505,    | no, waived  |
| 870.2600 Dermal Sensitization (Guinea    | 4182507     |             |
| Pig)                                     |             |             |
+------------------------------------------+-------------+-------------+
| 870.3050 14-Day Oral (Rat)               | 43935707    | yes         |
|                                          |             |             |
| 870.3100 Oral Subchronic (Rat)           | 136524      | no          |
|                                          |             |             |
| 870.3150 Oral Subchronic (Dog)           | 136525      | no          |
|                                          |             |             |
| 870.3200 14-Day Dermal (Rat)             | 43935705    | yes         |
|                                          |             |             |
| 870.3200 28-Day Dermal (Rabbit)          | 136526      | no          |
|                                          |             |             |
| 870.3250 90-Day Dermal (Rat)             | 42007301    | yes         |
|                                          |             |             |
| 870.3250 90-Day Dermal (Rat)             | 43935706    | no          |
|                                          |             |             |
| 870.4365 10-Day Inhalation (Rat)         | 136527      | no          |
|                                          |             |             |
| 870.3465 90-Day Inhalation (Rat)         | 41544701    | yes         |
+------------------------------------------+-------------+-------------+
| 870.3700a Developmental Toxicity (Rat)   | 46403       | no          |
|                                          |             |             |
| 870.3700b Developmental Toxicity         | 136528      | no          |
| (Rabbit)                                 |             |             |
|                                          | 41482508    | yes         |
| 870.3700a Developmental Toxicity (Rat)   |             |             |
|                                          | 43944401    | yes         |
| 870.3700a Developmental Toxicity (Rat)   |             |             |
|                                          | 41482509    | yes         |
| 870.3700b Developmental Toxicity         |             |             |
| (Rabbit)                                 |             |             |
+------------------------------------------+-------------+-------------+
| 870.3800 Reproduction                    | NA          | NA          |
+------------------------------------------+-------------+-------------+
| 870.4100a Chronic Toxicity (Rat)         | NA          | NA          |
|                                          |             |             |
| 870.4100a Chronic Toxicity (Mouse)       | NA          | NA          |
+------------------------------------------+-------------+-------------+
| 870.4200a Carcinogenicity (Rat)          | NA          | NA          |
|                                          |             |             |
| 870.4200b Carcinogenicity (Mouse)        | 470103024   | no          |
|                                          |             |             |
|                                          | 139484      |             |
|                                          |             |             |
|                                          | 139419      |             |
+------------------------------------------+-------------+-------------+
| 870.5100 Mutagenicity -- Bacterial       | 43935708    | yes         |
| Reverse Gene Mutation assay              |             |             |
|                                          | 43935709    | yes         |
| 870.5300 Mutagenicity -- Forward Gene    |             |             |
| Mutation test (TK locus)                 | 43935710    | yes         |
|                                          |             |             |
| 870.5395 Mutagenicity -- Mouse           | 40647505    | yes         |
| Erythrocyte Micronucleus test            |             |             |
|                                          |             |             |
| 870.5550 Mutagenicity -- Unscheduled DNA |             |             |
| synthesis                                |             |             |
+------------------------------------------+-------------+-------------+
| 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**

1.  **Acute Toxicity**

[Adequacy of database for Acute Toxicity]{.underline}: 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. [Number range CHAPTER]{.mark} 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 | **Study      | **MRID**   | **Results**  | *         |
| No.**       | Type**       |            |              | *Toxicity |
|             |              |            |              | C         |
|             |              |            |              | ategory** |
+-------------+--------------+------------+--------------+-----------+
| 870.1100    | Acute Oral   | 00070456   | LD~50~ = 794 | III       |
|             |              |            | mg/kg (M)    |           |
|             |              |            |              |           |
|             |              |            | LD~50~= 681  |           |
|             |              |            | mg/kg (F)    |           |
+-------------+--------------+------------+--------------+-----------+
| 870.1200    | Acute Dermal | 00070456   | LD~50~ =     | II        |
|             |              |            | 1.83 gm/kg\* |           |
|             |              |            | (combined)   |           |
+-------------+--------------+------------+--------------+-----------+
| 870.1300    | Acute        | 00070456   | LC~50~ \>200 | III       |
|             | Inhalation   |            | mg/kg        |           |
+-------------+--------------+------------+--------------+-----------+
| 870.2400    | Primary Eye  | 00070456   | Severely     | I         |
|             | Irritation   |            | Irritating   |           |
+-------------+--------------+------------+--------------+-----------+
| 870.2500    | Primary Skin | 00063214   | Corrosive    | I         |
|             | Irritation   |            |              |           |
+-------------+--------------+------------+--------------+-----------+
| 870.2600    | Skin         | 41482505,  | Sensitizer   | .....     |
|             | S            |            |              |           |
|             | ensitization | 41482507,  |              |           |
|             |              | 010809     |              |           |
+-------------+--------------+------------+--------------+-----------+

