Document ID: EPA-HQ-OPP-2006-0338-0020
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2006-12-29T05:00Z

August 10, 2006

Memorandum

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

		Active Ingredient: 	Didecyl dimethyl ammonium chloride (DDAC) 

		PC Code		069149	

DP Barcode:	 

From:		Timothy F. McMahon, Ph.D

		Senior Toxicologist

		Antimicrobials Division (7510C)

 

To:		Tracy Lantz, Chemical Review Manager

		Regulatory Management Branch I

		Antimicrobials Division (7510C)

  TOC \o "1-3" \h \z \u  

  HYPERLINK \l "_Toc131930515"  1.0	HAZARD CHARACTERIZATION	  PAGEREF
_Toc131930515 \h  3  

  HYPERLINK \l "_Toc131930516"  2.0	TOXICOLOGY DATA REQUIREMENTS	 
PAGEREF _Toc131930516 \h  5  

  HYPERLINK \l "_Toc131930517"  3.0	DATA GAPS	  PAGEREF _Toc131930517 \h
 5  

  HYPERLINK \l "_Toc131930518"  4.0	HAZARD ASSESSMENT	  PAGEREF
_Toc131930518 \h  6  

  HYPERLINK \l "_Toc131930519"  4.1	Acute Toxicity	  PAGEREF
_Toc131930519 \h  6  

  HYPERLINK \l "_Toc131930520"  4.2	Subchronic Toxicity	  PAGEREF
_Toc131930520 \h  7  

  HYPERLINK \l "_Toc131930521"  4.3	Prenatal Developmental Toxicity	 
PAGEREF _Toc131930521 \h  8  

  HYPERLINK \l "_Toc131930522"  4.4	Reproductive Toxicity	  PAGEREF
_Toc131930522 \h  9  

  HYPERLINK \l "_Toc131930523"  4.5	Chronic Toxicity	  PAGEREF
_Toc131930523 \h  10  

  HYPERLINK \l "_Toc131930524"  4.6	Carcinogenicity	  PAGEREF
_Toc131930524 \h  10  

  HYPERLINK \l "_Toc131930525"  4.7	Mutagenicity	  PAGEREF _Toc131930525
\h  11  

  HYPERLINK \l "_Toc131930526"  4.8	Neurotoxicity	  PAGEREF
_Toc131930526 \h  12  

  HYPERLINK \l "_Toc131930527"  4.9	Metabolism and Pharmacokinetics	 
PAGEREF _Toc131930527 \h  12  

  HYPERLINK \l "_Toc131930528"  5.0	TOXICITY ENDPOINT SELECTION	 
PAGEREF _Toc131930528 \h  12  

  HYPERLINK \l "_Toc131930529"  5.1	 See Section 7.1, Summary of
Toxicological Doses and Endpoint Selection,    Table 2.	  PAGEREF
_Toc131930529 \h  12  

  HYPERLINK \l "_Toc131930530"  5.2	Dermal Absorption	  PAGEREF
_Toc131930530 \h  12  

  HYPERLINK \l "_Toc131930531"  5.3	Classification of Carcinogenic
Potential	  PAGEREF _Toc131930531 \h  12  

  HYPERLINK \l "_Toc131930532"  6.0	FQPA CONSIDERATIONS	  PAGEREF
_Toc131930532 \h  13  

  HYPERLINK \l "_Toc131930533"  6.1	Developmental Toxicity Study
Conclusions	  PAGEREF _Toc131930533 \h  13  

  HYPERLINK \l "_Toc131930534"  6.2	Reproductive Toxicity Study
Conclusions	  PAGEREF _Toc131930534 \h  13  

  HYPERLINK \l "_Toc131930535"  6.3	Pre-and/or Postnatal Toxicity	 
PAGEREF _Toc131930535 \h  14  

  HYPERLINK \l "_Toc131930536"  6.4	Recommendation for a Developmental
Neurotoxicity Study	  PAGEREF _Toc131930536 \h  14  

  HYPERLINK \l "_Toc131930537"  7.0	SUMMARY OF TOXICOLOGICAL DOSES AND
ENDPOINTS FOR DDAC FOR USE IN HUMAN RISK ASSESSMENT	  PAGEREF
_Toc131930537 \h  15  

  HYPERLINK \l "_Toc131930538"  7.1	Summary Table of Toxicological Dose
and Endpoint Selection	  PAGEREF _Toc131930538 \h  15  

  HYPERLINK \l "_Toc131930539"  8.0	TOXICITY PROFILE TABLES	  PAGEREF
_Toc131930539 \h  18  

  HYPERLINK \l "_Toc131930540"  8.1	Acute Toxicity Profile Table (Table
5).	  PAGEREF _Toc131930540 \h  18  

  HYPERLINK \l "_Toc131930541"  LD50 = 4350 mg/kg (combined)	  PAGEREF
_Toc131930541 \h  19  

  HYPERLINK \l "_Toc131930542"  LD50 = 4350 mg/kg (males)	  PAGEREF
_Toc131930542 \h  19  

  HYPERLINK \l "_Toc131930543"  LD50 = 4350 mg/kg (females)	  PAGEREF
_Toc131930543 \h  19  

  HYPERLINK \l "_Toc131930544"  8.2	Subchronic, Chronic and Other
Toxicity Profiles Table (Table 6)	  PAGEREF _Toc131930544 \h  21  

  HYPERLINK \l "_Toc131930545"  9.0	REFERENCES	  PAGEREF _Toc131930545
\h  25  

 

	

1.0	HAZARD CHARACTERIZATION

  SEQ CHAPTER \h \r 1 Pursuant to PR Notice 88-2, grouping of quaternary
ammonium compounds was allowed, based on the numerous chemical
structures that represent these types of chemicals.  Grouping was
allowed into 4 broad categories, based on chemical structure: Group I
quaternary ammonium compounds (alkyl or hydroxy alkyl substituted
compounds, DDAC as representative); Group II non-halogenated benzyl
substituted quaternary ammonium compounds; Group III di- and
tri-chlorobenzyl substituted quaternary ammonium compounds; and Group
IV, quaternary ammonium compounds with unusual substituents.  DDAC, or
didecyl dimethyl ammonium chloride, is, as stated above, a member of the
Group I class of quaternary ammonium compounds.  Hazard data generated
for DDAC is representative of the hazard associated with this class of
quaternary ammonium chemicals.

