**UNITED STATES ENVIRONMENTAL PROTECTION AGENCY**

**WASHINGTON, D.C. 20460**

**OFFICE OF**

**PREVENTION, PESTICIDES AND**

**TOXIC SUBSTANCES**

February 27, 2006

**[Memorandum]{.underline}**

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

Active Ingredient: alkyl dimethyl benzyl amoinium chloride (ADBAC)

PC Code 069105

DP Barcode:

From: Timothy F. McMahon, Ph.D

Senior Toxicologist

Antimicrobials Division (7510C)

To: Jacqueline McFarlane, Chemical Review Manager

Regulatory Management Branch I

Antimicrobials Division (7510C)

[1.0 HAZARD CHARACTERIZATION Error! Bookmark not
defined.](#__RefHeading___Toc126490584)

[2.0 REQUIREMENTS Error! Bookmark not
defined.](#__RefHeading___Toc126490585)

[3.0 DATA GAP(S) Error! Bookmark not
defined.](#__RefHeading___Toc126490586)

[4.0 HAZARD ASSESSMENT Error! Bookmark not
defined.](#__RefHeading___Toc126490587)

[**4.1 Acute Toxicity** Error! Bookmark not
defined.](#__RefHeading___Toc126490588)

[**4.2 Subchronic Toxicity** Error! Bookmark not
defined.](#__RefHeading___Toc126490589)

[**4.3 Prenatal Developmental Toxicity** Error! Bookmark not
defined.](#__RefHeading___Toc126490590)

[**4.4 Reproductive Toxicity** Error! Bookmark not
defined.](#__RefHeading___Toc126490591)

[**4.5 Chronic Toxicity** Error! Bookmark not
defined.](#__RefHeading___Toc126490592)

[**4.6 Carcinogenicity** Error! Bookmark not
defined.](#__RefHeading___Toc126490593)

[**4.7 Mutagenicity** Error! Bookmark not
defined.](#__RefHeading___Toc126490594)

[**4.8 Neurotoxicity** Error! Bookmark not
defined.](#__RefHeading___Toc126490595)

[**4.9 Metabolism** Error! Bookmark not
defined.](#__RefHeading___Toc126490596)

[5.0 Toxicity Endpoint Selection Error! Bookmark not
defined.](#__RefHeading___Toc126490597)

[6.0 FQPA Considerations Error! Bookmark not
defined.](#__RefHeading___Toc126490598)

[7.0 Summary of Doses and Endpoints for ADBAC Error! Bookmark not
defined.](#__RefHeading___Toc126490599)

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**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); Group
II non-halogenated benzyl substituted quaternary ammonium compounds
(ADBAC as representative); Group III di- and tri-chlorobenzyl
substituted quaternary ammonium compounds; and Group IV, quaternary
ammonium compounds with unusual substituents. ADBAC, or alkyl dimethyl
benzyl ammonium chloride, is, as stated above, a member of the Group II
class of quaternary ammonium compounds. Hazard data generated for ADBAC
is representative of the hazard associated with this class of quaternary
ammonium chemicals.

In an acute oral toxicity study (MRID 45109204), the acute oral LD~50~
of ADBAC (82.26% a.i.) was determined to be 304.5 mg/kg (both sexes
combined) and was assigned Toxicity Category II. In an acute dermal
toxicity study (MRID 45109202), the acute dermal LD~50~ of ADBAC (82.26%
a.i.) was determined to be 930 mg/kg (both sexes combined) and was
assigned Toxicity Category II. In an acute inhalation toxicity study
(MRID 44885201), the acute LC~50~ of ADBAC (82.26% a.i.) was determined
to be 0.054 \< LC~50~ \< 0.51 mg/L and was assigned a Toxicity Category
II. The primary eye irritation study was waived and assigned a Toxcity
Category I for technical grade ADBAC (80% a.i). For primary dermal
irritation (MRID 45109201), ADBAC (82.26% a.i.) was corrosive to rabbits
(Toxicity Category I). In a dermal sensitization study (MRID 45109203),
ADBAC (82.26% a.i.) was not a sensitizer to guinea pigs. In a
photoallergy (light) sensitization study (MRID 40958501 and MRID
44825002), ADBAC (80% a.i.) was not a photosensitizer.

In a subchronic oral toxicity study in rats (MRID 40746601), ADBAC was
found to have a low order of toxicity, in that manifestations of
toxicity were non-specific (decreased body weight gain, food
consumption), and occurred at relatively high doses (LOAEL of 62
mg/kg/day in males, 308 mg/kg/day in females). This result was also
observed in chronic toxicity studies in rats and mice (MRIDs 41947501
and 41765201), where effects were also non -specific in nature
(decreased body weight gain and food consumption), and occurred at
relatively high doses. In a 21-day dermal toxicity study in guinea pigs
(MRID 41105801), no significant systemic effects were observed using a
chemical mixture of 4% ADBAC/6% DDAC, but denuding of the epidermal
layer was observed at the highest tested, 1000 mg/kg/day. In a 90-day
dermal toxicity study in rats (MRID 41499601) using technical grade
ADBAC , dermal applications of ADBAC (81.09% a.i.) to rats did not
elicit systemic or dermal toxicity up to the highest dose tested, 20
mg/kg/day, before dermal irritation became significant.

ADBAC has been examined for effects on development of the mammalian
fetus and effects on reproductive function. In developmental studies
with rats (range-finding MRID 42645101 and main study MRID 42351501) and
rabbits (range-finding MRID 42734401 and main study MRID 42392801),
developing fetuses showed no increased sensitivity to the toxicity of
ADBAC in relation to adult animals. In a 2-generation reproductive
toxicity study (MRID 41385001), effects on rat pups were observed in the
absence of maternal toxicity, raising some concern for the effects of
ADBAC on reproductive function. However, the effects observed were
non-specific (decreased pup body weight and weight gain during
lactation), and there were no effects of ADBAC on reproductive indices.

In a chronic toxicity study in dogs (MRID 43221101), groups of 4 male
and female beagle dogs per group received either 0, 120, 400, or 1200
ppm (0, 3.79, 13.1, or 33.8 mg/kg/day in males and 0, 3.67, 14.6, or
38.6 mg/kg/day in females) alkyl dimethyl benzyl ammonium chloride
\[ADBAC, 80% a.i.\] as a direct dietary admix for one year. Systemic
toxicity was observed at 13.1 mg/kg/day in males and 14.6 mg/kg/day in
females as reduced body weight gain (approximately 10% reduction) after
52 weeks of exposure. Food consumption was decreased in the 1200 ppm
males and females for the entire study period (approximately 15%
reduction in males and 5% reduction in females). Based on the data in
this study, the Systemic Toxicity NOAEL was 120 ppm (3.79 mg/kg/day in
males, 3.67 mg/kg/day in females) and the LOAEL was 400 ppm (13.1
mg/kg/day in males, 14.6 mg/kg/day in females) based on reduced body
weight gain.

ADBAC has been tested for carcinogenicity in long term studies with both
rats (MRID 41947501) and mice (MRID 41765201). In both studies, tested
to adequate dose levels, ADBAC was negative for induction of tumors in
both species. This result is supported by results of testing in a
battery of mutagenicity studies, including an HGPRT/CHO for ward
mutation assay (MRID 41012701), an in vivo bone marrow chromosome
aberration assay (MRID 40311101, supplement MRID 43037701), and an
unscheduled DNA synthesis (UDS) assay (MRIDs 42290801 and 42290802),
which show ADBAC to be negative for mutagenic effects.

The metabolism of ADBAC was investigated in MRID 41087701. The majority
of administered radioactive ADBAC is eliminated in feces from oral
administration. Intravenous administration also shows elimination of a
significant proportion of ADBAC in feces, indicating elimination through
the bile. Tissue retention of orally administered radioactivity is
negligible.

**2.0 TOXICOLOGY DATA REQUIREMENTS**

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

+-----------------------------------------+-------------+-------------+
| **Table 1: Toxicologic Data             |             |             |
| Requirements for ADBAC.**               |             |             |
+=========================================+=============+=============+
| **Test**                                | **          |             |
|                                         | Technical** |             |
+-----------------------------------------+-------------+-------------+
|                                         | *           | **          |
|                                         | *Required** | Satisfied** |
+-----------------------------------------+-------------+-------------+
| 870.1100 Acute Oral Toxicity (Rat) MRID | yes         | yes         |
| 45109204                                |             |             |
|                                         | yes         | yes         |
| 870.1200 Acute Dermal Toxicity (Rat)    |             |             |
| MRID 45109202                           | yes         | yes         |
|                                         |             |             |
| 870.1300 Acute Inhalation (Rat) MRID    | yes         | yes         |
| 44885201                                |             |             |
|                                         | yes         | yes         |
| 870.2400 Primary Eye Irritation         |             |             |
| (Rabbit) MRID 40919701 and supplement   | yes         | yes         |
| MRID 44825001                           |             |             |
|                                         | no          | NA          |
| 870.2500 Primary Dermal Irritation      |             |             |
| (Rabbit) MRID 45109201                  |             |             |
|                                         |             |             |
| 870.2600 Dermal Sensitization (Guinea   |             |             |
| pig) MRID 45109203                      |             |             |
|                                         |             |             |
| > Photosensitization (Guinea pigs) MRID |             |             |
| > 40958501 and supplement MRID 44825002 |             |             |
+-----------------------------------------+-------------+-------------+
| 870.3100 Oral Subchronic (Rat) MRID     | yes         | yes         |
| 40746601                                |             |             |
|                                         | yes         | yes         |
| 870.3200 21-Day Dermal (Guinea pig)     |             |             |
| MRID 41105801                           | yes         | yes         |
|                                         |             |             |
| 870.3250 90-Day Dermal (Rat) MRID       |             |             |
| 41499601                                |             |             |
+-----------------------------------------+-------------+-------------+
| 870.3700a Developmental Toxicity (Rat)  | yes         | yes         |
| MRID 42645101 (range-finding) MRID      |             |             |
| 42351501 (main study)                   | yes         | yes         |
|                                         |             |             |
| 870.3700b Developmental Toxicity (      | yes         | yes         |
| Rabbit) MRID 42734401 (range-finding)   |             |             |
| and 42392801 (main study)               |             |             |
|                                         |             |             |
| 870.3800 Reproduction (Rat) MRID        |             |             |
| 41385001                                |             |             |
+-----------------------------------------+-------------+-------------+
| 870.4100 Chronic Toxicity (dog) MRID    | yes         | yes         |
| 43221101                                |             |             |
+-----------------------------------------+-------------+-------------+
| 870.4200b Oncogenicity (Mouse) MRID     | yes         | yes         |
| 41765201                                |             |             |
|                                         | yes         | yes         |
| 870.4300 Chronic/Oncogenicity (Rat)     |             |             |
| MRID 41947501                           |             |             |
+-----------------------------------------+-------------+-------------+
| 870.5300 Mutagenicity---Gene Mutation   | yes         | yes         |
| (CHO) MRID 41012701                     |             |             |
|                                         | yes         | yes         |
| 870.5385 Mutagenicity---In vivo bone    |             |             |
| arrow chromosomal aberration test       | yes         | yes         |
| (mouse) MRID 40311101, supplement       |             |             |
| 43037701                                |             |             |
|                                         |             |             |
| 870.5550 Mutagenicity---Unscheduled DNA |             |             |
| synthesis (Rat hepatocyte) MRID         |             |             |
| 42290802 and 42290801                   |             |             |
+-----------------------------------------+-------------+-------------+
| 870.6100 Acute Delayed Neurotox. (Hen)  | no          | \-          |
|                                         |             |             |
| 870.6200 Acute Neurotox. Screening      | no          | \-          |
| Battery (Rat)                           |             |             |
|                                         | no          | \-          |
| 870.6300 Develop. Neuro                 |             |             |
+-----------------------------------------+-------------+-------------+
| 870.7485 Metabolism (Rat) MRID          | yes         | yes         |
| 40990701, supplemental MRIDs 41087701   |             |             |
| and 44783401                            |             |             |
+-----------------------------------------+-------------+-------------+

**3.0 DATA GAPS**

Number range CHAPTERA dermal absorption study is not available for
ADBAC. Until data are received that adequately address this science
issue, the value of 10% dermal absorption determined by the HIARC will
be used. Also, a repeated dose inhalation toxicity study is not
available for the technical grade ADBAC.

