UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON, D.C. 20460

3/16/12

MEMORANDUM

SUBJECT:

PC Code: 114801 OFFICE OF CHEMICAL SAFETY

AND POLLUTION PREVENTION

Methyloxazolidines. Human Health Scoping Document for

the Registration Review.

DP Barcode: D394307

Decision No.: 455125 Re g istration Nos.: NA

Petition No ( s ) .: NA Re g ulato ry Action : Re g istration Review

Risk Assessment T yp e: Sin g le chemical Re g istration Review Case No.: 3095

TXR No.: NA

MRID Nos. : NA

F ROM:

TO:

THRU: CAS No.: 51200-87-4

40 CFR: NA

William 

### J. Hazel, Ph.D.,

# Ch**i:.nce COOrdinato** **r~** - 

# 4

Jenny J. Tao, Toxicologist

,

# ~.**~** Timothy Dole, CIH, Industrial Hygienist

### ~..v..:;:tD.L..**~. ~V\-{**  Jonathan Chen, Ph.D., Incident Data

### ~**~** Risk Assessment and Science Support Branch (RASSB)

Antimicrobials Division (7510P)

Seiichi Murasaki, Chemical Review Manager Regulatory Management Branch II

Antimicrobials Division (751 OP) 

## ../J 

# A

Nader Elkassabany, Ph.D., Chief // 

### LA.- Timothy Leighton, Senior ScientistfTeam Leader
Risk Assessment and Science Support Branch (RASSB)

Antimicrobials Division (7510P)

Executive Summary

The Methyloxazolidines are formaldehyde-releasing industrial antimicrobial pesticides used in process water systems and to preserve liquid, water-based

materials during their manufacture, metalworking fluids, and in water systems
associated with oil and gas production. Dietary exposure from food is possible

due to the approved uses to preserve adhesives, inks, emulsions, mineral slurries, dispersed colors, and surfactants; label restrictions may be used to mitigate potential risks. Dietary exposure to dimethyloxazolidine residues from

Page 10f24Page 2 of 24 drinking water sources may also occur as a result of industrial discharges from facilities preserving liquid materials, waste water following use of preserved
househ old products, and metalworking facilities . Both residential and occupational handler and postapplication exposures are likely to occur. Additional toxicology , residue chemistry, and nondietary exposure data are recommended to be conducted. The toxicology s tudies expected to be needed

are: 90

- day rat inhalation toxicity study (870.3465) and a combined rat chronic toxicity/ carcinogenicity stud y (870.4 3 00). Residue chemistry studies needed are
Nature of the Residue on Surfaces ( No Guideline ) and Migration Studies ( No
Guideline ). The nondietary exposure studies needed are: indoor d ermal exposure studies (875.1100), indoor inhalation e xposure studies ( 875.1300),
small chamber emission studies ( 875.2500 ), surface residue dissipation studies (875.2300)

, data r eporting / c alculations (875.1600), and p roduct use information (875.1700) for all of the above

. A ssessment of the following h uman health risk s due to exposure to dim ethyloxazolidine , 2

- amino

- 2

- methyl

- 1

- propanol (AMP; a degradate), and HCHO are expected to be necessary :

1. D ietary risk s via food and drinking water
2. A dult r esidential dermal and inhalation risk s from use of preserved surface cleaners and laundry detergents and painting with preserved paint
3. R esidential postapplication dermal and in cidental oral risks to toddlers playing on floors cleaned with preserved cleaners

4. A ggregate risk of the above, as applicable

5. O ccupational handler dermal and inhalation risks from open

- pouring during material preservation and oil field treatments

6. O ccupational handler de rmal and inhalation risk s from use of preserved metal working fluids

7. Occupational handler dermal and inhalation risk s resulting from painting with preserved paints

Introduction

Registration Review Case 3095 contains the chemicals 4,4

- dimethyloxazolidine (PC Code 114801) and 3,4,4

- trimethyloxazolidine (PC Code 114802)

. Both of these compounds (PC Codes 814801 and 814802, respectively) as well as a mixture of the two (PC Code 814803; CAS No. 81099

- 36

- 7) are also approved as
intentionall y

- added inert ingredients (preservatives) in pesticide formulations. A s all registered products containing 3,4,4

- trimethyloxazolidine as an active ingredient have been voluntarily cancelled, this human health assessment will address only 4,4

- dimethyloxazol idine ( hereafter dimethyloxazolidine) used as an active ingredient.

Dim ethyloxazolidine is used as an active ingredient in industrial water systems
and in water

- based liquid materials as a preservative. The first product containing
dim ethyloxazolidine as an active ingredient was r egistered in the United States inPage 3 of 24 October, 1982 for use as an indoor commercial and industrial use preservative
and biocide in aqueous compositions such as adhesives ( some labels limit use to nonfood contact) , lubricants, die

- cast lubricants, mold release agents, mineral slurries, metalworking fluids, surfactants, latex paints, inks, resin emulsions, caulks, sealants, grouts, spackling, ready

- mix wallboard compounds, dispersed colors, dishwashing liquids, surface cleaners, laundry cleaners, and polishes

. It is also used as a preservative/slimicide in oil and gas production water systems to inhibit slime formation, iron

- oxidizing bacteria, and anaerobic sulfate

- reducing
bacteria. According to the Product Safety Assessment for Bioban CS

- 1135 Antimicrobial (Dow, 2011) , dimethyloxazolidine is used primarily for household

, institutional

, and industrial products, metalworking fluids , and paints. According to the Kline Biocides Report for 2004/2005 (Kline, 2006)

, dimethyloxazolidine is ranked number one for volume of estimated U.S. consumption as an in

- can preservative in p aints and coatings. In terms of volume

, it makes up 36% of consumption

. A summary of the registered uses is presented in Table 1.

Table 1

. D imethyloxazolidine Ant imicrobial Uses

Use Application Rate (In Terms of ai) Comments Adhesives, Caulks and Sealants 780

– 3900 ppm Nonfood on 3 of 5 labels
Consumer Household and Industrial Products 312

– 1560 ppm See Note 1 Die Cast Lubricants and Mold Release Agents 195

– 1560 ppm See Note 2 Emulsions (Wax and Resin) 780

– 3900 ppm Inks, Water Based 780

– 3900 ppm Metal Working Fluids 195

- 1560 ppm See Note 2
Mineral Slurries 312

- 1560 ppm Oilfield Water Systems 4

- 195 ppm Oilfield drilling muds and workover and completion fluids 390

– 780 ppm

Paint (In

- can preservative) 780

– 3900 ppm
Surfactants 312

– 1560 ppm
Note 1 : Includes dishwashing liquids, laundry liquids, surface cleaners

, and polishes
Note 2 : Lower rates are for maintenance treatments.

There are no registered dimethyloxazolidine manufacturing

- use products (MP)

. The six end

- use product s (EP) containing dim ethyloxazolidine as an active ingredient are, therefore, produced by a n integrated formulation system

. A Reregistration Eligibility Decision (RED) was issued by EPA August, 1996

. All products were found eligible for reregistration in the RED. A dditional uses approved since the 19 9 6 RED were “Consumer, household, and institutional products” added to Dow’s 78% product (EPA Reg. No 464

- 660) label in its
12/9/09 revision . Under this heading were listed : dishwashing liquids, laundry cleaners, fabric softeners, surface cleaners, cleaning wipes, polishes, and car care products using rates of 312

- 1560 ppm on an active ingredient (ai) basis. These preserved materials may not be used where contact with food will occur. These use sites have not been added to any of the other five EP labels.

