Page 2 of 19 Drug Administration (FDA) as Generally Recogni zed as Safe (GRAS) when used as a food ingredient and an earlier re view considered it safe for use in cosmetics.

Isobutane is an asphyxiant and acute exposure may cau se tachypnea and tachycar dia. While direct contact with the liquid may cause burns, the va por has no effects on the skin and eyes. Sudden death has also been reported from abusive “sniffi ng” of products containing isobutane, especially lighter refills. In a safety assessment of is obutane as a cosmetic i ngredient (1982), dermal irritation in humans was very slight and transient erythema occurred randomly. Repeated inhalation exposure did not resu lt in any changes in electroe ncephalograms, adrenocortical function, pulmonary function, neur ological response, subjective response, cardiac function or cognitive response.

Acute toxicity data on isobutane were limited to inhalation exposure and eye and skin irritation. Isobutane was not acutely toxic via the inhalation r oute and was basically non- irritating to the skin and eye of rabbits.

Several studies were found in which monkeys, rabbits , and rats were exposed to formulations or to mixtures containing isobutane. No toxicity wa s reported for two species of monkeys and one species of rabbits exposed for 90 days to va rious formulations c ontaining isobutane.

No effects on survival, body weight, hematology, c linical pathology, or liver and kidney weights were observed in rats exposed to 0, 1000, or 4500 ppm (equivalent to 0, 623, or 2803 mg/kg/day)

of a 50:50 mixture of isobutane: isopentane for 13 weeks, however clinical signs included hunched posture, lethargy and crusted eyes in both expos ure groups. There were no clinical signs of toxicity observed and no gross or microscopic le sions seen in Sprague-Daw ley rats exposed to 0, 44, 432, or 4437 ppm (equivalent to 0, 27, 269 or 2763 mg/kg/day) of a mixture containing 25% each of n-butane, isobutane, n-pentane, and isopentane for 3 weeks.

No chronic toxicity or carcinogenicity studies with isobutane were identified.

In a four week subchronic toxicity study comb ined with reproduction/developmental toxicity screening and neurotoxicity screening study, Sprague Dawley CD rats were treate d with isobutane (purity 99.0%) to assess the repeat ed dose, reproductive and devel opmental toxicity potential of this material when administered by whole body i nhalation exposure. A no-observed-adverse effect level (NOAEL) of 9000 ppm (e quivalent to 5600 mg/kg/day) was concluded for general systemic/neurotoxic (parental) endpoints in this study. Based on decreased male and female fertility and increased post-implantation loss in the 9000 ppm group, the fert ility and reproductive endpoints NOAEL was determined to be 3000 ppm (equivalent to 1867 mg/ kg/day). There were no effects on offspring survival, body weight and development up to post-natal day 4. A NOAEL of 9000 ppm was concluded for developmental effects. No effects on functional observation battery (FOB) parameters and motor activ ity were observed in this study.

In terms of neurotoxicity, acute toxicity studies show effects on the central nervous system (CNS) with rodents more sensitive than dogs. Exposure to a concentration of 55% isobutane was lethal in dogs, while 41-52% isobutane was lethal to mi ce within 2-3 minutes. The 10-minute EC50 for CNS effects was listed as 200,000 ppm (equivalent to 124560 mg/kg/day) for the rat.Page 3 of 19 Several tests were found measuri ng the cardiopulmonary toxicity of isobutane. No effects were seen at in anesthetized Rhesus monkeys exposed for 5 minutes to 5% isob utane through a tracheal

cannula. Effects on the heart were shown in the dog with co ncentration-related decreased contractility, pressure, and output measured betw een 2-10% isobutane. M ongrel dogs were also anesthetized and exposed to isobu tane through a tracheal cannula. Blood pressure and heart rate were not affected by exposure. All concentratio ns significantly increased pulmonary resistance and decreased pulmonary compliance. Similarly, anesthetized male Osburn-Mendel rats exposed to 27% isobutane showed apnea after 8.7 mi nutes of exposure followed by cardiac arrest; decreased respiratory rate, tidal volume, a nd pulmonary compliance and increased airway

resistance were also found. In another test w ith anesthetized male Sw iss mice, 20-40% isobutane did not induce cardiac arrhythmia, but did sensitiz e the heart to epinephr ine-induced arrhythmia.

