Page 1 of 31 February 27, 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) Page 2 of 31 1.0 HAZARD CHARACTERIZATION............................................................................. 3 2.0 TOXICOLOGY DATA REQUIREMENTS ................................................................ 6 3.0 DATA GAPS.................................................................................................................. 6 4.0 HAZARD ASSESSMENT............................................................................................. 7 4.1 Acute Toxicity........................................................................................................................................................ 7 4.2 Subchronic Toxicity.............................................................................................................................................. 8 4.3 Prenatal Developmental Toxicity...................................................................................................................... 10 4.4 Reproductive Toxicity ........................................................................................................................................ 11 4.5 Chronic Toxicity.................................................................................................................................................. 12 4.6 Carcinogenicity ................................................................................................................................................... 12 4.7 Mutagenicity........................................................................................................................................................ 14 4.8 Neurotoxicity ....................................................................................................................................................... 14 4.9 Metabolism and Pharmacokinetics .................................................................................................................. 14 5.0 TOXICITY ENDPOINT SELECTION...................................................................... 14 5.1 See Section 7.1, Summary of Toxicological Doses and Endpoint Selection, Table 2.............................. 15 5.2 Dermal Absorption............................................................................................................................................. 15 5.3 Classification of Carcinogenic Potential .......................................................................................................... 15 6.0 FQPA CONSIDERATIONS ....................................................................................... 15 6.1 Developmental Toxicity Study Conclusions .................................................................................................... 15 6.2 Reproductive Toxicity Study Conclusions....................................................................................................... 16 6.3 Pre and/ or Postnatal Toxicity ........................................................................................................................... 16 6.4 Recommendation for a Developmental Neurotoxicity Study........................................................................ 16 7.0 SUMMARY OF TOXICOLOGICAL DOSES AND ENDPOINTS FOR DDAC FOR USE IN HUMAN RISK ASSESSMENT................................................................................ 17 7.1 Summary Table of Toxicological Dose and Endpoint Selection ................................................................... 17 8.0 TOXICITY PROFILE TABLES ................................................................................ 20 8.1 Acute Toxicity Profile Table ( Table 5). ............................................................................................................ 20 LD50 = 4350 mg/ kg ( combined) ...................................................................................................................................... 21 LD50 = 4350 mg/ kg ( males)............................................................................................................................................. 21 LD50 = 4350 mg/ kg ( females).......................................................................................................................................... 21 8.2 Subchronic, Chronic and Other Toxicity Profiles Table ( Table 6) .............................................................. 23 9.0 REFERENCES............................................................................................................ 27 Page 3 of 31 1.0 HAZARD CHARACTERIZATION 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 trichlorobenzyl 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 0.7 mg/ L; Toxicity Category III was assigned. For primary eye irritation, DDAC was found to be corrosive ( Toxicity Category I) in two primary eye irritation studies in rabbits, MRIDs 41394404 [ 65% a. i.] and 42161602 [ 80% a. i]. For primary dermal irritation, DDAC ( 80% a. i.) was found to be corrosive ( Toxicity Category I) in a primary dermal irritation study in rabbits ( MRID 42161601). For dermal sensitization, DDAC was found to be a slight sensitizer in one dermal sensitization study in guinea pigs ( MRID 42161603 [ 80% a. i.]) and not a sensitizer in another ( MRID 46367601 [ purity not reported]).