The mechanism of antimicrobial action of dimethyloxazolidine appears to be via
release of for maldehyde (HCHO). D imethyloxazolidine is rapidly hydrolyzed toPage 4 of 24 HCHO and AMP in water at pH 5, 7, and 9 but th e rate of hydrolysis during and after preservation of materials under actual use conditions is uncertain. As this is a hy drolysis reaction, it is r eversible depending on the conditions; for example, AMP is used commercially as an HCHO

- scavenger. The product s are for indoor
commercial and industrial use . Treatment concentrations (application rate s) as a material preservative are equivalent to 195

- 3900 ppm on an ai basis

. In oil and gas production water systems, c oncentrations used are 4

- 195 ppm on an ai
basis

.

The Agency has conducted a screening of the available human exposure and mammalian toxicology data for dim ethyloxazolidine as well as the curre nt policies, use patterns, and most recent risk assessments

. A n 11 / 30 /11 Google
Scholar search of the published literature revealed no studies pertaining to the hazard or human exposure to residues of dimethyloxazolidine. The principal
source of information for this Scoping Document w as the August, 1996 RED document. Four studies of the toxicity of dimethyloxazolidine and one of the toxicity of AMP , a metabolite, have been submitted by Dow since the 1996 RED was published. Th e findings are summari zed below as well as recommendations
as to the need for additional hazard and exposure data and the need for the
conduct of human health risk assessments.

Section 1. Chemical Identity and Generic Physical/C hemical Properties

.

Table 2

. Chemical Identity of Dim ethyloxazolidine
Common Name Dim ethyloxazolidine
Chemical Name s 4,4

- Dimethyloxazolidine
Trade Name s Bioban CS

- 1135; Bioban CS

- 40L; Nuosept 101; Nuosept 166; Troysan 186; Troysan 192

Molecular Formula C 5 H 11 NO Molecular Weight 101.1 5
PC Code 114801 CAS Registry Number 51200

- 87

- 4 Registration Review
Case No. 3095

Chemical Structure

D im ethyloxazolidine is miscible in water, ethanol and acetone and has a log K O/W of 0.73 . It is a liquid at room temperature

. It is estimated using EPI Suite to have a boiling point of 136.13 °C, a vapor pressure of 7.58 mmHg

, and a Henry’s Law
Constant of 1 x 10 - 6 atm

- m 3 /mole at 25 °C. Based on a hydrolysis study, dimethyloxazolidine is hydrolyzed within mi nutes at pH 5, 7, and 9 to AMP and
HCHO

.Page 5 of 24 Section 2. Toxicology

a. Acute Toxicity

The Agency is rely ing on the acute toxicity studies available at the time of the

1996 RED for registration review. D imethyloxazolidine is corrosive to the eyes (Toxicity Category I) yet only slightly irritating to the skin (Toxicity Category IV) and it is not a dermal sensitizer. Acute oral, dermal, and inhalation toxicities are of moderate concern (Toxicity Category II I). The acute toxicity data are adequate to support currently

- registered uses. The Agency does not anticipate that any additional technical acute toxicity information is needed.

b. Subchronic Toxicity

Three subchronic toxicity studies are available test ing dimethyloxazolidine. In a
90

- day oral toxicity study (MRID 47117001) , male and female Crl:CD(SD) rats ( 8 animals/sex/dose group ) were administered dimethyloxazolidine (62.6% ai) in polyethylene glycol 400 (PEG 400) . The doses were 0, 25, 75, 150, or 30 0 mg/kg/day by gavage, once a day, 5 days a week, for 90 day s . Preliminary review of the study revealed a NOAEL of 75 mg/kg/day for males based on observed clinical toxicity (mortality in both male and females, lower mean body weight in males, higher relative kidney and liver weights, and lesions in the stomach) and histopathological findings (stomach and liver) occurring at the
LOAEL of 150 mg/kg/day. A final conclusion has not yet been reached pending completion of a comprehensive review of the study.

In the older of two 90

- day dermal toxicity stud ies (MRID 00138227) , Sprague

Dawley rats ( 15 animals /sex/group ) were administered aqueous

- ethanolic (1:1) solutions of dimethyloxazolidine ( 78% ai) via the dermal route . The doses were 0 (1:1 water/ethanol vehicle), 1.95, 19.5, or 195 mg/kg/day, once daily , 5 days a week, for 13 weeks. [ Note that the daily exposure duration was unspecified as
was whether the treat ed area was occluded. ] Enlarged lung, heart, liver, spleen, and adrenals, as well as moderate and severe skin reaction including thickening and ulcerations, were found in animals in the high

- dose group. Microscopic examination revealed severe ulcerative response s in the skin. Based on these test results, the dermal and systemic LOAEL was 195 mg/kg/day and the dermal and systemic NOAEL was 19.5 mg/kg/day. Due to the uncertainties associated with this older study, the Agency has great er confidence in the dermal toxicity study summarized below (MRID 43322601)

.

In the more recent 90

- day dermal toxicity study (MRID 43322601) , male and female CD (Sprague

- Dawley derived) Crl:CD ® BRVAF/Plus ® rats ( 10
animal s/sex/group) were administered dimethyloxazolidine (75.95% ai) in aqueous solutions, via the dermal route with the expos ed area occluded . The
doses were 0, 1, 30, or 100 mg/kg/day for 6 consecutive hours a day, 5 days a week, for 4 or 13 weeks. All animals were sacrificed after 4 weeks for humanePage 6 of 24 reasons at the 100

- mg/kg/day dose due to severe reactions. The systemic
LOAEL for males was 100 mg/kg/day based on decreased body weight gain ; a systemic LOAEL was not es tablished for females (>100 mg/kg/day). The systemic NOAEL was 30 mg/kg/day for males and ≥100 mg/kg/da y for females.
The LOAEL for dermal irritation wa s 30 mg/kg/day base d on microscopic changes, including inflammation, ulceration, and acanthosis in both males and
females and the NOAEL for dermal irritation was 1 mg/kg/day. If the dermal irritation endpoint from this study is chosen for dermal risk assessment, the NOAEL dose will need to be converted to the equivalent μg/cm 2 dose.

The Agency anticipates t hat exposure via the inhalation route is associated with both residential and occupational scenarios yet t here are no subchronic inhalation toxicity data for dimethyloxazolidine. Although the Agency can estimate inhalation risks using the HCHO inhalation toxicity endpoint , a subchronic inhalation toxicity study dosing with dimethyloxazolidine per se is expected to be needed due to the high vapor pressure of dimethyloxazolidine , its rapid rate of hydrolysis to HCHO and AMP, and the potential for different adverse effects and target organs when dimethyloxazolidine and AMP are inhaled.

c. Developmental Toxicity

Two developmental toxicity studies are available for dimethyloxazolidine in
rabbits. In one study (MRID 00157806)

, dimethyloxazolidine was administered to
New Zealand rabbits at doses of 0, 30, 100

, or 300 mg/kg/day on gestation days 7 through 19. The maternal toxicity LOAEL was 30 mg/kg/day based on local dermal irritation and the maternal toxicity NOAEL was not established. Dose

related lo cal dermal irritation was observed at all dosage levels including erythema, edema, atonia, desquamation, coriaceousness, eschar

, and bruising. There was no developmental toxicity related to the test material at any dose level
tested. The N OAEL for developm ental toxicity was considered to be 300 mg/kg/day (highest dose tested) and a LOAEL was not established.

