February 27, 2006

**[Memorandum]{.underline}**

Subject: Toxicology Disciplinary Chapter for the Re-Registration
Eligibility Decision (RED) Risk Assessment

Active Ingredient: Didecyl dimethyl ammonium chloride (DDAC)

PC Code 069149

DP Barcode:

From: Timothy F. McMahon, Ph.D

Senior Toxicologist

Antimicrobials Division (7510C)

To: Tracy Lantz, Chemical Review Manager

Regulatory Management Branch I

Antimicrobials Division (7510C)

[1.0 HAZARD CHARACTERIZATION 3](#__RefHeading___Toc131930515)

[2.0 TOXICOLOGY DATA REQUIREMENTS 5](#__RefHeading___Toc131930516)

[3.0 DATA GAPS 5](#__RefHeading___Toc131930517)

[4.0 HAZARD ASSESSMENT 6](#__RefHeading___Toc131930518)

[**4.1** **Acute Toxicity** 6](#__RefHeading___Toc131930519)

[**4.2** **Subchronic Toxicity** 7](#__RefHeading___Toc131930520)

[**4.3** **Prenatal Developmental Toxicity**
8](#__RefHeading___Toc131930521)

[**4.4** **Reproductive Toxicity** 9](#__RefHeading___Toc131930522)

[**4.5** **Chronic Toxicity** 10](#__RefHeading___Toc131930523)

[**4.6** **Carcinogenicity** 10](#__RefHeading___Toc131930524)

[**4.7** **Mutagenicity** 11](#__RefHeading___Toc131930525)

[**4.8** **Neurotoxicity** 12](#__RefHeading___Toc131930526)

[**4.9** **Metabolism and Pharmacokinetics**
12](#__RefHeading___Toc131930527)

[5.0 TOXICITY ENDPOINT SELECTION 12](#__RefHeading___Toc131930528)

[**5.1** **See Section 7.1, Summary of Toxicological Doses and Endpoint
Selection, Table 2.** 12](#__RefHeading___Toc131930529)

[**5.2** **Dermal Absorption** 12](#__RefHeading___Toc131930530)

[**5.3** **Classification of Carcinogenic Potential**
12](#__RefHeading___Toc131930531)

[6.0 FQPA CONSIDERATIONS 13](#__RefHeading___Toc131930532)

[**6.1** **Developmental Toxicity Study Conclusions**
13](#__RefHeading___Toc131930533)

[**6.2** **Reproductive Toxicity Study Conclusions**
13](#__RefHeading___Toc131930534)

[**6.3** **Pre-and/or Postnatal Toxicity**
14](#__RefHeading___Toc131930535)

[**6.4** **Recommendation for a Developmental Neurotoxicity Study**
14](#__RefHeading___Toc131930536)

[7.0 SUMMARY OF TOXICOLOGICAL DOSES AND ENDPOINTS FOR DDAC FOR USE IN
HUMAN RISK ASSESSMENT 15](#__RefHeading___Toc131930537)

[**7.1** **Summary Table of Toxicological Dose and Endpoint Selection**
15](#__RefHeading___Toc131930538)

[8.0 TOXICITY PROFILE TABLES 18](#__RefHeading___Toc131930539)

[**8.1** **Acute Toxicity Profile Table (Table 5).**
18](#__RefHeading___Toc131930540)

[LD~50~ = 4350 mg/kg (combined) 19](#__RefHeading___Toc131930541)

[LD~50~ = 4350 mg/kg (males) 19](#__RefHeading___Toc131930542)

[LD~50~ = 4350 mg/kg (females) 19](#__RefHeading___Toc131930543)

[**8.2** **Subchronic, Chronic and Other Toxicity Profiles Table (Table
6)** 21](#__RefHeading___Toc131930544)

[9.0 REFERENCES 25](#refheading___toc131930545)

[]{#__RefHeading___Toc131930515 .anchor}**1.0 HAZARD CHARACTERIZATION**

Number range CHAPTERPursuant to PR Notice 88-2, grouping of quaternary
ammonium compounds was allowed, based on the numerous chemical
structures that represent these types of chemicals. Grouping was allowed
into 4 broad categories, based on chemical structure: Group I quaternary
ammonium compounds (alkyl or hydroxy alkyl substituted compounds, DDAC
as representative); Group II non-halogenated benzyl substituted
quaternary ammonium compounds; Group III di- and tri-chlorobenzyl
substituted quaternary ammonium compounds; and Group IV, quaternary
ammonium compounds with unusual substituents. DDAC, or didecyl dimethyl
ammonium chloride, is, as stated above, a member of the Group I class of
quaternary ammonium compounds. Hazard data generated for DDAC is
representative of the hazard associated with this class of quaternary
ammonium chemicals.

DDAC was assigned Toxicity Category II in two acute oral toxicity
studies in rats, MRIDs 41394404 \[65% a.i.; LD~50~ = 262 mg/kg
(combined)\] and 42296101 \[80% a.i.; LD~50~ = 238 mg/kg (combined)\].
DDAC was assigned Toxicity Category III in two acute dermal toxicity
studies in rabbits, MRIDs 42053801 \[65% a.i.; LD~50~ = 2930 mg/kg
(combined)\] and 00071158 \[50% a.i.; LD~50~ = 4350 mg/kg (combined)\].
For acute inhalation toxicity (MRID 00145074; TRID 455201010), the
LC~50~ of DDAC (purity not reported) was reported as 0.7 mg/L; Toxicity
Category **III** was assigned. For primary eye irritation, DDAC was
found to be corrosive (Toxicity Category I) in two primary eye
irritation studies in rabbits, MRIDs 41394404 \[65% a.i.\] and 42161602
\[80% a.i\]. For primary dermal irritation, DDAC (80% a.i.) was found to
be corrosive (Toxicity Category I) in a primary dermal irritation study
in rabbits (MRID 42161601). For dermal sensitization, DDAC was found to
be a slight sensitizer in one dermal sensitization study in guinea pigs
(MRID 42161603 \[80% a.i.\]) and not a sensitizer in another (MRID
46367601 \[purity not reported\]).

For subchronic toxicity, the database includes a 90-day oral toxicity
test in rats (MRID 40966302), a 90-day oral study in dogs (MRID
40262901), two 21-day dermal toxicity studies with product formulations
(MRIDs 41105801 and 45656601), and a 90-day dermal toxicity study in
rats using the technical grade (MRID 41305901). In the 90-day rat oral
feeding study (MRID 40966302), incidence of gross pathological
observations and non-neoplastic lesions, including a higher incidence of
glycogen depletion in the liver and contracted spleens were observed. In
the 21-day dermal toxicity study in guinea pigs, MRIDs 40565301 and
41105801, a 1:5 dilution of HS sanitizing solution (containing 6% DDAC
and 4% alkyl dimethyl benzyl ammonium chloride) at the high dose (1000
mg/kg/day) resulted in skin irritation was observed in week 2 of the
study, body weights decreased in week 3 of the study, and a slight
elevation of basophils and eosinophils as well as a slight elevation of
SGPT and SGOT**.** In a 21-day dermal toxicity study in rats using
SS0853-01 ( 0.13% a.i., MRID 45656601), no toxicity was observed at any
dose level tested **.** In the 90-day dog feeding study (MRID 40269201),
no treatment-related clinical chemistry, hematology, urinalysis, or
pathological findings were observed.

In the 90-day dermal toxicity test in rats (MRID 41305901), systemic
toxicity was not observed and clinical and gross findings (erythema,
edema, exfoliation, excoriation and ulceration) were limited to the
treated skins.

For developmental toxicity, the data from two developmental toxicity
studies, one in the rat (MRID 41886701, range-finder MRID 42746901) and
another in the rabbit (MRID 41018701), do not indicate Number range
CHAPTERincreased susceptibility in rats or rabbits from *in utero* and
postnatal exposure to DDAC. In the rat developmental toxicity study
(MRID 41886701), developmental toxicity (skeleton variations) was
observed only at treatment levels which also resulted in maternal
toxicity (audible respiration). In the rabbit developmental toxicity
study, developmental toxicity (decreased fetal body weight and increased
number of dead fetuses) occurred at levels which also resulted in
maternal toxicity (hypo activity, audible respiration, and decreased
body weight gain).

For reproductive toxicity, the toxicity database for DDAC includes a
2-generational reproductive toxicity study in rats (MRID 41804501). In
this study, 28/sex/dose (both F0 and F1) Sprague-Dawley CD rats were fed
a diet containing DDAC (80.8% a.i.) at dosage levels of 0, 300, 750, or
1500 ppm (during premating, for both sexes = 22, 56, and 133 mg/kg/day).
The effects in offspring (decreased pup body weight/weight gain)
occurred at the same dose level as maternal effects (decreased maternal
body weight/weight gain and food consumption), 1500 ppm. The NOAEL for
this study is 750 ppm (56 mg/kg/day) and the LOAEL for this study is
1500 ppm (113 mg/kg/day).

In a 1-year dog feeding study (MRID 41970401), beagle dogs were given
doses of 0, 3, 10, or 20/30 mg/kg/day in the diet. Treatment-related
clinical signs (soft/mucoid feces, emesis) were observed frequently in
high-dose animals, and total cholesterol levels were significantly
decreased in high-dose females.

DDAC was not carcinogenic when administered in the diet in 2-year
chronic/ carcinogenicity studies in rats (MRID 41965101) and mice (MRID
41802301). In the rat study, an increase in incidence of interstitial
cell adenomas in the tested were reported, but the incidence was with in
the range of historical controls. In the mouse study, no
treatment-related effects were noted in the incidence of clinical signs,
deaths, and gross and histopathological observations.

For mutagenicity, DDAC was negative in a battery of tests. In the Ames
test (MRID 40282201, supplemental information MRID 44005801), DDAC was
not mutagenic with or without metabolic activation. In a forward gene
mutation test (MRID 93014008, reformat of 40895202), DDAC was negative
for induction of gene mutations in CHO cells at the HGPRT locus with and
without metabolic activation. In an in vitro chromosome aberration test
(MRID 41252601), Number range CHAPTERDDAC did not induce chromosome
aberration in the Chinese hamster ovary (CHO) cells with or without
metabolic activation. In an unscheduled DNA synthesis (UDS) assay (MRID
93014007, reformat of 40895201), DDAC did not cause UDS in primary rat
hepatocytes.

Although there are no neurotoxicity studies available in the database,
the available toxicity for DDAC show no evidence for neurotoxic effects.

Number range CHAPTERIn a rat pharmacokinetics/ metabolism study (MRID
41617101 and addendum MRID 41385101), single oral doses of ^14^C-DDAC (5
or 50 mg/kg) or repeated dose (34 ppm of DDAC in the diet for 14 days
and then one single dose of 5 mg/kg of ^14^C-DDAC) were given to both
male and female rats. DDAC was mostly excreted in the feces within 3
days principally as parent compound and metabolites. The elimination
pattern and metabolic profile was not substantially altered by the dose
or exposure duration. Male and female rats showed similar elimination
patterns, but females metabolized DDAC more extensively than males. Four
major metabolites were identified as oxidation products with oxidation
confined to the decyl side chains.

[]{#__RefHeading___Toc131930516 .anchor}**2.0 TOXICOLOGY DATA
REQUIREMENTS**

Number range CHAPTERThe Toxicology database for DDAC is listed in the
following table.

+-----------------------------------------+-------------+-------------+
| **Table 1: Toxicologic Data             |             |             |
| Requirements for DDAC.**                |             |             |
+=========================================+=============+=============+
| **Test**                                | **          |             |
|                                         | Technical** |             |
+-----------------------------------------+-------------+-------------+
|                                         | *           | **          |
|                                         | *Required** | Satisfied** |
+-----------------------------------------+-------------+-------------+
| 870.1100 Acute Oral Toxicity (Rat)      | yes         | yes         |
| MRIDs 41394404, 42296101                |             |             |
|                                         | yes         | yes         |
| 870.1200 Acute Dermal Toxicity (Rabbit) |             |             |
| MRIDs 42053801, 00071158                | yes         | yes         |
|                                         |             |             |
| 870.1300 Acute Inhalation (Rat) MRID    | yes         | yes         |
| 00145074                                |             |             |
|                                         | yes         | yes         |
| 870.2400 Primary Eye Irritation         |             |             |
| (Rabbit) MRIDs 41394404,                | yes         | yes         |
|                                         |             |             |
| 42161602                                |             |             |
|                                         |             |             |
| 870.2500 Primary Dermal Irritation      |             |             |
| (Rabbit) MRIDs 42161601                 |             |             |
|                                         |             |             |
| 870.2600 Dermal Sensitization (Guinea   |             |             |
| pig) MRIDs 42161603, 46367601           |             |             |
+-----------------------------------------+-------------+-------------+
| 870.3100 Oral Subchronic (Rat) MRID     | yes         | yes         |
| 40966302                                |             |             |
|                                         | yes         | yes         |
| 870.3150 Oral Subchronic (Dog) MRID     |             |             |
| 40262901                                | yes         | yes         |
|                                         |             |             |
| 870.3250 90-Day Dermal (Rat) MRID       |             |             |
| 41305901                                |             |             |
+-----------------------------------------+-------------+-------------+
| 870.3700a Developmental Toxicity (Rat)  | yes         | yes         |
| MRID 41886701, range-finding MRID       |             |             |
| 42746901                                | yes         | yes         |
|                                         |             |             |
| 870.3700b Developmental Toxicity(       | yes         | yes         |
| Rabbit) MRID 41018701                   |             |             |
|                                         |             |             |
| 870.3800 Reproduction (Rat) MRID        |             |             |
| 41804501                                |             |             |
+-----------------------------------------+-------------+-------------+
| 870.4100 Chronic (Dog) MRID 41970401    | yes         | yes         |
|                                         |             |             |
| 870.4300 Chronic/Carcinogenicity (Rat)  | yes         | yes         |
| MRID 41965101                           |             |             |
|                                         | yes         | yes         |
| 870.4300 Chronic/Carcinogenicity        |             |             |
| (Mouse) MRID 41802301                   |             |             |
+-----------------------------------------+-------------+-------------+
| 870.5100 Mutagenicity -- Bacterial      | yes         | yes         |
| Reverse Gene Mutation assay MRIDs       |             |             |
| 40282201, supplemental information      | yes         | yes         |
| 44005801                                |             |             |
|                                         | yes         | yes         |
| 870.5300 Mutagenicity -- Forward gene   |             |             |
| mutation test (HGPRT) MRID 93014008,    | yes         | yes         |
| reformat of 40895202                    |             |             |
|                                         |             |             |
| 870.5375 Mutagenicity -- Chromosome     |             |             |
| aberrations (CHO) MRID 41252601         |             |             |
|                                         |             |             |
| 870.5550 Mutagenicity -- Unscheduled    |             |             |
| DNA synthesis in primary rat            |             |             |
| hepatocytes MRID 93014007, reformat of  |             |             |
| 40895201                                |             |             |
+-----------------------------------------+-------------+-------------+
| 870.6100 Acute Delayed Neurotox. (Hen)  | no          | \-          |
|                                         |             |             |
| 870.6200 Acute Neurotox. Screening      | no          | \-          |
| Battery (Rat)                           |             |             |
|                                         | no          | \-          |
| 870.6300 Develop. Neuro                 |             |             |
+-----------------------------------------+-------------+-------------+
| 870.7485 Metabolism and                 | yes         | yes         |
| Pharmacokinetics MRID 41617101 and      |             |             |
| addendum MRID 41385101                  |             |             |
+-----------------------------------------+-------------+-------------+

[]{#__RefHeading___Toc131930517 .anchor}**3.0 DATA GAPS**

There are no data gaps in the toxicity database for DDAC.