> \*Octhilinone has a density of 1.03 gm/ml. = LD~50~ = 1.83 gm/kg

2.  **Subchronic Toxicity**

[Adequacy of database for Subchronic Toxicity]{.underline}: Number range
CHAPTERThe 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.

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 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.

3100. **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.

3150. **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.

**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.

3200. **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.

3250. **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)**

In a dermal subchronic toxicity study (MRID 43935706),
N-octylisothiazolone (94 ± 3% ai, Lot# K1217) was applied to the shaved
skin of ten young adult Sprague-Dawley CD rats/sex/dose at dose levels
of 0, 5, 25, or 125 mg/kg/day for 6 hours/day for 90 days.

Male and female rats in the 125 mg/kg treatment groups exhibited slight
to moderate (mean score ≤ 2.l 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 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.

**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 14^th^ 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/
NON-GUIDELINE** 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. However, the study was conducted
as a range-finding study and was not intended to fulfill a guideline
requirement.

**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/m^3^. 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/m^3^ groups. Clinical signs in the 6.39 mg/m^3^ 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/m^3^ 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/m^3^ 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/m^3^ 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/m^3^ group, **the LOAEL
for 13-week inhalation exposure is 6.39 mg/m^3^. The NOAEL is 0.64
mg/m^3^**.

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]{.underline}:
Number range CHAPTERThe 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**

In a developmental toxicity study (MRID 41482508), 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]{.underline}/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:]{.underline} Number range
CHAPTERThe 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.

5.  **Chronic Toxicity**

[Adequacy of database for Chronic Toxicity]{.underline}: Number range
CHAPTERThe 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.

6.  **Carcinogenicity**

[Adequacy of database for Carcinogenicity]{.underline}: 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.

4200. **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) F~1~
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) F~1~ mice/sex were fed diets containing 600 ppm
2-acetamidofluorene (AAF), 50 (C 57BL/6 x C3H/anf) F~1~ mice/sex/dose
received 4 mg/kg/day diethylnitrosamine (DEN), and 25 (C 57BL/6 x
C3H/anf) F~1~ 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) F~1~ 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.

7.  **Mutagenicity**

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

Number range CHAPTEROcthilinone 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*]{.underline}
(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. In an *in vitro* cytogenetics assay (MRID
40647503), OIT (Skane M-8, 46.7% a.i. in propylene glycol) was
presumptively positive for chromosome aberrations, as it could not be
determined whether the test material, experimental conditions, or a
combination of both was responsible for the effect.

**4.8 Neurotoxicity**

[Adequacy of database]{.underline} for the neurotoxicity of Octhilinone:
The database for the neurotoxicity of Octhilinone is considered
incomplete.

Although no neurotoxicity signs were seen in any of the toxicology
studies currently reviewed, a Neurotoxicity Screening Battery
requirement is held in reserve. A recently conducted subchronic toxicity
study in the rat with functional observations for neurotoxicity has been
submitted. Once review of this study is final, a determination for any
additional neurotoxicity studies can be made

**4.9 General Metabolism**

Number range CHAPTERNumber range CHAPTERA 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.

**5.0 Hazard Endpoint Selection**

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

**Table 5.**

2.  **Dermal Absorption**

    Dermal Absorption Factor: Number range CHAPTERSince a dermal
    endpoint was selected from a dermal toxicity study, a dermal
    absorption factor is not needed for Octhilinone.

3.  **Classification of Carcinogenic Potential**

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

6.  **FQPA Considerations**

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

    Number range CHAPTER

    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**

        A reproductive toxicity study was recently submitted. Once final
        review is complete, conclusions regarding the reproductive
        toxicity of OIT can be included.

        **6.3 Pre-and/or Postnatal Toxicity**

> A. [Determination of Susceptibility]{.underline}: Number range CHAPTER
> There is currently no evidence to suggest increased susceptibility to
> developmental or reproductive toxicity of OIT. A final determination
> can be made pending final review of the recently submitted
> reproductive toxicity study.