In the other developmental toxicity study (MRID 48543701)

, d imethyloxazolidine (64.2% ai ; Lot # TD0731LAD1) was administered in polyethylene glycol 400 (PEG 400) by gavage to 26 pregnant female N ew Zealand white rabbits/dose

. The dose levels were 0, 4, 12, or 40 mg/kg/day from D ays 7 through 27 of gestation. The maternal LOAEL wa s 40 mg/kg /da y based on : (i) decreased body weight gain (19.3% compared to controls) throughout treatment with decreases as high as 79% on gestation days (GD) 24

- 28; (ii) decreased food consumption (6.2

- 31% compared to controls) on GD 18

- 28; and (iii) gastrointestinal effects.
The maternal NOAEL was 12 mg/kg/day. As developmental effects were not observed at any dose, t he N OAEL for developmental toxicity may be considered
to be 40 mg/kg/day (highest dose tested) and a developmental LOAEL cannot be
establ ished.Page 7 of 24 d. Reproductive Toxicity

There were no reproductive toxicity studies available at the time of the 1996
RED. However, a two

- generation rat reproductive toxicity study (MRID 48566901) was submitted after the RED was issued. D imethyloxazolidine (62.6% ai; batch /lot # TD0731LAD1) was administered to 27 male and 27 female Crl:CD(SD) rats/dose by gavage at dose levels of 0, 20, 60, or 200 mg/kg/day for approximately 10 weeks prior to breeding, and continuing through breeding, gestation, and lactation for two genera tions. The parental systemic NOAEL wa s 20 mg/kg/day based on gast r opathological changes in the stomach and liver and increased liver weight occurring in both males and females at the LOAEL of 60 mg/kg/day

. The reproductive NOAEL was 60 mg/kg /day based on increased postimplantation loss (both generations) observed at 200 mg/kg/day dose level.

e . Chronic Toxicity /Carcinogenicity

A chronic tox icity study testing dimethyloxazolidine has not been conducted. Such studies are often required to characterize the hazard associated with dietary

, residential , and/or occupational exposure extending over a chronic or long

- term duration (>6 months). B oth chronic dietary (food and drinking water) exposure and long

- term occupational exposure (metal workers) scenarios are expected based on the currently

- approved dimethyloxazolidine uses. There is a
reference dose (RfD) of 0.2 mg/kg/day in IRIS for chronic oral exposure to HCHO

. H owever, no chronic toxicity studies are available for dimethyloxaz olidine to be used for assessment of potential chronic exposure concerns. In addition, both hydrolysis and pharmacokinetics / metabolism studies indicate that AMP, the primary metabolite of dimethyloxazolidine, i s stable for the duration of both
studies.

A study to determine the carcinogenic potential of dimethyloxazolidine has not been conducted. As with chronic toxicity studies, cancer studies are typically required to characterize the hazard associated with dietary, residential, and/or occupational expo sure extending over a chronic or long

- term duration (>6 months or as long as a lifetime). S uch human exposure scenarios are expected based on the currently

- approved dimethyloxazolidine uses. The Agency believes
that a carcinogenicity study is warranted to further evaluate the potential carcinogenicity of dimethyloxazolidine, based on the following evidence:

**•** Positive results in mutagenicity assays (mouse lymphoma assay and structural chromosome aberration)

.

**•** Potential indirect food

- contact and drinking water exposur es to dimethyloxazolidine. T he metabolism study clearly indicated that
HCHO was rapidly released when dimethylox azolidine was administered orally. Of the orally

- administered radioactivity, AMP in the
excreta accounted for about 90%. HCHO is classif ied as “Group B1; probable human carcinogen”

.Page 8 of 24 **•** Although EPA has a n acceptable cancer study for HCHO , it is via the inhalation route of exposure

.

**•** No carcinogenicity studies are available for dimeth yloxazolidine or its
metabolites HCHO or AMP to assess ca rcinogenic potential v ia the oral route of exposure.

g . Mutagenicity

D imethyloxazolidine was shown to be mutagenic in the L5178Y mouse lymphoma assay, with and without S9 activation (MRID 00126353) and i n a chromosomal aberration assay with Chinese hamster ovary cells, with and
without S9 activation (MRID 00126352) . Although negative results were shown in
four other mutagenicity assays (MRIDs 00076976, 00076977, 41577002, and 41577003) , they do not rule out the positive results observed in the mouse lymphoma assay and chromosomal aberration assay. Additionally, i n an in vivo
chromosomal aberration assay (metaphase analysis), dimethyloxazolidine was
found to be non mutagenic when tested up to the highest dose of 80 mg/kg (MRID 41577004) . H owever, the re is no confidence in the apparent lack of mutagenic potential of dimethyloxazolidine because this study did not include dosages high enough to induce any clinical or bone marrow toxicity (and was, therefore, found to be unacceptable )

.

h. Absorption, Distribution, Metabolism, and Elimination

A pharmacokinetics and metabolism study was conducted in which Fischer 344 rats were dosed with 86.1% radiochemical purity [5

- 14 C] dimethyloxazolidine by oral gavage or dermally under semi

- occlusive covering (MRID 48534001) ; note that the ring 2

- position is the carbon atom lost as HCHO. Orally

- administered dimethyloxazolidine was rapidly absorbed and eliminated in the urine, which
accounted for 91

- 99% of the dose (77

- 92% occurring within the first 48 hours);
fecal elimination accou nted for only 4

- 8% of the dose. D imethyloxazolidine was rapidly metabolized prior to reaching sys temic blood circulation. The majority (>80% in urine and

~ 8% in feces) of the orally

- administered radioactivity
recovered in the excreta from 14 C

- dimethyloxazolidine

- dosed rats was AMP. Dermally

- applied 14 C

- dimethyloxazolidine evaporated rapidly from the a pplication site, and only a small amount of radioactivity was detected in the skin application site ( ≤1% of the dose) and stratum corneum (≤0.05% of the dose) at 168 hours postdosing. Total dermal absorption of 14 C

- dimethyloxazolidine was determined
to be 13

- 15% of the dose, of which 11% was eliminated in the urine (

~ 8% eliminated within 48 hours) and <5% was eliminated in the feces. In blood, elimination of radioactivity was biphasic (α and β phases) for both orally

- and dermally

- administered dimethyloxazo lidine

. Only AMP (7

- 9% of administered dose) was detected in the urine of rats dosed with 14 C

- dimethyloxazolidine dermally

.Page 9 of 24 i. Toxicology Data Needs

A 90

- day rat inhalation toxicity study and a combined rat chronic toxicity/ carcinogenicity study using dimethyloxazolidine as test substance are needed to
characterize the subchronic and chronic toxicity and the oral carcinogenicity of dimethyloxazolidine and its degradates HCHO and AMP

. Dimethyloxazolidine

, AMP, and HCHO should be measured in the air of the chamber used for the inhalation toxicity study.

Toxicology of 2

- Amino

- 2

- Methyl

- 1

- P ropanol (AMP)

AMP is a degradate and metabolite of dimethyloxazolidine

. In a reproduction/ developmental toxicity screening test, AMP hydrochloride (99.7% purit y; lot CEC

200303541

- 12) was administered via the diet to groups of male and female CD rats (12/sex/dose) at doses of 0, 100, 300, or 1000 mg/kg/day (MRID 46479201)

. F emales were dosed daily for 2 weeks prior to breeding, through breeding ( 2 weeks), gestation ( 3 weeks), and through postpartum day 4 and were necropsied on postpartum day 5. Males were dosed 2 weeks prior to breeding and continuing through breeding ( 2 weeks ) until necropsy (test day 38). A preliminary review of the study reveale d the parental systemic LOAELs w ere 1000 mg/kg/day for males and 100 mg/kg/day for females, based on the histopathological changes in the liver (increased absolute and relative liver weights with a very slight degree of microvacuolization of periportal hep atocytes, with or without vacuolization of hepatocytes)

. The parental systemic NOAEL for males was 300 mg/kg/day and cannot be determined for females. The reproductive NOAEL was 100 mg/kg/day, based on a dose

- related post

implantation loss (embryo resorpti on) accompanied with decreased litter size, increased pup body weight, and decreased gestational body weight and body weight gain at the reproductive LOAEL of 300 mg/kg/day

. A final conclusion has not yet been reached pending completion of a comprehensive review of the study.

