Document ID: EPA-HQ-OPP-2006-0572-0002
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2006-10-27T04:00Z

EPA ANTIMICROBIALS DIVISION

 COMPANY NOTICE OF FILING TEMPLATE FOR PESTICIDE PETITIONS PUBLISHED IN
THE FEDERAL REGISTER

(2/27/06)

EPA Antimicrobials Division contact: Velma Noble, 703-308-6233

 ADVANCE \d12 

Lonza Inc.

[6F7045]

EPA has received a pesticide petition (6F7045) from Lonza Inc., 90
Boroline Road, Annandale, NJ, 07401 proposing, pursuant to section
408(d) of the Federal Food, Drug, and Cosmetic Act (FFDCA), 21 U.S.C.
346a(d), to amend 40 CFR part 180.940(a) by: 1)  increasing the end-use
(use-solution) concentration of the quaternary ammonium compounds,
di-n-alkyl (C8-10) dimethyl ammonium chloride from 150 ppm to 240 ppm
and  2) raising the maximum end-use concentration of all quaternary
ammonium compounds [a combination of di-n-alkyl (C8-10) dimethyl
ammonium chloride and either alkyl (C12-18) dimethyl benzyl ammonium
chloride or n-alkyl (C12-14) dimethyl ethyl benzyl ammonium chloride] in
the sanitizing solution from 200 ppm to 400 ppm.  EPA has determined
that the petition contains data or information regarding the elements
set forth in section 408 (d)(2) of the FFDCA; however, EPA has not fully
evaluated the sufficiency of the submitted data at this time or whether
the data supports granting of the petition.  Additional data may be
needed before EPA rules on the petition.

A. Residue Chemistry 

1.  Residue Data.  No residue data is being submitted pursuant to this
petition.  Instead, the petitioner has calculated the potential dietary
exposure due to the increased use-rates for the subject quaternary
ammonium compounds using a model developed by the Food and Drug
Administration (FDA). The FDA model assumes a residual value of 1 mg of
sanitizing solution per cm2 of food-contact surface and that all food
consumed by an individual in a single day contacts 4000 cm2 of
food-contact surfaces.  

 

2.  Analytical method.   An analytical method is not necessary since the
subject quaternary ammonium compounds are exempt from the requirement of
a tolerance.

3.  Magnitude of residues.  Based on the FDA model the petitioner
calculated that the proposed increase in use-rates will result in a
dietary concentration of 32 ppb for di-n-alkyl (C8-10) dimethyl ammonium
chloride and a concentration of 53 ppb for total quaternary ammonium
compounds.

.



B. Toxicological Profile

An extensive and complete toxicology data base has been compiled on
didecyl dimethyl ammonium chloride (DDAC), which is one of the
di-n-alkyl (C8-10) dimethyl ammonium chloride compounds.  The DDAC
safety data base, which includes sub-chronic, chronic, developmental and
reproductive toxicity studies, a mutagenicity battery and
pharmacokinetic studies, meets the Agency’s requirements for food-use
active ingredients.  

As per the Agency’s policy regarding the clustering of quaternary
ammonium compounds (refer to PR Notice 88-2), the safety studies
performed with DDAC can also be used for the safety evaluation of the
structurally similar dialkyl dimethyl quats - dioctyl dimethyl ammonium
chloride and octyl decyl dimethyl ammonium chloride - that are also the
subject of this petition.

The petitioner believes that low levels of the di-n-alkyl dimethyl
ammonium chloride compounds in the diet do not implicate any
toxicological endpoints of concern.  The basis for this position is that
all the effects observed in the DDAC safety studies are mediated through
the well-known antimicrobial and/or irritant properties of this
compound, which occur at levels significantly higher than the dietary
exposures that may result from its use on food-contact surfaces.

The DDAC safety studies that are pertinent to a dietary risk assessment
for DDAC and the related dialkyl dimethyl quaternary ammonium compounds
are summarized below. 

1.  Sub-chronic.  In the oral sub-chronic study, Sprague-Dawley rats (15
sex/group) were treated with DDAC, by gavage, at dose levels of 0, 100,
300, 600, 1000 and 3000 ppm for either 90 days (males) or 91 days
(females).  The equivalent mg/kg-b.w. doses are: 0, 6.2, 18.5, 36.8,
60.7 and 175.4 (males) and 0, 7.5, 22.3, 75.3, and 225.2 (females).  No
treatment-related effects were observed in any of the test animals at
doses up to 1000 ppm.  At 3000 ppm, high mortality occurred in both
males and females and the surviving animals showed markedly reduced body
weights, decreased serum glucose and protein concentrations, and fluid
or gas filled intestines at necropsy (MRID# 40966302).  

