UNITED STATES ENVIRONMENTAL PROTECTION AGENCY 

WASHINGTON, DC 20460 

OFFICE OF CHEMICAL SAFETY AND POLLUTION PREVENTION 

MEMORANDUM 

DATE: September 12, 2012 

SUBJECT: 4.4-Dimetbyloxazolidine (DMO): Responses to the Human Health Comments 

PC Code: 114801 DP Barcode: D405054 

Decision No.: N/A Registration No(s).: Multiple 

Petition No(s).: N/A Regulatory Action: N/ A 

Risk Assess Type: Single Chemical Case No.: 3095 

TXRNo.: N/A CAS No: 51200-87-4 

MRID No(s).: N/A 40 CFR: N/A 

TO: 

FROM: 

Seiichi Murasaki, Chemical Review Manager 

Regulatory Management Branch II (RMB II) 

Antimicrobials Division (AD) (751 P) 

Jenny J. Tao, Senior Toxicologist 

THRU: 

Risk Assessment and Science Supp rt Branch 

Antimicrobials Division 

Tim McMahan, Ph.D., Division Senior Toxicologist (peer reviewer)c:

 � 

Antimicrobials Division 

And 

Jonathan Chen, Ph.D., Senior Toxicologist (peer reviewer) _ _.,J;,� 

Timothy Leighton, Senior Scientist/Te� 

ead, Human He th earn ' 

Steve Weiss, Acting Branch Chief � (L/�--

Risk Assessment and Science Support Branch 

Antimicrobials Division 

This document contains the Agency's responses to the human health comments submitted by the public on the 

methyloxazolidines registration review case. 
Human Health Comments for the Methyloxazolidines Registration Review (Case 3095); Docket ID EPA-HQOPP-2012-0007 

Physicians Committee for Responsible Medicine (PCRM) 

Comment received on the combined chronic toxicity/carcinogenicity study (870.4300). 

Comment: 

To prevent the deaths of hundreds of animals, there are two options. 

First the Agency should investigate existing data on 2-methyl-2-aminopropanol (AMP) and formaldehyde 

(HCHO) and use it to the greatest extent possible for the risk assessment of 4,4-dimethyloxazolidine (DMO), 

instead of conducting a new study on the compound, since DMO undergoes rapid abiotic hydrolysis to AMP and 

HCHO after oral administration. Or, if the available data is not sufficient, only one study on the active 

ingredient DMO would be sufficient and would simulate the exposure scenario. 

Response: 

The Agency considers all available information, including the published literature, both on the parent and the 

metabolites, when conducting risk assessments. If it is found that existing studies/data are not adequate or 

sufficient, additional testing is required to complete the risk assessment and hazard characterization. 

The Agency has toxicological concerns for the parent compound DMO. Although chemically DMO releases 

HCHO in aqueous solution and results in AMP formation, which exists in equilibrium with DMO, the registrantsubmitted hydrolysis study (MRID 4166480 I) identified AMP only and indicated that "Due to the volatility of 

formaldehyde, its concentrations have not been considered during the study." Similarly, AMP was the major 

metabolite identified quantitatively; however, not a complete conversion from DMO, in the registrant-submitted 

metabolism study (MRID 48534001), and no formaldehyde was reported. The Agency does not have a clear 

picture of how DMO behaves in a biological system toxicologically, as the metabolism study didn't indicate that 

DMO was completely converted to its metabolites in the system. Therefore, additional studies are required for 

parent compound DMO based on potential exposures related to its uses. 

Comment: 

For AMP, PCRM found an EPA-validated chronic study in dogs via the oral route of exposure. There is also a 

report summarizing the absence of carcinogenic effects of AMP as a surrogate substance for TRIS AMINO. 

Finally, an ADME rat gavage study reported that AMP is rapidly absorbed and almost completely excreted 

without being metabolized3• These data demonstrate the Jack of carcinogenicity of AMP and no further 

carcinogenicity studies are needed. 

For HCHO, we found two chronic rat studies through the oral route of exposure. HCHO at different 

concentrations was given in drinking water for up to 2 years and various health effects, including 

carcinogenicity endpoints, were examined in both male and female rats. These data should satisfy the Agency's 

requirement for risk assessment and therefore no further studies are necessary. 