I n the pharmacokinetics and metabolism study discussed above ( MRID
48534001 )

, [1

- 14 C] AMP was also administered to two groups of ra ts (4 males only in each group) by oral gavage or dermal application for comparison to the parent compou nd, dimethyloxazolidine. On e group received a single oral dose (~ 18 mg/kg) of 14 C

- AMP and the other group w as dermally

- administered a dose
of 14 C

- AMP. Absorption, distribution, and elimination of AMP were nearly
identical to those of the parent compound, d imethyloxazolidine, with relatively faster absorption of AMP. Only ~ 4% of the orally

- administered radioactivity of the AMP dose was found in tissues at the end of the study. The total dermal absorption of 14 C

- AMP was ~ 43% of the dose of which 24% of the administered dose was eliminated in urine, 2% was eliminated in the feces, and 6% of the
dose was found in tissues. Dermal penetration of AMP was slower than the oralPage 10 of 24 dose. In the urine of rats, only AMP was detected whe ther dosed with 14 C

- AMP orally or dermally.

While preparing this document, OPP/AD realized that AMP is a High Production Volume (HPV) chemical in the EPA HPV Challenge Program (Dow Chemical Company, 2011). Toxicology study summaries included in the update d I U CLID data set have been submitted to the Office of Pollution, Prevention a nd Toxics (OPPT) in late 2011. A complete review of the study summaries and final decision for AMP for the Challenge Program is planned to be reached sometime
in 2012. AD may use the toxicological data generated on AMP for hazard characterization of dimethyloxazolidine upon completion of comprehensive reviews of the original study reports ( not the study summaries). Therefore, the studies summarized in the IUCLID data set may be re quired for submission to OPP during the risk assessment stage of the dimethyloxazolidine registration
review

.

Toxicology of Formaldehyde (HCHO)

HCHO is a degradate of dimethyloxazolidine and, as a consequence, EPA is requesting exposure data (air concentrations) to permit the conduct of HCHO
inhalation risk assessment s reflecting registered uses of dimethyloxazolidine

. Note that additional HCHO toxicology data , if any are needed , will not be
addressed in this R egistration Review because characterization of HCHO toxicity and the selection of endpoints for risk assessment ha ve been described in the
HCHO RED. The following statement addresses the status, as of 12/ 6 / 11 , of the
HCHO noncancer inhalation toxicity endpoint selection.

OPP developed the formaldehyde inhalation noncancer toxicological endpoint
used in th e RED through the established reregistration process, which includes stakeholder consultation and public comment. However, the r esult has not been subjected to an interagency review or external peer review. Because of time constraints imposed by statutory deadline, OPP could not consider all available

peer

- reviewed science (for example, the intentional human dosing toxicity
studies ). Thus, this value should be considered an interim value developed solely for the purposes of this determination and subject to future revision and subsequent peer review and should not be used in other contexts as EPA's opinion of the best available scie nce on the noncancer effects of formaldehyde.

Section 3. Dietary Exposure

a. Food Exposure

O ne of the Dow product label s (EPA Reg. No. 464

- 660; 6/27/11) lists use to prevent bacterial spoilage during the production, shelf

- life storage, and use of “Consumer, Household, and Institutional Products” including dishwashing liquids,Page 11 of 24 s urface cleaners, and cleaning wipes

. Although these uses could result in residues in food, t he label warning “N ot for use where contact with food will
occur” renders dietary (food) exposure unlikely. Five products are approved for

use to preserve such aqueous materials as inks, emulsions, adhesives, mineral slurries, dispersed colors, and surfactants ; EPA believes these materials may have food contact or be used to manufacture food contact materials

. On three of five product labels listing adhesives, use is limited to nonfood contact. If food contact is not intended for any uses on any of these product labels, label language should be inserted that clearly applies to all potent ial food

- contact materials on the entire label and that precludes use of the pesticide to preserve materials that may contact food, feed, or drinking water. Neither FDA nor EPA has established a tolerance or tolerance exemption in food as a result of use a s a direct or indirect food additive either as an active ingredient or as an inert ingredient. Note that AMP is the subject of several FDA food additive clearances but not as a preservative/antimicrobial

. The Agency believe s that dietary (food source) expo sure to the parent compound and AMP and risk assessment s addressing use of dimethyloxazolidine as an active ingredient are necessary at
this time unless all use sites o n all product labels are limited to nonfood contact

.

b. Drinking Water Exposure

A drinking water assessment has not been conducted for dimethyloxazolidine i n the past. The material preservative uses of dimethyloxazolidine are likely to have

waste water discharg es which may lead to contaminat ion of human and livestock drinking water ; the contaminating chemical species is expected to be largely AMP which is a stable hydrolytic and metabolic product of the parent compound

. AMP could potentially pass through wastewater treatment plants (WWTPs)

. Therefore, the Agency anticipates needing certa in environmental fate data listed
in the 3/16/12 Product Chemistry, Environmental Fate

, and Ecological Effects Scoping Document in support of Registration Review of Methyloxazolidines (S. Gowda, J. Breithaupt, and Z. Layton, AD/RASSB, D 39 4305 ). These data will be useful to determine whether, and to what extent, residues of dimethyloxazolidine (expected to be largely AMP) pass through a WWTP. Upon receipt and review,
these data will be used d uring the risk assessment stage of this Registration
Rev iew to determine the potential for discharged residues of dimethyloxazolidine (most likely largely AMP) to result in human dietary exposure via drinking water which may trigger a drinking water assessment

.

Section 4. Residential Exposure

Although no pesticide products containing dimethyloxazolidine are labeled for
residential use , c ertain materials preserved or treated with dimethyloxazolidine may result in expo sure of the general public and homeowners to the parent compound , AMP, and HCHO . Preserved materials may include: liquid soaps, fabric cleaning and care products, water

- based cleaning products, water bornePage 12 of 24 coatings (including paints) , water

- based adhesives, printing supplies, and polishes

. T o determine the conditions under which residential exposure to the parent compound , AMP, and/or HCHO are likely to occur from its use as a preservative, detailed use information are needed to elucidate the conditions, rates, and magnitude of HCHO and AMP release from dimethyloxazolidine under various conditions and in various materials (Appendix A, 875.1700 and 875.2700) . The remaining parent compound

, AMP , and HCHO in treated
materials and released into the air from preserved materials are to be determined
in small chamber studies to estimate potential residential exposure. This should
include the residential use of representative treated materials

. Note that the dermal irritation hazard endpoint (effect and dose) may be used to calculate
residential dermal risks ; this is determined on a case

- by

- case basis and will be decided during the risk assessment stage of the dimethyloxazolidine registration
review

. Refer to Table 3 for a summary of the residential scenarios needing to be assessed. Also, see Appendix A for d escription s of recommended exposure studies and rationale for their conduct

.