**4.0 HAZARD ASSESSMENT**

1.  **Acute Toxicity**

[Adequacy of database for Acute Toxicity]{.underline}: [Number range
CHAPTER]{.mark} The acute toxicity data for ADBAC are considered
adequate to support reregistration. The acute toxicity data for ADBAC
are summarized below in Table 2.

+---------+-----------------+-------------+---------------+---------+
| **Table |                 |             |               |         |
| 2.      |                 |             |               |         |
| Acute   |                 |             |               |         |
| T       |                 |             |               |         |
| oxicity |                 |             |               |         |
| Profile |                 |             |               |         |
| for     |                 |             |               |         |
| ADBAC** |                 |             |               |         |
+=========+=================+=============+===============+=========+
| **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 |                 | 45109204    | CHAPTERLD~50~ |         |
|         | (Purity 82.26%) |             | =304.5 mg/kg  |         |
| (§81-1) |                 |             | (combined)    |         |
|         |                 |             |               |         |
|         |                 |             | Number range  |         |
|         |                 |             | CHAPTERLD~50~ |         |
|         |                 |             | =510.9 mg/kg  |         |
|         |                 |             | (males)       |         |
|         |                 |             |               |         |
|         |                 |             | Number range  |         |
|         |                 |             | CHAPTERLD~50~ |         |
|         |                 |             | =280.8 mg/kg  |         |
|         |                 |             | (females)     |         |
+---------+-----------------+-------------+---------------+---------+
| 8       | Acute dermal,   | MRID        | Number range  | II      |
| 70.1200 | rat             | 45109202    | CHAPTERLD~50~ |         |
|         |                 |             | =930 mg/kg    |         |
| (§81-2) | (Purity 82.26%) |             | (combined)    |         |
|         |                 |             |               |         |
|         |                 |             | Number range  |         |
|         |                 |             | CHAPTERLD~50~ |         |
|         |                 |             | =1100 mg/kg   |         |
|         |                 |             | (males)       |         |
|         |                 |             |               |         |
|         |                 |             | Number range  |         |
|         |                 |             | CHAPTERLD~50~ |         |
|         |                 |             | =704 mg/kg    |         |
|         |                 |             | (females)     |         |
+---------+-----------------+-------------+---------------+---------+
| 8       | Acute           | MRID        | 0.054 \<      | II      |
| 70.1300 | inhalation, rat | 44885201    | Number range  |         |
|         |                 |             | CHAPTERLC~50~ |         |
| (§81-3) | (Purity 82.26%) |             | \< 0.51 mg/L  |         |
+---------+-----------------+-------------+---------------+---------+
| 8       | Primary eye     | waived      |               | I       |
| 70.2400 | irritation      |             |               |         |
|         |                 |             |               |         |
| (§81-4) |                 |             |               |         |
+---------+-----------------+-------------+---------------+---------+
| 8       | Primary dermal  | MRID        | Corrosive     | I       |
| 70.2500 | irritation,     | 45109201    |               |         |
|         | rabbit          |             |               |         |
| (§81-5) |                 |             |               |         |
|         | (Purity 82.26%) |             |               |         |
+---------+-----------------+-------------+---------------+---------+
| 8       | Dermal          | MRID        | Not a dermal  | NA      |
| 70.2600 | sensitization,  | 45109203    | sensitizer.   |         |
|         | guinea pigs     |             |               |         |
| (§81-6) |                 |             |               |         |
|         | (Purity 82.26%) |             |               |         |
+---------+-----------------+-------------+---------------+---------+
| Non-Gu  | Phot            | MRID        | Not a         | NA      |
| ideline | osensitization, | 40958501    | pho           |         |
|         | guinea pigs     | and         | tosensitizer. |         |
|         |                 | supplement  |               |         |
|         | (Purity 80%)    | 44825002    |               |         |
+---------+-----------------+-------------+---------------+---------+

2.  **Subchronic Toxicity**

[Adequacy of database for Subchronic Toxicity]{.underline}: Number range
CHAPTERThe database for subchronic toxicity of ADBAC is considered
complete. For oral toxicity, the database includes a 90-day oral
toxicity test in rats (MRID 40746601). For dermal toxicity, there is a
21-day dermal toxicity study in guinea pigs (MRID 40700700) and a 90-day
dermal toxicity study in rats (MRID 41499601).

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

Number range CHAPTERIn a subchronic oral toxicity study in rats (MRID
#40746601), male and female rats were administered ADBAC (79.7% a.i.) in
the diet for 13 weeks at dose levels of 0, 100, 500, 1000, 4000, or 8000
ppm. Increased mortality was observed at the 4000 and 8000 ppm dose
groups in both sexes. Decreased body weight, weight gain, food
consumption and increased incidence of microscopic lesions \[congestion
and edema of the G.I. tract, hemorrhaging of the lungs and brain\] were
also observed in males and females at 4000 ppm. The Systemic NOAEL for
males is 500 ppm and for females is 1000 ppm, based upon decreased body
weight and weight gain in males at 1000 ppm, and increased mortality,
decreased body weight gain and food consumption, and increased
microscopic lesions in female rats at 4000 ppm**.**

This study is classified as **acceptable**.

**870.3200 Subchronic (21-day dermal) Toxicity -- Guinea pig**

Number range CHAPTER 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
and1000 mg/kg, five days a week, for 21 days. 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 at 1000 mg/kg. 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 a denuded non-vascularized epidermal layer
at the application site.

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 produced no significant dermal or systemic
effects, and is considered a NOAEL for the study for dermal irritation
and systemic effects.

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

In a 90‑day dermal toxicity study (MRID 41499601), ADBAC (81.09% a.i.)
was applied at dose levels of 0, 2, 6, or 20 mg/kg/day to the clipped
backs of Sprague‑Dawley rats for 6‑8 hours per day, 5 days per week, for
13 weeks. Although higher doses were tested in a preliminary
range-finding study (6, 20, 60, 120, and 200 mg/kg/day), the high dose
selected for the main study (20 mg/kg/day) was chosen on the basis that
higher concentrations produced skin irritation that was considered
greater than slight.

A significant and dose‑related decrease in reticulocyte count was
observed in the 6‑ and 20‑mg/kg/day females. Decreases in reticulocyte
count are normally associated with regenerative responses to anemia.
However, no evidence of anemia was seen in other hematological
parameters. Furthermore, the decreased levels in treated females were
similar to the levels observed in control males. Thus, the decreasing
reticulocyte count was most likely not a biologically significant
finding.

A significant increase in hyperkeratosis was observed in treated skin of
high dose females, but this lesion was also observed in increased
incidence in male rats at all doses including controls.

**The NOAEL for dermal effects and the NOAEL for systemic effects were
20 mg/kg/day.**

**4.3 Prenatal Developmental Toxicity**

[Adequacy of database for Prenatal Developmental Toxicity]{.underline}:
Number range CHAPTERThe database for developmental toxicity of ADBAC is
considered complete. The database includes 2 developmental studies, one
in the rat (range-finding MRID 42645101 and main study MRID 42351501)
and another in the rabbit (range-finding MRID 42734401 and main study
MRID 42392801).

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

Number range CHAPTERIn a dose range-finding study for developmental
toxicity in rats (MRID \# 42645101), ADBAC (81.09%) was administered at
doses of 0, 25, 50, 100, 200, or 400 mg/kg/day to CD rats (5/dose) by
oral gavage on gestation days 6 through 15, inclusive. Doses ≥ 200
mg/kg/day resulted in 100% mortality; necropsy findings revealed a
distended and change in color of the stomach, and distended intestines
filled with mucoid fluid. These dams also exhibited clinical signs
including loose feces, perioral wetness and perioral encrustation,
ataxia, hypoactivity, urogenital area wetness, and audible respiration.
Maternal toxicity observed at 100 mg/kg/day was manifest as
significantly increased incidence of perioral wetness. The maternal
NOAEL and LOAEL are 50 and 100 mg/kg/day, respectively. The NOAEL for
developmental toxicity is 100 mg/kg/day based on no survival of dams at
200 and 400 mg/kg/day.

Number range CHAPTERIn a developmental toxicity study in rats (MRID \#
42351501), female Sprague-Dawley rats (25/dose) were administered ADBAC
(81.09% a.i.) by gavage at doses of 0, 10, 30, and 100 mg/kg on
gestation days 6 through 15 inclusive for assessment of developmental
toxicity. There was no mortality in maternal animals observed at any
dose level. At 100 mg/kg/day, one dam exhibited dehydration, unkempt
appearance, loose feces, and perioral wetness. At 30 mg/kg/day, one dam
was noted with perioral wetness, gasping, loose feces, and urine stains.
Decreased body weight gain (12-13%) was observed in maternal animals at
30 mg/kg/day during gestation days 6-15. Food consumption was not
consistently affected by treatment. There were no treatment-related
increases in the incidence of fetal external, visceral, or skeletal
abnormalities at any dose level. Based on the results of this study, the
Maternal NOAEL is 10 mg/kg/day, and the Maternal LOAEL is 30 mg/kg/day,
based on clinical signs and decreased body weight gain. The
Developmental toxicity NOAEL is 100 mg/kg/day, and the Developmental
toxicity LOAEL is \> 100 mg/kg/day. There was no evidence for
developmental toxicity of ADBAC in this study.

This study is classified as **acceptable**.

3700. **Prenatal Developmental Toxicity (Gavage) -- Rabbit**

Number range CHAPTERIn a dose range-finding study for developmental
toxicity in rabbits (MRID \# 42734401), ADBAC (81.09%) was administered
at doses of 0, 1, 3, 10, 30, or 60 mg/kg/day to pregnant New Zealand
White rabbits (5/dose) by oral gavage on gestation days 6 through 18.
Mortality was observed at doses of 30 and 60 mg/kg/day (2 and 5 does,
respectively). Audible respiration was observed at doses greater than or
equal to 10 mg/kg/day. At doses greater than or equal to 30 mg/kg/day,
clinical signs included hypoactivity, perioral wetness, and labored
breathing. At 60 mg/kg/day, clinical signs included paralysis, cold
extremities, prostration, slow respiration, emaciation, loose feces, and
perioral encrustation. Decreased body weight gain and food consumption
were observed at doses greater than or equal to 10 mg/kg/day.
Developmental toxicity was not observed at any of the doses tested. The
maternal NOAEL for the range-finding study is 3 mg/kg/day and the LOAEL
is 10 mg/kg/day, based on clinical signs and reduced body weight gain
and food consumption. There was no evidence of developmental toxicity of
ADBAC in this study.