B. [Proposed Hazard-based Special FQPA Safety Factor]{.underline}:
Number range CHAPTERNumber range CHAPTER 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./** | **MRID No. /**     | **Results**                |
|                    |                    |                            |
| **Study Type/ Test | **Classification/  |                            |
| Substance (%       | Doses**            |                            |
| a.i.)**            |                    |                            |
+--------------------+--------------------+----------------------------+
| 870.1100 (§81-1)   | MRID 00070456      | **Toxicity Category III**  |
|                    |                    |                            |
| Acute Oral         | Rats (5/sex/dose)  | LD~50~ = 794 mg/kg (males) |
| Toxicity (gavage)  |                    |                            |
| -- Rat             | 0, 100, 215, 464,  | = 681 mg/kg (females)      |
|                    | 1000, or 2150      |                            |
| Technical (85 -    | mg/kg              | Toxic effects included     |
| 95% a.i.)          |                    | 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           | MRID 00070456      | **Toxicity Category II**   |
|                    |                    |                            |
| Acute Dermal       | Rabbits            | LD~50~ = 1.83 gm/kg \*     |
| Toxicity -- Rabbit | (4/sex/dose)       |                            |
|                    |                    | [Dermal]{.underline}:      |
| Technical material | Single 24-hours    | Toxic effects included     |
| l(85 - 95% a.i.)   | dermal             | greenish colored areas,    |
|                    | applications made  | blanching, slight to       |
|                    | to clipped intact  | severe erythema, slight to |
|                    | and abraded skin   | severe edema, necrotic     |
|                    | at doses of 0,     | areas and coriaceous       |
|                    | 0.316, 1.0, 3.16,  | areas.                     |
|                    | 10, or 10 mL/kg    |                            |
|                    |                    | [Systemic]{.underline}:    |
|                    | **Acceptable -     | Depression was seen at the |
|                    | Guideline**        | two lower doses from 24    |
|                    |                    | hours thru day 4 to 6.     |
+--------------------+--------------------+----------------------------+
| Acute Inhalation   | MRID 00070456      | **Toxicity Category III**  |
| Toxicity -- Mouse  |                    |                            |
|                    | Total body         | **LC~50~ \> 200 mg/L**     |
| Technical material | exposure to a      | (nominal concentration)    |
| (95% a.i.)         | nominal            |                            |
|                    | concentration 200  | There were no deaths.      |
|                    | mg/L of 0.5%       | Increased activity was the |
|                    | solution for 1     | only clinical sign         |
|                    | hour               | exhibited by the rats      |
|                    |                    | exposed to the aerosol.    |
|                    | 10 mice/ sex/      |                            |
|                    | group              | Not Acceptable/Not         |
|                    |                    | guideline because of the 1 |
|                    | **Not              | hour duration of the       |
|                    | Acceptable/Not     | study.                     |
|                    | guideline**        |                            |
+--------------------+--------------------+----------------------------+
| 870.2400           | MRID 00070456      | **Toxicity Category I**    |
|                    |                    | (Corrosive)                |
| Primary eye        | 6 rabbits, 0.1 mL  |                            |
| irritation --      | of undiluted test  | Moderate to severe corneal |
| Rabbit             | material applied   | opacity, iritis, chemosis, |
|                    | to conjunctival    | discharge marked           |
| Technical material | sac of left eye;   | conjunctival redness or    |
| l(95% a.i.)        | eye was held       | blanching.                 |
|                    | closed for 1       |                            |
|                    | second following   |                            |
|                    | application; eyes  |                            |
|                    | were not rinsed    |                            |
|                    |                    |                            |
|                    | **Acceptable -     |                            |
|                    | Guideline**        |                            |
+--------------------+--------------------+----------------------------+
| 870.2500           | MRID 00063214      | **Toxicity Category I      |
|                    |                    | (**Corrosive)              |
| Primary Skin       | 24 hour Contact    |                            |
| irritation --      |                    | Study not acceptable,      |
| Rabbit             | **Not              | because of the 24 hour     |
|                    | Acceptable/Not     | duration of exposure       |
| (50% a.i.)         | guideline**        |                            |
|                    |                    | Not Acceptable/Not         |
|                    |                    | guideline because of the   |
|                    |                    | 14 hour duration of        |
|                    |                    | exposure.                  |
+--------------------+--------------------+----------------------------+