Response: 

As the metabolism study (ADME [absorption, distribution, metabolism, and elimination]) didn't indicate that 

DMO was completely converted to its metabolites, the Agency has chronic toxicity and cancer concerns for the 

parent compound DMO based on its use patterns, and there are no such studies available for DMO. Therefore, 

these data on DMO are required. 

Page 2 of7 
The mentioned study by Griffin (1990) for AMP was a non-GLP study conducted in 1988-1989. It was not 

conducted for the purpose of investigating cancer, although the study summary indicated "no neoplastic 

observations" at 6-month and 1-year timeframes. Additionally, dogs are not the preferred species for 

carcinogenicity studies. The Agency's test guidelines recommend rats and/or mice as the test animals for 

carcinogenicity studies. Although a robust summary of the dog study was submitted as IUCLID (International 

Uniform Chemical Information Database) database to the Agency for the HPV (High Production Volume 

[chemicals]) Challenge Program in OCSPP, the OPP requests a complete study report to allow a comprehensive 

review to determine whether the study is adequate for use in risk assessment. The registrant is encouraged to 

submit the complete study report of the one-year dog study for the Agency's review of its adequacy in support 

of methyloxazolidines registration review. 

We acknowledge the comments received on the non-cancer and cancer effects of formaldehyde. We are waiting 

for the IRIS (Integrated Risk Information System) response to the recommendations of the NAS (National 

Academy of Sciences) peer review of formaldehyde re-assessment to determine the implications for the 

assessment of DMO. No new data on formaldehyde are required at this time. 

Comment: 

We also encourage the use of (Q)SAR data in addition to existing data, and in place of new rat experimental 

data. When correctly applied, (Q)SARs can feasibly replace in vivo data in some instances; requesting (Q)SAR 

data in addition to in vivo data would increase Agency and registrant comfort and confidence with the use and 

evaluation of data from such methods. 

Response: 

In regard to QSAR, the Agency has and will continue to consider accepting SAR/QSAR ([quantitative] 

structure-activity relationship) predictions to fulfill data requirements on a case-by-case basis, based on the 

quality and completeness of information and supporting rationale provided. Registrants are encouraged to 

submit SAR/QSAR analyses with clear documentation of rationales to support the analysis. Agency will 

evaluate all the submitted information to determine the adequacy of the SAR/QSAR analysis. 

TROY CORPORATION 

Comment: Assumptions on DMO Metabolites 

While the Agency indicates it does have a study on cancer for formaldehyde via the inhalation route of exposure 

it indicates concerns over the degradation of DMO and concerns over formaldehyde under oral conditions of 

exposure. The literature on formaldehyde toxicity via differing means of exposure (oral, dermal and inhalation) 

are well documented and formaldehyde has not been implicated as an oral carcinogen. We would expect the 

Agency to address their concerns over formaldehyde toxicity by a) analyzing the hydrolysis data from the study 

proposed earlier and b) utilizing the vast amount of data available on formaldehyde from the literature. 

Response: 

The Agency will consider all available information, including the published literature, when conducting risk 

assessment for DMO. 

The required studies to address the Agency's toxicological concerns are for the parent compound DMO. 

Page 3 of7 
Although chemically DMO releases HCHO in aqueous solution and results in AMP formation, which exists in 

equilibrium with DMO, the submitted hydrolysis study (MRID 41664801) identified AMP only and indicated 

that "Due to the volatility of formaldehyde, its concentrations have not been considered during the study." 

Similarly, AMP was the major metabolite identified quantitatively in the submitted metabolism study (MRID 

48534001 ); however, the study failed to indicate that DMO was completely converted to its metabolites, and no 

formaldehyde was reported. Based on the findings of the metabolism study, the Agency does not have a clear 

picture of how DMO behaves in a biological system toxicologically. Therefore, additional studies are required 

for parent compound DMO based on potential exposures related to its uses. 

We acknowledge the comments received on the non-cancer and cancer effects of formaldehyde. We are waiting 

for the IRIS response to the recommendations of the NAS peer review of formaldehyde re-assessment to 

determine the implications for the assessment of DMO. No new data on formaldehyde are required at this time. 