Number range CHAPTERIn a developmental toxicity study in rabbits (MRID
\# 42392801), ADBAC (81.09%) was administered at doses of 0, 1, 3, or 9
mg/kg/day to pregnant New Zealand White rabbits (16/dose) by oral gavage
on gestation days 6 through 18, inclusive. There was no mortality or
abortions at any dose level. Hypoactivity and labored breathing were
observed at 9 mg/kg/day in 2 of 15 rabbits. There were no effects on
maternal body weight, food consumption, cesarean section observations,
or necropsy observations. In offspring, there was no evidence of
developmental toxicity at any dose level tested. The Maternal NOAEL is 3
mg/kg/day, and the Developmental NOAEL is 9 mg/kg/day. The Maternal
LOAEL is 9 mg/kg/day, based on clinical signs of toxicity, and the
Developmental LOAEL is \> 9 mg/kg/day. There was no evidence of
developmental toxicity of ADBAC in this study.

This study is classified as **acceptable**.

**4.4 Reproductive Toxicity**

[Adequacy of database for Reproductive:]{.underline} Number range
CHAPTERThe database for reproductive toxicity of ADBAC is considered
complete. The database includes an acceptable 2-generation reproduction
toxicity study in rats, MRID 41385001.

**870.3800 Reproduction and Fertility Effects -- Rat**

Number range CHAPTERIn a two-generation reproduction toxicity study in
rats (MRID \# 41385001), ADBAC (81.09%) was administered in the diet to
groups of male and female Sprague-Dawley rats (28/sex/dose) at dose
levels of 0, 300, 1000, or 2000 ppm over two generations. After 10 weeks
of dietary treatment, F0 parental animals were mated. F1 parental
animals were mated after 15 weeks of dietary treatment. Mean compound
consumption was 20.7, 68.2, and 134.7 mg/kg/day for F0 males, and 25.5,
81.3, and 164.7 mg/kg/day for F0 females. For the F1 males, mean
compound consumption was 19.1, 62.5, and 125.4 mg/kg/day, and 24.8,
78.5, and 157.1 mg/kg/day for F1 females.

There was no treatment-related mortality in parental animals at any dose
level, and there were no reported signs of clinical toxicity in parental
animals. Although some decrease in body weight was observed in both
generations at the top dose, the significant variability observed did
not qualify this as a treatment-related effect.

In pups of both generations, mean body weights at the top dose were
significantly reduced during lactation and post-weaning periods. There
were no adverse effects noted on gestational length, mating, fertility,
or other gestational indices.

Based on the results of this study, the Parental NOAEL = 146 mg/kg/day,
and the Parental LOAEL \> 146 mg/kg/day (highest dose tested). The
Developmental/Systemic NOAEL = 65.4/79.9 mg/kg/day (M/F), and the
Developmental /Systemic LOAEL = 130.1/160.9 mg/kg/day (M/F), based on
reduced pup body weight and weight gain during lactation \[doses for
both the F0 and F1 pups combined\].

This study is classified as **acceptable**.

**4.5 Chronic Toxicity**

[Adequacy of database for Chronic Toxicity]{.underline}: Number range
CHAPTERThe database for chronic toxicity of ADBAC is considered
adequate, including a chronic toxicity study in dogs (MRID 43221101) and
a combined chronic oral toxicity/carcinogencity study in rats (MRID
41947501).

4100. **Chronic Toxicity (Oral) -- Dog**

In a chronic toxicity study in dogs (MRID 43221101), groups of 4 male
and female beagle dogs per group received either 0, 120, 400, or 1200
ppm (0, 3.79, 13.1, or 33.8 mg/kg/day in males and 0, 3.67, 14.6, or
38.6 mg/kg/day in females) alkyl dimethyl benzyl ammonium chloride
\[ADBAC, 80% a.i.\] as a direct dietary admix for one year. Systemic
toxicity was observed at 400 ppm and above in female dogs and at 1200
ppm in males as reduced body weight gain (approximately 10% reduction)
after 52 weeks of exposure. Food consumption was decreased in the 1200
ppm males and females for the entire study period (approximately 15%
reduction in males and 5% reduction in females). Based on the data in
this study, the Systemic Toxicity NOAEL was 120 ppm (3.79 mg/kg/day in
males, 3.67 mg/kg/day in females) and the LOAEL was 400 ppm (13.1
mg/kg/day in males, 14.6 mg/kg/day in females) based on reduced body
weight gain.

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

Number range CHAPTERIn a chronic toxicity / carcinogenicity study (MRID
\# 41947501), ADBAC (81% purity) was administered in the diet to groups
of male and female Sprague-Dawley rats (50/sex/dose) at dose levels of
0, 300, 1000, and 2000 ppm (nominal doses of 13, 44, and 88 mg/kg/day in
males; 17, 57, and 116 mg/kg/day in females) for 104 weeks. Significant
decreases in group mean body weight were observed in male rats at the
2000 ppm dose level during weeks 1-26 of the study and then sporadically
thereafter. Body weights of high dose female rats were also
significantly decreased during weeks 1-60 of the study. Body weight gain
was decreased 11% on average in high dose males and 14% in high dose
females. There were no significant treatment-related effects on clinical
chemistry, hematology, or urinalysis. No treatment-related non
neoplastic gross or microscopic lesions were evident in any of the
treated groups of rats. There was no evidence of carcinogenicity of
ADBAC in this study. The Systemic toxicity NOAEL = 1000 ppm, (44
mg/kg/day \[M\]; 57 mg/kg/day \[F\]), and the Systemic toxicity LOAEL =
2000 ppm (88 mg/kg/day \[M\]; 116 mg/kg/day \[F\], based on decreased
body weight and weight gain. This study is classified as acceptable and
satisfies the guideline requirement for a chronic toxicity /
carcinogenicity study in rats.

6.  **Carcinogenicity**

[Adequacy of database for Carcinogenicity]{.underline}: The database for
the carcinogenicity of ADBAC is considered adequate. The database for
carcinogenicity includes the 104 week chronic toxicity/carcinogenicity
study in rats (MRID 41947501) described in 4.5 and an additional
carcinogenicity study in the mouse (MRID 41765201). Results of both
studies showed ADBAC to be negative for carcinogenicity.

**870.4200 Carcinogenicity (Oral) -- Mouse**

Number range CHAPTERIn a carcinogenicity study in mice (MRID \#
41765201), ADBAC (81% purity) was administered in the diet to male and
female CD-1 mice (60 sex/dose) at levels of 0, 100, 500, or 1500 ppm for
78 weeks (nominal doses of 14.9, 73.4 and 229.3 mg/kg/day in males;
17.8, 92.1 and 288.6 mg/kg/day in females). No significant differences
in the incidence of mortality were observed in treated animals versus
controls. No clinical signs of toxicity were observed at any dose level
tested. Significant reductions in group mean body weight were observed
at the high dose in male and female mice throughout the treatment period
with no significant reduction in food intake. There were no significant
treatment-related effects on organ weights, macroscopic, or microscopic
pathology in treated mice at any dose level. ADBAC was negative for
carcinogenicity in this study. The Systemic LOAEL = 1500 ppm in male and
female mice (229.3 / 288.6 mg/kg/day), based on reduced body weight. The
Systemic NOAEL = 500 ppm in male and female mice (73.4 / 92.1
mg/kg/day). This study is classified as acceptable and satisfies the
guideline requirement for a carcinogenicity study in mice.

**4.7 Mutagenicity**

Number range CHAPTERADBAC has been tested for mutagenicity in an HGPRT
assay in CHO cells for forward mutations (MRID 41012701), an in vivo
bone marrow chromosome aberration assay (MRID 40311101, supplemental
MRID 43037701), and an unscheduled DNA synthesis assay (MRID 42290802
and 4229080). Results of all of these studies were negative for ADBAC.

**4.8 Neurotoxicity**

[Adequacy of database for Neurotoxicity]{.underline}: Number range
CHAPTERThere are no studies specifically examining the Neurotoxicity of
ADBAC. Based on the lack of evidence for Neurotoxicity of ADBAC,
specific neurotoxicity studies are not required for ADBAC at this time.

**4.9 Metabolism and Pharmacokinetics**

[Adequacy of database for Metabolism and Pharmacokinetics]{.underline}:
Number range CHAPTERDisposition of ADBAC was examined in male and female
Sprague-Dawley rats (MRID 40990701, supplemental MRIDs 41087701 and
44783401) following a 10 mg/kg single dose by the oral or intravenous
route, following exposure to 100 ppm ADBAC for 14 days in the diet, or
after a single oral dose of 50 mg/kg. Ring-labeled test material was
used. Following oral administration, from 5-8% of the administered dose
was eliminated in urine and 90-98% in feces. No apparent differences in
disposition were noted between sexes. Following intravenous
administration, males eliminated 31% of the dose in urine and 44% in
feces, while females eliminated 21% in urine and 55% in feces following
intravenous administration. After oral administration, from 0.03-0.58%
of the administered dose was accounted for in tissues. After intravenous
administration, tissue residues accounted for 33-36% of the dose and
were observed mainly in the carcass. The results of this study indicate
that a majority of an administered dose of ADBAC is eliminated in feces
and involves biliary excretion.

**5.0 Toxicity Endpoint Selection**

**5.1 See Section 7.1, Summary of Toxicological Doses and Endpoint
Selection, Table 2.**

2.  **Dermal Absorption**

    [Dermal Absorption Factor]{.underline}: 10%

Number range CHAPTER Based upon the structure, molecular weight, ionized
state, and lack of lipophilicity, that dermal absorption of ADBAC would
not exceed 10%. This value will be used in dermal risk assessments.

3.  **Classification of Carcinogenic Potential**

Number range CHAPTERADBAC has been tested for carcinogenicity in both
rats and mice in studies reviewed by the Agency. Results of both studies
show ADBAC to be negative for carcinogenicity.

**1. [Combined Chronic Toxicity/Carcinogenicity Study in
Rats]{.underline}**

In a chronic toxicity / carcinogenicity study (MRID \# 41947501), ADBAC
(81% purity) was administered in the diet to groups of male and female
Sprague-Dawley rats (50/sex/dose) at dose levels of 0, 300, 1000, and
2000 ppm (nominal doses of 13, 44, and 88 mg/kg/day in males; 17, 57,
and 116 mg/kg/day in females) for 104 weeks. Significant decreases in
group mean body weight were observed in male rats at the 2000 ppm dose
level during weeks 1-26 of the study and then sporadically thereafter.
Body weights of high dose female rats were also significantly decreased
during weeks 1-60 of the study. Body weight gain was decreased 11% on
average in high dose males and 14% in high dose females. There were no
significant treatment-related effects on clinical chemistry, hematology,
or urinalysis. No treatment-related non neoplastic gross or microscopic
lesions were evident in any of the treated groups of rats. There was no
evidence of carcinogenicity of ADBAC in this study. The Systemic
toxicity NOAEL = 1000 ppm, (44 mg/kg/day \[M\]; 57 mg/kg/day \[F\]), and
the Systemic toxicity LOAEL = 2000 ppm (88 mg/kg/day \[M\]; 116
mg/kg/day \[F\], based on decreased body weight and weight gain. This
study is classified as acceptable and satisfies the guideline
requirement for a chronic toxicity / carcinogenicity study in rats.

