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 Registration Nos.: NA 

Petition No(s).: NA Regulatory Action: Registration Review 

Risk Assessment Type: Single chemical Registration Review Case No.: 3095 

TXR No.: NA 

MRID Nos.: NA 

FROM: 

TO: 

THRU: 

CAS No.: 51200-87-4 

40 CFR: NA 

William J. Hazel, Ph.D., Ch i:.nce COOrdinator~ -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 10f24 
Page 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 

household 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 studies expected to be needed 

are: 90-day rat inhalation toxicity study (870.3465) and a combined rat chronic 

toxicity/carcinogenicity study (870.4300). 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 dermal 

exposure studies (875.1100), indoor inhalation exposure studies (875.1300), 

small chamber emission studies (875.2500), surface residue dissipation studies

(875.2300), data reporting/calculations (875.1600), and product use information

(875.1700) for all of the above. Assessment of the following human health risks

due to exposure to dimethyloxazolidine, 2-amino-2-methyl-1-propanol (AMP; a 

degradate), and HCHO are expected to be necessary:

1. Dietary risks via food and drinking water

2. Adult residential dermal and inhalation risks from use of preserved surface 

cleaners and laundry detergents and painting with preserved paint

3. Residential postapplication dermal and incidental oral risks to toddlers 

playing on floors cleaned with preserved cleaners

4. Aggregate risk of the above, as applicable

5. Occupational handler dermal and inhalation risks from open-pouring 

during material preservation and oil field treatments

6. Occupational handler dermal and inhalation risks from use of preserved 

metal working fluids

7. Occupational handler dermal and inhalation risks 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 

intentionally-added inert ingredients (preservatives) in pesticide formulations. As 

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-dimethyloxazolidine (hereafter dimethyloxazolidine) used as an 

active ingredient.

Dimethyloxazolidine is used as an active ingredient in industrial water systems 

and in water-based liquid materials as a preservative. The first product containing

dimethyloxazolidine as an active ingredient was registered in the United States in 
Page 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 paints 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. Dimethyloxazolidine Antimicrobial 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 products (EP) containing dimethyloxazolidine as an active 

ingredient are, therefore, produced by an integrated formulation system. A 

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

products were found eligible for reregistration in the RED. Additional uses 

approved since the 1996 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 formaldehyde (HCHO). Dimethyloxazolidine is rapidly hydrolyzed to 
Page 4 of 24

HCHO and AMP in water at pH 5, 7, and 9 but the rate of hydrolysis during and 

after preservation of materials under actual use conditions is uncertain. As this is 

a hydrolysis reaction, it is reversible depending on the conditions; for example, 

AMP is used commercially as an HCHO-scavenger. The products are for indoor 

commercial and industrial use. Treatment concentrations (application rates) as a 

material preservative are equivalent to 195-3900 ppm on an ai basis. In oil and 

gas production water systems, concentrations 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 dimethyloxazolidine as well as the current 

policies, use patterns, and most recent risk assessments. An 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 was 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. The findings are summarized 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/Chemical Properties.

Table 2. Chemical Identity of Dimethyloxazolidine

Common Name Dimethyloxazolidine

Chemical Names 4,4-Dimethyloxazolidine

Trade Names Bioban CS-1135; Bioban CS-40L; Nuosept 101; 

Nuosept 166; Troysan 186; Troysan 192

Molecular Formula C5H11NO

Molecular Weight 101.15

PC Code 114801

CAS Registry Number 51200-87-4

Registration Review 

Case No.

3095

Chemical Structure

 

Dimethyloxazolidine is miscible in water, ethanol and acetone and has a log KO/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-m3

/mole at 25 °C. Based on a hydrolysis study, 

dimethyloxazolidine is hydrolyzed within minutes at pH 5, 7, and 9 to AMP and 

HCHO.
Page 5 of 24

Section 2. Toxicology

a. Acute Toxicity

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

1996 RED for registration review. Dimethyloxazolidine 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 III). 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 testing 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 300 

mg/kg/day by gavage, once a day, 5 days a week, for 90 days. 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 studies (MRID 00138227), SpragueDawley 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 treated 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 responses 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 greater 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 

animals/sex/group) were administered dimethyloxazolidine (75.95% ai) in 

aqueous solutions, via the dermal route with the exposed 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 humane 
Page 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 established for females (>100 mg/kg/day). The 

systemic NOAEL was 30 mg/kg/day for males and ≥100 mg/kg/day for females. 

The LOAEL for dermal irritation was 30 mg/kg/day based 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/cm2 dose.

