EPA does not agree to delete the last two (of three total) paragraphs discussing the health effects

associated with exposure to ethanol, and does not agree this language is “speculative , ” as OMB claims. This language is consistent with EPA’s previous statements about relevant available information on ethanol health effects (e.g., the 2010 RFS2 rule). As we have indicated in previous discussions, we have included this information because the ingestion literature is critical to understand the health endpoints of potential interest , and which populations may be most susceptible. Because health effects of ethanol are determined primarily by its concentration in the target tissue , and tissue concentrations associated with adverse health effects are achievable b y both the oral and inhalation routes , the literature on the effects of oral ethanol are essential to inform decisions about the health consequences of inhaled ethanol. As we indicate in the RI A, EPA is developing and evaluating pharmacokinetic models as tool s to compare quantitatively

the tissue concentrations achieved by oral and inhaled ethanol, and thus assess the health impacts of inhaled ethanol based on the extensive oral literatur e. 1 These models also enable extrapolating doses and effects across species (animal to human) to better characterize the health hazards and dose

- response relationships for low levels of ethanol exposure in the environment.
For the reasons articulate d a bove, t he EPA believes its summary of the available science on ethanol health effects is objective, balanced and transparent. The Agency also believes there is no scientific reason for changing our description of the current state of science. We have used this language consistently, whether we are talking about potential ethanol emission increases, as in the RFS2 rule, or decreases, as is the case with Tier 3. The language makes it clear that literature on inhalation exposure is limited, and that the Agen cy is evaluating the relevance of observed health effects to low level exposures in the environment.

1 Martin, S., et al. 2012. Development of multi

- route physiologically

- based pharmacokinetic models for ethanol in the adult, pregnant, and neonatal rat. Inhalation Toxicology 24(11) 698

- 722.Tier 3 RIA Health Effects Text on Ethanol

EPA is planning to develop an assessment of the health effects of exposure to ethanol, a compound which is n ot currentl y listed on EPA’s IRIS database. Extensive health effects data are available for ingestion of ethanol, while data on inhalation exposure effects are sparse. In developing the assessment, EPA is evaluating pharmacokinetic models as a means of e xtrapolating across species (animal to human) and across exposure routes (oral to inhalation) to better characterize the health hazards and dose

- response relationships for low levels of ethanol exposure in the environment.
The IARC has classified “alcoholi c beverages” as carcinogenic to humans based on sufficient evidence that malignant tumors of the oral cavit y, phary nx, larynx, esophagus, and liver are causall y related to the consumption of alcoholic beverages. i The U.S. DHHS in the 12 th Report on Carcin ogens also identified “alcoholic beverages” as a known human carcinogen (they have not evaluated the cancer risks specificall y from exposure to ethanol), with evidence for cancer of the mouth, phary nx, lary nx, esophagus, liver and breast. ii There are no st udies reporting carcinogenic effects from inhalation of ethanol. EPA is currentl y evaluating the available human and animal cancer data to identify which cancer t ype(s) are the most relevant to a human health assessment of low

- level oral and inhalation ex posure to ethanol. Noncancer health effects data are available from animal studies as well as epidemiology studies. The epidemiologic data were obtained from studies of alcoholic beverage consumption. Reported effects included neurological impairment, developmental effects, cardiovascular effects, immune sy stem depression, and effects on the liver, pancreas and reproductive s ys tem. iii There is evidence that children prenatally exposed via maternal ingestion of alcoholic beverages during pregnancy

are at increased risk of hy peractivity

and attention deficits, impaired motor coordination, a lack of regulation of social behavior or poor ps ychosocial functioning, and deficits in cognition, mathematical ability , verbal fluency , and spatial memory

. iv , v , vi , vii , viii , ix , x , xi Genetic factors influencing ethanol metabolism may render certain subpopulations more susceptible to the health effects of ethanol exposure b y altering internal levels of ethanol and/or its metabolites (e.g., acetaldeh yde).

i International Agency for Research on Cancer (IARC). (1988). Monographs on the evaluation of carcinogenic risk of chemicals to humans, Volume 44, Alcohol Drinking, World Health Organization, Lyon, France.

ii NTP. (2011). Report on Carcinogens, T we lfth Editio n. Research Triangle Park, NC: U.S. Department of Health and Human Services, Public Health Service, National Toxicology Program. 499 pp.
iii U.S. Department of Health and Human Services. (2000). 10th Special Report to the U.S. Congress on Alcohol and Health . June. 2000.
iv Goodlett CR, KH Horn, F Zhou. (2005). Alcohol teratogeniesis: mechanisms of damage and strategies for intervention. Exp. Biol. Med. 230:394

- 406.v Riley EP, CL McGee. (2005). Fetal alcohol spectrum disorders: an overview with emphasis on changes in brain

and behavior. Exp. Biol. Med. 230:357

- 365.
vi Zhang X, JH Sliwowska, J Weinberg. (2005). Prenatal alcohol exposure and fetal programming: effects on neuroendocrine and immune functio n. Exp. Biol. Med. 230:376

- 388.
vii Riley, E. P., McGee, C. L. and Sow ell, E. R. (2004). Teratogenic effects of alcohol: A decade of brain imaging. American Journal of Medical Genetics Part C: Seminars in Medical Genetics, 127C: 35

– 41. doi: 10.1002/ajmg.c.30 014
viii Gunzerath, L., Faden, V., Zakhari, S. and Warren, K. (2004), National Institute on Alcohol Abuse and Alcoholism Report on Moderate Drinking. Alcoholism: Clinical and Experimental Research, 28: 829

– 847. doi: 10.1097/01.ALC.0000128382.79375.B6
ix World Health Organization (WHO). (2004). Global status report on alcohol 2004. Geneva, Sw itzerland: Department of Mental Health and Substance Abuse. Available: http://www. who.int/substance_abuse/publications/global_status_report_2004_overview .pdf

x Chen W

- JA, SE Maier, SE Parnell, FR West. (2003). Alcohol and the developing brain: neuroanatomical studies. Alcohol Res. Health 27:174

- 180.
xi Driscoll CD, AP Streissguth, EP Riley. (1990). Prenatal alcohol exposure comparability of effects in humans and animal models. Neurotoxicol. Teratol. 12:231

- 238.