DDAC was assigned Toxicity Category II in two acute oral toxicity
studies in rats, MRIDs 41394404 [65% a.i.; LD50 = 262 mg/kg (combined)]
and 42296101 [80% a.i.; LD50 = 238 mg/kg (combined)].  DDAC was assigned
Toxicity Category III in two acute dermal toxicity studies in rabbits,
MRIDs 42053801 [65% a.i.; LD50 = 2930 mg/kg (combined)] and 00071158
[50% a.i.; LD50 = 4350 mg/kg (combined)].  For acute inhalation toxicity
(MRID 00145074; TRID 455201010), the LC50 of DDAC (purity not reported)
was reported as 0.07 mg/L; Toxicity Category II was assigned.  For
primary eye irritation, DDAC was found to be corrosive (Toxicity
Category I) in two primary eye irritation studies in rabbits, MRIDs
41394404 [65% a.i.] and 42161602 [80% a.i].  For primary dermal
irritation, DDAC (80% a.i.) was found to be corrosive (Toxicity Category
I) in a primary dermal irritation study in rabbits (MRID 42161601).  For
dermal sensitization, DDAC was found to be a slight sensitizer in one
dermal sensitization study in guinea pigs (MRID 42161603 [80% a.i.]) and
not a sensitizer in another (MRID 46367601 [purity not reported]).

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

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

For developmental toxicity, the data from two developmental toxicity
studies, one in the rat (MRID 41886701, range-finder MRID 42746901) and
another in the rabbit (MRID 41018701), do not indicate   SEQ CHAPTER \h
\r 1 increased susceptibility in rats or rabbits from in utero and
postnatal exposure to DDAC.  In the rat developmental toxicity study
(MRID 41886701), developmental toxicity (skeleton variations) was
observed only at treatment levels which also resulted in maternal
toxicity (audible respiration).  In the rabbit developmental toxicity
study, developmental toxicity (decreased fetal body weight and increased
number of dead fetuses) occurred at levels which also resulted in
maternal toxicity (hypo activity, audible respiration, and decreased
body weight gain).  

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

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

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

For mutagenicity, DDAC was negative in a battery of tests.  In the Ames
test (MRID 40282201, supplemental information MRID 44005801), DDAC was
not mutagenic with or without metabolic activation.  In a forward gene
mutation test (MRID 93014008, reformat of 40895202), DDAC was negative
for induction of gene mutations in CHO cells at the HGPRT locus with and
without metabolic activation.  In an in vitro chromosome aberration test
(MRID 41252601),   SEQ CHAPTER \h \r 1 DDAC did not induce chromosome
aberration in the Chinese hamster ovary (CHO) cells with or without
metabolic activation.  In an unscheduled DNA synthesis (UDS) assay (MRID
93014007, reformat of 40895201), DDAC did not cause UDS in primary rat
hepatocytes.

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

  SEQ CHAPTER \h \r 1 In a rat pharmacokinetics/ metabolism study (MRID
41617101 and addendum MRID 41385101), single oral doses of 14C-DDAC (5
or 50 mg/kg) or repeated dose (34 ppm of DDAC in the diet for 14 days
and then one single dose of 5 mg/kg of 14C-DDAC) were given to both male
and female rats.  DDAC was mostly excreted in the feces within 3 days
principally as parent compound and metabolites.  The elimination pattern
and metabolic profile was not substantially altered by the dose or
exposure duration.  Male and female rats showed similar elimination
patterns, but females metabolized DDAC more extensively than males. 
Four major metabolites were identified as oxidation products with
oxidation confined to the decyl side chains.

2.0	TOXICOLOGY DATA REQUIREMENTS

  SEQ CHAPTER \h \r 1 The Toxicology database for DDAC is listed in the
following table.

Table 1:  Toxicologic Data Requirements for DDAC.

Test 

	Technical

	Required	Satisfied

870.1100	Acute Oral Toxicity (Rat)   MRIDs  41394404, 42296101

870.1200	Acute Dermal Toxicity (Rabbit)  MRIDs 42053801, 00071158

870.1300	Acute Inhalation (Rat) MRID 00145074

870.2400	Primary Eye Irritation (Rabbit) MRIDs 41394404,

42161602

870.2500	Primary Dermal Irritation (Rabbit) MRIDs 42161601

870.2600	Dermal Sensitization (Guinea pig)   MRIDs 42161603, 46367601	

yes

yes

yes

yes

yes

yes	

yes

yes

yes

yes

yes

yes

870.3100	Oral Subchronic (Rat)   MRID 40966302

870.3150     Oral Subchronic (Dog)  MRID 40262901

870.3250     90-Day Dermal (Rat)  MRID 41305901	yes

yes

yes	yes

yes

yes

870.3700a	Developmental Toxicity (Rat) MRID 41886701, range-finding MRID
42746901

870.3700b	Developmental Toxicity( Rabbit) MRID 41018701

870.3800	Reproduction (Rat) MRID 41804501	

yes

yes

yes	

yes

yes

yes

870.4100    Chronic (Dog)  MRID 41970401

870.4300	Chronic/Carcinogenicity (Rat) MRID 41965101

870.4300	Chronic/Carcinogenicity (Mouse) MRID 41802301	yes

yes

yes	yes

yes

yes

870.5100	Mutagenicity – Bacterial Reverse Gene Mutation assay MRIDs
40282201, supplemental information 44005801

870.5300	Mutagenicity – Forward gene mutation test (HGPRT) MRID
93014008, reformat of 40895202

870.5375	Mutagenicity – Chromosome aberrations  (CHO) MRID 41252601

870.5550	Mutagenicity – Unscheduled DNA synthesis in primary rat
hepatocytes MRID 93014007, reformat of 40895201	

yes

yes

yes

yes	

yes

yes

yes

yes

870.6100	Acute Delayed Neurotox. (Hen)	

870.6200	Acute Neurotox. Screening Battery (Rat)	

870.6300	Develop. Neuro		no

no

no	-

-

-

870.7485     Metabolism and Pharmacokinetics MRID 41617101 and addendum
MRID 41385101	

yes	

yes

3.0	DATA GAPS

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

4.0	HAZARD ASSESSMENT

4.1	Acute Toxicity

Adequacy of database for Acute Toxicity:    SEQ CHAPTER \h \r 1  DDAC
was assigned Toxicity Category II in two acute oral toxicity studies in
rats, MRIDs 41394404 [65% a.i.; LD50 = 262 mg/kg (combined)] and
42296101 [80% a.i.; LD50 = 238 mg/kg (combined)].  DDAC was assigned
Toxicity Category III in two acute dermal toxicity studies in rabbits,
MRIDs 42053801 [65% a.i.; LD50 = 2930 mg/kg (combined)] and 00071158
[50% a.i.; LD50 = 4350 mg/kg (combined)].  For acute inhalation toxicity
(MRID 00145074; TRID 455201010), the LC50 of DDAC (purity not reported)
was reported as 0.07 mg/L; Toxicity Category II was assigned.  For
primary eye irritation, DDAC was found to be corrosive (Toxicity
Category I) in two primary eye irritation studies in rabbits, MRIDs
41394404 [65% a.i.] and 42161602 [80% a.i].  For primary dermal
irritation, DDAC (80% a.i.) was found to be corrosive (Toxicity Category
I) in a primary dermal irritation study in rabbits (MRID 42161601).  A
dermal sensitization study in guinea pigs using BARDAC 2280 80% a.i.
(MRID 46367601) showed that DDAC is not a dermal sensitizer.  The acute
toxicity data for DDAC are summarized below in Table 2.