**[2. Carcinogenicity Study in Mice]{.underline}**

In a carcinogenicity study in mice (MRID \# 41765201), ADBAC (81%
purity) was administered in the diet to male and female CD-1 mice (60
sex/dose) at levels of 0, 100, 500, or 1500 ppm for 78 weeks. No
significant differences in the incidence of mortality were observed in
treated animals versus controls. No clinical signs of toxicity were
observed at any dose level tested. Significant reductions in group mean
body weight were observed at the high dose in male and female mice
throughout the treatment period with no significant reduction in food
intake. There were no significant treatment-related effects on organ
weights, macroscopic, or microscopic pathology in treated mice at any
dose level. ADBAC was negative for carcinogenicity in this study. The
Systemic LOAEL = 1500 ppm in male and female mice (229.3 / 288.6
mg/kg/day), based on reduced body weight. The Systemic NOAEL = 500 ppm
in male and female mice (73.4 / 92.1 mg/kg/day). This study is
classified as acceptable and satisfies the guideline requirement for a
carcinogenicity study in mice.

**6.0 FQPA Considerations**

**6.1 Developmental Toxicity Study Conclusions**

Number range CHAPTERIn both the developmental toxicity study in the rat
and rabbit, there was no evidence of increased susceptibility to
offspring in these studies.

**6.2 Reproductive Toxicity Study Conclusions**

Number range CHAPTERThere was no evidence of a primary reproductive
toxicity effect of ADBAC based on the available data.

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

A. [Determination of Susceptibility]{.underline}

Number range CHAPTERThe HIARC determined from the available data that
there was no evidence for increased susceptibility of offspring to the
toxic effects of ADBAC.

B. [Proposed Hazard-based Special FQPA Safety Factor(s)]{.underline}:

Number range CHAPTERThe HIARC recommended that the FQPA safety factor be
**reduced to 1x** for ADBAC, based upon the existence of a complete
developmental and reproductive toxicity database and the lack of
evidence for increased susceptibility in these data.

**6.4 Recommendation for a Developmental Neurotoxicity Study**

Number range CHAPTERThere are no studies specifically examining
neurotoxicity of ADBAC. However, there was no evidence of neurotoxicity
from the available studies on ADBAC. The HIARC expressed concern that
some quaternary ammonium compounds could have the potential for
neurotoxicity, depending upon the length of the alkyl chains. However,
for ADBAC, neurotoxicity studies will not be required at this time.

Number range CHAPTER A developmental neurotoxicity study is not
recommended, based on the lack of evidence for neurotoxicity of ADBAC in
the available database.

**7.0 Summary of Toxicological Doses and Endpoints for ADBAC for Use in
Human Risk Assessment**

**7.1 Summary Table of Toxicological Dose and Endpoint Selection (Table
3)**

+------------+---------+------------------------+---------------------+
| Number     | **Dose  | **Target MOE/UF,**     | **Study and         |
| range      | Used in |                        | Toxicological       |
| CHAPT      | Risk    | **Special FQPA SF**    | Effects**           |
| EREXPOSURE | Asses   |                        |                     |
|            | sment** | **for Risk             |                     |
| SCENARIO   |         | Assessment**           |                     |
|            | *       |                        |                     |
|            | *(mg/kg |                        |                     |
|            | /day)** |                        |                     |
+------------+---------+------------------------+---------------------+
| Acute      | No      |                        |                     |
| Dietary    | appr    |                        |                     |
|            | opriate |                        |                     |
| (general   | e       |                        |                     |
| pop.,      | ndpoint |                        |                     |
| females    | was     |                        |                     |
| 13+)       | ide     |                        |                     |
|            | ntified |                        |                     |
|            | in the  |                        |                     |
|            | da      |                        |                     |
|            | tabase. |                        |                     |
|            | This    |                        |                     |
|            | risk    |                        |                     |
|            | ass     |                        |                     |
|            | essment |                        |                     |
|            | is not  |                        |                     |
|            | re      |                        |                     |
|            | quired. |                        |                     |
+------------+---------+------------------------+---------------------+
| Chronic    | NOAEL   | **FQPA SF** = 1        | Chronic             |
| Dietary    | =44     |                        | toxic               |
|            | mg      | **UF** = 100 (10x      | ity/carcinogenicity |
|            | /kg/day | inter-species          | -rat                |
|            |         | extrapolation, 10x     |                     |
|            |         | intra-species          | MRID 41947501       |
|            |         | variation)             |                     |
|            |         |                        | LOAEL = 88          |
|            |         |                        | mg/kg/day, based on |
|            |         |                        | decreased body      |
|            |         |                        | weight and weight   |
|            |         |                        | gain                |
+------------+---------+------------------------+---------------------+
|            |         | **Chronic RfD =** 0.44 |                     |
|            |         | mg/kg/day              |                     |
+------------+---------+------------------------+---------------------+
| Incidental | NOAEL = | **UF** = 100 (10x      | Developmental       |
| Oral       | 10      | inter-species          | Toxicity - Rat      |
| (s         | mg      | extrapolation, 10x     |                     |
| hort-term) | /kg/day | intra-species          | MRID 42351501       |
|            |         | variation)             |                     |
|            |         |                        | LOAEL = 30          |
|            |         | **FQPA SF** = 1        | mg/kg/day, based on |
|            |         |                        | clinical signs and  |
|            |         |                        | decreased body      |
|            |         |                        | weight gain.        |
+------------+---------+------------------------+---------------------+
| Incidental | NOAEL = | **UF** = 100 (10x      | Developmental       |
| Oral       | 10      | inter-species          | Toxicity - Rat      |
| (intermed  | mg      | extrapolation, 10x     |                     |
| iate-term) | /kg/day | intra-species          | MRID 42351501       |
|            |         | variation)             |                     |
|            |         |                        | LOAEL = 30          |
|            |         | **FQPA SF** = 1        | mg/kg/day, based on |
|            |         |                        | decreased body      |
|            |         |                        | weight and food     |
|            |         |                        | consumption.        |
+------------+---------+------------------------+---------------------+
| Short-Term | NOAEL=  | **UF** = 100 (10x      | 21-day dermal       |
|            | 500     | inter-species          | toxicity- guinea    |
| Dermal     | mg      | extrapolation, 10x     | pigs MRID 41105801  |
| (**        | /kg/day | intra-species          |                     |
| formulated |         | variation)             | LOAEL = 40 mg       |
| product**  | (333 g |                        | ai/kg/day, based on |
| (4%        | ai/cm2) | **FQPA SF** = 1        |                     |
| a.i.))^b^  |         |                        | denuded             |
|            |         |                        | non-vascularized    |
|            |         |                        | epidermal layer.    |
+------------+---------+------------------------+---------------------+
| Number     | **Dose  | **Target MOE/UF,**     | **Study and         |
| range      | Used in |                        | Toxicological       |
| CHAPT      | Risk    | **Special FQPA SF**    | Effects**           |
| EREXPOSURE | Asses   |                        |                     |
|            | sment** | **for Risk             |                     |
| SCENARIO   |         | Assessment**           |                     |
|            | *       |                        |                     |
|            | *(mg/kg |                        |                     |
|            | /day)** |                        |                     |
+------------+---------+------------------------+---------------------+
| Interme    | NOAEL = | **UF** = 100 (10x      | 90-day dermal       |
| diate-term | 20      | inter-species          | toxicity in rats    |
| dermal     | mg      | extrapolation, 10x     |                     |
| *          | /kg/day | intra-species          | MRID 41499601       |
| *technical |         | variation)             |                     |
| grade      | (80 g  |                        | highest dose (20 mg |
| a.i.**     | ai/cm2) |                        | ai/kg/day) tested   |
|            |         |                        | before irritation   |
| (80%       |         |                        | became significant  |
| a.i.)^c^   |         |                        | at day 43.          |
+------------+---------+------------------------+---------------------+
| Short-Term | No      |                        |                     |
| Dermal     | e       |                        |                     |
| (technical | ndpoint |                        |                     |
| grade      | ide     |                        |                     |
| a.i.)      | ntified |                        |                     |
|            | from    |                        |                     |
|            | the     |                        |                     |
|            | av      |                        |                     |
|            | ailable |                        |                     |
|            | data on |                        |                     |
|            | dermal  |                        |                     |
|            | irri    |                        |                     |
|            | tation. |                        |                     |
|            | Dermal  |                        |                     |
|            | irr     |                        |                     |
|            | itation |                        |                     |
|            | in the  |                        |                     |
|            | 90-day  |                        |                     |
|            | dermal  |                        |                     |
|            | t       |                        |                     |
|            | oxicity |                        |                     |
|            | study   |                        |                     |
|            | was not |                        |                     |
|            | evident |                        |                     |
|            | until   |                        |                     |
|            | day 43  |                        |                     |
|            | (MRID   |                        |                     |
|            | 414     |                        |                     |
|            | 99601). |                        |                     |
+------------+---------+------------------------+---------------------+
| Long-Term  | No      |                        |                     |
| Dermal     | appr    |                        |                     |
| (technical | opriate |                        |                     |
| grade      | e       |                        |                     |
| a.i.)      | ndpoint |                        |                     |
|            | iden    |                        |                     |
|            | tified. |                        |                     |
|            | No      |                        |                     |
|            | s       |                        |                     |
|            | ystemic |                        |                     |
|            | effects |                        |                     |
|            | o       |                        |                     |
|            | bserved |                        |                     |
|            | up to   |                        |                     |
|            | 20      |                        |                     |
|            | mg/     |                        |                     |
|            | kg/day, |                        |                     |
|            | highest |                        |                     |
|            | dose of |                        |                     |
|            | te      |                        |                     |
|            | chnical |                        |                     |
|            | grade   |                        |                     |
|            | that    |                        |                     |
|            | could   |                        |                     |
|            | be      |                        |                     |
|            | tested  |                        |                     |
|            | without |                        |                     |
|            | irr     |                        |                     |
|            | itation |                        |                     |
|            | e       |                        |                     |
|            | ffects. |                        |                     |
+------------+---------+------------------------+---------------------+
| Inh        | NOAEL=  | **UF** = 100 (10x      | Developmental       |
| alation^a^ | 3       | inter-species          | toxicity - rabbit   |
|            | mg      | extrapolation, 10x     |                     |
| (all       | /kg/day | intra-species          | MRID 42392801       |
| exposure   |         | variation, 10x         |                     |
| durations) |         | route-extrapolation)   | LOAEL = 9           |
|            |         |                        | mg/kg/day, based on |
|            |         | Note - an additional   | clinical signs of   |
|            |         | 10x is necessary for   | toxicity in         |
|            |         | route extrapolation.   | maternal animals.   |
|            |         | If risk estimates are  |                     |
|            |         | below an MOE of 1000,  |                     |
|            |         | a 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^ Formulated-based dermal endpoint = (20 mg/kg guinea pig x 0.43 kg
guinea pig x 1000 ug/mg) / 25.8cm^2^ area of guinea pig dosed = 333 µg
ai/cm^2^ .