[]{#__RefHeading___Toc131930518 .anchor}**4.0 HAZARD ASSESSMENT**

[]{#__RefHeading___Toc131930519 .anchor}**4.1 Acute Toxicity**

[Adequacy of database for Acute Toxicity]{.underline}: [Number range
CHAPTER]{.mark} DDAC was assigned Toxicity Category II in two acute oral
toxicity studies in rats, MRIDs 41394404 \[65% a.i.; LD~50~ = 262 mg/kg
(combined)\] and 42296101 \[80% a.i.; LD~50~ = 238 mg/kg (combined)\].
DDAC was assigned Toxicity Category III in two acute dermal toxicity
studies in rabbits, MRIDs 42053801 \[65% a.i.; LD~50~ = 2930 mg/kg
(combined)\] and 00071158 \[50% a.i.; LD~50~ = 4350 mg/kg (combined)\].
For acute inhalation toxicity (MRID 00145074; TRID 455201010), the
LC~50~ of DDAC (purity not reported) was reported as 0.07 mg/L; Toxicity
Category **I** was assigned. For primary eye irritation, DDAC was found
to be corrosive (Toxicity Category I) in two primary eye irritation
studies in rabbits, MRIDs 41394404 \[65% a.i.\] and 42161602 \[80%
a.i\]. For primary dermal irritation, DDAC (80% a.i.) was found to be
corrosive (Toxicity Category I) in a primary dermal irritation study in
rabbits (MRID 42161601). Two dermal sensitization studies (one
photoallergyl sensitization study in guinea pigs using BARDAC 2280 80%
a.i. \[MRID 42161603\]) and another dermal sensitization study in guinea
pigs using BARDAC 2280 80% a.i. (MRID 46367601) show that DDAC is not a
dermal sensitizer. The acute toxicity data for DDAC are summarized below
in Table 2.

+---------+-----------------+-------------+---------------+---------+
| **Table |                 |             |               |         |
| 2.      |                 |             |               |         |
| Acute   |                 |             |               |         |
| T       |                 |             |               |         |
| oxicity |                 |             |               |         |
| Profile |                 |             |               |         |
| for     |                 |             |               |         |
| DDAC**  |                 |             |               |         |
+=========+=================+=============+===============+=========+
| **Gu    | **Study Type/   | **MRID      | **Results**   | **T     |
| ideline | Test substance  | Number/     |               | oxicity |
| N       | (% a.i.)**      | Citation**  |               | Cat     |
| umber** |                 |             |               | egory** |
+---------+-----------------+-------------+---------------+---------+
| 8       | Acute oral, rat | MRID        | Number range  | II      |
| 70.1100 |                 | 41394404    | CHAPTERLD~50~ |         |
|         | (Purity 65%)    |             | =262 mg/kg    |         |
| (§81-1) |                 |             | (combined)    |         |
|         |                 |             |               |         |
|         |                 |             | Number range  |         |
|         |                 |             | CHAPTERLD~50~ |         |
|         |                 |             | =331 mg/kg    |         |
|         |                 |             | (males)       |         |
|         |                 |             |               |         |
|         |                 |             | Number range  |         |
|         |                 |             | CHAPTERLD~50~ |         |
|         |                 |             | =238 mg/kg    |         |
|         |                 |             | (females)     |         |
+---------+-----------------+-------------+---------------+---------+
| 8       | Acute oral, rat | MRID        | Number range  | II      |
| 70.1100 |                 | 42296101    | CHAPTERLD~50~ |         |
|         | (Purity 80%)    |             | =238 mg/kg    |         |
| (§81-1) |                 |             | (combined)    |         |
+---------+-----------------+-------------+---------------+---------+
| 8       | Acute dermal,   | MRID        | Number range  | III     |
| 70.1200 | rabbit          | 42053801    | CHAPTERLD~50~ |         |
|         |                 |             | =2930 mg/kg   |         |
| (§81-2) | (Purity 65%)    |             | (combined)    |         |
|         |                 |             |               |         |
|         |                 |             | Number range  |         |
|         |                 |             | CHAPTERLD~50~ |         |
|         |                 |             | =3140 mg/kg   |         |
|         |                 |             | (males)       |         |
|         |                 |             |               |         |
|         |                 |             | Number range  |         |
|         |                 |             | CHAPTERLD~50~ |         |
|         |                 |             | =2730 mg/kg   |         |
|         |                 |             | (females)     |         |
+---------+-----------------+-------------+---------------+---------+
| 8       | Acute           | MRID        | Number range  | I       |
| 70.1300 | inhalation, rat | 00145074    | CHAPTERLC~50~ |         |
|         |                 |             | (combined) =  |         |
| (§81-3) | (Purity not     | TRID        | 0.07 mg/L     |         |
|         | reported)       | 455201010   |               |         |
+---------+-----------------+-------------+---------------+---------+
| 8       | Primary eye     | MRID        | Number range  | I       |
| 70.2400 | irritation,     | 41394404    | CHAP          |         |
|         | rabbit          |             | TERCorrosive. |         |
| (§81-4) |                 |             |               |         |
|         | (Purity 65%     |             |               |         |
|         | a.i.)           |             |               |         |
+---------+-----------------+-------------+---------------+---------+
| 8       | Primary eye     | MRID        | Number range  | I       |
| 70.2400 | irritation,     | 42161602    | CHAP          |         |
|         | rabbit          |             | TERCorrosive. |         |
| (§81-4) |                 |             |               |         |
|         | (Purity 80%     |             |               |         |
|         | a.i.)           |             |               |         |
+---------+-----------------+-------------+---------------+---------+
| 8       | Primary dermal  | MRID        | Corrosive.    | I       |
| 70.2500 | irritation,     | 42161601    |               |         |
|         | rabbit          |             |               |         |
| (§81-5) |                 |             |               |         |
|         | (Purity 80%)    |             |               |         |
+---------+-----------------+-------------+---------------+---------+
| 8       | Dermal          | MRID        | Not a         | NA      |
| 70.2600 | sensitization,  | 46367601    | sensitizer.   |         |
|         | guinea pigs     |             |               |         |
| (§81-6) |                 |             |               |         |
|         | (Purity 80%)    |             |               |         |
+---------+-----------------+-------------+---------------+---------+

[]{#__RefHeading___Toc131930520 .anchor}**4.2 Subchronic Toxicity**

[Adequacy of database for Subchronic Toxicity]{.underline}: Number range
CHAPTERThe database for subchronic toxicity of DDAC is considered
complete. For oral toxicity, the database includes two studies, a 90-day
oral toxicity test in rats (MRID 40966302) and a 90-day oral study in
dogs (MRID MRID 40262901). For dermal toxicity, there are two 21-day
dermal studies using DDAC formulations, one in the rat (MRID 45656601)
and one in the guinea pig (MRIDs 40565301 and 41105801) and there is a
90-day dermal toxicity study using DDAC**,** technical grade, in rats
(MRID 41305901).

**870.3100 Subchronic (Oral) Toxicity - Rat**

Number range CHAPTERIn a 90-day rat feeding study (MRID 40966302), male
and female rats were given diets containing 0, 100, 300, 600, 1000, and
3000 ppm (respective mg/kg/day equivalents; 0, 6.2, 18.5, 36.8, 60.7 and
175 for males; 0, 7.5, 22.3, 44.4, 74.3 and 225.5 for females) DDAC for
13 weeks. High-dose animals showed increased mortality, decreased mean
body weights, body weight gain and food consumption, and increased
incidence of gross pathological observations and non-neoplastic lesions,
including a higher incidence of glycogen depletion in the liver and
contracted spleens. Additionally, high-dose females showed sinus
erythrocytosis and lymphoid hyperplasia of mesenteric lymph nodes.

From the results of this study, the NOAEL is 60.7 mg/kg/day for males
and 74.3 mg/kg/day for females. The LOAEL is 175.4 mg/kg/day for males
and 225.5 mg/kg/day for females. The LOAEL is based on increased
mortality, decreased mean body weights, body weight gain and food
consumption, and increased incidences of gross pathological lesions.

This study is classified as **acceptable**.

**870.3150 Subchronic (Oral) Toxicity - Dog**

Number range CHAPTERNumber range CHAPTERIn a 90-day dog feeding study
(MRID 40262901), male and female beagle dogs were given DDAC at doses of
0, 5, 15 and 50 mg/kg/day. High-dose animals experienced marked decrease
in body weight gain, food consumption and food efficiency. Clinical
chemistry, hematology, urinalysis, and pathological results did not
reveal any treatment-related effects.

Based on decreased body weight gain, food consumption and food
efficiency, for both males and females, the NOAEL is 15 mg/kg/day, and
the LOAEL is 50 mg/kg/day.

This study is classified as **acceptable**.

3250. **Subchronic (21-day dermal) Toxicity -- Guinea pig**

In a 21‑day dermal toxicity study (MRIDs 40565301 and 41105801), a 1:5
dilution of HS‑sanitizing carpet shampoo (containing 6% didecyl dimethyl
ammonium chloride and 4% alkyl dimethyl benzyl ammonium chloride) was
applied to a 2 inch square area of the shaved dorsal trunk of 5 male and
5 female guinea pigs at doses of 500 and 1000 mg/kg, five days a week,
for 21 days. Actual doses to the skin based on 6% DDAC in the
formulation were calculated to be 30 and 65 mg/kg a.i. (communication
from registrant). There was no mortality or signs of clinical toxicity
noted. Signs of skin irritation were noted during the second week of
treatment and the report stated that the response intensified during the
third week of treatment. Body weight was decreased in treated males and
females by 7% and 11% vs untreated animals at week 3. Results of
hematology and clinical chemistry measurements indicated a slight
elevation of basophils and eosinophils as well as a slight elevation of
SGPT and SGOT but statistics were not performed on these data.
Histologically, the skin irritation was described as sloughing of the
stratum corneum as a result of defatting.

Although this study was identified with several deficiencies (HED
document 007757, from the 1/31/90 review by Pamela Hurley, Ph.D.), the
data are useful for determining a level of concern for dermal irritation
and systemic effects after short‑term exposure to ADBAC. In this case,
the 500 mg/kg dose level (30 mg/kg a.i.)produced no significant dermal
or systemic effects, and is considered a NOAEL for the study for dermal
irritation and systemic effects.

**870.3200 Subchronic (21-day dermal) Toxicity -- Rat**

Number range CHAPTERIn a 21-day dermal toxicity study (MRID 456566-01),
SS0853.01 (100% pure) was administered directly to the skin of CD
\[Crl:CD (SD) IGS BR\] rats (10/sex/group) at doses of 100, 500, and
1000 mg/kg-day. The dermal route of exposure was chosen because it is a
possible route of human exposure. Doses for this study were determined
by the Sponsor to achieve a gradient of toxic effects. The high-dose
level was selected per OPPTS 870-3200 and was considered to show signs
of toxicity. The mid-dose level was selected as an additional dose in
order to evaluate any potential toxicological effects.

No treatment-related effects on clinical observations (including
expanded clinical observations), motor activity, dermal irritation,
ophthalmic observations, body weights or body weight changes, food
consumption, clinical pathology parameters, terminal body weights, mean
absolute or relative organ weights, or macroscopic or microscopic
observations were observed. Analyses of hindlimb strength, food
consumption, hematology and clinical chemistry parameters, and relative
organ weights showed significantly reduced hindlimb strength in female
rats at 500 and 1000 mg/kg/day. However, there were no other indications
of effects on motor function in male or female rats at any dose tested.
Numerous microscopic changes in the liver were observed, but were noted
to be test system-related due to the torso wrapping procedure. The
systemic NOAEL for SS0853-01 is 1000 mg/kg-day in this study, and the
systemic LOAEL is \> 1000 mg/kg/day.