Table 2.  Acute Toxicity Profile for DDAC

Guideline Number	Study Type/ Test substance (% a.i.)	MRID Number/
Citation	Results	Toxicity Category

870.1100

(§81-1)	Acute oral, rat

(Purity 65%)	MRID 41394404	  SEQ CHAPTER \h \r 1 LD50 =262 mg/kg
(combined)

  SEQ CHAPTER \h \r 1 LD50 =331 mg/kg (males)

  SEQ CHAPTER \h \r 1 LD50 =238 mg/kg (females)	II

870.1100

(§81-1)	Acute oral, rat

(Purity 80%)	MRID 42296101	  SEQ CHAPTER \h \r 1 LD50 =238 mg/kg
(combined)	II

870.1200

(§81-2)	Acute dermal, rabbit

(Purity 65%)	MRID 42053801	  SEQ CHAPTER \h \r 1 LD50 =2930 mg/kg
(combined)

  SEQ CHAPTER \h \r 1 LD50 =3140 mg/kg (males)

  SEQ CHAPTER \h \r 1 LD50 =2730 mg/kg (females)	III

870.1300

(§81-3)	Acute inhalation, rat

 (Purity not reported)	MRID 00145074

TRID 455201010	  SEQ CHAPTER \h \r 1 LC50 (combined) = 0.07 mg/L	II

870.2400

(§81-4)	Primary eye irritation, rabbit

(Purity 65% a.i.)	MRID 41394404	  SEQ CHAPTER \h \r 1 Corrosive.	I

870.2400

(§81-4)	Primary eye irritation, rabbit

(Purity 80% a.i.)	MRID 42161602	  SEQ CHAPTER \h \r 1 Corrosive.	I

870.2500

(§81-5)	Primary dermal irritation, rabbit

(Purity 80%)	MRID 42161601	Corrosive.	I

870.2600

(§81-6)	Dermal sensitization, guinea pigs

(Purity 80%)	MRID 46367601	Not a sensitizer.	NA

4.2	Subchronic Toxicity

Adequacy of database for Subchronic Toxicity:    SEQ CHAPTER \h \r 1 The
database for subchronic toxicity of DDAC is considered complete.  For
oral toxicity, the database includes two studies, a 90-day oral toxicity
test in rats (MRID 40966302) and a 90-day oral study in dogs (MRID MRID
40262901).  For dermal toxicity, there are two 21-day dermal studies
using DDAC formulations, one in the rat (MRID 45656601) and one in the
guinea pig (MRIDs 40565301 and 41105801) and there is a 90-day dermal
toxicity study using DDAC, technical grade, in rats (MRID 41305901).

870.3100	Subchronic (Oral) Toxicity - Rat

  SEQ CHAPTER \h \r 1 In a 90-day rat feeding study (MRID 40966302),
male and female rats were given diets containing 0, 100, 300, 600, 1000,
and 3000 ppm (respective mg/kg/day equivalents; 0, 6.2, 18.5, 36.8, 60.7
and 175 for males; 0, 7.5, 22.3, 44.4, 74.3 and 225.5 for females) DDAC
for 13 weeks.  High-dose animals showed increased mortality, decreased
mean body weights, body weight gain and food consumption, and increased
incidence of gross pathological observations and non-neoplastic lesions,
including a higher incidence of glycogen depletion in the liver and
contracted spleens.  Additionally, high-dose females showed sinus
erythrocytosis and lymphoid hyperplasia of mesenteric lymph nodes.  

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

This study is classified as acceptable.

870.3150	Subchronic (Oral) Toxicity - Dog

  SEQ CHAPTER \h \r 1   SEQ CHAPTER \h \r 1 In a 90-day dog feeding
study (MRID 40262901), male and female beagle dogs were given DDAC at
doses of 0, 5, 15 and 50 mg/kg/day.  High-dose animals experienced
marked decrease in body weight gain, food consumption and food
efficiency.  Clinical chemistry, hematology, urinalysis, and
pathological results did not reveal any treatment-related effects.

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

This study is classified as acceptable.

Subchronic (21-day dermal) Toxicity – Guinea pig

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

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

870.3200	Subchronic (21-day dermal) Toxicity – Rat

  SEQ CHAPTER \h \r 1 In a 21-day dermal toxicity study (MRID
456566-01), SS0853.01 (100% pure) was administered directly to the skin
of CD [Crl:CD (SD) IGS BR] rats (10/sex/group) at doses of 100, 500, and
1000 mg/kg-day.  The dermal route of exposure was chosen because it is a
possible route of human exposure.  Doses for this study were determined
by the Sponsor to achieve a gradient of toxic effects.  The high-dose
level was selected per OPPTS 870-3200 and was considered to show signs
of toxicity.  The mid-dose level was selected as an additional dose in
order to evaluate any potential toxicological effects.

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

This study is classified as Acceptable – Guideline.

870.3250	Subchronic (90-day dermal) Toxicity – Rat

  SEQ CHAPTER \h \r 1 In a 90-day rat dermal study (MRID 41305901),
Sprague-Dawley rats (15/sex/group) received repeated dermal dosing of
the test compound at 0, 2, 6, and 12 mg/kg/day for 6 hours/day, 5
days/week for 13 weeks.  No treatment-related effects were noticed in
mortality, weight gain, food consumption, or systemic toxicity. 
Toxicity was limited to treated skin of mid-dose females and high-dose
males and females.  The clinical and gross findings (erythema, edema,
exfoliation, excoriation and ulceration) were confirmed by
histopathological examination, where increased incidence of
hyperkeratosis, acanthosis, epidermitis, dermatitis and ulceration were
noted.  

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

This study is classified as Acceptable – Guideline.

4.3	Prenatal Developmental Toxicity

Adequacy of database for Prenatal Developmental Toxicity:    SEQ CHAPTER
\h \r 1 The database for developmental toxicity of DDAC is considered
complete.  The database includes 2 developmental studies, one in the rat
(MRID 41886701) and another in the rabbit (MRID 41018701).

870.3700	Prenatal Developmental Toxicity (Gavage) Study – Rat

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

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

This study is classified as acceptable.

870.3700	Prenatal Developmental Toxicity (Gavage) Study – Rabbit

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

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

This study is classified as acceptable.

4.4	Reproductive Toxicity

Adequacy of database for Reproductive:    SEQ CHAPTER \h \r 1 The
database for reproductive toxicity of DDAC is considered complete.  The
database includes an acceptable 2-generation reproduction toxicity study
in rats, MRID 41804501.