For subchronic toxicity, the database includes a 90 day oral toxicity test in rats ( MRID 40966302), a 90 day oral study in dogs ( MRID 40262901), two 21 day dermal toxicity studies with product formulations ( MRIDs 41105801 and 45656601), and a 90 day dermal toxicity study in rats using the technical grade ( MRID 41305901). In the 90 day rat oral feeding study ( MRID 40966302), incidence of gross pathological observations and non neoplastic lesions, including a higher incidence of glycogen depletion in the liver and contracted spleens were observed. In the 21 day dermal toxicity study in guinea pigs, MRIDs 40565301 and 41105801, a 1: 5 dilution of HS sanitizing solution ( containing 6% DDAC and 4% alkyl dimethyl benzyl ammonium chloride) at the high dose ( 1000 mg/ kg/ day) resulted in skin irritation was observed in week 2 of the study, body weights decreased in week 3 of the study, and a slight elevation of basophils and eosinophils as well as a slight elevation of SGPT and SGOT. In a 21 day dermal toxicity study in rats using SS0853 01 ( 0.13% a. i., MRID 45656601), no toxicity was observed at any dose level tested . In the 90 day dog feeding study ( MRID 40269201), no treatmentrelated 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 Page 4 of 31 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 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), 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.

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 Page 5 of 31 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. Page 6 of 31 2.0 TOXICOLOGY DATA REQUIREMENTS The Toxicology database for DDAC is listed in the following table.

Table 1: Toxicologic Data Requirements for DDAC.

Technical Test 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, rangefinding 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 ................................................................................................... 870.6200 ................................................................................................... 870.6300 ................................................................................................... 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. Page 7 of 31 4.0 HAZARD ASSESSMENT 4.1 Acute Toxicity Adequacy of database for Acute Toxicity: 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 I was assigned. For primary eye irritation, DDAC was found to be corrosive ( Toxicity Category I) in two primary eye irritation studies in rabbits, MRIDs 41394404 [ 65% a. i.] and 42161602 [ 80% a. i]. For primary dermal irritation, DDAC ( 80% a. i.) was found to be corrosive ( Toxicity Category I) in a primary dermal irritation study in rabbits ( MRID 42161601). Two dermal sensitization studies ( one photoallergyl sensitization study in guinea pigs using BARDAC 2280 80% a. i. [ MRID 42161603]) and another dermal sensitization study in guinea pigs using BARDAC 2280 80% a. i. ( MRID 46367601) show that DDAC is not a dermal sensitizer. The acute toxicity data for DDAC are summarized below in Table 2.

Table 2. Acute 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 LD50 = 262 mg/ kg ( combined)

LD50 = 331 mg/ kg ( males) LD50 = 238 mg/ kg ( females) II 870.1100 ( § 81 1) Acute oral, rat ( Purity 80%) MRID 42296101 LD50 = 238 mg/ kg ( combined) II 870.1200 ( § 81 2) Acute dermal, rabbit ( Purity 65%) MRID 42053801 LD50 = 2930 mg/ kg ( combined) LD50 = 3140 mg/ kg ( males) LD50 = 2730 mg/ kg ( females) III 870.1300 ( § 81 3) Acute inhalation, rat ( Purity not reported) MRID 00145074 TRID 455201010 LC50 ( combined) = 0.07 mg/ L I Page 8 of 31 Table 2. Acute Toxicity Profile for DDAC Guideline Number Study Type/ Test substance (% a. i.) MRID Number/ Citation Results Toxicity Category 870.2400 ( § 81 4) Primary eye irritation, rabbit ( Purity 65% a. i.) MRID 41394404 Corrosive. I 870.2400 ( § 81 4) Primary eye irritation, rabbit ( Purity 80% a. i.) MRID 42161602 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: 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 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. Highdose 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. Page 9 of 31 870.3150 Subchronic ( Oral) Toxicity  Dog 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.