Table 3. Residential Exposure Scenarios for D imethyloxazolidine (DMO)

. Scenario Chemical Exposure Routes Duration Using treated surface cleaners and laundry detergents D M O and AMP Formaldehyde Dermal and Inhalation
Inhalation Short

- term and
Intermediate

- t erm Painting with treated paints (Airless spray and brush/roller) DM O and AMP Formaldehyde Dermal and Inhalation
Inhalation Short

- t erm Toddlers playing on floors cleaned
with treated surface cleaners DM O and AMP Dermal/ Incidental Oral Short

- term and
Intermediate

- t erm

Section 5. Aggregate Risk

Dietary (food) exposure to dimethyloxazolidine and AMP could potentially occur as a result of registered uses. Although dimethyloxazolidine residues of concern ( dimethyloxazolidine and HCHO) are not likely to reach drinking water as a result of industrial discharges, the potential for exposure to the stable degradate AMP in drinking water is much greater . Therefore, contami nation of drinking water will be revisited upon receipt of the biodegradability studies proposed to be required
in the 3/16/12 Product Chemistr y, Environmental Fate, and Ecological Effects Scoping Document in Support of Registration Review of Methyloxazolidines ( S. Gowda, J. Breithaupt, and Z. Layton; D 394305 )

. These data will be useful to determine whether, and to what extent, residues of dimethyloxazolidine pass through a WWTP.

Residential exposure of applicators/users and postapplication ex posure of adults
and children to dimethyloxazolidine , AMP, and HCHO resulting from use of
several dimethyloxazolidine

- preserved homeowner products is likely to occur.
There are also industrial and cosmetic sources and other background sources of
HCHO that contribute to ambient air concentrations of HCHO. Numerous other
antimicrobials release HCHO as their mechanism of antimicrobial action and/orPage 13 of 24 as a degradation product. Any or all of these sources of HCHO that are determined to be likely to co

- occur are ex pected to be aggregated during the risk assessment stage of the Methyloxazolidine Registration Review. However, the
antimicrobial sources of HCHO compared to the overall sources of HCHO are expected not to substantially contribute to the overall ambient le vels of HCHO in
the environment. The specifics of necessary aggregate assessments will be determined during the risk assessment stage of Registration Review.

Section 6. Occupational Exposure

Dimethyloxazolidine product s are added to water

- based liquid materials during
the manuf acturing process or, in some cases, on site . The EP label s are silent on the type of loading and mixing equipment to be used which indicates that open

pour loading is permissible ; the only exceptions are two of three products that require use of a metering pump when making additions to oilfield and gas water systems

. L abel s instruct handler s to wear goggles or face shield and rubber gloves (chemical

- resistant on three of six EP labels)

. During open

- pour activities

, painting, and me tal

- working, dermal and inhalation exposure of workers to dimethyloxazolidine , AMP, and HCHO is expected. In a controlled hydrolysis study

, dimethyloxazolidine was rapidly hydrolyzed in water buffered to pH 5, 7, and 9 yielding HCHO and the stable degradate AMP. However, the rate of hydrolysis during and after preservation of materials under actual use conditions
is uncertain. Dimethyloxazolidine, AMP, and HCHO all pose potential worker
inhalation exposure concerns. S ince the rate s at which dimethyloxazolidine is hydrolyzed to generate AMP and HCHO under actual use conditions are unknown, the Agency cannot reliably estimate occupational exposure to either
the parent compound , AMP, or HCHO

.

T o estimate occupational exposure to dimethyloxazolidine, AMP, and HCHO

, data are recommended including detailed application information to elucidate the
factors (pH, temperature, etc.) influencing rate and magnitude of hydrolysis of dimethyloxazolidine in various materials . To estimate poten tial occupational

exposure during manufacture of preserved materials and treatment and use of other liquids

, exposure studies and small chamber studies are recommended for representative scenario s (summarized in Table 4)

.

Table 4. Occupational Exposure Scenarios for D imethyloxazolidine (DMO).
Scenario Chemical Exposure Routes Duration Open

- pour liquids during material preservation and oil field treatments D M O and AMP Formaldehyde Dermal and Inhalation
Inhalation Intermediate

- t erm

Using treated metal

- working fluids D M O and AMP Formaldehyde Dermal and Inhalation
Inhalation Long

- t erm Painting with treated paints (Airless spray and brush/roller) D M O and AMP Formaldehyde Dermal and Inhalation
Inhalation Intermediate

- t ermPage 14 of 24 Section 7. Cumulative Risk

Unlike other pesticides for which EPA has followed a cumulative risk approach based on a common mechanism of toxicity, EPA has not made a common mechanism of toxicity finding as to dimethyloxazolidine and any other
substances

. For the purposes of this Registration Review , therefore, EPA has not
assumed that dimethyloxazolidine has a common mechanism of toxicity with
other substances. For information regarding EPA’s efforts to determine which chemicals have a common mechanism of toxicity and to evaluate the cumulative effects of such chemicals, see the policy statements released by EPA’s Office of Pesticide Programs concerning common me chanism determinations and procedures for cumulating effects from substances found to have a common
mechanism on EPA’s website at http://www.epa.gov/pesticides/cumulative/.

Section 8. Endocrine Dis rupt ion Screening Program

As required by FIFRA and FFDCA, EPA reviews numerous studies to assess potential adverse outcomes from exposure to chemicals. Collectively, these studies include acute, subchronic and chronic toxicity, including assessments of carcinogenicity, neurotoxicity, developmental, reproductive, and general or systemic toxicity. These studies include endpoints which may be susceptible to endocrine influence, including effects on endocrine t arget organ histopathology, organ weights, estrus cyclicity, sexual maturation, fertility, pregnancy rates, reproductive loss, and sex ratios in offspring. For ecological hazard assessments, EPA evaluates acute tests and chronic studies that assess growth, developmental and reproductive effects in different taxonomic groups. As part of its reregistration decision , EPA reviewed these data and selected the most sensitive endpoints for relevant risk assessment scenarios from the existing
hazard database. Howev er, as required by FFDCA section 408(p), 4,4

- dimethyloxazolidine is subject to the endocrine screening part of the Endocrine Disruptor Screening Program (EDSP).

EPA has developed the EDSP to determine whether certain substances (including pesticide active and other ingredients) may have an effect in humans or wildlife similar to an effect produced by a “naturally occurring estrogen, or other such endocrine effects as the Administrator may designate.” The EDSP employs a two

- tiered approach to making the sta tutorily required determinations. Tier 1 consists of a battery of 11 screening assays to identify the potential of a chemical substance to interact with the estrogen, androgen, or thyroid (E, A, or T) hormonal systems. Chemicals that go through Tier 1 scre ening and are found to have the potential to interact with E, A, or T hormonal systems will proceed to the next stage of the EDSP where EPA will determine which, if any, of the Tier 2 tests are necessary based on the available data. Tier 2 testing is desig ned to identify any adverse endocrine

- related effects caused by the substance, and
establish a dose

- response relationship between the dose and the E, A, or T
effect.Page 15 of 24 Under FFDCA section 408(p), the Agency must screen all pesticide chemicals.
Between Octobe r 2009 and February 2010, EPA issued test orders/data call

- ins for the first group of 67 chemicals, which contains 58 pesticide active ingredients and 9 inert ingredients. 4,4

- Dimethyloxazolidine is not among the group of 58 pesticide active ingredients on the initial list to be screened under the EDSP. Accordingly, as part of registration review, EPA will issue future EDSP
orders/data call

- ins, requiring the submission of EDSP screening assays for 4,4

- dimethyloxazolidine

. For further information on the sta tus of the EDSP, the policies and procedures, the list of 67 chemicals, future lists, the test guidelines and the Tier 1 screening battery, please visit our website: http://www.epa.gov/endo/.