The Agency anticipates that exposure via the inhalation route is associated with 

both residential and occupational scenarios yet there 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. Doserelated local 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 NOAEL for developmental 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), dimethyloxazolidine

(64.2% ai; Lot # TD0731LAD1) was administered in polyethylene glycol 400 

(PEG 400) by gavage to 26 pregnant female New Zealand white rabbits/dose. 

The dose levels were 0, 4, 12, or 40 mg/kg/day from Days 7 through 27 of 

gestation. The maternal LOAEL was 40 mg/kg/day 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, the NOAEL for developmental toxicity may be considered 

to be 40 mg/kg/day (highest dose tested) and a developmental LOAEL cannot be 

established.
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. Dimethyloxazolidine (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 generations. The parental systemic NOAEL was 

20 mg/kg/day based on gastropathological 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 toxicity 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). Both 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. However, no chronic toxicity studies are available for dimethyloxazolidine 

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, is 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 exposure extending over a chronic or long-term duration (>6 

months or as long as a lifetime). Such 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 exposures to 

dimethyloxazolidine. The metabolism study clearly indicated that 

HCHO was rapidly released when dimethyloxazolidine was 

administered orally. Of the orally-administered radioactivity, AMP in the 

excreta accounted for about 90%. HCHO is classified as “Group B1; 

probable human carcinogen”.
Page 8 of 24

• Although EPA has an acceptable cancer study for HCHO, it is via the 

inhalation route of exposure.

• No carcinogenicity studies are available for dimethyloxazolidine or its 

metabolites HCHO or AMP to assess carcinogenic potential via the 

oral route of exposure.

g. Mutagenicity

Dimethyloxazolidine was shown to be mutagenic in the L5178Y mouse 

lymphoma assay, with and without S9 activation (MRID 00126353) and in 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, in an in vivo

chromosomal aberration assay (metaphase analysis), dimethyloxazolidine was 

found to be nonmutagenic when tested up to the highest dose of 80 mg/kg

(MRID 41577004). However, there 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-

14C]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 accounted for only 4-8% of the dose. Dimethyloxazolidine was 

rapidly metabolized prior to reaching systemic blood circulation. The majority 

(>80% in urine and ~8% in feces) of the orally-administered radioactivity 

recovered in the excreta from 14C-dimethyloxazolidine-dosed rats was AMP. 

Dermally-applied 14C-dimethyloxazolidine evaporated rapidly from the application 

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 14C-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 dimethyloxazolidine. Only AMP (7-9% of administered 

dose) was detected in the urine of rats dosed with 14C-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-Propanol (AMP)

AMP is a degradate and metabolite of dimethyloxazolidine. In a reproduction/

developmental toxicity screening test, AMP hydrochloride (99.7% purity; lot CEC200303541-12) 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). 

Females 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 revealed the parental systemic LOAELs were 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 hepatocytes, 

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 postimplantation loss (embryo resorption) 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.

In the pharmacokinetics and metabolism study discussed above (MRID 

48534001), [1-

14C]AMP was also administered to two groups of rats (4 males 

only in each group) by oral gavage or dermal application for comparison to the 

parent compound, dimethyloxazolidine. One group received a single oral dose 

(~18 mg/kg) of 14C-AMP and the other group was dermally-administered a dose 

of 14C-AMP. Absorption, distribution, and elimination of AMP were nearly 

identical to those of the parent compound, dimethyloxazolidine, 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 14C-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 oral 
Page 10 of 24

dose. In the urine of rats, only AMP was detected whether dosed with 14C-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 updated IUCLID 

data set have been submitted to the Office of Pollution, Prevention and 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 required 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 assessments reflecting registered uses of dimethyloxazolidine. 

Note that additional HCHO toxicology data, if any are needed, will not be 

addressed in this Registration Review because characterization of HCHO toxicity 

and the selection of endpoints for risk assessment have 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 the RED through the established reregistration process, which includes 

stakeholder consultation and public comment. However, the result 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 science on the noncancer effects of formaldehyde.

Section 3. Dietary Exposure

a. Food Exposure

One of the Dow product labels (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

surface cleaners, and cleaning wipes. Although these uses could result in 

residues in food, the label warning “Not 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 potential 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 as 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 believes that dietary (food 

source) exposure to the parent compound and AMP and risk assessments

addressing use of dimethyloxazolidine as an active ingredient are necessary at 

this time unless all use sites on all product labels are limited to nonfood contact.

b. Drinking Water Exposure

A drinking water assessment has not been conducted for dimethyloxazolidine in 

the past. The material preservative uses of dimethyloxazolidine are likely to have 

waste water discharges which may lead to contamination 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 certain 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, D394305). 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 during the risk assessment stage of this Registration 

Review 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, certain materials preserved or treated with dimethyloxazolidine

may result in exposure 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, waterborne
Page 12 of 24

coatings (including paints), water-based adhesives, printing supplies, and 

polishes. To 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 descriptions of recommended exposure 

studies and rationale for their conduct.