**This study is classified as Acceptable -- Guideline.**

**870.3250 Subchronic (90-day dermal) Toxicity -- Rat**

Number range CHAPTERIn a 90-day rat dermal study (MRID 41305901),
Sprague-Dawley rats (15/sex/group) received repeated dermal dosing of
the test compound at 0, 2, 6, and 12 mg/kg/day for 6 hours/day, 5
days/week for 13 weeks. No treatment-related effects were noticed in
mortality, weight gain, food consumption, or systemic toxicity. Toxicity
was limited to treated skin of mid-dose females and high-dose males and
females. The clinical and gross findings (erythema, edema, exfoliation,
excoriation and ulceration) were confirmed by histopathological
examination, where increased incidence of hyperkeratosis, acanthosis,
epidermitis, dermatitis and ulceration were noted.

The systemic NOAEL is gr**e**ater than 12 mg/kg/day (highest dose
tested). The dermal LOAEL for dermal toxicity is 6 mg/kg/day. The dermal
NOAEL is 2 mg/kg/day.

This study is classified as **Acceptable -- Guideline**.

[]{#__RefHeading___Toc131930521 .anchor}**4.3 Prenatal Developmental
Toxicity**

[Adequacy of database for Prenatal Developmental Toxicity]{.underline}:
Number range CHAPTERThe database for developmental toxicity of DDAC is
considered complete. The database includes 2 developmental studies, one
in the rat (MRID 41886701) and another in the rabbit (MRID 41018701).

**870.3700 Prenatal Developmental Toxicity (Gavage) Study -- Rat**

Number range CHAPTERIn a rat developmental toxicity study (MRID
41886701, and range-finding MRID 42746901), female Sprague-Dawley rats
(25/group) were administered DDAC (80.8% a.i.) in deionized water orally
by gavage at doses of 0, 1, 10, and 20 mg/kg/day on gestation days (GD)
6-15, inclusive. On GD 21, dams were sacrificed, subjected to gross
necropsy, and all fetuses examined externally, viscerally, and
skeletally for malformations/variations. Maternal toxicity was observed
at the mid and high dose group in the form of audible respiration with
the high dose presenting with other observations. Further, a treatment
related decrease in body weight gain was noted during the dosing period
(gestation days 6-15), the dosing period plus post dosing period
(gestation days 6-21) and for the corrected body weight gains for the
high dose. There was also low food efficiency compared with controls
during the dosing period for the mid and high dose group.

The maternal LOAEL is 10 mg/kg/day, based on reductions in body weight
gain and clinical signs of toxicity (audible respiratory). The maternal
NOAEL is 1 mg/kg/day**.** Developmental toxicity was noted at the high
dose in the form of increased incidences of skeletal variations.
Therefore, the developmental toxicity LOAEL is 20 mg/kg/day based on an
increased incidence of skeletal variations, and the developmental
toxicity NOAEL is 10 mg/kg/day.

This study is classified as **acceptable**.

**870.3700 Prenatal Developmental Toxicity (Gavage) Study -- Rabbit**

Number range CHAPTERIn a rabbit developmental toxicity study (MRID
410187-01), female New Zealand White rabbits (16/group) were
administered DDAC (80.8% a.i.) daily via gavage at dose levels of 0, 1,
3, and 10 mg/kg/day on gestational days 6-18, inclusive. Maternal
toxicity was observed at the mid and high dose group in the form of hypo
activity, labored and/or audible respiration, and decreased body weight
gain during the dosing period. In addition, at 10 mg/kg/day, there was
an increased incidence of mortality. Therefore, the maternal LOAEL is 3
mg/kg/day, based on reductions in body weight gain and clinical signs of
toxicity (hypo activity and audible respiratory).

The maternal NOAEL is 1 mg/kg/day**.** Developmental toxicity was noted
at high dose in the form of decreased fetal body weight and increased
number of dead fetuses. Therefore, the developmental toxicity LOAEL is
10 mg/kg/day based on decreased fetal body weight and increased number
of dead fetuses. The developmental toxicity NOAEL is 3 mg/kg/day.

This study is classified as **acceptable**.

[]{#__RefHeading___Toc131930522 .anchor}**4.4 Reproductive Toxicity**

[Adequacy of database for Reproductive:]{.underline} Number range
CHAPTERThe database for reproductive toxicity of DDAC is considered
complete. The database includes an acceptable 2-generation reproduction
toxicity study in rats, MRID 41804501.

3800. **Reproduction and Fertility Effects -- Rat**

Number range CHAPTERIn a two-generation reproduction study (MRID
418045-01), 28/sex/dose ( both F0 and F1) Sprague-Dawley CD Rats were
fed a diet containing DDAC (80.8% a.i.) at dosage levels of 0, 300, 750,
and 1500ppm (during premating, for both sexes = 22, 56, and 113
mg/kg/day, for males = 20, 50, and 103 mg/kg/day and for females = 24,
61, and 122 mg/kg/day). No compound-related mortalities were observed in
either sex or generation. No compound-related clinical signs were
observed in either sex or generation.

Based on decreased body weight/weight gain and food consumption, the
parental Toxicity NOAEL = 750ppm (56 mg/kg/day); LOAEL = 1500ppm (113
mg/kg/day) . Based on decreased pup body weight/weight gain, the
reproductive toxicity NOAEL = 750ppm (56 mg/kg/day); LOAEL = 1500ppm
(113 mg/kg/day).

This study is classified as **acceptable**.

[]{#__RefHeading___Toc131930523 .anchor}**4.5 Chronic Toxicity**

[Adequacy of database for Chronic Toxicity]{.underline}: Number range
CHAPTERThe database for chronic toxicity of DDAC is considered adequate,
including a chronic oral toxicity study in dogs (MRID 41970401).

**870.4100 Chronic Toxicity (Oral feed) -- Dog**

Number range CHAPTERIn a chronic, 1-year toxicity study (MRID 41970401),
males and female beagle dogs were administered DDAC (80.8% a.i.) at
dosage levels of 0, 3, 10 and 20/30 mg/kg/day (dosing at 30 mg/kg/day
was not tolerated well and was discontinued on day 31; dosing was
resumed at day 36 at 20mg/kg/day). No treatment-related deaths occurred
during the study. The treatment-related clinical signs (soft/mucoid
feces, emesis) were observed frequently in high-dose animals. Hematology
or urinalysis results were normal. Total cholesterol levels were
significantly decreased in high-dose females. Gross and
histopathological findings did not reveal any treatment-related effects.

Based on increased incidence of clinical observations (emesis and
soft/mucoid feces) in males and females and decreased total cholesterol
levels in females, the NOAEL for both male and females is 10 mg/kg/day,
and the LOAEL is 20 mg/kg/day.

This study is classified as **Acceptable -- Guideline.**

[]{#__RefHeading___Toc131930524 .anchor}**4.6 Carcinogenicity**

[Adequacy of database for Carcinogenicity]{.underline}: The database for
the carcinogenicity of DDAC is considered adequate. The database for
carcinogenicity includes two combined chronic/carcinogenicity studies,
one in the rat (MRID 41965101) and one in the mouse (MRID 41802301).

**870.4300 Combined Chronic /Carcinogenicity (Oral) -- Rat**

Number range CHAPTERIn a two-year rat carcinogenicity study (MRID
41965101), 60 Sprague-Dawley CD rats per sex per group were fed diets
containing DDAC (80.8% a.i.) at 0, 300, 750 or 1500 ppm (mg/kg/day
equivalents: 0, 13, 32, and 64 for males and 0, 16, 41, and 83 for
females) for two years. High-dose animals showed significant, but slight
(\<10%) decreases in mean body weight during the study. Treatment
related effects consisted of increased incidence of sinusoidal blood,
hemosiderosis and histiocytosis in the mesenteric lymph nodes of high
dose animals. In addition, an increase in the incidence of interstitial
cell adenomas in testes was reported. In this study, the incidences of
this tumor for control and treated animals are: Control 1 (5%, 3/60);
Control 2 (5% 3/60), 300ppm (12.5%, 1/8), 750ppm (17.9%, 5/28), and
1500ppm (11.7%, 6/60). However, because the incidence was within the
historical incidence range, this effect was not considered treatment
related. (See **Table 3**)

**Table 3: Incidence of Testicular Interstitial Adenomas in Male
Sprague-Dawley Rats for the Studies conducted at Bushy Run Research
Center since 1987 ^1,2^**

  ------------------ --------------------- -------------- ---------- ---------- ---------- ----------
  **Study**          **Dates of In-Life    **Group^3^**                                    
                     Phase**                                                               

  **DDAC**           **06/3/88 to          **3/60**       **3/60**   **1/18**   **5/28**   **7/60**
                     06/19/90**                                                            

  **Historical       **03/22/88 to         **3/59**       **1/60**   **-**      **-**      **-**
  Control #1**       03/27/90**                                                            

  **Historical       **03/08/89 to         **4/59**       **7/60**   **-**      **-**      
  Control #2**       03/13/91**                                                            

  **Historical       **04/29/91 to         **1/60**       **6/60**   **-**      **-**      **-**
  Control #3**       05/04/93**                                                            
  ------------------ --------------------- -------------- ---------- ---------- ---------- ----------

Note: 1. Data provided by Bushy Run Research Center (1995, MRID
43613801).

2.  All rats were from Charles River Breeding Laboratories, Portage MI.

3.  C~1~ - Control Group 1; C~2~ - Control Group 2; L - Low-dose Group;
    M - Mid -dose Group; and H- High-dose group.

**The NOEL for both sexes is 750 ppm. The LOEL for both sexes is 1500
ppm, based on increased incidence of nonneoplastic lesionsin the
mesenteric lymph nodes.**

**This study is classified as Acceptable -- Guideline.**

**870.4300 Combined Chronic/Carcinogenicity (Oral) -- Mouse**

Number range CHAPTERIn a 78-week mouse feeding carcinogenicity study
(MRID 41802301), 60 CD-1 mice per sex per group were fed diets
containing DDAC (Batch \# B-1889, 80.8% a.i.) at levels of 0, 100, 500
or 1000 ppm (mg/kg/day equivalents:0, 15.0, 76.3, and 155.5 for males
and 0, 18.6, 93.1, and 193.1 for females). No treatment-related effects
were noted in the incidence of clinical signs, deaths, gross and
histopathological observations. Hematological values were comparable
among all study groups.

The **NOAEL** for both male and females is 500 ppm (76.3 mg/kg/day for
males and 93.1 mg/kg/day for females), and the **LOAEL** is1500ppm
(155.5 mg/kg/day for males; 193.1 mg/kg/day for females). The **LOAEL**
is based on decreases in mean body weights and body weight gains.

**At the dose level tested, DDAC was not carcinogenic.**

This study is classified as **Acceptable -- Guideline**.

[]{#__RefHeading___Toc131930525 .anchor}**4.7 Mutagenicity**

Number range CHAPTERIn the Ames test, with or without the microsomal
activation (S-9 fraction), DDAC was not mutagenic to *Salmonella
typhimurium* tester strains (MRID 40282201 and supplemental information
MRID 44005801).

In a forward gene mutation assays (MRID 93014008, reformat of 40895202)
demonstrated that DDAC was negative for induction of gene mutations in
CHO cells at the HGPRT locus, with levels of DDAC ranging from 1-10
μg/ml without S9 induction and 1-26 μg/ml with S9 induction. Severe
toxicity was demonstrated at doses of **≥**10 μg/ml (-S9) and **≥ 25**
μg/ml (+S9).

In an *in vitro* chromosome aberration test (MRID 41252601), DDAC failed
to induce chromosome aberrations in Chinese hamster ovary (CHO) cells
harvested 26 hours after exposure to DDAC at concentrations of 1-8 μg/ml
without microsomal fraction (S9) induction or DDAC at concentrations of
2-8 μg/ml with S9 induction. Cytotoxic effects were observed at DDAC
concentrations 16 μg/ml (with or without S9).

In an *in vitro* mutagenicity test (MRID 93014007, reformat of
40895201), DDAC did not induce unscheduled DNA Synthesis (UDS) in
primary rat hepatocytes treated with DDAC at doses up to 2.00 μg/ml.
Higher concentrations (4.0 μg/mL) of DDAC were severely cytotoxic.

[]{#__RefHeading___Toc131930526 .anchor}**4.8 Neurotoxicity**

[Adequacy of database for Neurotoxicity]{.underline}: Number range
CHAPTERNumber range CHAPTERAlthough a neurotoxicity study is not
available in the database, the available toxicity data for DDAC show no
evidence for neurotoxic effects.

[]{#__RefHeading___Toc131930527 .anchor}**4.9 Metabolism and
Pharmacokinetics**

[Adequacy of database for Metabolism and Pharmacokinetics]{.underline}:
Number range CHAPTERNumber range CHAPTERIn a rat pharmacokinetics/
metabolism study (MRID 41617101 and addendum 41385101), single oral
doses of ^14^C-DDAC (5 or 50 mg/kg) or repeated dose (34 ppm of DDAC in
the diet for 14 days and then one single dose of 5 mg/kg of ^14^C-DDAC)
were gave to both male and female rats. DDAC was mostly excreted in the
feces within 3 days principally as parent compound and metabolites. The
elimination pattern and metabolic profile was not substantially altered
by the dose or exposure duration. Male and female rats showed similar
elimination patterns, but females metabolized DDAC more extensively than
males. Four major metabolites were identified as oxidation products with
oxidation confined to the decyl side chains.

[]{#__RefHeading___Toc131930528 .anchor}**5.0 TOXICITY ENDPOINT
SELECTION**

[]{#__RefHeading___Toc131930529 .anchor}**5.1 See Section 7.1, Summary
of Toxicological Doses and Endpoint Selection, Table 2.**

[]{#__RefHeading___Toc131930530 .anchor}**5.2 Dermal Absorption**

[Dermal Absorption Factor]{.underline}: Number range CHAPTERThe dermal
absorption factor is not required since route appropriate toxicity data
are available for DDAC.