870.3250 Subchronic ( 21 day dermal) Toxicity   Guinea pig In a 21 day dermal toxicity study ( MRIDs 40565301 and 41105801), a 1: 5 dilution of HS sanitizing carpet shampoo ( containing 6% didecyl dimethyl ammonium chloride and 4% alkyl dimethyl benzyl ammonium chloride) was applied to a 2 inch square area of the shaved dorsal trunk of 5 male and 5 female guinea pigs at doses of 500 and 1000 mg/ kg, five days a week, for 21 days. Actual doses to the skin based on 6% DDAC in the formulation were calculated to be 30 and 65 mg/ kg a. i. ( communication from registrant). There was no mortality or signs of clinical toxicity noted. Signs of skin irritation were noted during the second week of treatment and the report stated that the response intensified during the third week of treatment. Body weight was decreased in treated males and females by 7% and 11% vs untreated animals at week 3. Results of hematology and clinical chemistry measurements indicated a slight elevation of basophils and eosinophils as well as a slight elevation of SGPT and SGOT but statistics were not performed on these data. Histologically, the skin irritation was described as sloughing of the stratum corneum as a result of defatting.

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

870.3200 Subchronic ( 21 day dermal) Toxicity   Rat 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. Page 10 of 31 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 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: 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 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 Page 11 of 31 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 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: The database for reproductive toxicity of DDAC is considered complete. The database includes an acceptable 2 generation reproduction toxicity study in rats, MRID 41804501.

870.3800 Reproduction and Fertility Effects   Rat 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. Page 12 of 31 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: 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 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 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. Highdose animals showed significant, but slight (< 10%) decreases in mean body weight during the Page 13 of 31 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). 2. All rats were from Charles River Breeding Laboratories, Portage MI. 3. 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 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. Page 14 of 31 This study is classified as Acceptable   Guideline.

4.7 Mutagenicity 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).

In a forward gene mutation assays ( MRID 93014008, reformat of 40895202) demonstrated that DDAC was negative for induction of gene mutations in CHO cells at the HGPRT locus, with levels of DDAC ranging from 1 10 µ g/ ml without S9 induction and 1 26 µ g/ ml with S9 induction. Severe toxicity was demonstrated at doses of   10 µ g/ ml ( S9) and   25 µ g/ 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 µ g/ ml without microsomal fraction ( S9) induction or DDAC at concentrations of 2 8 µ g/ ml with S9 induction. Cytotoxic effects were observed at DDAC concentrations 16 µ g/ 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 µ g/ ml. Higher concentrations ( 4.0 µ g/ mL) of DDAC were severely cytotoxic.

4.8 Neurotoxicity Adequacy of database for Neurotoxicity: 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: 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 Page 15 of 31 5.1 See Section 7.1, Summary of Toxicological Doses and Endpoint Selection, Table 2.

5.2 Dermal Absorption Dermal Absorption Factor: The dermal absorption factor is not required since route appropriate toxicity data are available for DDAC.

5.3 Classification of Carcinogenic Potential DDAC is not likely to be a human carcinogen based on following reasons:

1. All the DDAC mutagenicity studies were negative; 2. and DDAC was not carcinogenic in the rat and mouse carcinogenic studies ( MRIDs 41965 01 and 418023 01)

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

6.0 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.

6.1 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 Page 16 of 31 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): 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. Page 17 of 31 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 NOAEL( development al) = 10 mg/ kg/ day FQPA SF = 1 UF = 100 ( 10x inter species extrapolation, 10x intraspecies variation) Prenatal Developmental Toxicity  Rat MRID 41886701 LOAEL = 20 mg/ kg/ day based on increased incidence of skeletal variations. Acute Dietary ( Females 13+)

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.

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 Dietary ( general population)

Chronic RfD = 0.1 mg/ kg/ day Non Dietary Exposures Incidental Oral Short Term NOAEL( development al) = 10 mg/ kg/ day Target MOE = 100 ( 10x interspecies extrapolation, 10x intraspecies 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 interspecies extrapolation, 10x intraspecies variation) FQPA SF = 1 Chronic Toxicity Study  Dog MRID 41970401 LOAEL = 20 mg/ kg/ day based on increased incidence Page 18 of 31 Exposure Scenario Dose Used in Risk Assessment ( mg/ kg/ day) Target MOE/ UF, Special FQPA SF for Risk Assessment Study and Toxicological Effects 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 Fg/ cm2) b Target MOE = 100 ( 10x interspecies extrapolation, 10x intraspecies 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 interspecies extrapolation, 10x intraspecies variation, 10x routeextrapolation