^c^ TGAI-based dermal endpoint = (20 mg ai/kg rat x 0.2 kg rat x 1000
ug/mg) / 50cm^2^ area of rat dosed = 80 µg ai/cm^2^

**8.0 Toxicity Profile Tables**

**8.1 Acute Toxicity Profile Table (Table 4).**

+--------------------+--------------------+----------------------------+
| **Table 4. Acute   |                    |                            |
| Toxicity Profile   |                    |                            |
| for ADBAC.**       |                    |                            |
+====================+====================+============================+
| **Guideline No./** | **MRID No.         | **Results**                |
|                    | (Year)/**          |                            |
| **Study Type/ Test |                    |                            |
| Substance (%       | **Citation/        |                            |
| a.i.)**            | Classification/    |                            |
|                    | Doses**            |                            |
+--------------------+--------------------+----------------------------+
| 870.1100 (§81-1)   | MRID 45109204      | **Toxicity Category II**   |
|                    |                    |                            |
| Acute Oral         | **Acceptable**     | LD~50~ = 304.5 mg/kg       |
| Toxicity -- Rats   |                    | (combined)                 |
|                    | Females: 0, 100,   |                            |
| Purity 82.26%      | 250, 500, or 510   | LD~50~ = 510.9 mg/kg       |
|                    | mg/kg              | (males)                    |
|                    |                    |                            |
|                    | Males: 0, 500,     | LD~50~ = 280.8 mg/kg       |
|                    | 510, 525, 600, or  | (females)                  |
|                    | 750 mg/kg          |                            |
|                    |                    | Two 200 mg/kg females,     |
|                    | Rats (5/sex/dose)  | four 500 mg/kg/ females,   |
|                    |                    | three males, and four      |
|                    |                    | females in the 510 mg/kg   |
|                    |                    | group and all males in the |
|                    |                    | 525, 600, and 750 mg/kg    |
|                    |                    | groups were dead by Day 6. |
|                    |                    | Breathing abnormalities,   |
|                    |                    | decreased activity, wobbly |
|                    |                    | gait, salivation, apparent |
|                    |                    | hypothermia, soft/mucoid   |
|                    |                    | stools, diarrhea,          |
|                    |                    | decreased/ no defacation,  |
|                    |                    | fecal/urine stain,         |
|                    |                    | piloerection, rough        |
|                    |                    | haircoat, hunched          |
|                    |                    | postures, dehydration,     |
|                    |                    | ocular discharge,          |
|                    |                    | decreased food             |
|                    |                    | consumption, and/or dark   |
|                    |                    | material around the facial |
|                    |                    | area were noted from most  |
|                    |                    | of the rats with recovery  |
|                    |                    | by Day 13 or earlier. Two  |
|                    |                    | surviving 510 mg/kg males  |
|                    |                    | lost weight during the     |
|                    |                    | first week of study, but   |
|                    |                    | gained weight during the   |
|                    |                    | second week. All other     |
|                    |                    | surviving rats gained      |
|                    |                    | weight during the study.   |
|                    |                    | The decedents had abnormal |
|                    |                    | content and/or reddened    |
|                    |                    | mucosa in the digestive    |
|                    |                    | tract, dark red thymus,    |
|                    |                    | and/or fluid contents in   |
|                    |                    | the thoracic cavity,       |
|                    |                    | abnormal content in the    |
|                    |                    | small intestines and/or    |
|                    |                    | thickened stomach mucosa.  |
+--------------------+--------------------+----------------------------+
| 870.1200 (§81-2)   | MRID 45109202      | **Toxicity Category II**   |
|                    |                    |                            |
| Acute Dermal       | **Acceptable**     | LD~50~ = 930 mg/kg         |
| Toxicity -- Rats   |                    | (combined)                 |
|                    | 0, 500, 1000, or   |                            |
| Purity 82.26%      | 2000 mg/kg         | LD~50~ = 1100 mg/kg        |
|                    |                    | (males)                    |
|                    | Rats (5/sex/dose)  |                            |
|                    |                    | LD~50~ = 704 mg/kg         |
|                    |                    | (females)                  |
|                    |                    |                            |
|                    |                    | Five 2000 mg/kg/ females   |
|                    |                    | were found dead on Day 1.  |
|                    |                    | One 500 mg/kg female, one  |
|                    |                    | male and four females in   |
|                    |                    | the 1000 mg/kg group, and  |
|                    |                    | five 2000 mg/kg were found |
|                    |                    | dead by Day 4. Irregular   |
|                    |                    | respirations, hunched      |
|                    |                    | postures, hypoactivity,    |
|                    |                    | coldness to the touch,     |
|                    |                    | reduced fecal volume,      |
|                    |                    | tremors, ataxia, and/or    |
|                    |                    | dypsnea were noted for the |
|                    |                    | decedents prior to death.  |
|                    |                    | Hypoactivity, hunched      |
|                    |                    | postures, reduced fecal    |
|                    |                    | volume, and/or irregular   |
|                    |                    | respiration were noted for |
|                    |                    | some of the surviving rats |
|                    |                    | with recovery by Day 3.    |
|                    |                    | Erythema and edema were    |
|                    |                    | noted at dose site from    |
|                    |                    | most of the rats. Eschar   |
|                    |                    | was also noted at the dose |
|                    |                    | site from surviving rats.  |
|                    |                    | All surviving rats had     |
|                    |                    | normal body weight gains.  |
|                    |                    | No gross abnormalities     |
|                    |                    | were noted from the        |
|                    |                    | surviving rats and one     |
|                    |                    | female decedent in the     |
|                    |                    | 1000 mg/kg/ group. The     |
|                    |                    | other decedents had        |
|                    |                    | slightly/moderately red    |
|                    |                    | lungs, discolored livers,  |
|                    |                    | and/or                     |
|                    |                    | red/black/green/yellow     |
|                    |                    | intestines.                |
+--------------------+--------------------+----------------------------+
| 870.1300 (§81-3)   | MRID 44885201      | **Toxicity Category II**   |
|                    |                    |                            |
| Acute Inhalation   | **Acceptable**     | 0.054 \< LC~50~ \> 0.51    |
| Toxicity -- Rats   |                    | mg/L                       |
|                    | 0.054 or 0.51 mg/L |                            |
| Purity 82.26% a.i. |                    | 0.054 mg/L group: All      |
|                    | Rats (5/sex/dose)  | animals survived. Animal   |
|                    |                    | displayed ocular and nasal |
|                    |                    | discharge, irregular       |
|                    |                    | respiration, dypsnea,      |
|                    |                    | hunched posture, and       |
|                    |                    | hypoactivity. Irregular    |
|                    |                    | respiration and/or         |
|                    |                    | hypoactivity persisted in  |
|                    |                    | several rats upon removal  |
|                    |                    | from the exposure chamber  |
|                    |                    | and some animals also      |
|                    |                    | developed facial staining  |
|                    |                    | or reduced fecal volume.   |
|                    |                    | All rats recovered from    |
|                    |                    | the above symptoms by Day  |
|                    |                    | 2 and appeared active and  |
|                    |                    | healthy for the remainder  |
|                    |                    | of the study, gaining      |
|                    |                    | bodyweight over the entire |
|                    |                    | 14-day observation period. |
|                    |                    | No gross abnormalities     |
|                    |                    | were noted in animals when |
|                    |                    | necropsied.                |
|                    |                    |                            |
|                    |                    | 0.51 mg/L group: All       |
|                    |                    | animals died. During       |
|                    |                    | exposure, animals          |
|                    |                    | exhibited ocular and nasal |
|                    |                    | discharge, irregular       |
|                    |                    | respiration, dypsnea,      |
|                    |                    | gasping, hunched posture,  |
|                    |                    | and hypoactivity prior to  |
|                    |                    | death. Gross necropsy of   |
|                    |                    | one animal revealed        |
|                    |                    | discoloration and edema of |
|                    |                    | the lungs. Gross           |
|                    |                    | abnormalities were not     |
|                    |                    | noted in the other         |
|                    |                    | animals.                   |
+--------------------+--------------------+----------------------------+
| 870.2400 (§81-4)   | waived             | **Toxicity Category I**    |
|                    |                    |                            |
| Primary eye        |                    |                            |
| irritation --      |                    |                            |
| Rabbits            |                    |                            |
+--------------------+--------------------+----------------------------+
| 870.2500 (§81-5)   | MRID 45109201      | **Toxicity Category I**    |
|                    |                    |                            |
| Primary dermal     | **Acceptable**     | Corrosive. The rabbit had  |
| irritation --      |                    | well-defined erythema one  |
| Rabbits            | 0.5 mL BQ451-8, 40 | hour after patch removal.  |
|                    | hours              | The erythema intensified   |
| Purity 82.26%      |                    | to severe by 24 hours and  |
|                    | 1 female rabbit    | persisted through 72       |
|                    |                    | hours. Moderate edema was  |
|                    |                    | noted on the rabbit one    |
|                    |                    | hour after patch removal,  |
|                    |                    | but reduced to slight by   |
|                    |                    | 24 hours through 72 hours. |
|                    |                    | The application site       |
|                    |                    | showed superficial eschar  |
|                    |                    | by 24 through 48 hours and |
|                    |                    | signs of dermal corrosion  |
|                    |                    | by 72 hours. The primary   |
|                    |                    | dermal irritation index    |
|                    |                    | was 5.8.                   |
+--------------------+--------------------+----------------------------+
| 870.2600 (§81-6)   | MRID 45109203      | **Not a Sensitizer.**      |
|                    |                    |                            |
| Dermal             | **Acceptable**     | Faint usually confluent to |
| sensitization --   |                    | moderate erythema was      |
| Guinea pigs        | Induction: 0.4 mL  | noted on all animals after |
|                    | of 2% w/w test     | the first induction. Very  |
| Purity 82.26%      | material in        | faint usually nonconfluent |
|                    | distilled water    | to moderate erythema was   |
|                    | with occlusive 25  | noted on 19/20 animals and |
|                    | mm Hilltop Chamber | severe erythema was noted  |
|                    | for 6 hours,       | on 1/20 animals after the  |
|                    | once/week, 3 weeks | second induction. Faint    |
|                    |                    | usually confluent to       |
|                    | Challenge Period:  | severe erythema was noted  |
|                    | 27 days            | on all animals after the   |
|                    |                    | third induction. Eschar    |
|                    | Challenge dose:    | was noted on 2/20 animals  |
|                    | 0.4 mL of 0.5% w/w | 48 hours after the third   |
|                    | test material in   | induction. Desquammation   |
|                    | distilled water    | was noted on one animal 24 |
|                    | under occlusion    | hours after the third      |
|                    | for 6 hours.       | induction with resolution  |
|                    |                    | by 48 hours. After three   |
|                    | Control: 0.4 mL of | weekly inductions, dermal  |
|                    | 0.5% w/w test      | irritation suggestive of   |
|                    | material in        | sensitization was not      |
|                    | distilled water at | observed on the test       |
|                    | challenge only.    | animals after challenge.   |
|                    |                    | The study report included  |
|                    | Guinea pigs (20    | DNCB positive control      |
|                    | test animals, 10   | study which was carried    |
|                    | controls; 24       | out within six months of   |
|                    | males, 6 females)  | the current study. The     |
|                    |                    | results were appropriate.  |
+--------------------+--------------------+----------------------------+
| Non-Guideline      | MRID 40958501,     | **Not a Photoallergen at   |
|                    | supplement MRID    | the dose levels tested.**  |
| Photoallergy --    | 44825002           |                            |
| Guinea pigs        |                    | Primary irritation:        |
|                    | **Acceptable       |                            |
| Purity 80%         | -Nonguideline**    | Severe irritation was      |
|                    |                    | observed in animals        |
|                    | Primary irritation | exposed to 10, 25, 50, or  |
|                    | study:             | 100% ADBAC.                |
|                    |                    |                            |
|                    | (4 guinea          | Photosensitization test:   |
|                    | pigs/sex/dose)     |                            |
|                    |                    | In the test material       |
|                    | 0.3 mL of 0, 0.5,  | group, there was a 0 of 10 |
|                    | 1, 2.5, 5, 10, 25, | incidence of grade 1       |
|                    | 50, or 100 percent | responses and a 6 of 10    |
|                    | in distilled water | incidences of grade +      |
|                    | for 4 hours,       | responses following the    |
|                    | followed by UV     | challenge dose. The 24 and |
|                    | irradiation 30     | 48 hour severity indices   |
|                    | minutes later in   | were 0.3 and 0.1,          |
|                    | half of the        | respectively.              |
|                    | exposed animals    |                            |
|                    |                    | In the vehicle control,    |
|                    | Sensitization      | there was a 0 of 10        |
|                    | study:             | incidence of grade 1       |
|                    |                    | responses and a 4 of 10    |
|                    | (5 guinea          | incidence grade +          |
|                    | pigs/sex/group)    | responses following the    |
|                    |                    | challenge dose. The 24 and |
|                    | treated for 4      | 48 hour severity indices   |
|                    | hours, followed by | were 0.2 and 0.1,          |
|                    | UV radiation       | respectively.              |
|                    | exposure           |                            |
|                    | approximately 30   | In the naïve test group,   |
|                    | minutes following  | there was a 0 of 10        |
|                    | dosing in all      | incidence of grade 1       |
|                    | animals            | response and a 5 of 10     |
|                    |                    | incidence of grade +       |
|                    | Induction:         | responses following the    |
|                    |                    | challenge dose. The 24 and |
|                    | Test group: 0.3 mL | 48 hour severity indices   |
|                    | of 0.5% ADBAC,     | were 0.3 and 0.3,          |
|                    | lowered to 0.25%   | respectively.              |
|                    | for doses 5 to 9   |                            |
|                    |                    | In the positive control    |
|                    | Vehicle control:   | animal group, there was a  |
|                    | 0.3 mL of vehicle  | 2 of 10 incidence of grade |
|                    | Naïve control: No  | 1 response and a 7 of 10   |
|                    | application        | incidence of grade +       |
|                    |                    | responses following the    |
|                    | Positive control:  | challenge dose. The 24 and |
|                    | 0.3 mL of musk     | 48 hour severity indices   |
|                    | ambrette (25% in   | were 0.6 and 0.6,          |
|                    | acetone)           | respectively.              |
|                    |                    |                            |
|                    | Monday, Wednesday, | There was no significant   |
|                    | Friday for 3 weeks | difference in the mean     |
|                    | (9 doses)          | body weight between the    |
|                    |                    | test material animal group |
|                    | Challenge Period:  | and the vehicle control or |
|                    | 12 days            | the naïve control during   |
|                    |                    | the study.                 |
|                    | Challenge dose:    |                            |
|                    |                    |                            |
|                    | Test group: 0.3 mL |                            |
|                    | of 0.5% ADBAC      |                            |
|                    |                    |                            |
|                    | Vehicle control:   |                            |
|                    | 0.3 mL of 0.5%     |                            |
|                    | ADBAC              |                            |
|                    |                    |                            |
|                    | Naïve control: 0.3 |                            |
|                    | mL of 0.5% ADBAC   |                            |
|                    |                    |                            |
|                    | Positive control:  |                            |
|                    | 0.3 mL of musk     |                            |
|                    | ambrette (25% in   |                            |
|                    | acetone)           |                            |
|                    |                    |                            |
|                    | Single dose        |                            |
+--------------------+--------------------+----------------------------+