[]{#__RefHeading___Toc131930531 .anchor}**5.3 Classification of
Carcinogenic Potential**

**Number range CHAPTERDDAC** is not likely to be a human carcinogen
based on following reasons:

1.  All the DDAC mutagenicity studies were negative;

2.  and DDAC was not carcinogenic in the rat and mouse carcinogenic
    studies (MRIDs 41965-01 and 418023-01)

Therefore, the Health Effects Division (HED) Hazard Identification
Assessment Review Committee (HIARC) reviewed the data and classified
DDAC as not likely to be a human carcinogen based on the lack of
evidences of carcinogenicity in mice or rats (EPA, 2000).

6.  []{#__RefHeading___Toc131930532 .anchor}**FQPA CONSIDERATIONS**

There is no evidence DDAC will induce neurotoxic effects. In addition,
there is no quantitative or qualitative evidence of increased
susceptibility to fetus following *in utero* exposure in the prenatal
developmental toxicity studies or in the offspring when exposed to
adults in the two generation reproductive study. Therefore, DDAC will
not cause FQPA concern.

1.  []{#__RefHeading___Toc131930533 .anchor}**Developmental Toxicity
    Study Conclusions**

In the developmental toxicology ‑ Rabbits (MRID \#~~:~~ 410187‑01),
female New Zealand White Rabbits (16/dose) were administered DDAC (81%
a.i.) via gavage on gestation days 6 -- 18, inclusive, at dose levels of
0, 1, 3, or 10 mg/kg/day. The maternal toxicity NOAEL = 1 mg/kg/day;
LOAEL = 3 mg/kg/day based on increased incidence of clinical signs (hypo
activity, labored and/or audible respiration) and decreased body weight
gain during the dosing period. The developmental toxicity NOAEL = 3
mg/kg/day; LOAEL = 10 mg/kg/day based on decreased fetal body weight and
an increased number of dead fetuses reported.

In the developmental toxicology ‑ Rats (MRID \#~~:~~ 418867‑01), female
Sprague‑Dawley CD Rats (25/dose) were administered DDAC via gavage on
gestation days 6 -- 15, inclusive, at dose levels of 0, 1, 10 and 20
mg/kg/day. The maternal toxicity NOAEL = 1 mg/kg/day; LOAEL = 10
mg/kg/day based on decreased body weight/weight gain. The developmental
toxicity NOAEL = 10 mg/kg/day; LOAEL = 20 mg/kg/day based on several
variations were reported (split anterior arch of the atlas, poorly
ossified thoracic centrum, bilobed thoracic centrum, unilateral short
rib, poorly ossified parietal, and poorly ossified sternebrae).

[]{#__RefHeading___Toc131930534 .anchor}**6.2 Reproductive Toxicity
Study Conclusions**

In the two generation Reproductive toxicity ‑ Rats (MRID #: 418045‑01),
Sprague-Dawley CD Rats (28/sex/dose) were fed a diet containing DDAC
(80.8% a.i.) at dosage levels of 0, 300, 750, or 1500ppm (during
premating, for males = 20, 50, or 103 mg/kg/day and for females = 24,
61, or 122 mg/kg/day). Reproductive Toxicity NOAEL = 750ppm (56
mg/kg/day); LOAEL = 1500ppm (113 mg/kg/day) based on decreased pup body
weight/weight gain were reported.

[]{#__RefHeading___Toc131930535 .anchor}**6.3 Pre-and/or Postnatal
Toxicity**

A. [Determination of Susceptibility:]{.underline} There was no
quantitative or qualitative evidence of increased susceptibility to rat
or rabbit fetus following *in utero* exposure in the prenatal
developmental toxicity studies or in the offspring when exposed to
adults in the two generation reproductive study.

B. [Proposed Hazard-based Special FQPA Safety Factor(s)]{.underline}:
Number range CHAPTERThe HIARC recommended that the FQPA safety factor be
removed for DDAC because there is no quantitative or qualitative
evidence of increased susceptibility to fetus following *in utero*
exposure in the prenatal developmental toxicity studies or in the
offspring when exposed to adults in the two generation reproductive
study.

[]{#__RefHeading___Toc131930536 .anchor}**6.4 Recommendation for a
Developmental Neurotoxicity Study**

The Committee concluded that evidence does not support a need for a
Developmental Neurotoxicity study.

[]{#__RefHeading___Toc131930537 .anchor}**7.0 SUMMARY OF TOXICOLOGICAL
DOSES AND ENDPOINTS FOR DDAC FOR USE IN HUMAN RISK ASSESSMENT**

[]{#__RefHeading___Toc131930538 .anchor}**7.1 Summary Table of
Toxicological Dose and Endpoint Selection**

+-------------------+------------+----------------+---+----------------+
| **Exposure**      | **Dose     | **Target       | * |                |
|                   | Used in    | MOE/UF,**      | * |                |
| **Scenario**      | Risk       |                | S |                |
|                   | As         | **Special FQPA | t |                |
|                   | sessment** | SF**           | u |                |
|                   |            |                | d |                |
|                   | **(mg      | **for Risk     | y |                |
|                   | /kg/day)** | Assessment**   | a |                |
|                   |            |                | n |                |
|                   |            |                | d |                |
|                   |            |                | T |                |
|                   |            |                | o |                |
|                   |            |                | x |                |
|                   |            |                | i |                |
|                   |            |                | c |                |
|                   |            |                | o |                |
|                   |            |                | l |                |
|                   |            |                | o |                |
|                   |            |                | g |                |
|                   |            |                | i |                |
|                   |            |                | c |                |
|                   |            |                | a |                |
|                   |            |                | l |                |
|                   |            |                | E |                |
|                   |            |                | f |                |
|                   |            |                | f |                |
|                   |            |                | e |                |
|                   |            |                | c |                |
|                   |            |                | t |                |
|                   |            |                | s |                |
|                   |            |                | * |                |
|                   |            |                | * |                |
+===================+============+================+===+================+
| **Acute Dietary** | **NO       | **FQPA SF** =  | P |                |
|                   | AEL**(deve | 1              | r |                |
| (Females 13+)     | lopmental) |                | e |                |
|                   | = 10       | **UF** = 100   | n |                |
|                   | mg/kg/day  | (10x           | a |                |
|                   |            | inter-species  | t |                |
|                   |            | extrapolation, | a |                |
|                   |            | 10x            | l |                |
|                   |            | intra-species  | D |                |
|                   |            | variation)     | e |                |
|                   |            |                | v |                |
|                   |            |                | e |                |
|                   |            |                | l |                |
|                   |            |                | o |                |
|                   |            |                | p |                |
|                   |            |                | m |                |
|                   |            |                | e |                |
|                   |            |                | n |                |
|                   |            |                | t |                |
|                   |            |                | a |                |
|                   |            |                | l |                |
|                   |            |                | T |                |
|                   |            |                | o |                |
|                   |            |                | x |                |
|                   |            |                | i |                |
|                   |            |                | c |                |
|                   |            |                | i |                |
|                   |            |                | t |                |
|                   |            |                | y |                |
|                   |            |                |   |                |
|                   |            |                | - |                |
|                   |            |                | R |                |
|                   |            |                | a |                |
|                   |            |                | t |                |
|                   |            |                |   |                |
|                   |            |                | M |                |
|                   |            |                | R |                |
|                   |            |                | I |                |
|                   |            |                | D |                |
|                   |            |                | 4 |                |
|                   |            |                | 1 |                |
|                   |            |                | 8 |                |
|                   |            |                | 8 |                |
|                   |            |                | 6 |                |
|                   |            |                | 7 |                |
|                   |            |                | 0 |                |
|                   |            |                | 1 |                |
|                   |            |                |   |                |
|                   |            |                | * |                |
|                   |            |                | * |                |
|                   |            |                | L |                |
|                   |            |                | O |                |
|                   |            |                | A |                |
|                   |            |                | E |                |
|                   |            |                | L |                |
|                   |            |                | * |                |
|                   |            |                | * |                |
|                   |            |                | = |                |
|                   |            |                | 2 |                |
|                   |            |                | 0 |                |
|                   |            |                | m |                |
|                   |            |                | g |                |
|                   |            |                | / |                |
|                   |            |                | k |                |
|                   |            |                | g |                |
|                   |            |                | / |                |
|                   |            |                | d |                |
|                   |            |                | a |                |
|                   |            |                | y |                |
|                   |            |                | b |                |
|                   |            |                | a |                |
|                   |            |                | s |                |
|                   |            |                | e |                |
|                   |            |                | d |                |
|                   |            |                | o |                |
|                   |            |                | n |                |
|                   |            |                | i |                |
|                   |            |                | n |                |
|                   |            |                | c |                |
|                   |            |                | r |                |
|                   |            |                | e |                |
|                   |            |                | a |                |
|                   |            |                | s |                |
|                   |            |                | e |                |
|                   |            |                | d |                |
|                   |            |                | i |                |
|                   |            |                | n |                |
|                   |            |                | c |                |
|                   |            |                | i |                |
|                   |            |                | d |                |
|                   |            |                | e |                |
|                   |            |                | n |                |
|                   |            |                | c |                |
|                   |            |                | e |                |
|                   |            |                | o |                |
|                   |            |                | f |                |
|                   |            |                | s |                |
|                   |            |                | k |                |
|                   |            |                | e |                |
|                   |            |                | l |                |
|                   |            |                | e |                |
|                   |            |                | t |                |
|                   |            |                | a |                |
|                   |            |                | l |                |
|                   |            |                | v |                |
|                   |            |                | a |                |
|                   |            |                | r |                |
|                   |            |                | i |                |
|                   |            |                | a |                |
|                   |            |                | t |                |
|                   |            |                | i |                |
|                   |            |                | o |                |
|                   |            |                | n |                |
|                   |            |                | s |                |
|                   |            |                | . |                |
+-------------------+------------+----------------+---+----------------+
|                   | **Acute    |                |   |                |
|                   | RfD =**    |                |   |                |
|                   | 0.1        |                |   |                |
|                   | mg/kg/day  |                |   |                |
|                   | (Females   |                |   |                |
|                   | age 13+)   |                |   |                |
+-------------------+------------+----------------+---+----------------+
| **Acute dietary** | an acute   |                |   |                |
|                   | dietary    |                |   |                |
| (general pop.)    | endpoint   |                |   |                |
|                   | for the    |                |   |                |
|                   | general    |                |   |                |
|                   | population |                |   |                |
|                   | was not    |                |   |                |
|                   | identified |                |   |                |
|                   | in the     |                |   |                |
|                   | database   |                |   |                |
|                   | for DDAC.  |                |   |                |
+-------------------+------------+----------------+---+----------------+
| **Chronic         | **NOAEL**  | **FQPA SF** =  |   | Chronic        |
| Dietary**         | = 10       | 1              |   | Toxicity       |
|                   |            |                |   | Study - Dog    |
| (general          | mg/kg/day  | **UF** = 100   |   |                |
| population)       |            | (10x           |   | MRID 41970401  |
|                   |            | inter-species  |   |                |
|                   |            | extrapolation, |   | **LOAEL** = 20 |
|                   |            | 10x            |   | mg/kg/day      |
|                   |            | intra-species  |   | based on       |
|                   |            | variation      |   | increased      |
|                   |            |                |   | incidence of   |
|                   |            |                |   | clinical signs |
|                   |            |                |   | in males and   |
|                   |            |                |   | females and    |
|                   |            |                |   | decreased      |
|                   |            |                |   | total          |
|                   |            |                |   | cholesterol    |
|                   |            |                |   | levels in      |
|                   |            |                |   | females.       |
+-------------------+------------+----------------+---+----------------+
|                   | **Chronic  |                |   |                |
|                   | RfD =**    |                |   |                |
|                   | 0.1        |                |   |                |
|                   | mg/kg/day  |                |   |                |
|                   |            |                |   |                |
|                   | Dermal,    |                |   |                |
|                   | Short-Term |                |   |                |
|                   | (technical |                |   |                |
|                   | a.i.)      |                |   |                |
|                   |            |                |   |                |
|                   | NOAEL = 2  |                |   |                |
|                   |            |                |   |                |
|                   | UF =       |                |   |                |
|                   | 100Based   |                |   |                |
|                   | on         |                |   |                |
|                   | increased  |                |   |                |
|                   | dermal     |                |   |                |
|                   | clinical   |                |   |                |
|                   | and gross  |                |   |                |
|                   | findings   |                |   |                |
|                   |            |                |   |                |
|                   | Rat 90-day |                |   |                |
|                   | Dermal     |                |   |                |
|                   | Study      |                |   |                |
|                   |            |                |   |                |
|                   | MRID       |                |   |                |
|                   | 413059-01  |                |   |                |
+-------------------+------------+----------------+---+----------------+
| **Non-Dietary     |            |                |   |                |
| Exposures**       |            |                |   |                |
+-------------------+------------+----------------+---+----------------+
| **Incidental      | **NO       | **Target MOE** |   | Prenatal       |
| Oral**            | AEL**(deve | = 100 (10x     |   | Developmental  |
|                   | lopmental) | inter-species  |   | Toxicity - Rat |
| Short-Term        | = 10       | extrapolation, |   |                |
|                   | mg/kg/day  | 10x            |   | MRID 41886701  |
|                   |            | intra-species  |   |                |
|                   |            | variation)     |   | **LOAEL** = 20 |
|                   |            |                |   | mg/kg/day      |
|                   |            | **FQPA SF** =  |   | based on       |
|                   |            | 1              |   | increased      |
|                   |            |                |   | incidence of   |
|                   |            |                |   | skeletal       |
|                   |            |                |   | variations.    |
+-------------------+------------+----------------+---+----------------+
| **Incidental      | **NOAEL**  | **Target MOE** |   | Chronic        |
| Oral**            | = 10       | = 100 (10x     |   | Toxicity       |
|                   | mg/kg/day  | inter-species  |   | Study - Dog    |
| Intermediate-Term |            | extrapolation, |   |                |
|                   |            | 10x            |   | MRID 41970401  |
|                   |            | intra-species  |   |                |
|                   |            | variation)     |   | **LOAEL** = 20 |
|                   |            |                |   | mg/kg/day      |
|                   |            | **FQPA SF** =  |   | based on       |
|                   |            | 1              |   | increased      |
|                   |            |                |   | incidence of   |
|                   |            |                |   | clinical signs |
|                   |            |                |   | in males and   |
|                   |            |                |   | females and    |
|                   |            |                |   | decreased      |
|                   |            |                |   | total          |
|                   |            |                |   | cholesterol    |
|                   |            |                |   | levels in      |
|                   |            |                |   | females.       |
+-------------------+------------+----------------+---+----------------+
| **Dermal,         | No         |                |   |                |
| Short-term**      | endpoint   |                |   |                |
| (formulated       | i          |                |   |                |
| product, 0.13%    | dentified. |                |   |                |
| a.i.)             | No dermal  |                |   |                |
|                   | or         |                |   |                |
|                   | systemic   |                |   |                |
|                   | effects    |                |   |                |
|                   | identified |                |   |                |
|                   | in the     |                |   |                |
|                   | 21-day     |                |   |                |
|                   | dermal     |                |   |                |
|                   | toxicity   |                |   |                |
|                   | study      |                |   |                |
|                   | (MRID      |                |   |                |
|                   | 45656601)  |                |   |                |
|                   | up to and  |                |   |                |
|                   | including  |                |   |                |
|                   | the limit  |                |   |                |
|                   | dose of    |                |   |                |
|                   | 1000       |                |   |                |
|                   | mg/kg/day  |                |   |                |
+-------------------+------------+----------------+---+----------------+
| **Dermal,         | **NOAEL    | **Target MOE** |   | 90-day Dermal  |
| Short-term**      | (dermal)** | = 100 (10x     |   | Toxicity - Rat |
| (TGAI 80% diluted | = 2        | inter-species  |   |                |
| to 0.1%)          | mg/kg/day  | extrapolation, |   | MRID 41305901  |
|                   |            | 10x            |   |                |
|                   | (8.0       | intra-species  |   | **LOAEL** = 6  |
|                   | g         | variation)     |   | mg/kg/day      |
|                   | /cm^2^)^b^ |                |   | based on       |
|                   |            |                |   | increased      |
|                   |            |                |   | clinical and   |
|                   |            |                |   | gross findings |
|                   |            |                |   | (erythema,     |
|                   |            |                |   | edema,         |
|                   |            |                |   | exfoliation,   |
|                   |            |                |   | excoriation,   |
|                   |            |                |   | and            |
|                   |            |                |   | ulceration)    |
+-------------------+------------+----------------+---+----------------+
| **Dermal,         | No         |                |   |                |
| Intermediate- and | a          |                |   |                |
| Long-term**       | ppropriate |                |   |                |
| (formulated       | endpoint   |                |   |                |
| product)          | i          |                |   |                |
|                   | dentified. |                |   |                |
+-------------------+------------+----------------+---+----------------+
| **Inhalation,     | **NOAEL**  | **Target MOE** |   | Prenatal       |
| Short-Term**      | = 10       | = 100 (10x     |   | Developmental  |
|                   | mg         | inter-species  |   | Toxicity - Rat |
|                   | /kg/day^a^ | extrapolation, |   |                |
|                   |            | 10x            |   | MRID 41886701  |
|                   |            | intra-species  |   |                |
|                   |            | variation, 10x |   | **LOAEL** = 20 |
|                   |            | route-         |   | mg/kg/day      |
|                   |            | extrapolation) |   | based on       |
|                   |            |                |   | increased      |
|                   |            | **DB UF**- an  |   | incidence of   |
|                   |            | additional 10x |   | skeletal       |
|                   |            | is necessary   |   | variations.    |
|                   |            | for route      |   |                |
|                   |            | extrapolation. |   |                |
|                   |            | If risk        |   |                |
|                   |            | estimates are  |   |                |
|                   |            | below an MOE   |   |                |
|                   |            | of 1000, a     |   |                |
|                   |            | confirmatory   |   |                |
|                   |            | inhalation     |   |                |
|                   |            | toxicity study |   |                |
|                   |            | may be         |   |                |
|                   |            | required.      |   |                |
+-------------------+------------+----------------+---+----------------+
| **Inhalation,     | **NOAEL**  | **Target MOE** |   | Chronic        |
| Intermediate- and | = 10       | = 100 (10x     |   | Toxicity       |
| Long-Term**       |            | inter-species  |   | Study - Dog    |
|                   | mg         | extrapolation, |   |                |
|                   | /kg/day^a^ | 10x            |   | MRID 41970401  |
|                   |            | intra-species  |   |                |
|                   |            | variation, 10x |   | **LOAEL** = 20 |
|                   |            | route-         |   | mg/kg/day      |
|                   |            | extrapolation) |   | based on       |
|                   |            |                |   | **increased    |
|                   |            | **DB UF**- an  |   | incidence of   |
|                   |            | additional 10x |   | clinical signs |
|                   |            | is necessary   |   | in males and   |
|                   |            | for route      |   | females and**  |
|                   |            | extrapolation. |   | decreased      |
|                   |            | If risk        |   | total          |
|                   |            | estimates are  |   | cholesterol    |
|                   |            | below an MOE   |   | levels in      |
|                   |            | of 1000, a     |   | females.       |
|                   |            | confirmatory   |   |                |
|                   |            | inhalation     |   |                |
|                   |            | toxicity study |   |                |
|                   |            | may be         |   |                |
|                   |            | required.      |   |                |
+-------------------+------------+----------------+---+----------------+