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 interspecies extrapolation, 10x intraspecies variation, 10x routeextrapolation

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. 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. Page 19 of 31 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 µ g/ cm2 . Page 20 of 31 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 Page 21 of 31 Table 5. Acute Toxicity Profile for DDAC. Guideline No./ Study Type/ Test Substance (% a. i.) MRID No. ( Year)/ Citation/ Classification/ Doses Results 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 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. Page 22 of 31 Table 5. Acute Toxicity Profile for DDAC. Guideline No./ Study Type/ Test Substance (% a. i.) MRID No. ( Year)/ Citation/ Classification/ Doses Results challenge dose of 0.1% w/ v, followed by UVA and UVB irradiation Guinea pigs ( 5/ sex) 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. Page 23 of 31 8.2 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 Page 24 of 31 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 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/ kgday 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)

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 highdose 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. Page 25 of 31 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 870.3700 ( § 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).

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 highdose females. Gross and histopathological findings did not reveal any treatment related effects. 870.4300 ( § 83 5) Combined Chronic/ Carcinogenicity ( feed)  Rat MRID 41965101 Rats ( 60/ sex/ dose) Acceptable  Guideline High dose animals showed significant, but slight (< 10%) decreases in mean body weight during the study. Treatment related effects consisted of increased Page 26 of 31 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 DDAC purity 80.8% 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)] 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 Strains TA98 and TA100 exposed to 31.2, 62.5, 125, 250, 500, or 1000 ug/ plate with and without metabolic activation Negative 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. Page 27 of 31 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 870.5550 ( § 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.

9.0 REFERENCES 41394404 ( MRID) Myers, R.; Christopher, S. ( 1989) NP 1 Plus ( Concentrate): Acute Toxicity and Primary Irritation Studies: Lab Project Number: 52 642. Unpublished study prepared by Bushy Run Research Center. 31 p.

42296101 ( MRID) Morris, T. ( 1992) Acute Oral Toxicity in Rats Median Lethal Dosage Page 28 of 31 Determination with Didecylammoniumchloride ( DDAC): Lab Project Number: 91 8114 21 ( A). Unpublished study prepared by Hill Top Biolabs, Inc. 153 p.

42053801 ( MRID) Myers, R.; Christopher, S. ( 1991) Sapstain Control Chemical NP 1: Acute Percutaneous Toxicity Study in the Rabbit: Lab Project Number: 54 588. Unpublished study prepared by Bushy Run Research Center ( BRRC). 17 p.

00071158 ( MRID) Nitka, S.; Palanker, A. L.; Lally, E.; et al. ( 1980) Acute Dermal LDI50^ in Rabbits ( FIFRA): Experiment Reference No. 8044 10. Final rept. ( Unpublished study received Feb 2, 1981 under 6836 51; prepared by Consumer Product Testing Co., Inc., sub mitted by Lonza, Inc., Fair Lawn, N. J.; CDL: 244350 A)

00145074 ( MRID) Dudek, R. ( 1984) Four Hour Acute Aerosol Inhalation Toxicity Study in Rats of Micro Emulsion Concentrate Type A: Toxigenics Study No. 420 1485. Unpublished study prepared by Toxigenics, Inc. 44 p.

42161602 ( MRID) Morris, T. ( 1991) Primary Eye Irritation Study in Rabbits with Didecyldimethylammoniumchloride ( DDAC): Lab Project Number: 91 8114 21 C. Unpublished study prepared by Hill Top Biolabs, Inc. 30 p.

42161601 ( MRID) Morris, T. ( 1991) Primary Skin Irritation Study in Rabbits with Didecyldimethylammoniumchloride ( DDAC): Lab Project Number: 91 8114 21 B. Unpublished study prepared by Hill Top Biolabs, Inc. 29 p.