| 870.2600           | MRID 41482505,     | **Sensitizer**             |
|                    | 41482507           |                            |
| Dermal             |                    | Not Acceptable/Not         |
| Sensitization --   | **Not              | guideline because of the   |
| Guinea Pig         | Acceptable/Not     | lack of a positive         |
|                    | guideline**        | 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        | **MRID Number**    | **Results**                |
| Number/**          | **Classification/  |                            |
|                    | Doses**            |                            |
| **Study Type/**    |                    |                            |
|                    |                    |                            |
| **Test Substance   |                    |                            |
| (% a.i.)**         |                    |                            |
+--------------------+--------------------+----------------------------+
| Non-Guideline      | MRID 43935707      | Clinical observations and  |
|                    |                    | gross pathology findings   |
| 14-day             | **Acceptable       | indicated dose-related     |
| intragastric       | -Nonguideline**    | signs of toxicity in all   |
| intubation - Rat   |                    | treatment groups.          |
|                    | Octhilinone        | Observations of salivation |
| Purity 96% a.i.    | administered       | and abnormal position      |
|                    | orally at 0, 100,  | increased in incidence and |
| Batch K1217        | 500 and 2000 ppm   | frequency of occurrence    |
|                    | (equivalent to 0,  | with increasing dose       |
|                    | 7.0, 34.6, or      | level. Piloerection, soft  |
|                    | 139.9 mg/kg/day)   | feces, and excessive       |
|                    |                    | urination were also noted  |
|                    | Rats (10/sex/dose) | 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           | MRID 00136524      | **Subchronic Toxicity:**   |
|                    |                    |                            |
| 90-day oral - Rat  | **Unacceptable --  | **NOAEL, LOAEL not         |
|                    | Not upgradeable**  | determined**.              |
| Purity not         |                    |                            |
| reported           | Octhilinone        | There was no effect on     |
|                    | administered       | survival, feed efficiency, |
| Lot SW 70/0293     | orally at 0, 100,  | urinalysis, or gross and   |
|                    | 500 and 2000 ppm   | microscopic pathology.     |
|                    | (equivalent to 0,  | Body weight, body weight   |
|                    | 7.0, 34.6, or      | gain, and feed consumption |
|                    | 139.9 mg/kg/day)   | were low during the first  |
|                    |                    | week of treatment for      |
|                    | Rats (10/sex/dose) | 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           | MRID 00136525      | **Subchronic Toxicity:**   |
|                    |                    |                            |
| 90-day oral - Dog  | **Unacceptable --  | **NOAEL, LOAEL not         |
|                    | Not Upgradeable**  | established.**             |
| Purity 100%        |                    |                            |
|                    | Dogs (4/sex/dose)  | Data were highly variable, |
| Lot SW 70/0293     |                    | even at the initial        |
|                    | 0, 100, 500 or     | measurement, making it     |
|                    | 2000 ppm           | 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 -    | MRID 43935705      | **Dermal Irritation**      |
| Rat                |                    |                            |
|                    | **Acceptable --    | **NOAEL = 10 mg/kg/day**   |
| Purity 96%         | Non-Guideline**    |                            |
|                    |                    | **LOAEL = 100 mg/kg/day**, |
| Batch K 1217       | 5 rats/sex/dose    | based on dermal irritation |
|                    |                    | in both males and females. |
|                    | 0, 10, 100, 1000   |                            |
|                    | mg/kg/day for 14   | There were no              |
|                    | days               | 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/k/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 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           | MRID 00136526      | **Dermal irritation:**     |
|                    |                    |                            |
| 21-day dermal -    | **Unacceptable --  | **NOAEL not established.** |
| Rabbit             | Not upgradeable**  |                            |
|                    |                    | **LOAEL = 1%** based on    |
| Purity 50%         | Rabbits            | dermal irritation          |
|                    | (10sex/dose)       | (clinical findings and     |
|                    |                    | microscopic findings) in   |
|                    | 0, 1% or 10%, for  | both males and females.    |
|                    | 6 hours/day, 5     |                            |
|                    | days/week, for 3   | **Systemic Toxicity:**     |
|                    | weeks. Half of the |                            |
|                    | animals were       | **NOAEL not determined     |
|                    | abraded, half      | (males).**                 |
|                    | intact.            |                            |
|                    |                    | **NOAEL = 1% (females).**  |
|                    | Vehicle control:   |                            |