UF = uncertainty factor, FQPA SF = FQPA safety factor, NOAEL = no
observed adverse effect level, LOAEL = lowest observed adverse effect
level, RfD = reference dose, MOE = margin of exposure, LOC = Level of
concern, NA = Not Applicable.

Number range CHAPTER^a^An additional uncertainty factor of 10x is
applied for use of an oral endpoint for route-to-route extrapolation to
determine if a confirmatory inhalation toxicity study is warranted.

^b^ TGAI-based dermal endpoint = (2 mg/kg rat x 0.2 kg rat x 1000 ug/mg)
/ 50cm^2^ area of rat dosed = 8.0 µg/cm^2^ .

[]{#__RefHeading___Toc131930539 .anchor}**8.0 TOXICITY PROFILE TABLES**

[]{#__RefHeading___Toc131930540 .anchor}**8.1 Acute Toxicity Profile
Table (Table 5).**

+--------------------+--------------------+----------------------------+
| **Table 5. Acute   |                    |                            |
| Toxicity Profile   |                    |                            |
| for DDAC.**        |                    |                            |
+====================+====================+============================+
| **Guideline No./** | **MRID No.         | **Results**                |
|                    | (Year)/**          |                            |
| **Study Type/ Test |                    |                            |
| Substance (%       | **Citation/        |                            |
| a.i.)**            | Classification/    |                            |
|                    | Doses**            |                            |
+--------------------+--------------------+----------------------------+
| 870.1100 (§81-1)   | MRID 41394404      | **Toxicity Category II**   |
|                    |                    |                            |
| Acute Oral         | **Acceptable**     | LD~50~ = 262 mg/kg         |
| Toxicity -- Rats   |                    | (combined)                 |
|                    | Females: 0, 100,   |                            |
| DDAC purity 65%    | 200, or 400 mg/kg  | LD~50~ = 331 mg/kg (males) |
|                    |                    |                            |
|                    | Males: 0, 100,     | LD~50~ = 238 mg/kg         |
|                    | 200, 283, 336, or  | (females)                  |
|                    | 400 mg/kg          |                            |
|                    |                    | Signs of toxicity included |
|                    | Rats (5/sex/dose)  | sluggishness, lacrimation, |
|                    |                    | diarrhea, and a brown      |
|                    |                    | stain on the               |
|                    |                    | periurogenital fur, red    |
|                    |                    | discharge on the facial    |
|                    |                    | fur and emaciation. Deaths |
|                    |                    | occurred at 1 to 4 days.   |
|                    |                    | Survivors recovered at 2   |
|                    |                    | to 5 days. Necropsy of     |
|                    |                    | rats that died revealed    |
|                    |                    | discolored stomachs        |
|                    |                    | (yellow or red to purple), |
|                    |                    | hemorrhaged stomachs, one  |
|                    |                    | stomach adhering to liver, |
|                    |                    | red to brown intestines,   |
|                    |                    | dark red livers, and       |
|                    |                    | thoracic cavities filled   |
|                    |                    | with red to clear liquid.  |
|                    |                    | Two males had blood in the |
|                    |                    | urine. In survivors, there |
|                    |                    | were no remarkable gross   |
|                    |                    | lesions.                   |
+--------------------+--------------------+----------------------------+
| 870.1100 (§81-1)   | MRID 42296101      | **Toxicity Category II**   |
|                    |                    |                            |
| Acute Oral         | **Acceptable**     | LD~50~ = 238 mg/kg         |
| Toxicity -- Rats   |                    | (combined)                 |
|                    | Range-finding:     |                            |
| DDAC Purity 80%    |                    | **NOAEL = 10 mg/kg**       |
|                    | Rats (5/sex/dose)  |                            |
|                    | administered       | The observations for the   |
|                    | single oral dose   | third phase of the study   |
|                    | of BARDAC 2280     | ranged from minimal        |
|                    | undiluted at 0.16, | effects to no clear        |
|                    | 0.4, 1.0, or 4.0   | treatment-related effects. |
|                    | g/kg or as a 20%   | The most prevalent         |
|                    | w/v formulation in | clinical signs during the  |
|                    | water at 0.0632    | observation period         |
|                    | g/kg               | included urine and fecal   |
|                    |                    | stains, saliva discharge   |
|                    | Main study:        | and stains, dried red      |
|                    |                    | stains on muzzle and       |
|                    | Rats (5/sex/dose)  | around the eyes, eye       |
|                    | given single oral  | squinting, piloerection,   |
|                    | dose of DDAC in 5% | ataxia, body tremors,      |
|                    | w/v formulation in | labored and shallow        |
|                    | water at 0.1, 0.2, | respiration, **s**light to |
|                    | 0.3, or 0.5 g/kg   | severe depression, viscous |
|                    |                    | red blood-like discharge   |
|                    | Identification of  | from the mouth, bloated    |
|                    | NOAEL following    | appearance to the abdomen, |
|                    | single dose:       | and spasms in the          |
|                    |                    | abdominal area. With the   |
|                    | Single oral doses  | exception of one animal,   |
|                    | of DDAC in 5% w/v  | all animals that survived  |
|                    | formulation in     | the observation period     |
|                    | water at 0.01      | exhibited no gross         |
|                    | (5/sex), 0.0**2**  | pathologic findings.       |
|                    | (2/sex), or 0.03   |                            |
|                    | (2/sex) g/kg       |                            |
+--------------------+--------------------+----------------------------+
| 870.1200 (§81-2)   | MRID 42053801      | **Toxicity Category III**  |
|                    |                    |                            |
| Acute Dermal       | **Acceptable**     | LD~50~ = 2930 mg/kg        |
| Toxicity --        |                    | (combined)                 |
| Rabbits            | 0, 2000, 2830, or  |                            |
|                    | 4000 mg/kg         | LD~50~ = 3140 mg/kg        |
| DDAC Purity 65%    |                    | (males)                    |
|                    | Rabbits            |                            |
|                    | (5/sex/dose)       | LD~50~ = 2730 mg/kg        |
|                    |                    | (females)                  |
|                    |                    |                            |
|                    |                    | Skin reactions included    |
|                    |                    | erythema, edema, necrosis, |
|                    |                    | ulceration, ecchymoses,    |
|                    |                    | fissuring, alopecia,       |
|                    |                    | desquamation, and scabs.   |
|                    |                    | Signs of systemic toxicity |
|                    |                    | observed were              |
|                    |                    | sluggishness, prostration  |
|                    |                    | (in 2), diarrhea (in 1),   |
|                    |                    | and persistent weight loss |
|                    |                    | (with emaciation in some   |
|                    |                    | animals). Four rabbits     |
|                    |                    | died at 3 to 3.5 hours.    |
|                    |                    | However, most deaths       |
|                    |                    | occurred at 2 to 7 days.   |
|                    |                    | Necropsy of the decedents  |
|                    |                    | revealed dark red lungs,   |
|                    |                    | hemorrhaged intestines (in |
|                    |                    | 1), gas or liquid-filled   |
|                    |                    | intestines (in 2), dark    |
|                    |                    | purple thymus, and purple  |
|                    |                    | and enlarged kidneys (in   |
|                    |                    | 1). Gross lesions apparent |
|                    |                    | in survivors at necropsy   |
|                    |                    | included dark red lungs    |
|                    |                    | (in 1), enlarged spleen,   |
|                    |                    | tan or purple kidneys (1   |
|                    |                    | with multiple red foci),   |
|                    |                    | an excessive amount of     |
|                    |                    | blood in the kidneys (of   |
|                    |                    | 1), and a trace amount of  |
|                    |                    | blood in the urine of 1.   |
+--------------------+--------------------+----------------------------+
| 870.1200 (§81-2)   | MRID 00071158      | **Toxicity Category III**  |
|                    |                    |                            |
| Acute Dermal       | **Acceptable**     | []{#_                      |
| Toxicity --        |                    | _RefHeading___Toc131930541 |
| Rabbits            | 0, 2000, 5000, or  | .anchor}LD~50~ = 4350      |
|                    | 8000 mg/kg         | mg/kg (combined)           |
| DDAC Purity 50%    |                    |                            |
|                    | Rabbits            | []{#_                      |
|                    | (3/sex/dose)       | _RefHeading___Toc131930542 |
|                    |                    | .anchor}LD~50~ = 4350      |
|                    |                    | mg/kg (males)              |
|                    |                    |                            |
|                    |                    | []{#_                      |
|                    |                    | _RefHeading___Toc131930543 |
|                    |                    | .anchor}LD~50~ = 4350      |
|                    |                    | mg/kg (females)            |
+--------------------+--------------------+----------------------------+
| 870.1300 (§81-3)   | MRID 00145074,     | **Toxicity Category III**  |
|                    | TRID 455201010     |                            |
| Acute Inhalation   |                    | LC~50~ = 0.07 mg/L         |
| Toxicity -- Rats   | **Acceptable**     |                            |
|                    |                    | At necropsy, no gross      |
| Purity not         | 0, 0.05, 0.09,     | lesions were observed in   |
| reported           | 0.03, 0.25, or     | 48 of the 60 test rats.    |
|                    | 4.54 mg/L (for 4   | Abnormalities of the       |
|                    | hours), or~~r~~    | liver, ear, skin, urinary  |
|                    | 1.36 mg/L (for 2   | bladder, kidneys, stomach, |
|                    | hours)             | intestine, cecum, and      |
|                    |                    | lungs were noted among the |
|                    | Rats (5/sex/dose)  | remaining rats.            |
+--------------------+--------------------+----------------------------+
| 870.2400 (§81-4)   | MRID 41394404      | **Toxicity Category I**    |
|                    |                    |                            |
| Primary eye        | **Acceptable**     | Corrosive. Instillation of |
| irritation --      |                    | 0.1 mL of NP-1 Plus        |
| Rabbits            | 0.1 mLof NP-1 Plus | (concentrate) resulted in  |
|                    | (concentrate)      | severe corneal opacity; it |
| DDAC Purity 80%    |                    | was impossible to score    |
|                    | Rabbits (2         | the iris throughout the    |
|                    | animals)           | test. Necrosis of the      |
|                    |                    | conjuncticas and the       |
|                    |                    | nictitating membrane was   |
|                    |                    | apparent at one hour       |
|                    |                    | prohibiting the scoring of |
|                    |                    | conjunctival redness.      |
|                    |                    | Moderate chemosis of the   |
|                    |                    | conjunctivae was observed  |
|                    |                    | in bathocytes at one hour  |
|                    |                    | developing into severe     |
|                    |                    | swelling at 24 hours. Each |
|                    |                    | rabbit also exhibited a    |
|                    |                    | purulent ocular discharge  |
|                    |                    | at 24 hours. Because of    |
|                    |                    | the persistent severe      |
|                    |                    | irritation evident aat 48  |
|                    |                    | hours, both animals were   |
|                    |                    | sacrificed.                |
+--------------------+--------------------+----------------------------+
| 870.2400 (§81-4)   | MRID 42161602      | **Toxicity Category I**    |
|                    |                    |                            |
| Primary eye        | **Acceptable**     | Corrosive. The total       |
| irritation --      |                    | irritation score for the   |
| Rabbits            | 0.1 mL of BARDAC   | single animal was 94 (110  |
|                    | (80% a.i.) for 1   | maximum) **at the one hour |
| DDAC Purity 80%    | hour               | interval**. The test       |
|                    |                    | material produced extreme  |
|                    | 1 male rabbit      | corneal opacity, ititis,   |
|                    |                    | and conjunctival           |
|                    |                    | irritation after 1 hour.   |
|                    |                    | The eye of this animal     |
|                    |                    | also appears misshapen.    |
|                    |                    | Due to the evidence of     |
|                    |                    | corrosion (misshapen eye)  |
|                    |                    | exhibited in this single   |
|                    |                    | animal, the study was      |
|                    |                    | terminated following the 1 |
|                    |                    | hour reading without       |
|                    |                    | testing additional         |
|                    |                    | animals.                   |
+--------------------+--------------------+----------------------------+
| 870.2500 (§81-5)   | MRID 42161601      | **Toxicity Category I**    |
|                    |                    |                            |
| Primary dermal     | **Acceptable**     | Corrosive. Severe          |
| irritation --      |                    | irritation persisted 24    |
| Rabbits            | 0.5 mL BARDAC (80% | hours following            |
|                    | a.i.), 4 hours     | application. Changes noted |
| **DDAC** Purity    |                    | in the coloration and/or   |
| 80%                | 1 male rabbit      | texture of the skin        |
|                    |                    | included coriaceousness,   |
|                    |                    | blanching, green-brown     |
|                    |                    | discoloration, brown/dark  |
|                    |                    | red discoloration, and     |
|                    |                    | necrosis. Due to the       |
|                    |                    | evidence of corrosion      |
|                    |                    | exhibited in this animal   |
|                    |                    | at the 24 hour reading,    |
|                    |                    | this study was terminated  |
|                    |                    | without testing additional |
|                    |                    | animals.                   |
+--------------------+--------------------+----------------------------+
| 870.2600 (§81-6)   | MRID 421616303     | **Not a photosensitizer.** |
|                    |                    |                            |
| Dermal             | **Acceptable**     | The incidence of grade 1   |
| sensitization --   |                    | responses in the test      |
| Guinea pigs        | Induction: 0.1%    | group (1/10) was           |
|                    | w/v test material, | comparable to the          |
| **DDAC** Purity    | followed by UVA    | incidence of grade 1       |
| 80%                | and UVB            | responses in the naïve     |
|                    | irradiation        | control group (2/10). The  |
|                    |                    | test material was not      |
|                    | Challenge Period:  | considered to have caused  |
|                    | 10-14 days         | photosensitization.        |
|                    |                    |                            |
|                    | Challenge dose:    | The positive control       |
|                    | 0.1% w/v, followed | without irradiation did    |
|                    | by UVA and UVB     | not clearly exhibit        |
|                    | irradiation        | contact sensitization.     |
|                    |                    |                            |
|                    | Control: No        |                            |
|                    | induction,         |                            |
|                    | received challenge |                            |
|                    | dose of 0.1% w/v,  |                            |
|                    | followed by UVA    |                            |
|                    | and UVB            |                            |
|                    | irradiation        |                            |
|                    |                    |                            |
|                    | Guinea pigs        |                            |
|                    | (5/sex)            |                            |
+--------------------+--------------------+----------------------------+
| 870.2600 (§81-6)   | MRID 46367601      | **Not a sensitizer.**      |
|                    |                    |                            |
| Dermal             | **Acceptable**     | Erythema scores ranged     |
| sensitization --   |                    | from 0.05 to 0.10 in the   |
| Guinea pigs        | Induction: 0.25,   | test animals and from 0.05 |
|                    | 0.5, or 0.75% w/w  | to 0.20 in the controls. A |
| **DDAC** Purity    | mixture in         | positive response was not  |
| 80%                | distilled water,   | observed in any of the     |
|                    | once a week for 3  | test or control animals.   |
|                    | weeks              |                            |
|                    |                    |                            |
|                    | Challenge Period:  |                            |
|                    | 27 days            |                            |
|                    |                    |                            |
|                    | Challenge dose: or |                            |
|                    | 0.1% w/w mixture   |                            |
|                    | in distilled water |                            |
|                    |                    |                            |
|                    | Control: 10 guinea |                            |
|                    | pigs, no           |                            |
|                    | induction,         |                            |
|                    | received challenge |                            |
|                    | dose of 0.1% w/w   |                            |
|                    |                    |                            |
|                    | Guinea pigs (20)   |                            |
+--------------------+--------------------+----------------------------+

2.  []{#__RefHeading___Toc131930544 .anchor}**Subchronic, Chronic and
    Other Toxicity Profiles Table (Table 6)**