Dow Chemical Company (Dow) 

Human Health 

Comment: 

Measuremellls t�f AMP: In a study comparing the in vivo pharmacokinetics and fate of DMO and AMP in rats, 

orally administered 14C-DMO was rapidly absorbed and eliminated in urine. Total urinary elimination accounted 

for 91-99% of the dose, most (77-92%) occurring within the first 48 hours. Fecal elimination accounted for only 

4-8%. Absorption, distribution, and elimination of AMP were almost identical to DMO with slightly faster 

absorption. Only 3-4% of the dose was found in tissues at the end of the study. DMO was rapidly metabolized, 

apparently prior to reaching the systemic blood circulation. Only AMP, one of the major metabolites of DMO, 

was detected blood samples. The time-course decline of AMP derived radioactivity from plasma and RBC was 

almost identical to DMO. Only AMP was detected in the blood collected from the rats dosed with AMP at quite 

consistent concentrations found in rats dosed at equimolar concentration of DMO. Based on the data from this 

study measurements of AMP are not warranted since studies carried out with DMO is essentially systemically 

equivalent to AMP. 

Comment: 

Measurements��{ Formaldehyde: The dose-response curve for formaldehyde-induced systemic toxicity and 

carcinogenicity are well characterized. This point coupled with the known irritating properties of DMO which 

limit the amount of test material that can be humanely administered to animals in toxicity studies, precludes the 

likelihood that metabolism of DMO to formaldehyde will achieve systemic levels of toxicological concern. Thus 

measuring formaldehyde in a subchronic or chronic/oncogenicity studies carried out with DMO will not 

contribute new information key for the human risk assessment. 

The Agency has indicated that products containing formaldehyde as an active ingredient will be evaluated under 

the Registration Review Case 0556 (EPA's formaldehyde RED). With respect to this proposed approach Dow 

provides the following comments relative to the formaldehyde RED. 

Page 4 of7 
Toxicology of Fonnnldehyde 

Comment: 

Non-cancer endpoint 

The 100 ppb threshold for non-cancer effects for occupational exposure selected by the OPPTS is not based 

upon the best available science on formaldehyde. Dow suggests OPPTS use generally accepted ACGIH ceiling 

value of 0.3 ppm for occupational exposure. 

Comment: 

Two major reviews (Paustenbach et at. 1997; Noise! et at. 2007) and a recent well designed study (Lang et al. 

2008) have shown clearly that irritation symptoms are not different in controls versus those that are exposed 

below at least 300 ppb (0.3 ppm). Controlled chamber studies (e.g., Lang et at. 2008) are superior to other types 

of studies because they eliminate uncontrolled variables, particularly confounding exposures to other potential 

irritants (e.g., particulates, phenol and sodium hydroxide), that may affect self-reporting of symptoms. 

Unfortunately, we understand that OPPTS may not be able to include these studies in their evaluation due to 

Human Subject Review Board (HSRB) policy considerations. 

Comment: 

Rather than relying on Horvath et at. ( 1988), Dow recommends that the OPPTS base its analysis on Noise! et at. 

(2007), the peer-reviewed journal publication of the more detailed IRSST (2006) assessment on formaldehyde 

by the same authors. Consistent with EPA's policy, Noise! et at. (2007) is based on human exposure rather than 

controlled human chamber studies and can be used for deriving a no-observed-adverse-effect-level (NOAEL) 

for the non-cancer endpoint for formaldehyde. If, however, the agency continues to derive its regulatory levels 

from Horvath et at. ( 1986), we suggest consideration of the following factors noted in an expert review by 

Paustenbach et al. (1997) and Bender (2002): 

The importance of controls was evidenced in the study by Horvath et al. (1988) for both changes in pulmonary 

function and sensory irritation. For example, the control group reported burning of the nose, stuffy nose, itching 

nose, and eyes burning or watering with frequencies of 2, 14, 8, and 9%, respectively. A more detailed analysis 

of Horvath's data by Paustenbach et al. (1997) revealed that 4% reported throat irritation and 24% with eye 

irritation at exposure between 0.4 and 1 ppm formaldehyde. At levels greater than I ppm, 34% reported throat 

irritation and 50% responded with eye irritation. It was further stated that there was no evidence of throat 

irritation at formaldehyde levels less than 0.4 ppm. 

Comment: 

Uncertainty Factor (UF) 

Applying a 1 0-fold uncertainty factor to the OPPTS-derived 100 ppb threshold to determine the residential 

exposure of 1 0 ppb is not based upon the best available science for formaldehyde. 