Reproduction and Fertility Effects – Rat

  SEQ CHAPTER \h \r 1 In a two-generation reproduction study (MRID
418045-01), 28/sex/dose ( both F0 and F1) Sprague-Dawley  CD Rats were
fed a diet containing DDAC (80.8% a.i.) at dosage levels of 0, 300, 750,
and 1500ppm (during premating,   for both sexes = 22, 56, and 113
mg/kg/day,  for males  = 20, 50, and 103 mg/kg/day and for females = 
24, 61, and 122 mg/kg/day).   No compound-related mortalities were
observed in either sex or generation.  No compound-related clinical
signs were observed in either sex or generation.   

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

This study is classified as acceptable.

4.5	Chronic Toxicity

Adequacy of database for Chronic Toxicity:   SEQ CHAPTER \h \r 1 The
database for chronic toxicity of DDAC is considered adequate, including
a chronic oral toxicity study in dogs (MRID 41970401).

870.4100	Chronic Toxicity (Oral feed) – Dog

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

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

This study is classified as Acceptable – Guideline.

4.6	Carcinogenicity

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

870.4300	Combined Chronic /Carcinogenicity (Oral) – Rat

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

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

Study	Dates of In-Life Phase 	Group3

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

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

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

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

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

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

C1 - Control Group 1; C2 - Control Group 2; L - Low-dose Group; M - Mid
-dose Group; and H- High-dose group.

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

This study is classified as Acceptable – Guideline.

870.4300	Combined Chronic/Carcinogenicity (Oral) – Mouse

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

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

At the dose level tested, DDAC was not carcinogenic.

This study is classified as Acceptable – Guideline.

4.7	Mutagenicity

  SEQ CHAPTER \h \r 1 In the Ames test, with or without the microsomal
activation (S-9 fraction), DDAC was not mutagenic to Salmonella
typhimurium tester strains (MRID 40282201 and supplemental information
MRID 44005801).   

nging from 1-10 μg/ml without S9 induction and 1-26 μg/ml with S9
induction.  Severe toxicity was demonstrated at doses of ≥10 μg/ml
(-S9) and ≥ 25 μg/ml (+S9).

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

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

4.8	Neurotoxicity

Adequacy of database for Neurotoxicity:    SEQ CHAPTER \h \r 1   SEQ
CHAPTER \h \r 1 Although a neurotoxicity study is not available in the
database, the available toxicity data for DDAC show no evidence for
neurotoxic effects.

	4.9	Metabolism and Pharmacokinetics

Adequacy of database for Metabolism and Pharmacokinetics:    SEQ CHAPTER
\h \r 1   SEQ CHAPTER \h \r 1 In a rat pharmacokinetics/ metabolism
study (MRID 41617101 and addendum 41385101), single oral doses of
14C-DDAC (5 or 50 mg/kg) or repeated dose (34 ppm of DDAC in the diet
for 14 days and then one single dose of 5 mg/kg of  14C-DDAC) were gave
to both male and female rats.  DDAC was mostly excreted in the feces
within 3 days principally as parent compound and metabolites.  The
elimination pattern and metabolic profile was not substantially altered
by the dose or exposure duration.  Male and female rats showed similar
elimination patterns, but females metabolized DDAC more extensively than
males.  Four major metabolites were identified as oxidation products
with oxidation confined to the decyl side chains.

5.0	TOXICITY ENDPOINT SELECTION

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

5.2	Dermal Absorption

Dermal Absorption Factor:    SEQ CHAPTER \h \r 1 The dermal absorption
factor is not required since route appropriate toxicity data are
available for DDAC.

5.3	Classification of Carcinogenic Potential

  SEQ CHAPTER \h \r 1 DDAC is not likely to be a human carcinogen based
on following reasons:

All the DDAC mutagenicity studies were negative; 

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

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

FQPA CONSIDERATIONS

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

Developmental Toxicity Study Conclusions

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

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

	6.2	Reproductive Toxicity Study Conclusions

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

	6.3	Pre-and/or Postnatal Toxicity

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

B.  Proposed Hazard-based Special FQPA Safety Factor(s):   SEQ CHAPTER
\h \r 1 The HIARC recommended that the FQPA safety factor be removed for
DDAC because there is no quantitative or qualitative evidence of
increased susceptibility to fetus following in utero exposure in the
prenatal developmental toxicity studies or in the offspring when exposed
to adults in the two generation reproductive study.

6.4	Recommendation for a Developmental Neurotoxicity Study

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

7.0	SUMMARY OF TOXICOLOGICAL DOSES AND ENDPOINTS FOR DDAC FOR USE IN
HUMAN RISK ASSESSMENT

7.1	Summary Table of Toxicological Dose and Endpoint Selection  

Exposure

Scenario	

Dose Used in Risk Assessment

(mg/kg/day)	

Target MOE/UF,

Special FQPA SF

for Risk Assessment	

Study and Toxicological Effects

Acute Dietary

(Females 13+)	

NOAEL(developmental) = 10 mg/kg/day

	

FQPA SF = 1

UF = 100 (10x inter-species extrapolation, 10x intra-species variation)	

Prenatal Developmental Toxicity - Rat

MRID 41886701

LOAEL = 20 mg/kg/day based on increased incidence of skeletal
variations.

	

Acute RfD = 0.1 mg/kg/day (Females age 13+)

Acute dietary

(general pop.)

	

an acute dietary endpoint for the general population was not identified
in the database for DDAC.

Chronic Dietary

(general population)

	

NOAEL = 10

mg/kg/day	

FQPA SF = 1

UF = 100 (10x inter-species extrapolation, 10x intra-species variation	

Chronic Toxicity Study - Dog

MRID 41970401

LOAEL = 20 mg/kg/day based on increased incidence of clinical signs in
males and females and decreased total cholesterol levels in females. 

	

Chronic RfD = 0.1 mg/kg/day

Dermal, Short-Term (technical a.i.)

 

NOAEL = 2 

UF = 100Based on increased dermal clinical and gross findings

Rat 90-day Dermal Study

MRID 413059-01

Non-Dietary Exposures

Incidental Oral

Short-Term	

NOAEL(developmental) = 10 mg/kg/day

	

Target MOE = 100 (10x inter-species extrapolation, 10x intra-species
variation)

FQPA SF = 1

	

Prenatal Developmental Toxicity - Rat

MRID 41886701

LOAEL = 20 mg/kg/day based on increased incidence of skeletal
variations.

Incidental Oral

Intermediate-Term	

NOAEL  = 10 mg/kg/day

	

Target MOE = 100 (10x inter-species extrapolation, 10x intra-species
variation)

FQPA SF = 1	

Chronic Toxicity Study - Dog

MRID 41970401

LOAEL = 20 mg/kg/day based on increased incidence of clinical signs in
males and females and decreased total cholesterol levels in females. 