+--------------------+--------------------+----------------------------+
| **Table 6:         |                    |                            |
| Subchronic,        |                    |                            |
| Chronic and Other  |                    |                            |
| Toxicity Profiles  |                    |                            |
| for DDAC.**        |                    |                            |
+====================+====================+============================+
| **Guideline        | **MRID Number      | **Results**                |
| Number/**          | (Year)/**          |                            |
|                    |                    |                            |
| **Study Type/**    | **Citation/**      |                            |
|                    | **Classification/  |                            |
| **Test Substance   | Doses**            |                            |
| (% a.i.)**         |                    |                            |
+--------------------+--------------------+----------------------------+
| 870.3100 (§82-1)   | MRID 40966302      | **Systemic toxicity:**     |
|                    |                    |                            |
| 90-Day Oral (      | **Acceptable --    | **NOAEL = 1000 ppm**       |
| Diet) --Rat        | Guideline**        |                            |
|                    |                    | **= 60.7 mg/kg/day         |
| DDAC purity        | 0, 100, 300, 600,  | (males)**                  |
| **80.8%**          | 1000, or 3000 ppm  |                            |
|                    |                    | **= 74.3 mg/kg/day         |
|                    | \[0, 6.2, 18.5,    | (females)**                |
|                    | 36.8, 60.7, or     |                            |
|                    | 175.4 mg/kg        | **LOAEL = 3000 ppm**       |
|                    | (males),           |                            |
|                    |                    | **= 175.4 mg/kg/day        |
|                    | 0, 7.5, 22.3,      | (males)**                  |
|                    | 44.4, 74.3, or     |                            |
|                    | 225.5 mg/kg/day    | **= 225.5 mg/kg/day        |
|                    | (females)\]        | (females**), based on      |
|                    |                    | increased mortality,       |
|                    |                    | decreased mean body        |
|                    |                    | weights, body weight gain  |
|                    |                    | and food consumption, and  |
|                    |                    | increased incidences of    |
|                    |                    | gross pathological         |
|                    |                    | lesions**.** High-dose     |
|                    |                    | animals showed increased   |
|                    |                    | mortality, decreased mean  |
|                    |                    | body weights, body weight  |
|                    |                    | gain and food consumption, |
|                    |                    | and increased incidence of |
|                    |                    | gross pathological         |
|                    |                    | observations and           |
|                    |                    | non-neoplastic lesions,    |
|                    |                    | including a higher         |
|                    |                    | incidence of glycogen      |
|                    |                    | depletion in the lover and |
|                    |                    | contracted spleens.        |
|                    |                    | Additionally, high-dose    |
|                    |                    | females showed sinus       |
|                    |                    | erythrocytosis and         |
|                    |                    | lymphoid hyperplasia of    |
|                    |                    | mesenterin lymph nodes.    |
+--------------------+--------------------+----------------------------+
| 870.3100 (§82-1)   | MRID 40262901      | **Systemic toxicity:**     |
|                    |                    |                            |
| 90-Day Oral (Feed) | **Acceptable --    | **NOAEL = 15 mg/kg/day**   |
| --Dog              | Guideline**        |                            |
|                    |                    | **LOAEL = 50 mg/kg/day,**  |
| DDAC purity not    | 0, 5, 15, or 50    | based on decreased body    |
| reported           | mg/kg/day          | weight gain, food          |
|                    |                    | consumption, and food      |
|                    |                    | efficiency.                |
|                    |                    |                            |
|                    |                    | High-dose animals          |
|                    |                    | experienced marked         |
|                    |                    | decrease in body weight    |
|                    |                    | gain, food consumption,    |
|                    |                    | and food efficiency, for   |
|                    |                    | both males and females.    |
+--------------------+--------------------+----------------------------+
| 870.3200 (§82-3)   | MRID 40565301 and  | **Systemic Toxicity**      |
|                    | 41105801           |                            |
| 21-day dermal --   |                    | **NOAEL = 500 mg/kg/day**  |
| Guinea pig         | Acceptable -       |                            |
|                    | Nonguideline       | **LOAEL \> 1000            |
| 1:5 solution with  |                    | mg/kg/day**, based on      |
| DDAC purity 4%     | Guinea pigs        | decreased body weights, a  |
|                    | (5/sex/dose)       | slight elevation of        |
|                    |                    | basophils and eosiniphils  |
|                    | 0, 500, or 1000    | as well as a slight        |
|                    | mg/kg/day, 5       | elevation of SGPT and      |
|                    | days/week, 21 days | SGOT.                      |
|                    |                    |                            |
|                    |                    | **Dermal Toxicity**        |
|                    |                    |                            |
|                    |                    | **NOAEL = 500 mg/kg/day**  |
|                    |                    |                            |
|                    |                    | **LOAEL = 1000             |
|                    |                    | mg/kg/day**, based on      |
|                    |                    | sloughing of the stratum   |
|                    |                    | corneum as a result of     |
|                    |                    | defatting**.**             |
|                    |                    |                            |
|                    |                    | There was no mortality or  |
|                    |                    | signs of clinical toxicity |
|                    |                    | noted. Signs of skin       |
|                    |                    | irritation were noted      |
|                    |                    | during the second week of  |
|                    |                    | treatment and the report   |
|                    |                    | stated that the response   |
|                    |                    | intensified during the     |
|                    |                    | third week of treatment.   |
|                    |                    | Body weight was decreased  |
|                    |                    | in treated males and       |
|                    |                    | females by 7% and 11% vs   |
|                    |                    | untreated animals at week  |
|                    |                    | 3. Results of hematology   |
|                    |                    | and clinical chemistry     |
|                    |                    | measurements indicated a   |
|                    |                    | slight elevation of        |
|                    |                    | basophils and eosinophils  |
|                    |                    | as well as a slight        |
|                    |                    | elevation of SGPT and SGOT |
|                    |                    | but statistics were not    |
|                    |                    | performed on these data.   |
|                    |                    | Histologically, the skin   |
|                    |                    | irritation was described   |
|                    |                    | as sloughing of the        |
|                    |                    | stratum corneum as a       |
|                    |                    | result of defatting.       |
+--------------------+--------------------+----------------------------+
| 870.3200 (§82-3)   | MRID 45656601      | **Systemic Toxicity**      |
|                    |                    |                            |
| 21-day dermal --   | Acceptable -       | **NOAEL = 1000 mg/kg/day   |
| Rat                | Guideline          | (highest dose tested)**    |
|                    |                    |                            |
| SS0853.01 (DDAC    | Rats (10/sex/dose) | **LOAEL \> 1000 mg/kg/day  |
| 0.13%)             |                    | (not established)**        |
|                    | 0, 100, 500, or    |                            |
|                    | 1000 mg/kg/day     | No treatment-related       |
|                    |                    | effects on clinical        |
|                    |                    | observations (including    |
|                    |                    | expanded clinical          |
|                    |                    | observations), motor       |
|                    |                    | activity, dermal           |
|                    |                    | irritation, ophthalmic     |
|                    |                    | observations, body weights |
|                    |                    | or body weight changes,    |
|                    |                    | food consumption, clinical |
|                    |                    | pathology parameters,      |
|                    |                    | terminal body weights,     |
|                    |                    | mean absolute or relative  |
|                    |                    | organ weights, or          |
|                    |                    | macroscopic or microscopic |
|                    |                    | observations were          |
|                    |                    | observed. Analyses of      |
|                    |                    | hindlimb strength, food    |
|                    |                    | consumption, hematology    |
|                    |                    | and clinical chemistry     |
|                    |                    | parameters, and relative   |
|                    |                    | organ weights showed       |
|                    |                    | significantly reduced      |
|                    |                    | hindlimb strength in       |
|                    |                    | female rats at 500 and     |
|                    |                    | 1000 mg/kg/day. However,   |
|                    |                    | there were no other        |
|                    |                    | indications of effects on  |
|                    |                    | motor function in male or  |
|                    |                    | female rats at any dose    |
|                    |                    | tested. Numerous           |
|                    |                    | microscopic changes in the |
|                    |                    | liver were observed, but   |
|                    |                    | were noted to be test      |
|                    |                    | system-related due to the  |
|                    |                    | torso wrapping procedure.  |
|                    |                    | The systemic NOAEL for     |
|                    |                    | SS0853-01 is 1000          |
|                    |                    | mg/kg-day in this study,   |
|                    |                    | and the systemic LOAEL is  |
|                    |                    | \> 1000 mg/kg/day          |
+--------------------+--------------------+----------------------------+
| 870.3250 (§82-3)   | MRID 41305901      | **Systemic Toxicity**      |
|                    |                    |                            |
| 90-day dermal -    | **Acceptable -     | **NOAEL \> = 12            |
| Rat                | Guideline**        | mg/kg/day** (highest dose  |
|                    |                    | tested)                    |
| DDAC purity        | Rats (15/sex/dose) |                            |
| **80.8%**          |                    | **LOAEL \> 20 mg/kg/day**  |
|                    | 0, 2, 6, or 12     | (not established)          |
|                    | mg/kg/day, 6       |                            |
|                    | hours/day, 5       | **Dermal Toxicity**        |
|                    | days/week, 13      |                            |
|                    | weeks              | **NOAEL = 2 mg/kg/day**    |
|                    |                    |                            |
|                    |                    | **LOAEL = 6 mg/kg/day**,   |
|                    |                    | based on effects on        |
|                    |                    | treated skin, including    |
|                    |                    | erythema, edema,           |
|                    |                    | exfoliation, excoriation,  |
|                    |                    | hyperkeratosis,            |
|                    |                    | acanthosis, epidermitis,   |
|                    |                    | dermatitis, and            |
|                    |                    | ulceration.                |
|                    |                    |                            |
|                    |                    | No treatment-related       |
|                    |                    | effects were noticed in    |
|                    |                    | mortality, weight gain,    |
|                    |                    | food consumption, or       |
|                    |                    | systemic toxicity.         |
|                    |                    |                            |
|                    |                    | Toxicity was limited to    |
|                    |                    | the treated skin of        |
|                    |                    | mid-dose females and the   |
|                    |                    | high-dose males and        |
|                    |                    | females. The clinical and  |
|                    |                    | gross findings (erythema,  |
|                    |                    | edema, exfoliation,        |
|                    |                    | excoriation, and           |
|                    |                    | ulceration) were confirmed |
|                    |                    | by histopathological       |
|                    |                    | examination, where         |
|                    |                    | increased incidence of     |
|                    |                    | hyperkeratosis,            |
|                    |                    | acanthosis, epidermitis,   |
|                    |                    | dermatitis, and ulceration |
|                    |                    | were noted.                |
+--------------------+--------------------+----------------------------+
| 870.3700 (§83-3)   | MRID 41886701,     | **Maternal Toxicity**      |
|                    | range-finding MRID |                            |
| Developmental      | 42746901           | **NOAEL = 1 mg/kg/day**    |
| (gavage) - Rat     |                    |                            |
|                    | **Acceptable -     | **LOAEL = 10 mg/kg/day**,  |
| DDAC purity 80.8%  | Guideline**        | based on decreased body    |
|                    |                    | weight gain and clinical   |
|                    | Females rats       | signs (audible             |
|                    | (25/dose)          | respiration)               |
|                    |                    |                            |
|                    | 0, 1, 10, or 20    | **Number range             |
|                    | mg/kg/day, GD      | CHAPTERDevelopmental       |
|                    | 6-15, inclusive    | Toxicity**                 |
|                    |                    |                            |
|                    |                    | **NOAEL = 10 mg/kg/day**   |
|                    |                    |                            |
|                    |                    | **LOAEL = 20 mg/kg/day,**  |
|                    |                    | based on increased         |
|                    |                    | incidence of skeletal      |
|                    |                    | variations.                |
|                    |                    |                            |
|                    |                    | Maternal toxicity was      |
|                    |                    | observed at the mid- and   |
|                    |                    | high-dose groups in the    |
|                    |                    | form of audible            |
|                    |                    | respiration with the high  |
|                    |                    | dose presenting with other |
|                    |                    | observations. Further, a   |
|                    |                    | treatment-related decrease |
|                    |                    | in body weight gain was    |
|                    |                    | noted during the dosing    |
|                    |                    | period (GD 6-15), the      |
|                    |                    | dosing period plus         |
|                    |                    | post-dosing (GD 6-21) and  |
|                    |                    | for the corrected body     |
|                    |                    | weight gains for the high  |
|                    |                    | dose. There was also low   |
|                    |                    | food efficiency compared   |
|                    |                    | with controls during the   |
|                    |                    | dosing period for the mid- |
|                    |                    | and high-dose groups.      |
|                    |                    |                            |
|                    |                    | Developmental toxicity was |
|                    |                    | noted at the high dose in  |
|                    |                    | the form of increased      |
|                    |                    | incidences of skeletal     |
|                    |                    | variations.                |
+--------------------+--------------------+----------------------------+
| 870.3700 (§83-3)   | MRID 41018701      | **Maternal Toxicity**      |
|                    |                    |                            |
| Developmental      | **Acceptable --    | **NOAEL = 1 mg/kg/day**    |
| (gavage) -- Rabbit | Guideline**        |                            |
|                    |                    | **LOAEL = 3 mg/kg/day**,   |
| DDAC purity 80.8%  | Females rabbits    | based on reductions in     |
|                    |                    | body weight gain and       |
|                    | 0, 1, 3, or 10     | clinical signs of toxicity |
|                    | mg/kg/day, GD      | (hypo activity and audible |
|                    | 6-18,              | respiration).              |
|                    | **inclusive**      |                            |
|                    |                    | **Number range             |
|                    |                    | CHAPTERDevelopmental       |
|                    |                    | Toxicity**                 |
|                    |                    |                            |
|                    |                    | **NOAEL = 3 mg/kg/day**    |