Table 3. Residential Exposure Scenarios for Dimethyloxazolidine (DMO).

Scenario Chemical Exposure Routes Duration 

Using treated surface cleaners and 

laundry detergents

DMO and AMP

Formaldehyde

Dermal and Inhalation

Inhalation

Short-term and

Intermediate-term

Painting with treated paints

(Airless spray and brush/roller)

DMO and AMP

Formaldehyde

Dermal and Inhalation

Inhalation Short-term

Toddlers playing on floors cleaned

with treated surface cleaners DMO and AMP Dermal/Incidental Oral

Short-term and

Intermediate-term

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, contamination of drinking water will 

be revisited upon receipt of the biodegradability studies proposed to be required 

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; D394305). 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 exposure 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/or 
Page 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 expected 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 levels 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 products are added to water-based liquid materials during 

the manufacturing process or, in some cases, on site. The EP labels are silent on 

the type of loading and mixing equipment to be used which indicates that openpour 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. Labels instruct handlers to wear goggles or face shield and rubber 

gloves (chemical-resistant on three of six EP labels). During open-pour activities, 

painting, and metal-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. Since the rates 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.

To 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 potential occupational 

exposure during manufacture of preserved materials and treatment and use of 

other liquids, exposure studies and small chamber studies are recommended for 

representative scenarios (summarized in Table 4).

Table 4. Occupational Exposure Scenarios for Dimethyloxazolidine (DMO).

Scenario Chemical Exposure Routes Duration 

Open-pour liquids during material 

preservation and oil field treatments

DMO and AMP

Formaldehyde

Dermal and Inhalation

Inhalation Intermediate-term

Using treated metal-working fluids

DMO and AMP

Formaldehyde

Dermal and Inhalation

Inhalation Long-term

Painting with treated paints

(Airless spray and brush/roller)

DMO and AMP

Formaldehyde

Dermal and Inhalation

Inhalation Intermediate-term
Page 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 mechanism 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 Disruption 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 target 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. However, 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 statutorily 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 screening 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 designed 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 October 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 status 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 dimethyloxazolidine have 

been reported based on a search of OPP’s databases.

Section 11. Conclusions

a. Data Needs

Toxicology Data Needs

The Agency recommends that the following toxicology studies be conducted 

using the parent compound as test substance (utility and rationale provided in 

Appendix A):

• 90-Day Rat Inhalation Toxicity (measure parent, AMP, and HCHO in the 

chamber air) (GLN 870.3465)

• Combined Chronic Toxicity/Carcinogenicity in Rats (GLN 870.4300)

Residue Chemistry Data Needs

The Agency recommends that the following residue chemistry studies be 

conducted to determine whether residues of dimethyloxazolidine transfer to food 
Page 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, emulsions, 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/Occupational 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 to permit assessment of several residential and occupational handler 

and postapplication/bystander scenarios. 

Table 5. Occupational and Residential Exposure Studies Needed for Dimethyloxazolidine

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 treatmentsA

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 cleanersB

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 to food from preserved

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 

exposure to residues of concern (dimethyloxazolidine, AMP, and/or 
Page 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 dimethyloxazolidine, AMP, and HCHO using preserved surface cleaners and 

laundry detergents.

• Residential dermal and inhalation risks to adults exposed to dimethyloxazolidine, AMP, and HCHO painting with preserved paints (airless 

sprayer and brush/roller).

• Residential dermal and incidental oral risks 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. However, the details of 

any needed aggregate assessments will be determined during the risk 

assessment stage of this Registration Review.

• Occupational handler dermal and inhalation risks to dimethyloxazolidine, 

AMP, and HCHO resulting from open-pouring of liquid EPs for oil-field 

water system treatment and in manufacturing facilities to preserve waterbased materials.

• Occupational dermal and inhalation risk to workers exposed to dimethyloxazolidine, AMP, and HCHO using treated metal-working fluids.

• Occupational dermal and inhalation risk to painters exposed to dimethyloxazolidine, 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 

dimethyloxazolidine 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 their 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. 

The 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 or 
Page 18 of 24

sole use of these materials. Dow is urged to provide 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 Rubber Gloves” to 

be consistent with the two Dow products. This apples to Troy’s EPA Reg. 