42161603 ( MRID) Morris, T. ( 1991) Photoallergy Study in Guinea Pigs with Didecyldimethylammoniumchloride ( DDAC): Lab Project Number: 91 8114 21 D. Unpublished study prepared by Hill Top Biolabs, Inc. 77 p.

46367601 ( MRID) Merkel, D. ( 2004) Dermal Sensitization Test in Guinea Pigs ( Buehler Method): Bardac 2280. Project Number: 15512, P328/ TRS. Unpublished study prepared by Product Safety Labs and Food Products Laboratory and Precision Analytical Services, Inc. 25 p.

40966302 ( MRID) Van Miller, J. ( 1988) Ninety day Dietary Subchronic Oral Toxicity Study with Didecyldimethylammoniumchloride in Rats: Laboratory Project ID: 51 506. Unpublished study prepared by Bushy Run Research Center, Union Carbide. 262 p.

40262901 ( MRID) Bailey, D. ( 1975) 90 day Feeding Study in Dogs with a Quaternary Ammonium Sanitizer: Bardac 22: Laboratory Project ID: 2224a. Unpublished study prepared by Food & Drug Research Laboratories, Inc. 89 p.

40565301 ( MRID) Rose, G. ( 1988) Acute Toxicology ( EP): HS Sanitizing Carpet Shampoo: Laboratory Project ID B 6 27. Unpublished study prepared by Envirocon. 21 p. Page 29 of 31 41105801 ( MRID) Rose, G. ( 1989) Acute Toxicology ( EP): HS Sanitizing Carpet Shampoo: Project ID: B6 27. Unpublished study prepared by Envirocon. 36 p.

45656601 ( MRID) Henwood, S. ( 2001) 21 Day Dermal Toxicity Study with SS0853.01 in Rats: Final Report: Lab Project Number: 6114 398: DRD: SSBTS00.040 52068. Unpublished study prepared by Covance Laboratories Inc. 538 p. { OPPTS 870.3200}

41305901 ( MRID) Gill, M; Van Miller, J. ( 1989) Ninety day Subchronic Dermal Toxicity Study with Didecyldimethylammonium chloride in Rats: Lab Project Number: 51 554. Unpublished study prepared by Bush Run Research Center, Union Carbide. 244 p.

41886701 ( MRID) Neeper Bradley, T. ( 1991) Development Toxicity Evaluation of Didecyldimethylammoniumchloride Administered by Gavage to CD ( Sprague Dawley) Rats: Lab Project Number: 53 534. Unpublished Study prepared by Bushy Run Research Center. 282 p.

42746901 ( MRID) Neeper Bradley, T. ( 1993) Developmental Toxicity Dose Range Finding Study of Didecyldimethylammoniumchloride Administered by Gavage to CD ( Sprague Dawley) Rats: Lab Project Number: 53 533. Unpublished study prepared by Bushy Run Research Center. 106 p.

41018701 ( MRID) Tyl, R. ( 1989) Developmental Toxicity Study of Didecyldimethylammonium chloride Administered by Gavage to New Zealand White Rabbits: Project ID: 51 590. Unpublished study prepared by Bushy Run Research Center. 164 p.

41886701 ( MRID) Neeper Bradley, T. ( 1991) Development Toxicity Evaluation of Didecyldimethylammoniumchloride Administered by Gavage to CD ( Sprague Dawley) Rats: Lab Project Number: 53 534. Unpublished Study prepared by Bushy Run Research Center. 282 p.

41804501 ( MRID) Neeper Bradley, T. ( 1991) Two Generation Reproduction Study in Sprague Dawley ( CD) Rats with Didecyldimethylammonium chloride Administered in the Diet: Lab Project Number: 52 648. Unpublished study prepared by Bushy Run Research Ctr. 758 p.

41970401 ( MRID) Schulze, G. ( 1991) Chronic Oral Toxicity Study of Didecyldimethylammonium chloride in Dogs: Final Report: Lab Project Number: 2545 102. Unpublished study prepared by Halzeton Washington, Inc. 335 p.