|                    |                    |                            |
|                    |                    | **LOAEL = 10 mg/kg/day,**  |
|                    |                    | based on decreased fetal   |
|                    |                    | body weight and increased  |
|                    |                    | number of dead fetuses.    |
|                    |                    |                            |
|                    |                    | **At the 10 mg/kg/day dose |
|                    |                    | level, 4/16 does died      |
|                    |                    | prior to GD 12.** There    |
|                    |                    | were no abortions at any   |
|                    |                    | dose level. Hypoactivity   |
|                    |                    | and labored breathing were |
|                    |                    | observed at 3 mg/kg/day in |
|                    |                    | 2 of 15 rabbits. There     |
|                    |                    | were no effects on         |
|                    |                    | cesarean section           |
|                    |                    | observations, or necropsy  |
|                    |                    | observations at scheduled  |
|                    |                    | necropsy                   |
|                    |                    |                            |
|                    |                    | Developmental toxicity was |
|                    |                    | noted at the high dose in  |
|                    |                    | the form of decreased      |
|                    |                    | fetal body weight and      |
|                    |                    | increased number of dead   |
|                    |                    | fetuses.                   |
+--------------------+--------------------+----------------------------+
| 870.8700 (§83-4)   | MRID 41804501      | **Parental toxicity:**     |
|                    |                    |                            |
| Reproduction       | **Acceptable --    | **NOAEL = 750 ppm**        |
| (Feed) -- Rat      | Guideline**        |                            |
|                    |                    | **= 56 mg/kg/day**         |
| DDAC purity 80.8 % | Rats (28/sex/dose) |                            |
|                    |                    | **LOAEL = 1500 ppm**       |
|                    | **Premating**: 0,  |                            |
|                    | 300, 750, or 1500  | **= 113 mg/kg/day**, based |
|                    | ppm                | on decreased body          |
|                    |                    | weight/weight gain and     |
|                    | \[0, 20, 50, or    | food consumption           |
|                    | 103 mg/kg/day      |                            |
|                    | (males), 0, 24,    | **Reproductive toxicity:** |
|                    | 61, or 122         |                            |
|                    | mg/kg/day          | **NOAEL = 750 ppm**        |
|                    | (females)\]        |                            |
|                    |                    | **= 56 mg/kg/day**         |
|                    |                    |                            |
|                    |                    | **LOAEL = 1500 ppm**       |
|                    |                    |                            |
|                    |                    | **= 113 mg/kg/day**, based |
|                    |                    | on decreased pup body      |
|                    |                    | weight/weight gain         |
|                    |                    |                            |
|                    |                    | No compound-related        |
|                    |                    | mortalities were observed  |
|                    |                    | in either sex or           |
|                    |                    | generation. Decreased body |
|                    |                    | weight/weight gain were    |
|                    |                    | observed in parental       |
|                    |                    | animals and pups in both   |
|                    |                    | generations.               |
+--------------------+--------------------+----------------------------+
| 870.4100 (§83-1)   | MRID 41970401      | **Systemic Toxicity**      |
|                    |                    |                            |
| Chronic Toxicity   | **Acceptable --    | **NOAEL = 10 mg/kg/day**   |
| (feed) - Dog       | Guideline**        |                            |
|                    |                    | **LOAEL = 20 mg/kg/day,**  |
| DDAC purity        | Dogs               | based on increased         |
| **80.8%**          | (**4**/sex/dose)   | incidence of clinical      |
|                    |                    | observations (emesis and   |
|                    | 0, 3, 10, or 20/30 | soft/mucoid feces) in      |
|                    | mg/kg/day          | males and females and      |
|                    |                    | decreased total            |
|                    |                    | cholesterol levels in      |
|                    |                    | females                    |
|                    |                    |                            |
|                    |                    | Dosing at 30 mg/kg/day was |
|                    |                    | not tolerated well and was |
|                    |                    | discontinued on Day 31;    |
|                    |                    | dosing was resumed at Day  |
|                    |                    | 36 at 20 mg/kg/day.        |
|                    |                    |                            |
|                    |                    | No treatment-related       |
|                    |                    | deaths occurred during the |
|                    |                    | study. The                 |
|                    |                    | treatment-related clinical |
|                    |                    | signs (soft/mucoid feces,  |
|                    |                    | emesis) were observed      |
|                    |                    | frequently in high-dose    |
|                    |                    | animals. Hematology or     |
|                    |                    | urinalysis results were    |
|                    |                    | normal. Total cholesterol  |
|                    |                    | levels were significantly  |
|                    |                    | decreased in high-dose     |
|                    |                    | females. Gross and         |
|                    |                    | histopathological findings |
|                    |                    | did not reveal any         |
|                    |                    | treatment-related effects. |
+--------------------+--------------------+----------------------------+
| 870.4300 (§83-5)   | MRID 41965101      | High-dose animals showed   |
|                    |                    | significant, but slight    |
| Combined           | Rats (60/sex/dose) | (\<10%) decreases in mean  |
| Chron              |                    | body weight during the     |
| ic/Carcinogenicity | **Acceptable -     | study. Treatment-related   |
| (feed) - Rat       | Guideline**        | effects consisted of       |
|                    |                    | increased incidence of     |
| DDAC purity 80.8%  | 0, 300, 750, or    | sinusoidal blood,          |
|                    | 1500 ppm for 2     | hemosiderosis and          |
|                    | years              | histiocytosis in the       |
|                    |                    | mesenteric lymph nodes of  |
|                    | \[0, 13, 32, or 64 | high dose animals. In      |
|                    | mg/kg/day (males)  | addition, an increase in   |
|                    | and 0, 16, 41, or  | the incidence of           |
|                    | 83 mg/kg/day       | interstitial cell adenomas |
|                    | (females)\]        | in testes was reported. In |
|                    |                    | this study, the incidences |
|                    |                    | of this tumor for control  |
|                    |                    | and treated animals are:   |
|                    |                    | Control 1 (5%, 3/60);      |
|                    |                    | Control 2 ( 5%, 3/60); 300 |
|                    |                    | ppm (12.5%, 1/8), 750 ppm  |
|                    |                    | (17.9%, 5/28), and 1500    |
|                    |                    | ppm (11.7%, 7/60).         |
|                    |                    | However, because the       |
|                    |                    | incidence was within the   |
|                    |                    | historical incident range, |
|                    |                    | this effect was not        |
|                    |                    | considered                 |
|                    |                    | treatment-related.         |
+--------------------+--------------------+----------------------------+
| 870.4300 (§83-5)   | MRID 41802301      | **Systemic Toxicity**      |
|                    |                    |                            |
| Combined           | Mice (60/sex/dose) | **NOAEL = 500 ppm**        |
| Chron              |                    |                            |
| ic/Carcinogenicity | **Acceptable -     | **= 76.3 mg/kg/day         |
| (feed) - Mouse     | Guideline**        | (males)**                  |
|                    |                    |                            |
| DDAC purity 80.8%  | 0, 100, 500, or    | **= 93.1 mg/kg/day         |
|                    | 1000 ppm for 78    | (females**                 |
|                    | weeks              |                            |
|                    |                    | **LOAEL = 1000 ppm**       |
|                    | \[0, 15.0, 76.3,   |                            |
|                    | or 155.5 mg/kg/day | **= 155.5 mg/kg/day        |
|                    | (males),           | (males)**                  |
|                    |                    |                            |
|                    | 0, 18.6, 93.1, or  | **= 193.1 mg/kg/day        |
|                    | 193.1 mg/kg/day    | (females),** based on      |
|                    | (females)\]        | decreases in mean body     |
|                    |                    | weight and body weight     |
|                    |                    | gains.                     |
|                    |                    |                            |
|                    |                    | No treatment-related       |
|                    |                    | effects were noted in the  |
|                    |                    | incidence of clinical      |
|                    |                    | signs, deaths, gross and   |
|                    |                    | histopathological          |
|                    |                    | observations.              |
|                    |                    | Hematological values were  |
|                    |                    | comparable among all study |
|                    |                    | groups.                    |
|                    |                    |                            |
|                    |                    | **There was no evidence of |
|                    |                    | carcinogenicity of DDAC in |
|                    |                    | this study.**              |
+--------------------+--------------------+----------------------------+
| 870.5100 (§84-2)   | MRID 40282201 and  | **Negative**               |
|                    | supplemental       |                            |
| Bacterial reverse  | information MRID   | Cytotoxicty was seen at    |
| mutation test      | 44005801           | concentrations ≥ 65.5      |
|                    |                    | ug/plate without S9 and at |
| DDAC purity 50%    | **Acceptable**     | 125 or 250 ug/plate with   |
|                    |                    | S9. All strains responded  |
|                    | Strains TA1535,    | in the expected manner to  |
|                    | TA1537, and TA1538 | the appropriate positive   |
|                    | exposed to 3.9,    | control. There was no      |
|                    | 7.8, 15.6, 31.2,   | indication of a mutagenic  |
|                    | 62.5, or 125       | effect at any dose with or |
|                    | ug/plate with and  | without metabolic          |
|                    | without metabolic  | activation.                |
|                    | activation         |                            |
|                    |                    |                            |
|                    | Strains TA98 and   |                            |
|                    | TA100 exposed to   |                            |
|                    | 31.2, 62.5, 125,   |                            |
|                    | 250, 500, or 1000  |                            |
|                    | ug/plate with and  |                            |
|                    | without metabolic  |                            |
|                    | activation         |                            |
+--------------------+--------------------+----------------------------+
| 870.5300 (§84-4)   | MRID ~~93014007~~  | **Negative**               |
|                    | **93014008**,      |                            |
| Mammalian cell     | reformat of        | The mutant frequency of    |
| forward gene       | 40895202           | the nonactivation vehicle  |
| mutation -- CHO    |                    | and positive controls in   |
| cells              | CHO cells          | each trial were            |
|                    |                    | acceptable.                |
| DDAC purity        | **Acceptable**     |                            |
| 80~~.8~~%          |                    |                            |
|                    | 10 doses, ranging  |                            |
|                    | from 1.0 to 13.0   |                            |
|                    | ug/mL were applied |                            |
|                    | without metabolic  |                            |
|                    | activation         |                            |
|                    |                    |                            |
|                    | Doses ranging from |                            |
|                    | 1.0 to 40.0 ug/mL  |                            |
|                    | applined in the    |                            |
|                    | presence of        |                            |
|                    | metabolic          |                            |
|                    | activation (S9)    |                            |
|                    |                    |                            |
|                    | Vehicle control:   |                            |
|                    | deionized water    |                            |
+--------------------+--------------------+----------------------------+
| 870.5375 (§84-2)   | MRID 41252601      | **Negative**               |
|                    |                    |                            |
| *In Vitro*         | **Acceptable**     | There was no reproducible  |
| mammalian          |                    | evidence that P0151        |
| chromosome         | 0, 2, 4, 8, or 16  | induces chromosomal        |
| aberration test    | ug/mL in the       | aberrations in either the  |
|                    | presence of        | presence or absence of     |
| DDAC purity 80%    | metabolic          | metabolic activation.      |
|                    | activation for 6   | There was no indication of |
|                    | hours              | chromosomal ploidy changes |
|                    |                    | in cultures exposed to     |
|                    | 0, 1, 2, 4, or 8   | P0151 in either the        |
|                    | ug/mL in the       | presence or absence of S9  |
|                    | absence of         | mix. Concurrent positive   |
|                    | metabolic          | controls demonstrated the  |
|                    | activation for 24  | sensitivity of the test    |
|                    | hours              | system and the metabolic   |
|                    |                    | activity of Sp mix.        |
+--------------------+--------------------+----------------------------+
| 870.5550 (§84-2)   | MRID 93014007,     | **Negative**               |
|                    | reformat of        |                            |
| Unscheduled DNA    | 40895201           | The test material was      |
| synthesis assay    |                    | lethal at concentrations   |
|                    | **Acceptable**     | exceeding 4.00 ug/mL and   |
| DDAC purity        |                    | excessively toxic at 4.00  |
| 80~~.8~~%          | Rat hepatocytes    | ug/mL. Moderately high     |
|                    |                    | toxicity was observed at   |
|                    | Test               | 2.00 ug/mL (74.6%          |
|                    | concentrations     | survival), however normal  |
|                    | ranged from 0.050  | cellular morphology was    |
|                    | to 10.0 ug/mL      | observed and analysis      |
|                    |                    | could be performed.        |
|                    |                    |                            |
|                    |                    | The test material did not  |
|                    |                    | induce significant changes |
|                    |                    | in the nuclear labeling of |
|                    |                    | rat primary hepatocytes    |
|                    |                    | for an applied             |
|                    |                    | concentration range of     |
|                    |                    | 2.00 to 0.050 ug/mL        |
+--------------------+--------------------+----------------------------+
| 870.7485 (§85-1)   | MRID 41617101 and  | The pharmacokinetics data  |
|                    | addendum MRID      | collectively indicate that |
| Metabolism - Rat   | 41385101           | DDAC is poorly absorbed by |
|                    |                    | the oral route but is      |
| DDAC purity 40%    | Rats (5/sex/dose)  | principally eliminated as  |
|                    |                    | parent compound and        |
|                    | **Acceptable**     | metabolites (possibly due  |
|                    |                    | to intestinal micro flora) |
|                    | Experiment 1:      | in the feces. Most DDAC is |
|                    | Single oral dose   | excreted within 3 days     |
|                    | of 5 or 50 mg/kg   | after dosing. The          |
|                    | **of ^14^C-DDAC**  | elimination pattern and    |
|                    |                    | metabolic profile is not   |
|                    | Experiment 2:      | substantially altered by   |
|                    | Repeat dose of 34  | the dose or exposure       |
|                    | ppm in feed for 14 | duration. Males and        |
|                    | days, **followed   | females show similar       |
|                    | by a single dose   | elimination with females   |
|                    | of 5 mg/kg of      | but differ somewhat in the |
|                    | ^14^C-DDAC.**      | extent of metabolism with  |
|                    |                    | females metabolizing DDAC  |
|                    |                    | more extensively. Four     |
|                    |                    | major metabolites were     |
|                    |                    | identified by mass         |
|                    |                    | spectrometry as oxidation  |
|                    |                    | products with oxidation    |
|                    |                    | confined to the two decyl  |
|                    |                    | side chains. A plausible   |
|                    |                    | metabolic scheme was       |
|                    |                    | proposed.                  |
+--------------------+--------------------+----------------------------+