Nos. 5383-82 and 5383-90 and ISP’s EPA Reg. Nos. 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 Methyloxazolidines. D394305. 

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

U.S. EPA. 1996. Reregistration Eligibility Decision (RED) for 4,4,-Dimethyloxazolidine, United States Environmental Protection Agency, August, 1996.
Page 19 of 24

Appendix A

Dimethyloxazolidine is a broad-spectrum antimicrobial pesticide formulated as 

liquid soluble concentrates 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 cleaners, 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 other 

hydrolysis product is 2-amino-2-methyl-1-propanol (AMP). Therefore, this

Registration Review addresses potential risks associated with exposure to 

dimethyloxazolidine, AMP, and HCHO. EPA prepared a separate formaldehyde 

RED to address potential risks associated 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

Guideline 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 handlers using direct-pour methods and breathing vapors as well as 

aerosols during or after use/application 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 dimethyloxazolidine and will result in significant 

inhalation exposure professionally and in the home. In addition, there is a concern for worker 

exposure to HCHO released during degradation of dimethyloxazolidine (which is required for 

antimicrobial activity). A 90-day inhalation toxicity study has not been conducted and 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 scenarios (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 decisions without these 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 workers (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 including 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 study 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 dietary 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 conduct 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/Carcinogenicity Study (Rat)

Rationale for Requiring the Data

A chronic toxicity/carcinogenicity 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 (metalworking fluids); (ii) a number of positive mutagenicity studies; and (iii) release of 

formaldehyde, a probable human carcinogen. The migration of residues from dimethyloxazolidinetreated food contact materials and working with metalworking fluids pose long-term exposure and 

potential carcinogenicity concerns. The study would provide insight into toxicity and carcinogenic 

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/carcinogenicity 

study. The Agency has never assessed dietary exposure and carcinogenic risk associated with the 

registered uses of dimethyloxazolidine. 

2) How will the data be used?

The data will 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/carcinogenicity 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 be 
Page 21 of 24

selected/calculated for use 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 confidence 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 the 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 cancer risk assessments. 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

These residue chemistry studies will result in chemical-specific, quantitative dietary exposure 

data that the Agency will use in risk assessments. Dimethyloxazolidine and its degradates are 

determined in foods after contact with surfaces bearing or containing dimethyloxazolidinecontaining 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 treated 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 Dimethyloxazolidine RED was published August, 1996 which means 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. This 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 

volatilization, 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 whether 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 be 
Page 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 foodcontact surfaces 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 surfaces 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 

Agency’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 dimethyloxazolidine, AMP, and HCHO are expected during the 

open-pour additionA of liquid products during materials preservation and oil-field treatments. These 

exposures were not assessed in the RED because no endpoints of concern were identified. 

Occupational exposures to HCHO were deferred to OSHA and were not assessed in the RED. If 

additional toxicological studies for dimethyloxazolidine are required during registration review and 

endpoints of concern are identified from these studies, then the exposures to dimethyloxazolidine will 

need to be assessed 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, metalworking fluids and 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 Handlers Exposure Database (PHED). The existing Chemical 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 exposure 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 

additionA of liquid products and during the use of treated materials including paintsB

, metalworking 

fluids and household surface cleanersB

.

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 onerous 
Page 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 (Floors and Carpets)

Guideline Numbers: 875.2300

Rationale for Requiring the Data

Dermal and incidental oral exposures to dimethyloxazolidine 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 dimethyloxazolidine. These exposures were not assessed in the RED because no 

endpoints of concern were identified. If additional toxicological studies for dimethyloxazolidine are 

required during registration review and endpoints of concern are identified from these studies, then 

the exposures to dimethyloxazolidine 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 dimethyloxazolidine exposures that result from the 

use of floor and carpet cleaners preserved with dimethyloxazolidine. 

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 exposures to 

dimethyloxazolidine from its use in household cleaners generate a risk of concern that requires 

mitigation. This mitigation could include reduction of the application rate or elimination of the use. If 

surface residue data are not available, then the 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 dimethyloxazolidine, AMP, and HCHO are expected during and after 

application of paints treated with dimethyloxazolidine. 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-releasing antimicrobial pesticides such as 

Troysan 174, CTAC, and HHT has indicated, however, that HCHO exposures could be significant.

Practical Utility of the Data
Page 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 dimethyloxazolidine, 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 

dimethyloxazolidine, AMP, and HCHO from the use of dimethyloxazolidine 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. 

Study 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.

Practical 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 default assumptions that might overestimate the 

actual risk.