|                    | 1% Tween           | **LOAEL = 1% (males)**     |
|                    | 80/distilled water | based on body weight gain. |
|                    | solution           |                            |
|                    |                    | **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           | MRID 42007301      | **Dermal Toxicity:**       |
|                    |                    |                            |
| 90-day dermal -    | **Acceptable -     | **NOAEL: \<2.97 (0.3%)     |
| Rat                | Guideline**        | mg/kg/day**                |
|                    |                    |                            |
| Purity 99.1%       | Rats (10/sex/dose) | **LOAEL: =2.97 (0.3%)      |
|                    |                    | mg/kg/day,** based on skin |
|                    | 0, 2.97, 5.95 and  | irritation:                |
|                    | 14.87 mg/kg/day    | hyperkeratosis,            |
|                    | (0, 0.3%, 0.6% and | acanthosis, foci of        |
|                    | 1.5%), 5 days/week | necrosis, eschar           |
|                    | for 13 weeks       | 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           | MRID 43935706      | **NOAEL not established.** |
|                    |                    |                            |
| 90-day dermal -    | **Supplemental**   | **LOAEL not established.** |
| Rat                |                    |                            |
|                    | Rats (10/sex/dose) | Male and female rats in    |
| Purity 99.1%       |                    | the 125 mg/kg treatment    |
|                    | 0, 5, 25 or 125    | groups exhibited slight to |
|                    | mg/kg/day for 6    | moderate (mean score       |
|                    | hours/day for 90   | \<=2.1 on a scale of 0 to  |
|                    | days               | 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      | MRID 00136527      | **NOAEL and LOAEL could    |
|                    |                    | not be determined.**       |
| 10-day             | **Unacceptable --  |                            |
| inhalation - Rat   | Not upgradeable**  | Animals in the 10%         |
|                    |                    | exposure group were found  |
| Purity 50%         | Whole-body         | dead or sacrificed due to  |
|                    | inhalation         | moribundity 9/10 males and |
|                    | exposure to 2 mg/L | 7/10 females died as early |
|                    | of 0, 1% or 10%    | as Day 3. Clinical signs   |
|                    | solution, 1 hour   | of toxicity related to     |
|                    | per day, for 10    | treatment were nose        |
|                    | days               | shuffling (1% and 10%),    |
|                    |                    | dried red material around  |
|                    | 5 rats from each   | the eyes (10%), gasping    |
|                    | treatment group    | (10%), lacrimation (10%),  |
|                    | were sacrificed    | red nasal exudate (10%),   |
|                    | and necropsied at  | and coughing (10%);        |
|                    | Day 12; rest of    | preening, hypoactivity,    |
|                    | animals sacrificed | wet hair, excessive water  |
|                    | and necropsied Day | consumption, and wheezing  |
|                    | 26.                | were exhibited in control  |
|                    |                    | and treated animals. Data  |
|                    | 10                 | were highly variable,      |
|                    | Rats/sex/exposure  | making it difficult to     |
|                    |                    | determine                  |
|                    | Vehicle: propylene | treatment-related effects. |
|                    | glycol             | Weight loss was observed   |
|                    |                    | in the 10%-RH-893-50%      |
|                    | Purity: 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         | MRID 41544701      | **NOAEL: 0.64 mg/m3**      |
|                    |                    |                            |
| 90-day             | **Acceptable       | **LOAEL: 6.39 mg/m3,**     |
| inhalation - Rat   | -Guideline**       | based on decreased body    |
|                    |                    | weights, fluid in the      |
| Purity 42%         | 11                 | uterus, and the pulmonary  |
|                    | Rats/sex/exposure  | histopathological findings |
|                    |                    | at the terminal sacrifice  |
|                    | 0.05, 0.64 and     | for males and females in   |
|                    | 6.39 mg/m3         | 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           | MRID 41482508      | **Maternal Toxicity:**     |
|                    |                    |                            |
| Developmental      | **Acceptable -     | **NOAEL = 5 mg/kg/day**    |
| (gavage) - Rat     | Guideline**        |                            |
|                    |                    | **LOAEL = 30 mg/kg/day,**  |
| Purity 43%         | Female rats        | based on death, salivation |
|                    | (25/dose)          | and decreased defecation,  |
|                    |                    | decreased body weight and  |
|                    | 0, 1, 5 or 30      | body weight gain,          |
|                    | mg/kg administered | decreased corrected body   |
|                    | orally, gestation  | weight and body weight     |
|                    | days 6-15,         | gain, and decreased food   |
|                    | inclusive.         | 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          | MRID 43944401      | **Maternal Toxicity:**     |