Dermal, Short-term (formulated product, 0.13% a.i.)	

No endpoint identified.  No dermal or systemic effects identified in the
21-day dermal toxicity study (MRID 45656601) up to and including the
limit dose of 1000 mg/kg/day

Dermal, Short-term (TGAI 80% diluted to 0.1%)	

NOAEL(dermal) = 2 mg/kg/day

(8.0 (g/cm2)b	

Target MOE = 10 (3x inter-species extrapolation, 3x intra-species
variation)

	

90-day Dermal Toxicity - Rat

MRID 41305901

LOAEL = 6 mg/kg/day based on increased clinical and gross findings
(erythema, edema, exfoliation, excoriation, and ulceration)

Dermal, Intermediate- and Long-term (formulated product)	

No appropriate endpoint identified. 

Inhalation, Short-Term

	

NOAEL   = 10 mg/kg/daya

	

Target MOE = 100 (10x inter-species extrapolation, 10x intra-species
variation, 10x route-extrapolation) 

DB UF- an additional 10x is necessary for route extrapolation.  If risk
estimates are below an MOE of 1000, a confirmatory inhalation toxicity
study may be required.	

Prenatal Developmental Toxicity - Rat

MRID 41886701

LOAEL = 20 mg/kg/day based on increased incidence of skeletal
variations.

 Inhalation, Intermediate- and Long-Term

	

NOAEL  = 10

mg/kg/daya	

 Target MOE = 100 (10x inter-species extrapolation, 10x intra-species
variation, 10x route-extrapolation) 

DB UF- an additional 10x is necessary for route extrapolation.  If risk
estimates are below an MOE of 1000, a confirmatory inhalation toxicity
study may be required.	

Chronic Toxicity Study - Dog

MRID 41970401

LOAEL = 20 mg/kg/day based on increased incidence of clinical signs in
males and females and decreased total cholesterol levels in females. 

     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.

  SEQ CHAPTER \h \r 1 aAn additional uncertainty factor of 10x is
applied for use of an oral endpoint for route-to-route extrapolation to
determine if a confirmatory inhalation toxicity study is warranted.

b TGAI-based dermal endpoint = (2 mg/kg rat x 0.2 kg rat x 1000 ug/mg) /
50cm2  area of rat dosed = 8.0 µg/cm2  .

8.0	TOXICITY PROFILE TABLES

	8.1	Acute Toxicity Profile Table (Table 5).

Table 5.  Acute Toxicity Profile for DDAC.

Guideline No./ 

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

Citation/ Classification/ Doses	Results

870.1100 (§81-1)	

Acute Oral Toxicity – Rats

DDAC purity 65%	MRID 41394404

Acceptable

Females: 0, 100, 200, or 400 mg/kg

Males: 0, 100, 200, 283, 336, or 400 mg/kg

Rats (5/sex/dose)	Toxicity Category II

LD50 = 262 mg/kg (combined)

LD50 = 331 mg/kg (males)

LD50 = 238 mg/kg (females)

Signs of toxicity included sluggishness, lacrimation, diarrhea, and a
brown stain on the periurogenital fur, red discharge on the facial fur
and emaciation.  Deaths occurred at 1 to 4 days.  Survivors recovered at
2 to 5 days.  Necropsy of rats that died revealed discolored stomachs
(yellow or red to purple), hemorrhaged stomachs, one stomach adhering to
liver, red to brown intestines, dark red livers, and thoracic cavities
filled with red to clear liquid.  Two males had blood in the urine.  In
survivors, there were no remarkable gross lesions. 

870.1100 (§81-1)	

Acute Oral Toxicity – Rats

DDAC Purity 80%	MRID 42296101

Acceptable

Range-finding:

Rats (5/sex/dose) administered single oral dose of BARDAC 2280 undiluted
at 0.16, 0.4, 1.0, or 4.0 g/kg or as a 20% w/v formulation in water at
0.0632 g/kg

Main study:

Rats (5/sex/dose) given single oral dose of DDAC in 5% w/v formulation
in water at 0.1, 0.2, 0.3, or 0.5 g/kg

Identification of NOAEL following single dose:

Single oral doses of DDAC in 5% w/v formulation in water at 0.01
(5/sex), 0.02 (2/sex), or 0.03 (2/sex) g/kg	Toxicity Category II

LD50 = 238 mg/kg (combined)

NOAEL = 10 mg/kg

The observations for the third phase of the study ranged from minimal
effects to no clear treatment-related effects.  The most prevalent
clinical signs during the observation period included urine and fecal
stains, saliva discharge and stains, dried red stains on muzzle and
around the eyes, eye squinting, piloerection, ataxia, body tremors,
labored and shallow respiration, slight to severe depression, viscous
red blood-like discharge from the mouth, bloated appearance to the
abdomen, and spasms in the abdominal area.  With the exception of one
animal, all animals that survived the observation period exhibited no
gross pathologic findings. 

870.1200 (§81-2)	

Acute Dermal Toxicity – Rabbits

DDAC Purity 65%	MRID 42053801

Acceptable

0, 2000, 2830, or 4000 mg/kg

Rabbits (5/sex/dose)	Toxicity Category III

LD50 = 2930 mg/kg (combined)

LD50 = 3140 mg/kg (males)

LD50 = 2730 mg/kg (females)

Skin reactions included erythema, edema, necrosis, ulceration,
ecchymoses, fissuring, alopecia, desquamation, and scabs.  Signs of
systemic toxicity observed were sluggishness, prostration (in 2),
diarrhea (in 1), and persistent weight loss (with emaciation in some
animals).  Four rabbits died at 3 to 3.5 hours.  However, most deaths
occurred at 2 to 7 days.  Necropsy of the decedents revealed dark red
lungs, hemorrhaged intestines (in 1), gas or liquid-filled intestines
(in 2), dark purple thymus, and purple and enlarged kidneys (in 1). 
Gross lesions apparent in survivors at necropsy included dark red lungs
(in 1), enlarged spleen, tan or purple kidneys (1 with multiple red
foci), an excessive amount of blood in the kidneys (of 1), and a trace
amount of blood in the urine of 1.