Section 9. Reliance on Human Studies

Past dimethyloxazolidine risk assessments have not relied on human studies.
There is

, therefore

, no current need to address the scientific soundness, ethical acceptability

, or need for review by the Human Studies Review Board that are required to use studies involving intentional exposure of human subjects in an
EPA risk assessment.

Section 10

. Human Incident Data

No human poisoning incidents involving exposure to d imethyloxazolidine have
been reported based on a search of OPP’s databases.

Section 1 1

. Conclusions

a. Data N eeds

Toxicology Data Needs

The Agency recommends tha t the following toxicology studies be conducted using the parent compound as test substance (utility and ra tionale provided in Appendix A):

**•** 90

- Day Rat Inhalation Toxicity (m easure parent, AMP, and HCH O in the
chamber air) (GLN 870.3465)

**•** Combined Chronic Toxicity/Carcinogenicity in Rats (GLN 870. 43 00)

Residue Chemistry Data Needs

The Agency recommends that the following residue chemistry studies be
conducted to determine whether residues of d imethyloxazolidine transfer to foodPage 16 of 24 from treated food contact surfaces, the nature/identity of such residues, and the magnitude of such transfer. The need for these studies is necessitated by the use of dimethyloxazolidine products to preserve inks, emulsi ons, adhesives, mineral slurries, dispersed colors, and surfactants which may contact food or be used to manufacture food packaging materials. These studies may be waived If label language is inserted that clearly prohibits use of the pesticide to preserve materials that may contact food, feed, or drinking water. The utility and rationale for needing the following studies are provided in Appendix A:

**•** Nature of the Residue on Surfaces ( No Guideline )

**•** Migration Studies ( No Guideline )

Residential/Occupation al Exposure Data Needs

The detailed use/process information and nondietary exposure studies provided
in Table 5 (utility and rationale provided in Appendix A) are proposed to be required t o permit assessment of several residential and occupational handler
and postapplication/bystander scenarios

.

Table 5. Occupational and Residential Exposure Studies Needed for D imethyloxazolidine Study Needed Guideline Applicable Exposure Scenarios Indoor Exposure, Dermal Indoor Exposure,
Inhalation
Data Reporting/Calculations 875.1100
875.1300
875.1600 Open

- pour liquids for material preservation or oil

- field treatments A Application of preserved paints using brush/roller or airless sprayer Use of treated metalworking fluids Trigger sprayer , wipe, and mop application of preserved cleaners

Small Chamber Emissions 875.2500 Postapplication inhalation exposure to treated paints ( dimethyloxazolidine

, AMP, and HCHO)
Surface Residue Dissipation 875.2300 Postapplication exposure to floors and carpets cleaned with preserved household cleaners B

Product Use Information 875.1700 All above scenarios A. If the labels are amended to require closed mixing/loading, then the exposure study for this scenario can be waived.
B. If this study is not conducted, the default transfer factor of 100% will be used.

b. Risk Assessments Needed

**•** A dietary ( food ) risk assessment will be needed to reflect residues of dimethyloxazolidine, AMP, and HCHO migrating t o food from preserve d inks, emulsions, adhesives, mineral slurries, dispersed colors, and
surfactants which may contact food or be used to manufacture food
contact materials

.

**•** A dietary ( drinking water) risk assessment will be needed to reflect discharges of treated waste water from metalworking shops and industries using dimethyloxazolidine to preserve inks, emulsions, adhesives, mineral slurries, dispersed colors, and surfactants which may have food contact. If the environmental fate studies provide evidence that drinking water

expo sure to residues of concern ( dimethyloxazolidine , AMP, and /orPage 17 of 24 HCHO) is not likely, a dietary risk ( drinking water) assessment will not be
needed.

**•** Residential dermal and inhalation risks to adults exposed to dimethyl

oxazolidine, AMP, and HCHO us ing preserved surface cleaners and laundry detergents

.

**•** Residential dermal and inhalation risks to adults exposed to dimethyl

oxazolidine, AMP, and HCHO paint ing with preserved paints (airless sprayer and brush/roller).

**•** Residential dermal and incidental oral r isks to toddlers exposed to dimethyloxazolidine, AMP, and HCHO playing on floors cleaned with preserved surface cleaners

.

**•** At this point, it appears as though aggregate risk will consist of residential and dietary (food and drinking water) exposures . Howeve r, the details of any needed aggregate assessments will be determined during the risk assessment stage of this Registration Review.

**•** Occupational handler dermal and inhalation risk s to dimethyloxazolidine

, AMP, and HCHO resulting from open

- pour ing of liquid EP s for oil

- field water system treatment and in manufacturing facilities to preserve water

based materials

.

**•** Occupational dermal and inhalation risk to workers exposed to dimethyl

oxazolidine, AMP, and HCHO using treated metal

- working fluids

.

**•** Occupational dermal and inhalation risk to painters exposed to dimethyl

oxazolidine, AMP, and HCHO applying preserved paints using an airless sprayer and brush/roller.

c. Label Issues

**•** A number of materials are approved to be preserved with one or more dimethyloxazol idine products that may have food contact or that may be
used to manufacture food contact materials. These include inks, emulsions, adhesives, mineral slurries, dispersed colors, and surfactants. Three of five product labels listing adhesives prohibit thei r use for food

contact applications whereas the other two are silent on this issue . If food contact is not intended for any uses, label language should be inserted that clearly precludes use of the pesticide to preserve materials that may contact food, feed, or drinking water. If food contact use is desired, this
should be specifically stated on the label . If a given label remains silent on this issue, it will be assumed that food contact use of the above may

occur.

**•** Dow’s EPA Reg. No. 464

- 660 is the only product bearing use to preserve various “Consumer, Household, and Institutional Products” but the label
also states “Not for use where contact with food will occur.” Three of these materials are dishwashing liquids, surface cleaners, and cleaning wipes.
T he Agency will be considering the practicality and enforceability of prohibiting use on food

- contact surfaces such as countertops, dishes, utensils, etc. when such uses are widely considered to be the major orPage 18 of 24 sole use of these materials. Dow is urged to p rovide information supporting this apparent disconnect, e.g., perhaps packaging or marketing of preserved materials render use of that product on nonfood

- contact dishes and surfaces (perhaps laboratory glassware or car seats) feasible and practical.

**•** Troy’s EPA Reg. No. 5383

- 82 bears use in Oilfield water systems but does not require that additions be made using a metering pump as the two other labels bearing this use do . It will be assumed in the occupational risk assessment for this product/use combination that open

- pouring is permitted . This will result in significantly greater handler exposure than if a closed system is used.

**•** It is recommended that the rubber gloves required as PPE for applicators and other handlers be specifically “Chemical Resistant Rub ber Gloves” to be consistent with the two Dow products. This apples to Troy’s EPA Reg.
No s . 5383

- 82 and 5383

- 90 and ISP’s EPA Reg. No s

. 1529

- 32 and 1529

- 37.

References

U.S. EPA. Jenny J. Tao. 12/14/11. 4,4

- Dimethyloxazolidine: Summary of
Mammalian Toxicology Data for the Registration Review Scoping Document.
D394385.

U.S. EPA. S. Gowda , J. Breithaupt, and Z. Layton

. 3/16/12

. Product Chemistry, Environmental Fate, and Ecological Effects Scoping Document in Support of Registration Review of Methyloxa zolidines

. D 394305

.