2.  **Subchronic, Chronic and Other Toxicity Profiles Table (Table 5)**

+--------------------+--------------------+----------------------------+
| **Table 5:         |                    |                            |
| Subchronic,        |                    |                            |
| Chronic and Other  |                    |                            |
| Toxicity Profiles  |                    |                            |
| for ADBAC.**       |                    |                            |
+====================+====================+============================+
| **Guideline        | **MRID Number      | **Results**                |
| Number/**          | (Year)/**          |                            |
|                    |                    |                            |
| **Study Type/**    | **Citation/**      |                            |
|                    | **Classification/  |                            |
| **Test Substance   | Doses**            |                            |
| (% a.i.)**         |                    |                            |
+--------------------+--------------------+----------------------------+
| 870.3100 (§82-1)   | MRID 40746601      | **Systemic toxicity:**     |
|                    |                    |                            |
| 90-Day Oral (Feed) | **Acceptable --    | **NOAEL = 500 ppm \[31.2   |
| --Rat              | Guideline**        | mg/kg/day\] (males)**      |
|                    |                    |                            |
| 79.7% a.i.         | (15/sex/dose)      | **= 1000 ppm \[76.7        |
|                    |                    | mg/kg/day\] (females)**    |
|                    | 0, 100, 500, 1000, |                            |
|                    | \[**0, 6.3, 31.2   | **LOAEL = 1000 ppm \[62.0  |
|                    | and 62.0 mg/kg/day | mg/kg/day\] (males),**     |
|                    | for males and 0,   | based on decreased body    |
|                    | 7.9, 38.3 and 76.7 | weight and weight gain     |
|                    | mg/kg/day for      |                            |
|                    | females\]** 4000,  | **= 4000 ppm \[\>76.7      |
|                    | or 8000 ppm        | mg/kg/day\] (females),**   |
|                    |                    | based on increased         |
|                    |                    | mortality, decreased body  |
|                    |                    | weight gain, and food      |
|                    |                    | consumption, and increased |
|                    |                    | microscopic lesions.       |
|                    |                    |                            |
|                    |                    | Increased mortality was    |
|                    |                    | observed at the 4000 and   |
|                    |                    | 8000 ppm dose groups in    |
|                    |                    | both sexes **which did not |
|                    |                    | allow for daily compound   |
|                    |                    | consumption to be          |
|                    |                    | calculated**. Decreased    |
|                    |                    | body weight, weight gain,  |
|                    |                    | food consumption and       |
|                    |                    | increased incidence of     |
|                    |                    | microscopic lesions        |
|                    |                    | \[congestion and edema of  |
|                    |                    | the g.i. tract,            |
|                    |                    | hemorrhaging of the lungs  |
|                    |                    | and brain\] were also      |
|                    |                    | observed in males and      |
|                    |                    | females at                 |
|                    |                    | **[\>]{.underline}** 4000  |
|                    |                    | ppm.                       |
+--------------------+--------------------+----------------------------+
| 870.3200 (§82-2)   | MRID 41105801      | **Systemic toxicity:**     |
|                    |                    |                            |
| 21-Day Dermal --   | **Acceptable --    | **NOAEL = 500 mg/kg/day**  |
| Guinea pig         | Guideline**        |                            |
|                    |                    | **LOAEL = 1000             |
| HS Sanitizing      | 5 guinea           | mg/kg/day**, based on      |
| Shampoo (**4**%    | pigs/sex/dose      | decreases in body weight   |
| a.i.)              |                    | in females                 |
|                    | 0, 500, 1000       |                            |
|                    | mg/kg/day in       | **Dermal toxicity:**       |
|                    | HS-sanitizing      |                            |
|                    | carpet shampoo at  | **NOAEL = 500 mg/kg/day**  |
|                    | a 1:5 dilution,    |                            |
|                    | 24-hour exposure,  | **LOAEL = 1000             |
|                    | 5 days per week,   | mg/kg/day**, based on      |
|                    | for 3 weeks        | denuding of the epidermal  |
|                    |                    | layer                      |
|                    |                    |                            |
|                    |                    | Number range CHAPTEROver   |
|                    |                    | the course of the study,   |
|                    |                    | body weight losses of      |
|                    |                    | between 6-11% were         |
|                    |                    | observed in male and       |
|                    |                    | female guinea pigs. There  |
|                    |                    | were no reported           |
|                    |                    | mortalities or clinical    |
|                    |                    | signs of toxicity. Slight  |
|                    |                    | reduction in food          |
|                    |                    | consumption (2-5%) was     |
|                    |                    | observed over the course   |
|                    |                    | of this study. There were  |
|                    |                    | no significant             |
|                    |                    | treatment-related effects  |
|                    |                    | on hematology or clinical  |
|                    |                    | chemistry. Histological    |
|                    |                    | examination of the skin    |
|                    |                    | showed that the            |
|                    |                    | non-vascularized epidermal |
|                    |                    | layer was denuded, while   |
|                    |                    | the dermal or corium layer |
|                    |                    | and basement membrane      |
|                    |                    | appeared normal. There     |
|                    |                    | were no treatment-related  |
|                    |                    | effects reported on the    |
|                    |                    | liver and kidney.          |
+--------------------+--------------------+----------------------------+
| 870.3250 (§82-3)   | MRID 41499601      | **Systemic and Dermal      |
|                    |                    | toxicity**                 |
| 90-day dermal -    | **Core -           |                            |
| Rat                | Supplementary**    | **NOAEL \> = 20            |
|                    |                    | mg/kg/day** (highest dose  |
| ADBAC purity       | Rats (15/sex/dose) | tested)                    |
| 81.09%             |                    |                            |
|                    | 0, 2, 6, or 20     | **LOAEL \> 20 mg/kg/day**  |
|                    | mg/kg/day, 6-8     | (not established)          |
|                    | hours/day, 5       |                            |
|                    | days/week, 13      | A significant and          |
|                    | weeks              | dose-related decrease in   |
|                    |                    | reticulocyte count was     |
|                    |                    | observed in the 6- and     |
|                    |                    | 20-mg/kg/day females.      |
|                    |                    | Decreases in reticulocyte  |
|                    |                    | count are normally         |
|                    |                    | associated with            |
|                    |                    | regenerative responses to  |
|                    |                    | anemia. However, no        |
|                    |                    | evidence of anemia was     |
|                    |                    | seen in other              |
|                    |                    | hematological parameters.  |
|                    |                    | Furthermore, the decreased |
|                    |                    | levels in treated females  |
|                    |                    | were similar to the levels |
|                    |                    | observed in control males. |
|                    |                    | Thus, the decreasing       |
|                    |                    | reticulocyte count was     |
|                    |                    | most likely not a          |
|                    |                    | biologically significant   |
|                    |                    | finding.                   |
+--------------------+--------------------+----------------------------+
| Range-finding      | MRID 42645101      | **Maternal Toxicity**      |
| Developmental      |                    |                            |
| (gavage) - Rat     | **Acceptable -     | **NOAEL = 50 mg/kg/day**   |
|                    | Guideline**        |                            |
| ADBAC purity       |                    | **LOAEL = 100 mg/kg/day**, |
| 81.09%             | CD rats (5/dose)   | based on significantly     |
|                    |                    | increased incidence of     |
|                    | 0, 25, 50, 100,    | perioral wetness.          |
|                    | 200, or 400        |                            |
|                    | mg/kg/day, GD      | **Number range             |
|                    | 6-15, inclusive    | CHAPTERDevelopmental       |
|                    |                    | Toxicity**                 |
|                    |                    |                            |
|                    |                    | **NOAEL = 100 mg/kg/day**  |
|                    |                    |                            |
|                    |                    | **LOAEL = 200 mg/kg/day,** |
|                    |                    | based on no survival of    |
|                    |                    | dams.                      |
|                    |                    |                            |
|                    |                    | Doses ≥ 200 mg/kg/day      |
|                    |                    | resulted in 100%           |
|                    |                    | mortality; necropsy        |
|                    |                    | findings revealed a        |
|                    |                    | distended and change in    |
|                    |                    | the color of the stomach,  |
|                    |                    | and distended intestines   |
|                    |                    | filled with mucoid fluid.  |
|                    |                    | These dams also exhibited  |
|                    |                    | clinical signs including   |
|                    |                    | loose feces, perioral      |
|                    |                    | wetness and perioral       |
|                    |                    | encrustation, ataxia,      |
|                    |                    | hypoactivity, urogenital   |
|                    |                    | area wetness, and audible  |
|                    |                    | respiration. Maternal      |
|                    |                    | toxicity observed at 100   |
|                    |                    | mg/kg/day was manifest as  |
|                    |                    | significantly increased    |
|                    |                    | incidence of perioral      |
|                    |                    | wetness.                   |
+--------------------+--------------------+----------------------------+
| 870.3700 (§83-3)   | MRID 42351501      | **Maternal Toxicity**      |
|                    |                    |                            |
| Developmental      | **Acceptable -     | **NOAEL = 10 mg/kg/day**   |
| (gavage) - Rat     | Guideline**        |                            |
|                    |                    | **LOAEL = 30 mg/kg/day**,  |
| ADBAC purity       | Females rats       | based on clinical signs    |
| 81.09%             | (25/dose)          | and decreased body weight  |
|                    |                    | gain.                      |
|                    | 0, 10, 30, or 100  |                            |
|                    | mg/kg/day, GD      | **Number range             |
|                    | 6-15, inclusive    | CHAPTERDevelopmental       |
|                    |                    | Toxicity**                 |
|                    |                    |                            |
|                    |                    | **NOAEL \>= 100            |
|                    |                    | mg/kg/day**, highest dose  |
|                    |                    | tested.                    |
|                    |                    |                            |
|                    |                    | **LOAEL \> 100             |
|                    |                    | mg/kg/day,** not           |
|                    |                    | established.               |
|                    |                    |                            |
|                    |                    | There was no mortality in  |
|                    |                    | maternal animals observed  |
|                    |                    | at any dose level. At 100  |
|                    |                    | mg/kg/day, one dam         |
|                    |                    | exhibited dehydration,     |