First, Moser et al. (2005), demonstrated the median level of formaldehyde in human breath was 4.3 parts per 

billion (ppb) with levels of 6.3 ppb, 40 ppb and 73 ppb for the 75'h, 97.5'h percentile and maximum, 

respectively. Given these results, applying a 1 0-fold safety factor to an already overly conservative value for 

occupational exposure ( 1 00 ppb) for residential exposure ( 10 ppb) seems inappropriate. 

Second, the value of using a "safe level" of 1 0 pbb for the general population is questionable as this also is 

within the range of ambient indoor and personal exposure measurements. As cited in HEI Air Toxics Review 

Panel (2007), "Weisel et al. (2005) determined an average indoor residential concentration for Elizabeth, N.J., 

Houston, TX, and Los Angeles, CA. of 21.6 uglm3 (17.6 ppb)." Personal exposures were similar for New York 

Page 5 of7 
City high school students (Kinney et at. 2002): the average concentration in the summer was 28.5 uglm3 (23 

ppb) and 11.5 uglm3 (9.3 ppb) for winter. 

Third, in regards to the 1 0-fold uncertainty factor for "sensitive populations" for residential exposure, 

Paustenbach et al. (1997) concluded in their extensive review that "asthmatics were not particularly sensitive to 

the airway effects of formaldehyde;" and the German BfR (2006), which derived a "safe level" for the general 

population of 100 ppb (0.1 ppm), concluded in their review that no intraspecies safety factor was necessary. 

They pointed out that "children, in particular small babies, are a special subpopulation with respect to inhalation 

exposure. However, the special sensitivity of children is related to the respiration rate and the immature 

metabolism leading to higher internal exposure (Abraham et at. 2005ba: Abraham et at. 2005b ). There is, 

however, no indication that a higher sensitivity is present for locally acting substances at the portal of entry, in 

particular when the effect is related to the concentration, as is the case of formaldehyde." 

EPA has offered the following explanation for the 1 Ox intraspecies UF: The intraspecies UF is applied to 

account for variations in susceptibility within the human population (interhuman variability) and the possibility 

(given a lack of relevant data) that the database available is not representative of the dose/exposure-response 

relationship in the subgroups of the human population that are most sensitive to the health hazards of the 

chemical being assessed. In cases where the susceptible population is quite specifically defined (e.g., through 

knowledge of the chemical's mode of action) so that the resultant RfC is truly applicable to the susceptible 

population (although not necessarily to hypersensitive individuals), reduction of the intraspecies UF is warranted 

(EPA 2002). 

In the case of formaldehyde, the nature of the health effect does not suggest that there are particularly 

susceptible subpopulations which would warrant the application of the lOx intraspecies UF. 

Comment: 

Formaldehyde is a point of contact irritant. It does not have systemic effects. The scientific literature makes it 

clear that there are no particularly susceptible subpopulations for such effects. In fact, nasal irritation thresholds 

increase with age (Shusterman et al., 2003), certain lifestyle factors such as smoking (Shusterman et al., 2002 

and 2003), and in those individuals with nasal allergies (Shusterman et al., 2003). Mild to moderate asthmatics 

are not more sensitive to nasal irritants as compared to normal healthy subjects (Levi et al. 1990 and Opiekun et 

al. 2003) and anosmics show little variation in nasal irritation thresholds (Cometto-Mufiiz et al. 1990). 

Furthermore, habituation occurs with prolonged, repeated exposure to irritating chemicals such that subjects 

become less sensitive than naive individuals (Dalton et al. 2006). Although trigeminal nerve function has not 

been well studied in children, olfactory function measured in humans ranging from 5 to 99 years of age, showed 

peak performance occurred in the third through the fifth decades. Given the strong physiological link between 

the olfactory and trigeminal nerves, it suggests that children are likely to be less sensitive to sensory irritants 

than young adults (Doty et at. 1984). Overall young, healthy females were shown to be 14-30% more sensitive 

than males to nasal irritant exposures (Doty et al. 2004). 