Kline. 2004. Specialty Biocide North America 2004, Kline and Company, Inc.

U

. S

. EPA

. 1996. Re re gistration Eligibility Decision (RED) for 4,4,

- Dimethyl

oxazolidine, United States Environmental Protection Agency, August

, 1996

.Page 19 of 24 

## Appendix A

Dimethyloxazolidine is a broad

- spectrum antimicrobial pesticide formulated as liquid soluble concentrate s and registered for preservation of liquid water

- based materials during their manufacture such as adhesives, lubricants, die

- cast lubricants, mold release agents, mineral slurries, metalworking fluids, surfactants, latex paints, inks, resin emulsions, caulks, sealants, grouts, spackling, ready

- mix wallboard compounds, dispersed colors, dishwashing liquids, surface cleaners, laundry c leaners, and polishes

. It is also used as a preservative/slimicide in oil and gas production water systems

.

The antimicrobial activity of dimethyloxazolidine is due to the release of formaldehyde (HCHO) which cross

- links proteins including enzymes. The ot her hydrolysis product is 2

- amino

- 2

- methyl

- 1

- propanol (AMP). T herefore, th is Registration Review addresses potential risks associated with exposure to dimethyloxazolidine , AMP, and HCHO. EPA prepared a separate formaldehyde RED to address potentia l risks a ssociated with other sources of exposure to formaldehyde. This document is available in the formaldehyde public docket at http://www.regulations.gov in docket number EPA

- HQ

- OPP

- 2008

- 0121.

I. Need for

, and Uses of

, the Data

G uideline Number: 870.3465 Study Title: 90

- Day Inhalation Toxicity (Rat) Rationale for Requiring the Data

This study is required because dimethyloxazolidine is highly volatile, the hydrolysis product AMP is likely to be volatile, and HCHO . Also, there are several use scenarios that involve generation of
aerosols (such as painting). There is a likelihood of significant repeated inhalation exposure to homeowners and occupational handle rs using direct

- pour methods and breath ing vapors as well as aerosols during or after use/appl ication of materials preserved with dimethyloxazolidine , especially while painting with preserved paint or coatings. Many preserved homeowner, commercial, and institutional liquid spray products are preserved with dimet hyloxazolidine and will result in significant inhalation exposure p rofessionally and in the home. In addition, there is a concern for worker exposure to HCHO released during degradation of dimethyloxazolidine (which is require d for antimicrobial activity). A 90

- day inhalation toxicity study has not been conducted an d is required. The inhalation route is the major route of human exposure to dimethyloxazolidine per se and/or AMP for a number of scenarios and is also the major exposure route for HCHO for all s cenarios (because it is a volatile gas). The air concentrations of parent compound, AMP, and HCHO in the chamber should be
monitored. Practical Utility of the Data 1. How did the Agency make its earlier regulatory decision s without th ese data?

Residential risk has never been assessed for dimethyloxazolidine even though both dermal and inhalation routes of exposure are expected. Also, inhalation exposure and risk have never been assessed for occupational handlers and bystanders. There is no route

- specific study to appropriately use in a quantitative assessment, particularly via the inhalation route.Page 20 of 24 2. How will the data be used?

The data will be used to properly characterize and quantify the inhalation hazard and risks to : (i) occupational w orkers ( especially when working with paints and metalworking fluids) ; (ii) residential adults during painting and while using household surface cleaners; and (iii) children inhaling vapors and aerosols during and after use of preserved household products i ncluding paint, often a scenario resulting in the highest exposures

.

3. How could the data impact the Agency’s future decision

- making?

In the absence of inhalation toxicity data, the Agency would have to estimate inhalation risks using an oral toxicity stud y and rely on the assumption that absorption and toxicity of dimethyloxazolidine are the same via the oral and inhalation routes of exposure. Note that absorption of pesticides into the bloodstream via the lungs is often higher than that via the dietar y route and often many times higher
than via the dermal route. Paired with the requested chemical

- specific dimethyloxazolidine inhalation exposure data, the route

- specific 90

- day rat inhalation toxicity study on dimethyloxazolidine will permit EPA to condu ct residential and occupational risk assessments that are refined and in which there is a high degree of confidence.

Guideline Numbers: 870.4300 Study Title: Combined Chronic Toxicity/C arcinogenicity Study (Rat)

Rationale for Requiring the Data

A chronic toxicity/c arcinogenicity study is anticipated to be needed due to (i) chronic (>6 months) human exposure to dimethyloxazolidine and AMP via indirect food and drinking water sources and in the work place (metal working fluids); (ii) a number of posit ive mutagenicity studies; and (iii) release of formaldehyde, a probable human carcinogen. The migration of residues from dimethyloxazolidine

treated food contact materials and working with metalworking fluids pose long

- term exposure and potential carcinoge nicity concerns. The study would provide insight into toxicity and c arcinogenic potential of dimethyloxazolidine and AMP via chronic dietary and long

- term occupational exposures. It may also provide a toxicity/cancer endpoint applicable to risk assessment.

Practical Utility of the Data
1) How did the Agency make its earlier regulatory decision without these data?

No earlier regulatory decisions were made that would necessitate a chronic toxicity/c arcinogenicity study. The Agency has never assessed dieta ry exposure and carcinogenic risk associate d with the registered uses of dimethyloxazolidine.

2) How w ill the data be used?

The data w ill be used to characterize the long

- term effects and carcinogenic potential of dimethyloxazolidine and its stable hydrolysis product AMP via the oral route. A dietary risk
assessment and cancer assessment have never been conducted due to the lack of chronic toxicity/c arcinogenicity studies. A toxicity endpoint may be selected from this study for use in a quantitative chronic risk assessment. With the passage of FQPA in 1996 and ARTCA in 1998, EPA’s safety finding for registration under FIFRA must also meet the standard of safety for FFDCA Sec. 408. This means EPA must make a safety finding that aggregate risks are not of Agency concern; aggregate risks include chronic dietary risks form food and drinking water as well as residential risks regardless of duration. If the study is positive for carcinogenicity, a toxicity endpoint would bePage 21 of 24 selected/calculated for us e in a quantitative cancer risk assessment.

3) How could the data impact the Agency’s future decision making?

This study would greatly increase the Agency’s confidence in the hazard profile of dimethyloxazolidine which , in turn, increases the conf idence in future risk assessments and, hence, regulatory decisions. This study could be used as the source for selection of a chronic or long

- term toxicity endpoint for use in quantitative assessments of human risks. Positive carcinogenicity results
from t he study would necessitate evaluation by the Office of Pesticide Programs (OPP) Cancer Assessment Review Committee (CARC). This could result in calculation of a cancer slope factor or other measure of carcinogenic potency for use in quantitative human canc er risk assessment s . A cancer endpoint is often the most sensitive measure of hazard for a given pesticide which may result in human health risks of concern that would necessitate risk mitigation.

Guideline Number: No Guideline Study Title : Nature of the Residue on Surfaces Guideline Number: No Guideline Study Title: Migration Studies Rationale for Requiring the Data

Th ese residue chemistry studies will result in chemical

- specific, quantitative dietary exposure data that the Agency will use in risk assessments. D imethyloxazolidine and its degradates are determined in foods after contact with surfaces bearing or containing dimethyloxazolidine

containing products such as inks, emulsions, adhesives, mineral slurries, dispersed colors, and
surfactants

. The Nature of the Residue on Surfaces study will determine : whether residues persist on treated food

- contact surfaces ; the identity of those residues ; and a measured upper
limit on total surface residue level. The Migration Studies are automatically required but may be waived depending on the outcome of the Nature of the Residue on Surfaces study. Migration Studies determine the concentrations of specific residues of toxicological concern transferred
from treat ed food

- contact surfaces to various types of food coming in contact with these
surfaces. Practical Utility of the Data 1. How did the Agency make its earlier regulatory decisions without these data?