|                    |                    |                            |
| Developmental      | **Acceptable --    | **NOAEL = 30 mg/kg/day**   |
| (gavage) - Rat     | Guideline**        |                            |
|                    |                    | **LOAEL = 60 mg/kg/day,**  |
| Purity 94 ± 3%     | Female Rats        | based on reduced body      |
|                    | (25/dose)          | weight gains               |
|                    |                    |                            |
|                    | 0, 5, 30, or 60    | **Developmental Toxicity** |
|                    | mg/kg administered |                            |
|                    | orally, gestation  | **NOAEL \>= 60             |
|                    | days 6-15,         | mg/kg/day,** highest dose  |
|                    | inclusive.         | 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           | MRID 00046403      | **Maternal Toxicity:**     |
|                    |                    |                            |
| Developmental      | **Unacceptable --  | **NOAEL = 1000 ppm         |
| (gavage) - Rat     | Not upgradeable**  | (highest dose tested)**    |
|                    |                    |                            |
| Purity 96%         | Females rats       | **LOAEL - not              |
|                    | (18/dose)          | established.**             |
|                    |                    |                            |
|                    | 0, 200 or 1000 ppm | **Developmental            |
|                    | administered       | Toxicity:**                |
|                    | orally, gestation  |                            |
|                    | days 6-15,         | **NOAEL = 1000 ppm         |
|                    | inclusive.         | (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           | MRID 43935707      | **Short-term toxicity:**   |
|                    |                    |                            |
| Developmental      | **Acceptable --    | **NOAEL - not              |
| (gavage) - Rat     | Non-Guideline**    | established.**             |
|                    |                    |                            |
| Purity 96%         | Female Rats        | **LOAEL = 10 mg/kg/day,    |
|                    | (8/dose)           | based on clinical signs of |
|                    |                    | salivation and gross       |
|                    | 0, 10, 60, or 120  | pathology in the liver.**  |
|                    | mg/kg administered |                            |
|                    | orally, for 14     | Clinical observations and  |
|                    | days.              | 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.            |
+--------------------+--------------------+----------------------------+
| 870.3700           | MRID 41482509      | **Maternal Toxicity:**     |
|                    |                    |                            |
| Developmental      | **Acceptable -     | **NOAEL = 20 mg/kg/day**   |
| (gavage) - Rabbit  | Guideline**        |                            |
|                    |                    | **LOAEL = 80 mg/kg/day,**  |
| Purity 46.3%       | Female rabbits     | based on clinical signs of |
|                    | (19/dose)          | toxicity, decreased body   |
|                    |                    | weight and body weight     |
|                    | 0, 5, 20 or 80     | gains, and increased       |
|                    | mg/kg administered | number of abortions.       |
|                    | orally, gestation  |                            |
|                    | days 7-19,         | **Developmental            |
|                    | inclusive.         | 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           | MRIDs 00136528 and | **Maternal toxicity:**     |
|                    | 00058029           |                            |
| Developmental      |                    | **NOAEL- not established** |
| (gavage) - Rabbit  | **Unacceptable --  |                            |
|                    | Not upgradeable**  | **LOAEL = 6 mg/kg/day**    |
| Purity 96%         |                    | based on mortality, body   |
|                    | Females rabbits    | weight loss, decreased     |
| Lot SW 70/0293     | (15/dose)          | food consumption, and      |
|                    |                    | gross pathology findings.  |
|                    | 0, 6 or 60 mg/kg   |                            |
|                    | administered       | **Developmental            |
|                    | orally, gestation  | toxicity:**                |
|                    | days 6-18,         |                            |
|                    | inclusive.         | **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           | TRID 470103024     | There was no RH-893        |
|                    |                    | treatment effect on        |
| Carcinogenicity    | MRIDs 00139417,    | mortality, but both        |
| (gavage) - Mouse   | 00139419 and       | positive controls (i.e.,   |
|                    | 00139484           | DEN and AAF) caused an     |
| Purity: Not        |                    | increase in mortality. No  |
| reported           | **Unacceptable --  | clinical findings were     |
|                    | not upgradeable**  | attributed to chronic      |
|                    |                    | feeding of octhilinone.    |
|                    | Mice               | High-dose RH-893 mice      |
|                    | (125/sex/dose)     | generally had reduced body |
|                    |                    | weights in the beginning   |