The controlled human study by Lang et al. (2008) that measured sensory irritation used what can be considered 

a sensitive subpopulation; young, naive adults [i.e., male and females ages 18 to 40 years (mean age =26 years) 

with no prior occupational formaldehyde exposure]. In addition, Lang et al. (2008) controlled for the 

confounding of variable odor detection, and the threshold for sensory irritation was approximately 3 to 5 times 

higher than threshold ( 100 ppb) derived from the epidemiology study (Horvath et al. 1988) used by OPPTS to 

derive their proposed endpoint. Thus, the 100 ppb value from Horvath et al. ( 1988) can be considered adequate 

to protect a susceptible population. Accordingly, the lOx UF for intraspecies variation is unwarranted. 

Additionally, EPA has defined "susceptible subpopulations" in this way: 

"Susceptible subpopulations" is used here to refer both to life stages and to other factors that may predispose 

individuals to greater response to an exposure. Life stages may include the developing individual before and 

Page 6 of7 
after birth up to maturity (e.g., embryo, fetus, young child, adolescent), adults or aging individuals. Other 

susceptible subpopulations may include people with specific genetic polymorphisms that render them more 

vulnerable to a specific agent or people with specific diseases or pre-existing conditions (e.g., asthmatics). The 

term may also refer to gender differences, lifestyle choices, or nutritional state (USEPA 2002). 

The current hazard database for formaldehyde confirmed that it is unlikely to present a reproductive or 

developmental risk to embryos or pregnant women. An additional UF of I Ox for intraspecies variability is 

unnecessary since there are no data indicating a sensitive subpopulation for the critical health effect, sensory 

irritation. In fact, there are ample data to indicate that certain disease states, age and gender differences can 

impart less sensitivity. Thus, the current value of 100 ppb proposed for occupational exposure by USEPA 

OPPTS and recommended by the German BfR. (for general population) is considered to be adequately 

protective of particularly susceptible subpopulations without the application of l Ox intraspecies UF. 

Comment: 

Carcinogenic Endpoiul 

The preponderance of evidence suggests the use of a linear model to estimate excess lifetime cancer risk 

resulting from FA exposure is inappropriate. Formaldehyde acts at the portal of entry and shows a clear 

threshold (e.g. 0.3 ppm) for non-cancer effects such as irritation (Conolly et al. 2004). Therefore, controlling FA 

exposure based upon noncancer effects will protect against carcinogenic effects (Conolly et al. 2004). The 

biologically based CIIT model is the most appropriate model to estimate potential cancer risk. In fact, the CIIT 

model has been accepted by the USEPA Office of Air and Radiation. 

Hauptmann et al.'s (2003) update of the I 0-plant NCI formaldehyde cohort study indicates that increased 

associations with nasopharyngeal cancer (NPC) was likely unique to "Plant I ". Therefore, OPPTS should 

consider the recent publication by Marsh et al. (2007) that provide evidence that NPC may not be etiologically 

related to formaldehyde exposure. Marsh et al. (2007) demonstrated that individuals in Plant I had external 

employment in silver smithing and other metal working industries, which provided exposure to several agents 

that are known risk factors for upper respiratory system cancers (e.g., sulfuric acid mists, mineral acid, metal 

dusts and heat). 

In regards to the hypothesis that formaldehyde is a potential leukemogen, the OPPTS should consider the 

reanalysis (Marsh and Youk, 2004) of the NCI study (Hauptmann et al. 2003). The Marsh and Youk (2004) 

reanalysis suggest that a causal association between FA exposure and increased mortality from leukemia and 

myeloid leukemia is not supported. In addition, evidence for a biological mechanism indicating that 

formaldehyde is a leukemogen is lacking, and there are several detailed analyses available demonstrating the 

biological implausibility that formaldehyde would be capable of causing leukemia (Pyatt et al. 2008, Heck and 

Casanova 2004, Golden et al. 2006). To our knowledge, the only argument supporting a mechanism for 

leukemia formation from formaldehyde exposure has not been peer-reviewed outside of the USEPA (DeVoney 

et al. 2006 a,b ). 

Response: 

The required studies to address the Agency's toxicological concerns are for the parent compound DMO, and no 

measurements of the metabolites are warranted in these required toxicity studies. 

We acknowledge the comments received on the non-cancer and cancer effects of formaldehyde. We are waiting 

for the IRIS response to the recommendations of the NAS peer review of formaldehyde re-assessment to 

determine the implications for the assessment of DMO. No new data on formaldehyde are required at this time. 

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