|                    |                    | unkempt appearance, loose  |
|                    |                    | feces, and perioral        |
|                    |                    | wetness. At 30 mg/kg/day,  |
|                    |                    | one dam was noted with     |
|                    |                    | perioral wetness, gasping, |
|                    |                    | loose feces, and urine     |
|                    |                    | stains. Decreased body     |
|                    |                    | weight gain (12-**11**%)   |
|                    |                    | was observed in maternal   |
|                    |                    | animals at 30 **and 100**  |
|                    |                    | mg/kg/day during gestation |
|                    |                    | days 6-15. Food            |
|                    |                    | consumption was not        |
|                    |                    | consistently affected by   |
|                    |                    | treatment. There were no   |
|                    |                    | treatment-related          |
|                    |                    | increases in the incidence |
|                    |                    | of fetal external,         |
|                    |                    | visceral, or skeletal      |
|                    |                    | abnormalities at any dose  |
|                    |                    | level.                     |
|                    |                    |                            |
|                    |                    | **There was no evidence    |
|                    |                    | for developmental toxicity |
|                    |                    | of ADBAC in this study.**  |
+--------------------+--------------------+----------------------------+
| Range-finding      | MRID 42734401      | **Maternal Toxicity**      |
| Developmental      |                    |                            |
| (gavage) - Rabbit  | **Acceptable -     | **NOAEL = 3 mg/kg/day**    |
|                    | Guideline**        |                            |
| ADBAC purity       |                    | **LOAEL = 10 mg/kg/day**,  |
| 81.09%             | Females rabbits    | based on clinical signs    |
|                    | (5/dose)           | and reduced body weight    |
|                    |                    | gain and food consumption  |
|                    | 0, 1, 3, 10, 30 or |                            |
|                    | 60 mg/kg/day, GD   | Mortality was observed at  |
|                    | 6-18 **inclusive** | doses of 30 and 60         |
|                    |                    | mg/kg/day (2 and 5 does,   |
|                    |                    | respectively). Audible     |
|                    |                    | respiration was observed   |
|                    |                    | at doses greater than or   |
|                    |                    | equal to 10 mg/kg/day. At  |
|                    |                    | doses greater than or      |
|                    |                    | equal to 30 mg/kg/day,     |
|                    |                    | clinical signs included    |
|                    |                    | hypoactivity, perioral     |
|                    |                    | wetness, and labored       |
|                    |                    | breathing. At 60           |
|                    |                    | mg/kg/day, clinical signs  |
|                    |                    | included paralysis, cold   |
|                    |                    | extremities, prostration,  |
|                    |                    | slow respiration,          |
|                    |                    | emaciation, loose feces,   |
|                    |                    | and perioral encrustation. |
|                    |                    | Decreased body weight gain |
|                    |                    | and food consumption were  |
|                    |                    | observed at doses greater  |
|                    |                    | than or equal to 10        |
|                    |                    | mg/kg/day.                 |
|                    |                    |                            |
|                    |                    | **Developmental toxicity   |
|                    |                    | was not observed at any of |
|                    |                    | the doses tested.**        |
+--------------------+--------------------+----------------------------+
| 870.3700 (§83-3)   | MRID 42392801      | **Maternal Toxicity**      |
|                    |                    |                            |
| Developmental      | **Acceptable -     | **NOAEL = 3 mg/kg/day**    |
| (gavage) - Rabbit  | Guideline**        |                            |
|                    |                    | **LOAEL = 9 mg/kg/day**,   |
| ADBAC purity       | Females rabbits    | based on clinical signs of |
| 81.09%             | (16/dose)          | toxicity.                  |
|                    |                    |                            |
|                    | 0, 1, 3, or 9      | **Number range             |
|                    | mg/kg/day, GD 6-18 | CHAPTERDevelopmental       |
|                    |                    | Toxicity**                 |
|                    |                    |                            |
|                    |                    | **NOAEL \>= 9 mg/kg/day**, |
|                    |                    | highest dose tested.       |
|                    |                    |                            |
|                    |                    | **LOAEL \> 9 mg/kg/day,**  |
|                    |                    | not established.           |
|                    |                    |                            |
|                    |                    | There was no mortality or  |
|                    |                    | abortions at any dose      |
|                    |                    | level. Hypoactivity and    |
|                    |                    | labored breathing were     |
|                    |                    | observed at 9 mg/kg/day in |
|                    |                    | 2 of 15 rabbits. There     |
|                    |                    | were no effects on         |
|                    |                    | maternal body weight, food |
|                    |                    | consumption, cesarean      |
|                    |                    | section observations, or   |
|                    |                    | necropsy observations. In  |
|                    |                    | offspring, there was no    |
|                    |                    | evidence of developmental  |
|                    |                    | toxicity at any dose level |
|                    |                    | tested.                    |
|                    |                    |                            |
|                    |                    | **There was no evidence    |
|                    |                    | for developmental toxicity |
|                    |                    | of ADBAC in this study.**  |
+--------------------+--------------------+----------------------------+
| 870.8700 (§83-4)   | MRID 41385001      | **Parental toxicity:**     |
|                    |                    |                            |
| Reproduction       | **Acceptable --    | **NOAEL \>= 146            |
| (Feed) -- Rat      | Guideline**        | mg/kg/day**, highest dose  |
|                    |                    | tested                     |
| ADBAC purity       | Rats (28/sex/dose) |                            |
| 81.09%             |                    | **LOAEL \> 146             |
|                    | 0, 300, 1000, or   | mg/kg/day**, not           |
|                    | 2000 ppm           | established                |
|                    |                    |                            |
|                    | F0: 0, 20.7, 68.2, | **Developmental/systemic   |
|                    | or 134.7 mg/kg/day | toxicity:**                |
|                    | (males)            |                            |
|                    |                    | **NOAEL = 65.4 mg/kg/day   |
|                    | 0, 25.5, 81.3, or  | (males)**                  |
|                    | 164.7 mg/kg/day    |                            |
|                    | (females)          | **= 79.9 mg/kg/day         |
|                    |                    | (females)**                |
|                    | F1: 0, 19.1, 62.5, |                            |
|                    | or 125.4 mg/kg/day | **LOAEL = 130.1 mg/kg/day  |
|                    | (males)            | (males)**                  |
|                    |                    |                            |
|                    | 0, 24.8, 78.5, or  | **= 160.9 mg/kg/day        |
|                    | 157.1 mg/kg/day    | (females)**, based on      |
|                    | (females)          | reduced pup body weight    |
|                    |                    | and weight gain during     |
|                    |                    | lactation (doses combined  |
|                    |                    | for both F0 and F1         |
|                    |                    | generations)               |
|                    |                    |                            |
|                    |                    | There was no               |
|                    |                    | treatment-related          |
|                    |                    | mortality in parental      |
|                    |                    | animals at any dose level, |
|                    |                    | and there were no reported |
|                    |                    | signs of clinical toxicity |
|                    |                    | in parental animals.       |
|                    |                    | Although some decrease in  |
|                    |                    | body weight was observed   |
|                    |                    | in both generations at the |
|                    |                    | top dose, the significant  |
|                    |                    | variability observed did   |
|                    |                    | not qualify this as a      |
|                    |                    | treatment-related effect.  |
|                    |                    |                            |
|                    |                    | In pups of both            |
|                    |                    | generations, mean body     |
|                    |                    | weights at the top dose    |
|                    |                    | were significantly reduced |
|                    |                    | during lactation and       |
|                    |                    | post-weaning periods.      |
|                    |                    | There were no adverse      |
|                    |                    | effects noted on           |
|                    |                    | gestational length,        |
|                    |                    | mating, fertility, or      |
|                    |                    | other gestational indices. |
+--------------------+--------------------+----------------------------+
| 870.4100 (§83-1)   | MRID 43221101      | **Systemic Toxicity**      |
|                    |                    |                            |
| Chronic Toxicity   | **Acceptable --    | **NOAEL = 120 ppm**        |
| (feed) - Dog       | Guideline**        |                            |
|                    |                    | **= 3.79 mg/kg/day         |
| ADBAC purity 80%   | Dogs (4/sex/dose)  | (males)**                  |
|                    |                    |                            |
|                    | 0, 120, 400, or    | **= 3.67 mg/kg/day         |
|                    | 1200 ppm           | (females)**                |
|                    |                    |                            |
|                    | \[0, 3.79, 13.1,   | **LOAEL = 400 ppm**        |
|                    | or 33.8 mg/kg/day  |                            |
|                    | (males),           | **= 13.1 mg/kg/day         |
|                    |                    | (males)**                  |
|                    | 0, 3.67, 14.6, or  |                            |
|                    | 38.6 mg/kg/day     | **= 14.6 mg/kg/day         |
|                    | (females)\] for 1  | (females),** based on      |
|                    | year               | decreased body weight      |
|                    |                    | gain.                      |
|                    |                    |                            |
|                    |                    | Systemic toxicity was      |
|                    |                    | observed at 400 ppm and    |
|                    |                    | above in female dogs and   |
|                    |                    | at 1200 ppm in males as    |
|                    |                    | reduced body weight gain   |
|                    |                    | (approximately 10%         |
|                    |                    | reduction) after 52 weeks  |
|                    |                    | of exposure. Food          |
|                    |                    | consumption was decreased  |
|                    |                    | in the 1200 ppm males and  |
|                    |                    | females for the entire     |
|                    |                    | study period               |
|                    |                    | (approximately 15%         |
|                    |                    | reduction in males and 5%  |
|                    |                    | reduction in females).     |
+--------------------+--------------------+----------------------------+
| 870.4300 (§83-5)   | MRID 41947501      | **Systemic Toxicity**      |
|                    |                    |                            |
| Combined Chronic   | **Acceptable --    | **NOAEL = 1000 ppm**       |
| Toxicity/          | Guideline**        |                            |
| Carcinogenicity    |                    | **= 44 mg/kg/day (males)** |
| (feed) - Rat       | Rats (50/sex/dose) |                            |
|                    |                    | **= 57 mg/kg/day           |
| ADBAC purity 81%   | 0, 300, 1000, or   | (females)**                |