|                    | 0, 500 or 1000 ppm | of the study compared to   |
|                    | for 18 months      | 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) F~1~     |
|                    |                    | 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           | MRID 43935708      | **Negative**               |
|                    | **OK**             |                            |
| Bacterial reverse  |                    | There was no evidence of   |
| mutation test      | **Acceptable -     | induced mutant colonies    |
|                    | Guideline**        | over background at any     |
| Purity 96%         |                    | concentration in repeat    |
|                    | Strain: TA98,      | experiments.               |
|                    | TA100, TA102,      |                            |
|                    | TA1535, and TA     | N-octylisothiazolone (96%) |
|                    | 1537 of S. typh.   | was tested up to cytotoxic |
|                    | at 0.064, 0.32,    | concentrations and the     |
|                    | 1.6, 1.875, 3.75,  | limit concentration, 5000  |
|                    | 7.5, 8, 15, 30, or | ug/plate. The positive     |
|                    | 40 ug/plate        | controls induced the       |
|                    | (+/-S9)            | appropriate responses in   |
|                    |                    | the corresponding strains. |
+--------------------+--------------------+----------------------------+
| 870.5300           | MRID 43935709      | **Negative**               |
|                    | **OK**             |                            |
| Mammalian cell     |                    | N-Octylisothiazolone was   |
| forward gene       | **Acceptable -     | tested up to toxic         |
| mutation           | Guideline**        | concentrations and the     |
|                    |                    | limit of solubility.       |
| Purity 96%         | Test Cells: Mouse  | Mutation frequencies were  |
|                    | lymphoma L5178Y    | determined for             |
|                    | cells              | concentrations selected on |
|                    |                    | the basis of relative      |
|                    | Octhilinone        | survival. In the initial   |
|                    | administered in    | mutation assay,            |
|                    | the mutation       | concentrations selected    |
|                    | assays as follows: | were 0.156, 0.313, or      |
|                    |                    | 0.625 ug/ml nonactivated,  |
|                    | [Ini               | and 0.156, 0.313, 0.625,   |
|                    | tial]{.underline}: | or 1.25 ug/ml activated.   |
|                    | Doses: 0.156,      | In a repeat assay,         |
|                    | 0.313, 0.625       | concentrations selected    |
|                    | (without           | were 0.25, .0.5, .0.75, 1, |
|                    | activation) and    | or 1.25 ug/ml nonactivated |
|                    | 0.156, 0.313,      | and 0.5, 1, 1.5, 2, or 2.5 |
|                    | 0.625 or 1.25      | ug/ml activated. For these |
|                    | ug/ml (with S9     | concentrations, percent    |
|                    | activation)        | relative survival ranged   |
|                    |                    | from 27.4 to 100.7 without |
|                    | [Re                | activation and from 15.4   |
|                    | peat]{.underline}: | to 120.3 with activation   |
|                    | Doses: 0.25, 0.50, | in the initial assay; and  |
|                    | 0.75, 1, or 1.25   | from 11.2 to 82.9 without  |
|                    | ug/ml (without     | activation and from 14.6   |
|                    | activation); 0.50, | to 64.7 with activation in |
|                    | 1, 1.5, 2, or 2.5  | the repeat assay.          |
|                    | ug/ml (with S9     |                            |
|                    | activ.)            | 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           | MRID 43935710      | **Negative**               |
|                    | **OK**             |                            |
| Mouse Micronucleus |                    | There was no significant   |
| Test               | **Acceptable -     | increase in the frequency  |
|                    | Guideline**        | of MPCEs in bone marrow    |
| Purity 96%         |                    | after any OIT treatment    |
|                    | CD-1 Mice          | time; therefore, the test  |
|                    | (5/sex/dose)       | article is considered      |
|                    |                    | negative in this           |
|                    | Octhilinone        | micronucleus assay         |
|                    | administered       |                            |
|                    | orally at 163,     |                            |
|                    | 325, or 650        |                            |
|                    | mg/kg/day          |                            |
+--------------------+--------------------+----------------------------+
| 870.5385           | MRID 406475-05     | **Negative**               |
|                    |                    |                            |
| *In vitro*         | **Acce             | No increase in unscheduled |
| Unscheduled DNA    | ptable-Guideline** | DNA synthesis in rat       |
| Assay              |                    | hepatocytes up to toxic    |
|                    |                    | concentrations Positive    |
| 46.7% a.i.         |                    | controls gave the          |
|                    |                    | appropriate response.      |
+--------------------+--------------------+----------------------------+