The Agency has never considered any of the registered uses of dimethyloxazolidine to be food uses and, therefore, has never made a regulatory decision involving dietary risk or necessitating
these data

. The D imethyloxazolidine RED was published August, 1996 which mea ns the regulatory decisions had already been made before passage of FQPA and ARTCA. These two pieces of legislation require that, in order for these food

- contact uses to be registered under FIFRA, they must meet the safety standard of FFDCA section 408 . Th is includes the conduct of an aggregate risk assessment which necessitates having these data to reliably estimate dietary

exposure . These data include consideration of the dissipation/loss of surface residues via
volatiliz ation, identification of degradates, rates of residue migration to certain types of food depending on porosity, water or fat content, surface contact area, contact time, etc.

2. How will the data be used?

The Nature of the Residue on Surfaces study will be used to determine w hether the active ingredient remains on the treated food

- contact surface, whether it degrades, to what it degrades, and the upper limit on total food

- contact surface residues. This study may negate the need for a dietary risk assessment, may be used as an upper (yet more refined) exposure limit, and may bePage 22 of 24 used to either waive or provide direction for the Migration Studies. Migration Studies determine the concentrations of specific residues of toxicological concern transferred from treated food

contact surf aces to various types of food coming in contact with these surfaces.

3. How could the data impact the Agency’s future decision

- making?

If dimethyloxazolidine residues transfer from treated s urfaces to food , human exposure will
occur. These studies will permit the conduct of chemical

- specific, quantitative dietary risk assessments that are refined and in which the Agency has confidence. This information will permit a determination of which use patterns are expected to result in exposures less than the Age ncy’s level of concern, which ones must be supported by additional data, and which ones are likely to have risks of concern and, therefore, must be mitigated. In addition, these data will permit a realistic estimate of human aggregate risk.

Study Title: Indoor Exposure Dermal, Indoor Exposure Inhalation, Data Reporting and Calculations
Guideline Numbers: 875.1100, 875.1300, 875.1600 Rationale for Requiring the Data

Dermal and inhalation exposures to di methyloxazolidine , AMP, and HCHO are expected during the

open

- pour addition A of liquid products during materials preservation and oil

- field treatments. These exposures were not assessed in the RED because no endpoin ts of concern were identified.
O ccupational exposures to HCHO were deferred to OSHA and were not assessed in the RED. If additional toxicological studies for di methyloxazolidine are required during registration review and endpoints of concern are identified from these studies, then the exposures to di methyloxazolidine wil l
need to be assess ed during registration review. In addition, inhalation exposures to HCHO will need to be assessed during registration review.

Dermal and inhalation exposures are also expected during the use of preserved products such as paints, metalwo rking fluids a nd household surface cleaners. These exposures also were not
assessed in the RED.

Dermal and inhalation exposures from these scenarios are evident in exposure studies in the
Pesticide Hand lers Exposure Database (PHED). The existing Chemica l Manufacturer Association (CMA) data base and PHED for these scenarios are limited in scope for QA/QC and the number of replicates (i.e., number of times a worker is monitored for a specific activity)

. EPA presented the need for additional handler exposur e data to the January 2007 Science Advisory Panel (SAP) as well as to the April 2007 Human Studies Review Board (HSRB) and both groups agreed that additional data
are warranted. Practical Utility of the Data

1) How would the data be used?
The data would be used to assess dermal and inhalation exposures that result from the open

- pour addition A of liquid product s and during the use of treated materials including paints B , metalworking
fluids and household surface cleaners B

. 2) How could the data impact the Agency’s future decision making? The exposure data would be used to assess the risks of exposure and to determine if mitigation measures, such as closed system loading, decreased application rates or use of PPE are needed to
reduce these risks. If exposure data are not available, these assessments will have to be made using models which might lead to the overestimation of risk and the requirement for excessive and onerousPage 23 of 24 mitigation measures. A. If the labels are amended to require closed mixing/loading, the study for the open pour
scenario can be waived. B. There are proprietary studies that can be used as surrogate data for these exposure scenarios if data compensation issues are addressed

Study Title: Surface Residue Dissipation (Floo rs and Carpets)
Guideline Numbers: 875.2300 Rationale for Requiring the Data

Dermal and incidental oral exposures to di methyloxazolidine are expected for toddlers who sit or play on household floors and carpets after they are cleaned with floor or carpet cleaners that are preserved with di methyloxazolidine . These exposures were not assessed in the RED because no endpoin ts of concern were i dentified. If additional toxicological studies for di methyloxazolidine are required during registration review and endpoints of concern are identified from these studies, then the exposures to di methyloxazolidine will need to be assessed during registration review. Practical Utility of the Data

1) How would the data be used?
The surface residue data would be used to assess di methyloxazolidine exposures that result from the use of floor and carpet cleaners preserved with di methyloxazolidine

.

2) How could the data impact the Agency’s future decision making? The surface residue data will be used during registration review to decide if the exposu res to
di methyloxazolidine from its use in household cleaners generate a risk of con cern that requires mitigation. This mitigation could include reduction of the application r ate or elimination of the use. If surface residue data are not available, then th e standard assumption of 100 percent transferable surface residue will be used which might overestimate the risk and require excessive mitigation.

Study Title: Inhalation Exposure ( Small Chamber Emission Studies)
Guideline Numbers: 875.2500
Rationale for Requiring the Data

Inhalation exposures to di methyloxazolidine , AMP, and HCHO are expected during and after appl ication of paints treated with di methyloxazolidine . Exposures to both professional painters and
do

- it

- yourself painters are anticipated. Occupational exposures to HCHO were deferred to OSHA and
were not assessed in the RED. Residential exposures were not evaluated during the RED

. Chamber emission data subsequently obtained for other HCHO

- releas ing antimicrobial pesticides such as Troysan 174, CTAC, and HHT has indicated

, however, that HCHO exposures could be significant

. Practical Utility of the DataPage 24 of 24 1) How would the data be used? The chamber emission data will be used along with appropriate source models in the EPA’s Indoor Air Quality Model (IAQX) to assess inhalation exposures to di methyloxazolidine , AMP, and HCHO

.

2) How could the data impact the Agency’s future decision making ? The chamber emissions data will be used during registration review to decide if the exposure to
di methyloxazolidine , AMP, and HCHO from the use of di methyloxazolidine in paints generates a risk of concern that requires mitigation. This mitigation could include reduction of the application rate or elimination of the use. If chamber emissions data are not available, then worst

- case assumptions of
the HCHO emission rate will be used which might overestimate the risk and require excessive mitigation.

Stu dy Title: Product Use Information
Guideline Numbers: 875.1700 Rationale for Requiring the Data

Product use information serves as the basis for determining what exposure scenarios should be assessed and what assumptions and exposure data are needed to perform these assessments in a manner that does not over

- or underestimate the actual risk.

Practi cal Utility of the Data

1) How would the data be used? The product use information will be used to define and characterize the exposure scenarios that will
be assessed in the risk assessment.

2) How could the data impact the Agency’s future decision making? A complete description of product use would ensure that the risk assessment is inclusive of the types of exposures occurring during use and that these exposures are accurately assessed. Without product use information

, the Agency will have to use d efault assumptions that might overestimate the
actual risk.