|                    | 2000 ppm           |                            |
|                    |                    | **LOAEL = 2000 ppm**       |
|                    | \[0, 13, 44, or 88 |                            |
|                    | mg/kg/day (males), | **= 88 mg/kg/day (males)** |
|                    |                    |                            |
|                    | 0, 17, 57, or 116  | **= 116 mg/kg/day          |
|                    | mg/kg/day          | (females),** based on      |
|                    | (females)\] for    | decreased body weight and  |
|                    | 104 weeks          | weight gain.               |
|                    |                    |                            |
|                    |                    | Significant decreases in   |
|                    |                    | group mean body weight     |
|                    |                    | were observed in male rats |
|                    |                    | at the 2000 ppm dose level |
|                    |                    | during weeks 1-26 of the   |
|                    |                    | study and then             |
|                    |                    | sporadically thereafter.   |
|                    |                    | Body weights of high dose  |
|                    |                    | female rats were also      |
|                    |                    | significantly decreased    |
|                    |                    | during weeks 1-60 of the   |
|                    |                    | study. Body weight gain    |
|                    |                    | was decreased 11% on       |
|                    |                    | average in high dose males |
|                    |                    | and 14% in high dose       |
|                    |                    | females. There were no     |
|                    |                    | significant                |
|                    |                    | treatment-related effects  |
|                    |                    | on clinical chemistry,     |
|                    |                    | hematology, or urinalysis. |
|                    |                    | No treatment-related non   |
|                    |                    | neoplastic gross or        |
|                    |                    | microscopic lesions were   |
|                    |                    | evident in any of the      |
|                    |                    | treated groups of rats.    |
|                    |                    |                            |
|                    |                    | **There was no evidence of |
|                    |                    | carcinogenicity of ADBAC   |
|                    |                    | in this study.**           |
+--------------------+--------------------+----------------------------+
| 870.4200 (§82-2)   | MRID 41765201      | **Systemic Toxicity**      |
|                    |                    |                            |
| Carcinogenicity    | Mice (60/sex/dose) | **NOAEL = 500 ppm**        |
| (feed) - Mouse     |                    |                            |
|                    | **Acceptable -     | **= 73.4 mg/kg/day         |
| ADBAC purity 81%   | Guideline**        | (males)**                  |
|                    |                    |                            |
|                    | 0, 100, 500, or    | **= 92.1 mg/kg/day         |
|                    | 1500 ppm **\[14.9, | (females)**                |
|                    | 73.4 and 229.3     |                            |
|                    | mg/kg/day (males); | **LOAEL = 1500 ppm**       |
|                    | 17.8, 92.1 and     |                            |
|                    | 288.6 mg/kg/day    | **= 229.3 mg/kg/day        |
|                    | (females)\]** for  | (males)**                  |
|                    | 78 weeks           |                            |
|                    |                    | **= 288.6 mg/kg/day        |
|                    |                    | (females),** based on      |
|                    |                    | decreased body weight.     |
|                    |                    |                            |
|                    |                    | No significant differences |
|                    |                    | in the incidence of        |
|                    |                    | mortality were observed in |
|                    |                    | treated animals versus     |
|                    |                    | controls. No clinical      |
|                    |                    | signs of toxicity were     |
|                    |                    | observed at any dose level |
|                    |                    | tested. Significant        |
|                    |                    | reductions in group mean   |
|                    |                    | body weight were observed  |
|                    |                    | at the high dose in male   |
|                    |                    | and female mice throughout |
|                    |                    | the treatment period with  |
|                    |                    | no significant reduction   |
|                    |                    | in food intake. There were |
|                    |                    | no significant             |
|                    |                    | treatment-related effects  |
|                    |                    | on organ weights,          |
|                    |                    | macroscopic, or            |
|                    |                    | microscopic pathology in   |
|                    |                    | treated mice at any dose   |
|                    |                    | level.                     |
|                    |                    |                            |
|                    |                    | **There was no evidence of |
|                    |                    | carcinogenicity of ADBAC   |
|                    |                    | in this study.**           |
+--------------------+--------------------+----------------------------+
| 870.5300 (§84-2)   | MRID 41012701      | **Negative**               |
|                    |                    |                            |
| Mammalian cell     | HGPRT locus in CHO | Mutant frequencies of all  |
| forward gene       | cells              | cultures treated with the  |
| mutation -- HGPRT  |                    | test material were within  |
| locus in CHO cells | **Acceptable**     | the acceptable range for   |
|                    |                    | background mutant          |
| ADBAC purity 80%   | 0, 1.0, 2.0, 5.0,  | frequencies (0 to 15 x     |
|                    | 10.0, 20.0, 50.0,  | 10^-6^). In all of the     |
|                    | 100.0, 200.0,      | assays, no culture had a   |
|                    | 500.0, or 5000.0   | mutant frequency that was  |
|                    | **µg/ml**, with    | statistically elevated     |
|                    | and without        | over background levels and |
|                    | metabolic          | greater than 15 x 10^-6^.  |
|                    | activation         | Three toxic cultures in    |
|                    |                    | one nonactivation trial    |
|                    |                    | did achieve statistical    |
|                    |                    | significance. The          |
|                    |                    | significant mutant         |
|                    |                    | frequencies were within    |
|                    |                    | the acceptable background  |
|                    |                    | range and were not         |
|                    |                    | confirmed at equitoxic     |
|                    |                    | dose levels in the         |
|                    |                    | independent nonactivation  |
|                    |                    | trial. The significant     |
|                    |                    | cultures, in that one      |
|                    |                    | trial were apparently due  |
|                    |                    | to normal assay variation. |
|                    |                    | ADBAC was considered       |
|                    |                    | negative for inducing      |
|                    |                    | forward mutations at the   |
|                    |                    | HGPRT locus in CHO cells   |
|                    |                    | under the S9 metabolic     |
|                    |                    | activation and             |
|                    |                    | nonactivation conditions   |
|                    |                    | of this assay.             |
+--------------------+--------------------+----------------------------+
| 870.5385 (§84-2)   | MRID 40311101,     | **Negative**               |
|                    | supplement         |                            |
| In vivo mammalian  | 43037701           | []{.mark}                  |
| bone marrow        |                    |                            |
| chromosome         | Mice (5/sex/group) | One mouse of the 72-hour   |
| aberration test -- |                    | group was found dead on    |
| Mouse              | **Acceptable**     | the third day after        |
|                    |                    | treatment. The PCE/NCE     |
| ADBAC purity 80%   | Single dose of 400 | ratio was reduced in all   |
|                    | mg/kg, sacrificed  | test groups (as well as    |
|                    | at 24, 48, or 72   | the positive controls),    |
|                    | hours later        | but no alteration in MN    |
|                    |                    | from solvent control value |
|                    | Solvent control:   | was found in any timed     |
|                    | deionized water    | test group.                |
|                    |                    |                            |
|                    | Positive control:  | By contrast, the CP-group  |
|                    | Cyclosphosphamide  | evidenced a significant    |
|                    | (CP, 30 mg/kg)     | increase in MN-PCE.        |
+--------------------+--------------------+----------------------------+
| 870.5550 (§84-2)   | MRID 42290802      | **Negative**               |
|                    | **and 42290801**   |                            |
| Unscheduled DNA    | Rat hepatocytes    | The test article was       |
| synthesis -- Rat   |                    | lethal at 8.61 ug/mL, and  |
| hepatocytes        | **Acceptable**     | progressively cytotoxic at |
|                    |                    | doses equal to or above    |
| ADBAC purity 80%   | Tritiated          | 4.31 ug/mL. Treatments     |
|                    | thymidine          | producing moderate levels  |
|                    | (38Ci/mmol) for    | of cytotoxicity (**62.7**% |
|                    | 18.8 hours         | relative survival and      |
|                    | together with      | greater) as well as        |
|                    | 0.538, 1.08, 2.15, | non-toxic doses were       |
|                    | 4.31, 5.38, 6.46,  | analyzed for UDS. None of  |
|                    | 7.00, 7.54, 8.07,  | these analyzable           |
|                    | or 8.61 ug/mL      | treatments induced silver  |
|                    | ADBAC              | grain labeling different   |
|                    |                    | from solvent control. In   |
|                    | Solvent control:   | contrast, the mutagen      |
|                    | deionized water    | 2-AAF induced large        |
|                    |                    | increases in nuclear       |
|                    | Positive control:  | labeling in the absence of |
|                    | AAF, 0.10 ug/mL    | significant toxicity.      |
+--------------------+--------------------+----------------------------+
| 870.7485 (§85-1)   | MRID 40990701,     | Ring-labeled test material |
|                    | supplements        | was used. Following oral   |
| Metabolism and     | 41087701 and       | administration, from 5-8%  |
| Pharmacokinetics - | 44783401           | of the administered dose   |
| rats               |                    | was eliminated in urine    |
|                    | **Acceptable**     | and 90-98% in feces. No    |
| ADBAC purity 30%   |                    | apparent differences in    |
|                    | Group 1: Single    | disposition were noted     |
|                    | dose 10 mg/kg      | between sexes. Following   |
|                    | (oral or           | intravenous                |
|                    | intravenous)       | administration, males      |
|                    |                    | eliminated 31% of the dose |
|                    | Group 2: 100 ppm   | in urine and 44% in feces, |
|                    | ADBAC in diet for  | while females eliminated   |
|                    | 14 days            | 21% in urine and 55% in    |
|                    |                    | feces following            |
|                    | Group 3: Single    | intravenous                |
|                    | oral dose of 50    | administration. After oral |
|                    | mg/kg              | administration, from       |
|                    |                    | 0.03-0.58% of the          |
|                    |                    | administered dose was      |
|                    |                    | accounted for in tissues.  |
|                    |                    | After intravenous          |
|                    |                    | administration, tissue     |
|                    |                    | residues accounted for     |
|                    |                    | 33-36% of the dose and     |
|                    |                    | were observed mainly in    |
|                    |                    | the carcass. The results   |
|                    |                    | of this study indicate     |
|                    |                    | that a majority of an      |
|                    |                    | administered dose of ADBAC |
|                    |                    | is eliminated in feces and |
|                    |                    | involves biliary           |
|                    |                    | excretion.                 |
+--------------------+--------------------+----------------------------+

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[]{.mark}

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