8Number range CHAPTER.**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       | **Dose        | **Endpoint**   | **Study**        |
| Scenario**       | (mg/kg/day)** |                |                  |
|                  |               |                | \[Comments\]     |
+------------------+---------------+----------------+------------------+
| 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 | *             | [Systemic      | Developmental    |
| Oral**           | *[Systemic]{. | ]{.underline}: | Study            |
|                  | underline}:** | Mortality,     |                  |
| Short Term;      |               | decreased body | **Accept         |
|                  | NOAEL: 5      | weight and     | able/Guideline** |
| Intermediate     | mg/kg/day     | body weight    |                  |
| Term             |               | gain,          |                  |
|                  | MOE = 100 for | decreased food |                  |
| MRID 41482508    | Short-term    | consumption    |                  |
|                  |               |                |                  |
|                  | MOE = 300 for |                |                  |
|                  | Intermediate  |                |                  |
|                  | Term          |                |                  |
+------------------+---------------+----------------+------------------+
| 2\. **Short-term | **[Dermal     | [Derma]        | 14 Day Dermal    |
| (Dermal)** \[1   | Irritation]{. | {.underline}l: | Study            |
| Day to 30 Days\] | underline}:** | dermal         |                  |
|                  |               | irritation in  | **Acceptable     |
| MRID 43935705    | NOAEL: 10     | both sexes     | /Non-guideline** |
|                  | mg/kg/day     |                |                  |
| \[5 x 7 cm       |               | [Systemic      |                  |
| application      | (0.0674       | ]{.underline}: |                  |
| area\]           | mg/cm^2^)     | No systemic    |                  |
|                  |               | effects        |                  |
|                  | MOE = 10+     |                |                  |
|                  |               |                |                  |
|                  | *             |                |                  |
|                  | *[Systemic]{. |                |                  |
|                  | underline}:** |                |                  |
|                  | NOAEL: \>1000 |                |                  |
|                  | mg/kg/day     |                |                  |
|                  |               |                |                  |
|                  | MOE = 100     |                |                  |
+------------------+---------------+----------------+------------------+
| 4\.              | *             | [Systemic      | 90 Day Dermal    |
| **I              | *[Systemic]{. | ]{.underline}: | Study            |
| ntermediate-term | underline}:** |                |                  |
| (Dermal)**\*     | NOAEL: 5.95   | Decreases in   | **Accept         |
|                  | mg/kg/day     | HGB, HCT, RBC, | able/Guideline** |
| \[30 Days to 6   |               | albumin, and   |                  |
| Months\]         | MOE = 100     | total protein  |                  |
|                  |               | and a decrease |                  |
| MRID 42007301    |               | in body weight |                  |
|                  |               | gain in the    |                  |
| \[4 x 5 cm       |               | male           |                  |
| application      |               |                |                  |
| area\]           |               |                |                  |
+------------------+---------------+----------------+------------------+
| 5\. **Long-term  | Not Selected  | Not Selected   | Not Selected     |
| (Dermal)**       |               |                |                  |
|                  |               |                |                  |
| (\>6 Months)     |               |                |                  |
+------------------+---------------+----------------+------------------+
| 6\.              | ++            | Clinical signs | 90 Day           |
| **Inhalation**   |               | (rales,        | Inhalation       |
|                  | 2 hr HEC:     | dyspnea)       | Toxicity         |
| **(short/int     | 0.29 mg/m^3^  | decreases in   |                  |
| ermediate-term** |               | body weight    | **Accept         |
| \[0 to 30        | 4 hr HEC:     | gain, fluid in | able-Guideline** |
| Days\]/\[30 Days | 0.15 mg/m^3^  | uterus and     |                  |
| to 6 Months\]    |               | pulmonary and  |                  |
|                  | 6 hr HEC:     | nasal cavity   |                  |
| MRID 415447-01   | 0.10 mg/m^3^  | pathology      |                  |
|                  |               |                |                  |
|                  | 8 hr HEC:     |                |                  |
|                  | 0.073 mg/m^3^ |                |                  |
|                  |               |                |                  |
|                  | MOE = 30      |                |                  |
+------------------+---------------+----------------+------------------+

> \+ the use of dermal irritation is applied only for the short
> short-term dermal exposure scenario. A margin of exposure (MOE) of 10
> is used for the short-term assessment (3x inter-species variation, 3x
> intra-species variation).
>
> ++ Human Equivalent Concentrations (HECs) were calculated using the
> Regional Deposited Dose Ratio (RDDR) for nonhygroscopic particles and
> the study NOAEL of 0.64 mg/m^3^