41965101 ( MRID) Gill, M.; Chun, J.; Wagner, C. ( 1991) Chronic Dietary Toxicity/ Oncogenicity Study with Didecyldimethyl ammoniumchloride in Rats: Lab Project Number: 53/ 566. Unpublished study prepared by Bushy Run Research Center. 1649 p.

41802301 ( MRID) Gill, M.; Hermansky, S.; Wagner, C. ( 1991) Chronic Dietary Oncogenicity Study with Didecyldimethylammonium chloride in Mice: Lab Project Number: 53 528. Unpublished study prepared by Bushy Run Research Center. 1006 p. Page 30 of 31 40282201 ( MRID) Friederich, U.; Wurgler, F. ( 1982) Salmonella/ Mammalian Microsome Assay with Bardac 22. Unpublished study prepared by Institute of Toxicology, Swiss Federal Institute of Technology, and University of Zurich. 18 p.

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

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

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

41252601 ( MRID) Holmstrom, M.; Leftwich, D.; Leddy, I. ( 1986) PO151: Chromosomal Aberrations Assay with Chinese Hamster Ovary Cells in vitro: Proj. No. 735717. Unpublished study prepared by Lonza Inc. 36 p.

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

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

41617101 ( MRID) Selim, S. ( 1989) Absorption, Distribution, Metabolism 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. 014099. Page 31 of 31 USEPA ( 2000): Didecyl Dimethyl Ammonium Chloride: Toxicology Review. DP Barcode D260952.


[Federal Register: July 17, 2009 (Volume 74, Number 136)]
[Notices]
[Page 34738]
[DOCID:fr17jy09-34]

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DEPARTMENT OF ENERGY

Federal Energy Regulatory Commission

[Project No. 2816-041]

North Hartland, LLC; Notice of Application Accepted for Filing,
Soliciting Motions To Intervene and Protests, and Soliciting Comments,
Recommendations, Terms and Conditions