[]{#refheading___toc131930545 .anchor}**9.0 REFERENCES**

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42296101 (MRID) Morris, T. (1992) Acute Oral Toxicity in Rats\--Median
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42053801 (MRID) Myers, R.; Christopher, S. (1991) Sapstain Control
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00071158 (MRID) Nitka, S.; Palanker, A.L.; Lally, E.; et al. (1980)
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8044-10. Final rept. (Unpublished study received Feb 2, 1981 under
6836-51; prepared by Consumer Product Testing Co., Inc., sub- mitted by
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00145074 (MRID) Dudek, R. (1984) Four Hour Acute Aerosol Inhalation
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42161602 (MRID) Morris, T. (1991) Primary Eye Irritation Study in
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42161601 (MRID) Morris, T. (1991) Primary Skin Irritation Study in
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42161603 (MRID) Morris, T. (1991) Photoallergy Study in Guinea Pigs with
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46367601 (MRID) Merkel, D. (2004) Dermal Sensitization Test in Guinea
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40966302 (MRID) Van Miller, J. (1988) Ninety-day Dietary Subchronic Oral
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40262901 (MRID) Bailey, D. (1975) 90-day Feeding Study in Dogs with a
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40565301 (MRID) Rose, G. (1988) Acute Toxicology (EP): HS-Sanitizing
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41105801 (MRID) Rose, G. (1989) Acute Toxicology (EP): HS-Sanitizing
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45656601 (MRID) Henwood, S. (2001) 21-Day Dermal Toxicity Study with
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41305901 (MRID) Gill, M; Van Miller, J. (1989) Ninety-day Subchronic
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41886701 (MRID) Neeper-Bradley, T. (1991) Development Toxicity
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42746901 (MRID) Neeper-Bradley, T. (1993) Developmental Toxicity Dose
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41018701 (MRID) Tyl, R. (1989) Developmental Toxicity Study of
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41886701 (MRID) Neeper-Bradley, T. (1991) Development Toxicity
Evaluation of Didecyldimethylammoniumchloride Administered by Gavage to
CD (Sprague-Dawley) Rats: Lab Project Number: 53-534. Unpublished Study
prepared by Bushy Run Research Center. 282 p.

41804501 (MRID) Neeper-Bradley, T. (1991) Two-Generation Reproduction
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41970401 (MRID) Schulze, G. (1991) Chronic Oral Toxicity Study of
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41965101 (MRID) Gill, M.; Chun, J.; Wagner, C. (1991) Chronic Dietary
Toxicity/On- cogenicity Study with Didecyldimethyl-ammoniumchloride in
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41802301 (MRID) Gill, M.; Hermansky, S.; Wagner, C. (1991) Chronic
Dietary Oncogenicity Study with Didecyldimethylammonium chloride in
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40282201 (MRID) Friederich, U.; Wurgler, F. (1982)
Salmonella/Mammalian\--Microsome Assay with Bardac 22. Unpublished study
prepared by Institute of Toxicology, Swiss Federal Institute of
Technology, and University of Zurich. 18 p.

44005801 (MRID) Schoenig, G. (1996) Response to EPA Data Evaluation
Report for Study Entitled: \"Salmonella/Mammalian-Microsome Assay with
Bardac 22.\" Unpublished study prepared by Institute of Toxicology,
Swiss Federal Institute of Technology and University of Zurich. 14 p.

93014008 (MRID) Schoenig, G. (1990) Lonza Inc Phase 3 Summary of
40895202. Mutagenicity Test on Didecyldimethylammoniumchloride in the
CHO/ HGPRT Forward Mutation Assay: Project No. 10141-0-435. Prepared by
Hazleton Laboratories America, Inc. 17 p.

40895202 (MRID) Young, R. (1988) Mutagenicity Test on Didecyldimethyl
Ammonium Chloride (DDAC) in the CHO/HGPRT Forward Mutation Assay: HLA
Study No. 10141-0-435. Unpublished study prepared by Hazleton
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41252601 (MRID) Holmstrom, M.; Leftwich, D.; Leddy, I. (1986) PO151:
Chromosomal Aberrations Assay with Chinese Hamster Ovary Cells in vitro:
Proj. No. 735717. Unpublished study prepared by Lonza Inc. 36 p.

93014007 (MRID) Schoenig, G. (1990) Lonza Inc Phase 3 Summary of MRID
40895201. Mutagenicity Test on Didecyldimethylammoniumchloride in the
Rat Hepatocyte Unscheduled DNA Synthesis Assay: Project No. 10141-0-447.
Prepared by Hazleton Laboratories America, Inc. 14 p.

40895201 (MRID) Cifone, M. (1988) Mutagenicity Test on
Didecyldimethylammonium Chloride in the Rat Primary Hepatocyte
Unscheduled DNA Synthesis Assay: HLA Study No. 10141-0-447. Unpublished
study prepared by Hazleton Laboratories America, Inc. 60 p.

41617101 (MRID) Selim, S. (1989) Absorption, Distribution, Metabolism
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41385101 (MRID) Lin, P.; Selim, S. (1989) Addendum to Report Entitled
Absorption, Distribution, Metabolism and Excretion Studies of
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USEPA (2000): Didecyl Dimethyl Ammonium Chloride (DDAC) -- Report of the
Hazard Identification Assessment Review Committee. HED document No.
014099.

USEPA (2000): Didecyl Dimethyl Ammonium Chloride: Toxicology Review. DP
Barcode D260952.