**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).:**  **Mu ltiple**  **Petition No(s).:**  **N/A Regulatory**  **Action: N/**  **A Risk**  **Assess Type:**  **Single Chemical**  **Case No.:**  **3095 TXR** **No.: N/A**  **CAS No:**  **51200-87-4 MRID** **No(s).: N/A**  **40 CFR:**  **N/A**

**TO:**

**FROM: Seiichi**  **Mu rasaki,**  **Chemical Review**  **Ma nager** 

**Regulatory Ma** 

**nagement 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 Mc** **M ahan,**  **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**  **Me t** **hyloxazolidines Registration**  **Review (Case**  **3095); Docket**  **ID EPA-HQ** 

**OPP- 201** **2-0007**

**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 registrant**  **submitted 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** **TR IS**  **AM INO** 

**. Finally,**  **an ADME**  **rat gavage**  **study reported**  **that AMP**  **is rapidly**  **absorbed and**  **almost completely**  **excreted without**  **being metabolized** **3**

**• 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**  **(A DME**  **[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 "n** **o 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**  **(N ational**  **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)SA** **Rs can**  **feasibly replace**  **in vivo**  **data in**  **some instances;**  **requesting (Q)SA** **R 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 HCH** **O 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 "Du** **e 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 recomm** **endations 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 14** **C-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**  **(N OAEL)**  **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**  **OP PTS-derived**  **100 ppb**  **threshold to**  **determine the**  **residential exposure**  **of 1 0**  **ppb is**  **not based**  **upon the**  **best available**  **science for**  **formaldehyde. First,**  **Mo ser**  **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 "a** **sthmatics were**  **not particularly sensitive to**  **the airway**  **effects of** **formaldehyde;" and** **the German**  **BfR (2006),**  **which derived**  **a "s** **afe 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**  **"c hildren,**  **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).**  **Mi ld**  **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 O x**  **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**  **(N PC)**  **was likely**  **unique to**  **"Plant I**  **". Therefore,**  **OPPTS should**  **consider the**  **recent publication**  **by Ma**  **rsh 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**  **(M arsh**  **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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