July 10, 2009.
    Take notice that the following hydroelectric application has been
filed with the Commission and is available for public inspection:
    a. Application Type: Amendment of license to install a bypass flow
turbine generator unit.
    b. Project No.: 2816-041.
    c. Date Filed: January 6, 2009.
    d. Applicant: North Hartland, LLC (North Hartland)
    e. Name of Project: North Hartland.
    f. Location: The North Hartland Project is located at the U.S. Army
Corps of Engineers' (Corps) North Hartland Dam on the Ottauquechee
River in Windsor County, Vermont.
    g. Filed Pursuant to: Federal Power Act, 16 U.S.C. 791a-825r.
    h. Applicant Contact: Richard Norman, Essex Hydro Associates,
L.L.C., 55 Union Street, Boston, MA 02108. Tel:<PHONE_NUMBER>.
    i. FERC Contact: Vedula Sarma, telephone<PHONE_NUMBER>, and e-mail
address<EMAIL_ADDRESS>    j. Deadline for filing motions to intervene and protests, comments,
recommendations, preliminary terms and conditions is 60 days from the
issuance of this notice; reply comments are due 105 days from the
issuance date of this notice.
    Comments, protests, and interventions may be filed electronically
via the Internet in lieu of paper. See 18 CFR 385.2001(a)(1)(iii) and
the instructions on the Commission's Web site (http://www.ferc.gov)
under the ``e-filing'' link. The Commission strongly encourages
electronic filings.
    All documents (original and eight copies) filed by paper should be
sent to: Secretary, Federal Energy Regulatory Commission, 888 First
Street, NE., Washington, DC 20426. Please include the project number
(P-2816-041) on any comments or motions filed.
    The Commission's Rules of Practice and Procedure require all
interveners filing documents with the Commission to serve a copy of
that document on each person whose name appears on the official service
list for the project. Further, if an intervener files comments or
documents with the Commission relating to the merits of an issue that
may affect the responsibilities of a particular resource agency, they
must also serve a copy of the document on that resource agency. A copy
of any motion to intervene must also be served upon each representative
of the Applicant specified in the particular application.
    k. Description of Request: North Hartland proposes to install a
bypass flow turbine with a maximum capacity of 137.5 kW to utilize a
portion of the minimum flow discharge requirement of 40 cfs that is not
currently used for generating purposes. The project's hydraulic
capacity would increase from 810 cfs to 835 cfs, and the annual energy
production would increase by approximately 600,000 kWh.
    l. Locations of the Application: A copy of the application is
available for inspection and reproduction at the Commission's Public
Reference Room, located at 888 First Street, NE., Room 2A, Washington,
DC 20426, or by calling<PHONE_NUMBER>. This filing may also be viewed
on the Commission's Web site at http://www.ferc.gov using the
``eLibrary'' link. Enter the docket number excluding the last three
digits in the docket number field to access the document. You may also
register online at http://www.ferc.gov/docs-filing/esubscription.asp to
be notified via e-mail of new filings and issuances related to this or
other pending projects. For assistance, call 1-866-208-3676 or e-mail
<EMAIL_ADDRESS>for TTY, call<PHONE_NUMBER>. A copy is
also available for inspection and reproduction at the address in item
(h) above.
    m. Individuals desiring to be included on the Commission's mailing
list should so indicate by writing to the Secretary of the Commission.
    n. Comments, Protests, or Motions to Intervene: Anyone may submit
comments, a protest, or a motion to intervene in accordance with the
requirements of Rules of Practice and Procedure, 18 CFR 385.210, .211,
.214. In determining the appropriate action to take, the Commission
will consider all protests or other comments filed, but only those who
file a motion to intervene in accordance with the Commission's Rules
may become a party to the proceeding. Any comments, protests, or
motions to intervene must be received on or before the specified
comment date for the particular application.
    o. Any filings must bear in all capital letters the title
``COMMENTS'', ``PROTEST'', or ``MOTION TO INTERVENE'', as applicable,
and the Project Number of the particular application to which the
filing refers.
    p. Agency Comments: Federal, State, and local agencies are invited
to file comments on the described application. A copy of the
application may be obtained by agencies directly from the Applicant. If
an agency does not file comments within the time specified for filing
comments, it will be presumed to have no comments. One copy of an
agency's comments must also be sent to the Applicant's representatives.

Kimberly D. Bose,
Secretary.
[FR Doc. E9-16992 Filed 7-16-09; 8:45 am]

BILLING CODE 6717-01-P


[Federal Register Volume 76, Number 226 (Wednesday, November 23, 2011)]
[Notices]
[Page 72461]
[FR Doc No: 2011-30218]

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SECURITIES AND EXCHANGE COMMISSION

Proposed Extension of Existing Collection; Comment Request

Upon Written Request, Copies Available From: U.S. Securities and
Exchange Commission, Office of Investor Education and Advocacy,
Washington, DC 20549-0213.

Extension:
    Rule 9b-1; OMB Control No. 3235-0480; SEC File No. 270-429.