870.1200 (§81-2)	

Acute Dermal Toxicity – Rabbits

DDAC Purity 50%	MRID 00071158

Acceptable

0, 2000, 5000, or 8000 mg/kg

Rabbits (3/sex/dose)	Toxicity Category III

LD50 = 4350 mg/kg (combined)

LD50 = 4350 mg/kg (males)

LD50 = 4350 mg/kg (females)

870.1300 (§81-3)	

Acute Inhalation Toxicity – Rats

Purity not reported	MRID 00145074, TRID 455201010

Acceptable

0, 0.05, 0.09, 0.03, 0.25, or 4.54 mg/L (for 4 hours), orr 1.36 mg/L
(for 2 hours)

Rats (5/sex/dose)	Toxicity Category III

LC50 = 0.07 mg/L

At necropsy, no gross lesions were observed in 48 of the 60 test rats. 
Abnormalities of the liver, ear, skin, urinary bladder, kidneys,
stomach, intestine, cecum, and lungs were noted among the remaining
rats.

870.2400 (§81-4)	

Primary eye irritation – Rabbits

DDAC Purity 80%	MRID 41394404

Acceptable

0.1 mLof NP-1 Plus (concentrate)

Rabbits (2 animals)	Toxicity Category I

Corrosive.  Instillation of 0.1 mL of NP-1 Plus (concentrate) resulted
in severe corneal opacity; it was impossible to score the iris
throughout the test.  Necrosis of the conjuncticas and the nictitating
membrane was apparent at one hour prohibiting the scoring of
conjunctival redness.  Moderate chemosis of the conjunctivae was
observed in bathocytes at one hour developing into severe swelling at 24
hours.  Each rabbit also exhibited a purulent ocular discharge at 24
hours.  Because of the persistent severe irritation evident aat 48
hours, both animals were sacrificed.

870.2400 (§81-4)	

Primary eye irritation – Rabbits

DDAC Purity 80%	MRID 42161602

Acceptable

0.1 mL of BARDAC (80% a.i.) for 1 hour 

1 male rabbit	Toxicity Category I

Corrosive.  The total irritation score for the single animal was 94 (110
maximum) at the one hour interval.  The test material produced extreme
corneal opacity, ititis, and conjunctival irritation after 1 hour.  The
eye of this animal also appears misshapen.  Due to the evidence of
corrosion (misshapen eye) exhibited in this single animal, the study was
terminated following the 1 hour reading without testing additional
animals.

870.2500 (§81-5)

Primary dermal irritation – Rabbits

DDAC Purity 80%	MRID 42161601

Acceptable

0.5 mL BARDAC (80% a.i.), 4 hours

1 male rabbit	Toxicity Category I

Corrosive.  Severe irritation persisted 24 hours following application. 
Changes noted in the coloration and/or texture of the skin included
coriaceousness, blanching, green-brown discoloration, brown/dark red
discoloration, and necrosis.  Due to the evidence of corrosion exhibited
in this animal at the 24 hour reading, this study was terminated without
testing additional animals.

870.2600 (§81-6)	

Dermal sensitization – Guinea pigs

DDAC Purity 80%	MRID 421616303

Acceptable

Induction:  0.1% w/v test material, followed by UVA and UVB irradiation

Challenge Period:  10-14 days

Challenge dose:  0.1% w/v, followed by UVA and UVB irradiation

Control:  No induction, received challenge dose of 0.1% w/v, followed by
UVA and UVB irradiation

Guinea pigs (5/sex)	Not a  photosensitizer.

The incidence of grade 1 responses in the test group (1/10) was
comparable to the incidence of grade 1 responses in the naïve control
group (2/10).  The test material was not considered to have caused
photosensitization.

The positive control without irradiation did not clearly exhibit contact
sensitization.

870.2600 (§81-6)	

Dermal sensitization – Guinea pigs

DDAC Purity 80%	MRID 46367601

Acceptable

Induction:  0.25, 0.5, or 0.75% w/w mixture in distilled water, once a
week for 3 weeks

Challenge Period:  27 days

Challenge dose:  or 0.1% w/w mixture in distilled water

Control:  10 guinea pigs, no induction, received challenge dose of 0.1%
w/w

Guinea pigs (20)	Not a sensitizer.

Erythema scores ranged from 0.05 to 0.10 in the test animals and from
0.05 to 0.20 in the controls.  A positive response was not observed in
any of the test or control animals.

Subchronic, Chronic and Other Toxicity Profiles Table (Table 6)

Table 6:  Subchronic, Chronic and Other Toxicity Profiles for DDAC.

Guideline Number/

Study Type/

Test Substance (% a.i.)	MRID Number (Year)/

Citation/ Classification/ Doses	Results

870.3100 (§82-1)

90-Day Oral ( Diet) –Rat

DDAC purity 80.8% 	MRID 40966302

Acceptable – Guideline

0, 100, 300, 600, 1000, or 3000 ppm

[0, 6.2, 18.5, 36.8, 60.7, or 175.4 mg/kg (males),

0, 7.5, 22.3, 44.4, 74.3, or 225.5 mg/kg/day (females)]	Systemic
toxicity:

NOAEL = 1000 ppm

               = 60.7 mg/kg/day (males)

               = 74.3 mg/kg/day (females)

LOAEL = 3000 ppm

               = 175.4 mg/kg/day (males)

               = 225.5 mg/kg/day (females), based on increased
mortality, decreased mean body weights, body weight gain and food
consumption, and increased incidences of gross pathological lesions. 
High-dose animals showed increased mortality, decreased mean body
weights, body weight gain and food consumption, and increased incidence
of gross pathological observations and non-neoplastic lesions, including
a higher incidence of glycogen depletion in the lover and contracted
spleens.  Additionally, high-dose females showed sinus erythrocytosis
and lymphoid hyperplasia of mesenterin lymph nodes.

870.3100 (§82-1)

90-Day Oral (Feed) –Dog

DDAC purity not reported	MRID 40262901

Acceptable – Guideline

0, 5, 15, or 50 mg/kg/day	Systemic toxicity:

NOAEL = 15 mg/kg/day

LOAEL = 50 mg/kg/day, based on decreased body weight gain, food
consumption, and food efficiency.

High-dose animals experienced marked decrease in body weight gain, food
consumption, and food efficiency, for both males and females.

870.3200 (§82-3)

21-day dermal – Guinea pig

1:5 solution with DDAC purity 4%	MRID 40565301 and 41105801

Acceptable - Nonguideline

Guinea pigs (5/sex/dose)

0, 500, or 1000 mg/kg/day, 5 days/week, 21 days	Systemic Toxicity

NOAEL = 500 mg/kg/day

LOAEL > 1000 mg/kg/day, based on decreased body weights, a slight
elevation of basophils and eosiniphils as well as a slight elevation of
SGPT and SGOT.

Dermal Toxicity

NOAEL = 500 mg/kg/day

LOAEL = 1000 mg/kg/day, based on sloughing of the stratum corneum as a
result of defatting.