 

2.  Genotoxicity.    DDAC was evaluated in the standard mutagenicity
battery of tests: gene mutation (bacterial and mammalian assays);
chromosomal aberration and unscheduled DNA synthesis.  DDAC was negative
in all of these studies (MDID#’s 40895202; 41252601; 40895201).

3.  Reproductive and developmental toxicity.   A 2-generation
reproduction study with DDAC was conducted with Sprague-Dawley rats. 
Test animals were exposed to dosage levels of DDAC in the diet of 0,
300, 750 and 1500 ppm.  Well-defined parental and postnatal toxicity
were observed at the 1500 ppm dose level without any adverse effects on
reproductive performance.  No adverse effects were observed at any of
the other treatment levels (MRID # 41894501).  

Developmental toxicity studies were conducted in both the rat and
rabbit.  In the rat study, pregnant Sprague-Dawley rats were exposed to
DDAC on days 6 through 15 of gestation at doses of 0, 1, 10 and 20
mg/kg/day.  Maternal toxicity was noted at 10 and 20 mg/kg by the
characteristic clinical signs of audible respiration and gasping.  In
addition, body weight and food consumption were reduced at the 20 mg/kg
dose.  No treatment related developmental effects were observed at any
dose level.  The actual DDAC concentrations in the dosing solutions were
200, 2000 and 4000 ppm, respectively.  Since all of these concentrations
exceeded the minimum level of DDAC associated with effective
antimicrobial activity, the effects seen in the rat teratology study are
most likely due to the antimicrobial and irritant effects of DDAC (MRID#
41886701).

In the rabbit study, pregnant New Zealand White rabbits were exposed to
DDAC on days 6 through 18 of gestation at doses of 0, 1, 3 and 10
mg/kg/day.  At 10 mg/kg, 4/16 does died prior to day 13 and 1 doe at 10
mg/kg and 2 does at 10 mg/kg delivered early.  The incidence of dead
fetuses was significantly increased at 10 mg/kg and fetal weights per
litter were reduced at 10 mg/kg.  There were no treatment related
increases in the incidence of individual fetal malformations;
malformations by category or of total malformations at any dose level.
The actual DDAC concentrations in the dosing solutions that were
administered were 500, 1500 and 5000 ppm, respectively.  Since all of
these concentrations exceed the minimal level of DDAC associated with
effective antimicrobial activity, the effects seen in the study are most
likely due to the antimicrobial and irritant effects of DDAC (MRID#
41018701).  

4.  Chronic toxicity.  Chronic studies with DDAC were conducted in both
the dog and rat.  In the dog study, beagle dogs were treated with DDAC,
by gavage, at doses of 0, 3, 10 and 30 mg/kg/day for one-year.  Dosing
at the 30 mg/kg level was discontinued on day 31 and reinstated on day
36 at 20 mg/kg because of significant body weight and food consumption
depressions.  Treatment related changes in clinical pathology were mild
and limited to the high-dose group.  No treatment related changes were
noted in gross pathology examinations, organ weight data or from
histopathological examination of selected organs and tissues (MRID#
41970401).  

In the rat study (combined chronic/oncogenicity study), CD-rats were
administered DDAC in the diet at concentrations of 0, 300, 750 and 1500
ppm for at least 104 weeks.  The doses corresponded to 0, 13, 32 and 64
mg/kg/day for males and 0, 16, 41 and 83 mg/kg day for females.  The
only treatment related effect was a decrease in body weight and food
consumption in both males and females in the high-dose group.  No
treatment related clinical signs of toxicity were noted (MRID#
41965101).



5.  Carcinogenicity studies.   The oncogenic potential of DDAC was
evaluated in both the mouse and rat.  In the mouse study, CD-1 mice were
administered DDAC in the diet at concentrations of 0, 100, 500 and 1000
ppm for at least 78 weeks.  The doses corresponded to mean intake levels
of 0, 15, 76.3 and 155.5 mg/kg/day (males) and 0, 18.6, 93.1 and 193.1
(females).  No treatment related clinical signs of toxicity, increases
in palpable masses, changes in food consumption or differences in
histopathological findings were noted (MRID# 41802301).