    Notice is hereby given that pursuant to the Paperwork Reduction Act
of 1995 (44 U.S.C. 3501 et seq.) the Securities and Exchange Commission
(``Commission'') is soliciting comments on the existing collection of
information provided for the following rule: Rule 9b-1, Options
Disclosure Document (17 CFR 240.9b-1) under the Securities Exchange Act
of 1934 (15 U.S.C. 78 et seq.). The Commission plans to submit this
existing collection of information to the Office of Management and
Budget (``OMB'') for extension and approval.
    Rule 9b-1 (17 CFR 240.9b-1) sets forth the categories of
information required to be disclosed in an options disclosure document
(``ODD'') and requires the options markets to file an ODD with the
Commission 60 days prior to the date it is distributed to investors. In
addition, Rule 9b-1 provides that the ODD must be amended if the
information in the document becomes materially inaccurate or incomplete
and that amendments must be filed with the Commission 30 days prior to
the distribution to customers. Finally, Rule 9b-1 requires a broker-
dealer to furnish to each customer an ODD and any amendments, prior to
accepting an order to purchase or sell an option on behalf of that
customer.
    There are 9 options markets that must comply with Rule 9b-1. These
respondents work together to prepare a single ODD covering options
traded on each market, as well as amendments to the ODD. These
respondents file approximately 3 amendments per year. The staff
calculates that the preparation and filing of amendments should take no
more than eight hours per options market. Thus, the total compliance
burden for options markets per year is 216 hours (9 options markets x 8
hours per amendment x 3 amendments). The estimated cost for an in-house
attorney is $354 per hour,\1\ resulting in a total cost of compliance
for these respondents of $76,464 per year (216 hours at $354 per hour).
---------------------------------------------------------------------------

    \1\ The $354 per hour figure for an Attorney is from SIFMA's
Management & Professional Earnings in the Securities Industry 2010,
modified by Commission staff to account for an 1800-hour work-year
and multiplied by 5.35 to account for bonuses, firm size, employee
benefits and overhead.
---------------------------------------------------------------------------

    In addition, approximately 1,500 broker-dealers must comply with
Rule 9b-1. Each of these respondents will process an average of 3 new
customers for options each week and, therefore, will have to furnish
approximately 156 ODDs per year. The postal mailing or electronic
delivery of the ODD takes respondents no more than 30 seconds to
complete for an annual compliance burden for each of these respondents
of 78 minutes or 1.3 hours. Thus, the total compliance burden per year
is 1,950 hours (1,500 broker-dealers x 1.3 hours). The estimated cost
for a general clerk of a broker-dealer is $50 per hour,\2\ resulting in
a total cost of compliance for these respondents of $97,500 per year
(1,950 hours at $50 per hour).
---------------------------------------------------------------------------

    \2\ The $50 per hour figure for a General Clerk is from SIFMA's
Office Salaries in the Securities Industry 2010, modified by
Commission staff to account for an 1800-hour work-year and
multiplied by 2.93 to account for bonuses, firm size, employee
benefits and overhead. The staff believes that the ODD would be
mailed or electronically delivered to customers by a general clerk
of the broker-dealer or some other equivalent position.
---------------------------------------------------------------------------

    The total compliance burden for all respondents under this rule
(both options markets and broker-dealers) is 2,166 hours per year (216
+ 1,950), and the total compliance cost is $173,964 ($76,464 +
$97,500).
    Written comments are invited on: (a) Whether the proposed
collection of information is necessary for the proper performance of
the functions of the Commission, including whether the information
shall have practical utility; (b) the accuracy of the Commission's
estimates of the burden of the proposed collection of information; (c)
ways to enhance the quality, utility, and clarity of the information to
be collected; and (d) ways to minimize the burden of the collection of
information on respondents, including through the use of automated
collection techniques or other forms of information technology.
Consideration will be given to comments and suggestions submitted in
writing within 60 days of this publication.
    The Commission may not conduct or sponsor a collection of
information unless it displays a currently valid control number. No
person shall be subject to any penalty for failing to comply with a
collection of information subject to the PRA that does not display a
valid Office of Management and Budget (OMB) control number.
    Comments should be directed to: Thomas Bayer, Director/Chief
Information Officer, Securities and Exchange Commission, c/o Remi
Pavlik-Simon, 6432 General Green Way, Alexandria, Virginia 22312 or
send an email to<EMAIL_ADDRESS>Comments must be submitted
within 60 days of this notice.

    Dated: November 18, 2011.
Kevin M. O'Neill,
Deputy Secretary.
[FR Doc. 2011-30218 Filed 11-22-11; 8:45 am]
BILLING CODE 8011-01-P