There was no mortality or signs of clinical toxicity noted. Signs of
skin irritation were noted during the second week of treatment and the
report stated that the response intensified during the third week of
treatment. Body weight was decreased in treated males and females by 7%
and 11% vs untreated animals at week 3. Results of hematology and
clinical chemistry measurements indicated a slight elevation of
basophils and eosinophils as well as a slight elevation of SGPT and SGOT
but statistics were not performed on these data. Histologically, the
skin irritation was described as sloughing of the stratum corneum as a
result of defatting.

870.3200 (§82-3)

21-day dermal – Rat

SS0853.01 (DDAC 0.13%)	MRID 45656601

Acceptable - Guideline

Rats (10/sex/dose)

0, 100, 500, or 1000 mg/kg/day	Systemic Toxicity

NOAEL = 1000 mg/kg/day (highest dose tested)

LOAEL > 1000 mg/kg/day (not established)

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

870.3250 (§82-3)

90-day dermal - Rat

DDAC purity 80.8% 	MRID 41305901

Acceptable - Guideline

Rats (15/sex/dose)

0, 2, 6, or 12 mg/kg/day, 6 hours/day, 5 days/week, 13 weeks	Systemic
Toxicity

NOAEL > = 12 mg/kg/day (highest dose tested)

LOAEL > 20 mg/kg/day (not established)

Dermal Toxicity

NOAEL = 2 mg/kg/day

LOAEL = 6 mg/kg/day, based on effects on treated skin, including
erythema, edema, exfoliation, excoriation, hyperkeratosis, acanthosis,
epidermitis, dermatitis, and ulceration.

No treatment-related effects were noticed in mortality, weight gain,
food consumption, or systemic toxicity.

Toxicity was limited to the treated skin of mid-dose females and the
high-dose males and females.  The clinical and gross findings (erythema,
edema, exfoliation, excoriation, and ulceration) were confirmed by
histopathological examination, where increased incidence of
hyperkeratosis, acanthosis, epidermitis, dermatitis, and ulceration were
noted.

870.3700 (§83-3)

Developmental (gavage) - Rat

DDAC purity 80.8%	MRID 41886701, range-finding MRID 42746901

Acceptable - Guideline

Females rats (25/dose)

0, 1, 10, or 20 mg/kg/day, GD 6-15, inclusive	Maternal Toxicity

NOAEL = 1 mg/kg/day

LOAEL = 10 mg/kg/day, based on decreased body weight gain and clinical
signs (audible respiration)

  SEQ CHAPTER \h \r 1 Developmental Toxicity

NOAEL = 10 mg/kg/day

LOAEL = 20 mg/kg/day, based on increased incidence of skeletal
variations.

Maternal toxicity was observed at the mid- and high-dose groups in the
form of audible respiration with the high dose presenting with other
observations.  Further, a treatment-related decrease in body weight gain
was noted during the dosing period (GD 6-15), the dosing period plus
post-dosing (GD 6-21) and for the corrected body weight gains for the
high dose.  There was also low food efficiency compared with controls
during the dosing period for the mid- and high-dose groups. 

Developmental toxicity was noted at the high dose in the form of
increased incidences of skeletal variations.

870.3700 (§83-3)

Developmental (gavage) – Rabbit

DDAC purity 80.8%	MRID 41018701

Acceptable – Guideline

Females rabbits

0, 1, 3, or 10 mg/kg/day, GD 6-18, inclusive	Maternal Toxicity

NOAEL = 1 mg/kg/day

LOAEL = 3 mg/kg/day, based on reductions in body weight gain and
clinical signs of toxicity (hypo activity and audible respiration).

  SEQ CHAPTER \h \r 1 Developmental Toxicity

NOAEL = 3 mg/kg/day

LOAEL = 10 mg/kg/day, based on decreased fetal body weight and increased
number of dead fetuses.

At the 10 mg/kg/day dose level, 4/16 does died prior to GD 12.  There
were no abortions at any dose level.  Hypoactivity and labored breathing
were observed at 3  mg/kg/day in 2 of 15 rabbits.  There were no effects
on cesarean section observations, or necropsy observations at scheduled
necropsy 

Developmental toxicity was noted at the high dose in the form of
decreased fetal body weight and increased number of dead fetuses.

870.8700 (§83-4)

Reproduction (Feed) – Rat

DDAC purity 80.8 %	MRID 41804501

Acceptable – Guideline

Rats (28/sex/dose)

Premating: 0, 300, 750, or 1500 ppm

[0, 20, 50, or 103 mg/kg/day (males),  0, 24, 61, or 122 mg/kg/day
(females)]

	Parental toxicity:

NOAEL = 750 ppm

              = 56 mg/kg/day

LOAEL = 1500 ppm

               = 113 mg/kg/day, based on decreased body weight/weight
gain and food consumption

Reproductive toxicity:

NOAEL = 750 ppm

              = 56 mg/kg/day

LOAEL = 1500 ppm

               = 113 mg/kg/day, based on decreased pup body
weight/weight gain 

No compound-related mortalities were observed in either sex or
generation.  Decreased body weight/weight gain were observed in parental
animals and pups in both generations.

870.4100 (§83-1)

Chronic Toxicity (feed) - Dog

DDAC purity 80.8% 	MRID 41970401

Acceptable – Guideline

Dogs (4/sex/dose)

0, 3, 10, or 20/30 mg/kg/day	Systemic Toxicity

NOAEL = 10 mg/kg/day

LOAEL = 20 mg/kg/day, based on increased incidence of clinical
observations (emesis and soft/mucoid feces) in males and females and
decreased total cholesterol levels in females 

Dosing at 30 mg/kg/day was not tolerated well and was discontinued on
Day 31; dosing was resumed at Day 36 at 20 mg/kg/day.

No treatment-related deaths occurred during the study.  The
treatment-related clinical signs (soft/mucoid feces, emesis) were
observed frequently in high-dose animals.  Hematology or urinalysis
results were normal.  Total cholesterol levels were significantly
decreased in high-dose females.  Gross and histopathological findings
did not reveal any treatment-related effects.  

870.4300 (§83-5)

Combined Chronic/Carcinogenicity (feed) - Rat

DDAC purity 80.8%	MRID 41965101

Rats (60/sex/dose)

Acceptable - Guideline

0, 300, 750, or 1500 ppm for 2  years

[0, 13, 32, or 64 mg/kg/day (males) and 0, 16, 41, or 83 mg/kg/day
(females)]	High-dose animals showed significant, but slight (<10%)
decreases in mean body weight during the study.  Treatment-related
effects consisted of increased incidence of sinusoidal blood,
hemosiderosis and histiocytosis in the mesenteric lymph nodes of high
dose animals.  In addition, an increase in the incidence of interstitial
cell adenomas in testes was reported.  In this study, the incidences of
this tumor for control and treated animals are:  Control 1 (5%, 3/60);
Control 2 ( 5%, 3/60); 300 ppm (12.5%, 1/8), 750 ppm (17.9%, 5/28), and
1500 ppm (11.7%, 7/60).  However, because the incidence was within the
historical incident range, this effect was not considered
treatment-related.