In the rat study (combined chronic/oncogenicity study),  CD-rats were
administered DDAC in the diet at concentrations of 0, 300, 750 and 1500
ppm for at least 104 weeks.  The doses corresponded to 0, 12, 32 and 64
mg/kg/day (males) and 0, 16, 41 and 83 mg/kg (females).  The only
treatment related effect was a decrease in body weight and food
consumption in both males and females in the high-dose group.  No
treatment related clinical signs of toxicity were noted (MRID #
41965101).

6.  Animal metabolism.  The adsorption, distribution, metabolism and
excretion of DDAC was evaluated in the rat.  Radiolabeled DDAC was
administered as either a single low-dose, a single high-dose, a repeated
low-dose or a single low intravenous dose.  Almost all the administered
DDAC (89-99%) was excreted in the feces; less than 2.5% was excreted in
the urine.  Tissue residues of DDAC were less than 1% of the
administered dose in all groups (MRID# 41385101).  

7.  Endocrine effects.  No special studies investigating the potential
estrogenic or other endocrine effects of DDAC have been conducted. 
However, the standard battery of required toxicology studies has been
completed.  These include an evaluation of the potential effects on
reproduction and development, and an evaluation of the pathology of the
endocrine organs following repeated or long-term exposure to doses that
far exceed likely human exposures.  Based on these studies there is no
evidence to suggest that DDAC has an adverse effect on the endocrine
system.

C.  Dietary Exposure

The dietary intake estimates calculated by the petitioner are summarized
in the table below.  The estimates are based on dietary concentrations
of 32 ppb and 53 ppb for di-n-alkyl (C8-10) dimethyl ammonium chloride
and total quaternary ammonium compounds, respectively.  The value used
for the adult body weight is 60 kg and FDA’s value of 3000 grams per
day was used for total daily dietary intake.



      Compounds	

         ug/person/day	

        ug/kg-b.w./day

Di-n-alkyl (C8-10) dimethyl

ammonium chloride	

96	

1.6

Total quaternary ammonium compounds	

160	

2.66

The above dietary intake estimates are limited to adults.  Separate
estimates for dietary exposures to children have not been performed. 
The reason for only conducing adult dietary exposures is that the
petitioner believes, as described below, that the adult exposures are
worst-case and are significantly greater than child exposures.

(	The petition is limited to the use of the subject sanitizers in
commercial food-handling establishments, such as restaurants, bars, and
cafeterias.  The dietary estimates assume that a person eats all their
daily meals in such establishments.  It is highly unlikely that children
will receive all their daily meals in these or similar establishments.

(	The food-contact articles that are the major contributors to dietary
exposure are dinner plates and glassware since these articles have the
largest surface area.  The petitioner does not expect that children,
particularly young children, will regularly receive food on dinnerware
or use glassware when eating in public-eating establishments.



D. Cumulative Effects

There is no evidence to indicate or suggest that the subject quaternary
ammonium compounds  have any toxic effects on mammals that would be
cumulative with those of any other chemicals.

E. Safety Determination

There is a reasonable certainty that no harm to the U.S. population will
result from exposure to residues of di-n-alkyl (C8-10) dimethyl ammonium
chloride compounds when these compounds are used as sanitizer
ingredients in antimicrobial formulations applied to food-contact
surfaces in public-eating establishments at an end-use concentration of
240 ppm.  In addition, there is a reasonable certainty that no harm to
the U.S. population will result from exposure to the

combined residues of di-n-alkyl (C8-10) dimethyl ammonium chloride
compounds and either alkyl 

(C12-18) dimethyl benzyl ammonium chloride or n-alkyl (C12-14) dimethyl
ethyl benzylammonium chloride when these compounds are used as sanitizer
ingredients in antimicrobial formulations applied to food-contact
surfaces in public-eating establishments at a total end-use
concentration of 400 ppm.

As noted above, low dietary residues of n-alkyl (C8-10) dimethyl
ammonium chloride compounds do not implicate any toxicological endpoints
of concern.  Moreover, there is no available information to suggest that
the quaternary ammonium compounds have any affect on the endocrine
system nor are cumulative effects anticipated from the proposed increase
in end-use concentration.  Finally, oral exposures from the other uses
of the n-alkyl (C8-10) dimethyl ammonium chloride compounds are
anticipated to be minimal.

F. International Tolerances

No incompatibilities with international tolerances are expected.