870.4300 (§83-5)

Combined Chronic/Carcinogenicity (feed) - Mouse

DDAC purity 80.8%	MRID 41802301

Mice (60/sex/dose)

Acceptable - Guideline

0, 100, 500, or 1000 ppm for 78 weeks

[0, 15.0, 76.3, or 155.5 mg/kg/day (males),

0, 18.6, 93.1, or 193.1 mg/kg/day (females)]	Systemic Toxicity

NOAEL = 500 ppm

               = 76.3 mg/kg/day (males)

               = 93.1 mg/kg/day (females

LOAEL = 1000 ppm

               = 155.5 mg/kg/day (males)

                = 193.1 mg/kg/day (females), based on decreases in mean
body weight and body weight gains.

No treatment-related effects were noted in the incidence of clinical
signs, deaths, gross and histopathological observations.  Hematological
values were comparable among all study groups.

  

There was no evidence of carcinogenicity of DDAC in this study.

870.5100 (§84-2)

Bacterial reverse mutation test

DDAC purity 50%	MRID 40282201 and supplemental information MRID 44005801

Acceptable

Strains TA1535, TA1537, and TA1538 exposed to 3.9, 7.8, 15.6, 31.2,
62.5, or 125 ug/plate with and without metabolic activation

Stra湩⁳䅔㠹愠摮吠ㅁ〰攠灸獯摥琠⁯ㄳ㈮‬㈶㔮‬㈱
ⰵ㈠〵‬〵ⰰ漠⁲〱〰甠⽧汰瑡⁥楷桴愠摮眠瑩潨瑵洠
瑥扡汯捩愠瑣癩瑡潩൮万来瑡癩൥

Cytotoxicty was seen at concentrations ≥ 65.5 ug/plate without S9 and
at 125 or 250 ug/plate with S9.  All strains responded in the expected
manner to the appropriate positive control.  There was no indication of
a mutagenic effect at any dose with or without metabolic activation.

870.5300 (§84-4)

Mammalian cell forward gene mutation – CHO cells

DDAC purity 80.8%	MRID 93014007 93014008, reformat of 40895202

CHO cells

Acceptable

10 doses, ranging from 1.0 to 13.0 ug/mL were applied without metabolic
activation

Doses ranging from 1.0 to 40.0 ug/mL applined in the presence of
metabolic activation (S9)

Vehicle control:  deionized water	Negative

The mutant frequency of the nonactivation vehicle and positive controls
in each trial were acceptable.  

870.5375 (§84-2)

In Vitro mammalian chromosome aberration test

DDAC purity 80%	MRID 41252601

Acceptable

0, 2, 4, 8, or 16 ug/mL in the presence of metabolic activation for 6
hours

0, 1, 2, 4, or 8 ug/mL in the absence of metabolic activation for 24
hours	Negative

There was no reproducible evidence that P0151 induces chromosomal
aberrations in either the presence or absence of metabolic activation. 
There was no indication of chromosomal ploidy changes in cultures
exposed to P0151 in either the presence or absence of S9 mix. 
Concurrent positive controls demonstrated the sensitivity of the test
system and the metabolic activity of Sp mix.  

870.5550 (§84-2)

Unscheduled DNA synthesis assay

DDAC purity 80.8%	MRID 93014007, reformat of 40895201

Acceptable

Rat hepatocytes

Test concentrations ranged from 0.050 to 10.0 ug/mL	Negative

The test material was lethal at concentrations exceeding 4.00 ug/mL and
excessively toxic at 4.00 ug/mL.  Moderately high toxicity was observed
at 2.00 ug/mL (74.6% survival), however normal cellular morphology was
observed and analysis could be performed.

The test material did not induce significant changes in the nuclear
labeling of rat primary hepatocytes for an applied concentration range
of 2.00 to 0.050 ug/mL

870.7485 (§85-1)

Metabolism - Rat

DDAC purity 40%	MRID 41617101 and addendum MRID 41385101

Rats (5/sex/dose)

Acceptable

Experiment 1:  Single oral dose of 5 or 50 mg/kg of 14C-DDAC

Experiment 2:  Repeat dose of 34 ppm in feed for 14 days, followed by a
single dose of 5 mg/kg of 14C-DDAC.	The pharmacokinetics data
collectively indicate that DDAC is poorly absorbed by the oral route but
is principally eliminated as parent compound and metabolites (possibly
due to intestinal micro flora) in the feces.  Most DDAC is excreted
within 3 days after dosing. The elimination pattern and metabolic
profile is not substantially altered by the dose or exposure duration. 
Males and females show similar elimination with females but differ
somewhat in the extent of metabolism with females metabolizing DDAC more
extensively.  Four major metabolites were identified by mass
spectrometry as oxidation products with oxidation confined to the two
decyl side chains.  A plausible metabolic scheme was proposed.

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42161601 (MRID) Morris, T. (1991) Primary Skin Irritation Study in
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42161603 (MRID) Morris, T. (1991) Photoallergy Study in Guinea Pigs with
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46367601 (MRID) Merkel, D. (2004) Dermal Sensitization Test in Guinea
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40282201 (MRID) Friederich, U.; Wurgler, F. (1982)
Salmonella/Mammalian--Microsome Assay with Bardac 22. Unpublished study
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44005801 (MRID) Schoenig, G. (1996) Response to EPA Data Evaluation
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Bardac 22." Unpublished study prepared by Institute of Toxicology, Swiss
Federal Institute of Technology and University of Zurich. 14 p.

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

40895202 (MRID) Young, R. (1988) Mutagenicity Test on Didecyldimethyl
Ammonium Chloride (DDAC) in the CHO/HGPRT Forward Mutation Assay: HLA
Study No. 10141-0-435. Unpublished study prepared by Hazleton
Laboratories America, Inc. 68 p.

	

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s Assay with Chinese Hamster Ovary Cells in vitro: Proj. No. 735717.
Unpublished study prepared by Lonza Inc. 36 p.

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

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

41617101 (MRID) Selim, S. (1989) Absorption, Distribution, Metabolism
and Excretion Studies of Didecyldimethylammoniumchloride (DDAC): Lab
Project Number: P01421. Unpublished study prepared by Biological Test
Center. 197 p.

41385101 (MRID) Lin, P.; Selim, S. (1989) Addendum to Report Entitled
Absorption, Distribution, Metabolism and Excretion Studies of
Didecyldimethylammonium chloride (DDAC) in the Rat: Lab Project Number:
P01421. Unpublished study prepared by Biological Test Center. 269 p.

USEPA (2000): Didecyl Dimethyl Ammonium Chloride (DDAC) – Report of
the Hazard Identification Assessment Review Committee.  HED document No.
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