No evidence of an increase in mutation freque ncy was found in five strains of Salmonella typhimurium exposed to up to 50% isobutane in air. Strains TA98, TA100, TA1535, TA1537, and TA1538 were exposed for 6 hours with and without metabolic activation

The toxicity database is sufficient for isobutane an d potential exposure is ad equately characterized given the low toxicity of the chemical. In term s of hazard, there are low concerns and no residual uncertainties regarding prenatal and/or postnatal toxicity. Based on this information, there is no concern at this time for increased sensitivity to in fants and children to isobutane when used as an inert ingredient in pesticide formulations and a safe ty factor analysis has not been used to assess risk. For the same reason, EPA has determined that an additional safety factor is not needed to protect the safety of infants and children.

Residues of concern are not anticipated for di etary exposure (food and drinking water) or for residential exposure from the use of isobutane for th e proposed use pattern as an inert ingredient in pesticide products. EPA expects aggregate exposur e to isobutane to pose no appreciable dietary risk given that the data on isobutan e show a lack of any systemic toxi city via inhalation at doses of up 3,000 ppm (equivalent to 1867 mg/kg/day) and a l ack of any apparent developmental effects.

If released to the environment, isobutane is ex pected to exist in the atmosphere as a gas and volatilize rapidly from surface water and soil. Estimat ed volatilization half-lives from a river and lake are 2 hours and 3 days, respectively. Neither hydrolysis, nor direct photol ysis, is an important fate process. Data on potential toxicity to aquatic organisms were not found in the available

literature.

Taking into consideration all av ailable information on isobutane, EPA concludes that there is a reasonable certainty that no harm will result to th e general public or to infants and children from aggregate exposure to isobutane when used as an inert ingredient in pe sticide formulations. Therefore, the establishment of an exemp tion from tolerance under 40 CFR 180.910 and 40 CFR

180.930 for residues of isobutane when used as an inert ingredients in pr e- and post-harvest and animal applications in pesticide formulations, can be considered assessed as safe under section 408(q) of the FFDCA.Page 4 of 19 I. Background

Landis International, on behalf of Whitmire Micro-Gen, submitted a petition (9E7586) requesting an exemption from tolerance for residues of isobutan e when used as an in ert ingredient (aerosol propellant) in pesticide formulations applie d pre- and post-harves t under 40 CFR 180.910 and applied to animals under 40 CFR 180.930. EPA publishe d the Notice of Filing for this petition in the Federal Register on Octobe r 7, 2009 (74 FR 51597). No comments were received in response to this notice. This document provides an asse ssment of the risk to human health and the

environment for isobutane when used as an inert ingredient in pesticid e formulations and was based on information provided by the submitter and in formation available in the public literature.

II. Substance Identity

Table 1. Substance Identity for Isobutane Chemical abstracts service registry number (CAS RN) 75-28-5

National Chemical Inventories (NCI) name Not given Other names 1,1-dimethylet hane; 2-methylpropane

PC Code 800015

Chemical formula C 4 H 10 Chemical structure

III. Use Information

A. Pesticide Uses

Currently, isobutane is listed on “Inert Ingred ients Permitted for Use in Nonfood Use Pesticide Products.” It is widely used in nonfood use insec ticide products, including repellents, foggers and pet care products. (MRID 47727606)

B. Other Uses

Isobutane is also widely used in ot her products as a propellant. It is used in auto products, such as tire inflators, battery cleaners a nd home maintenance products, such as spray paints and sealants. Several products used inside the home also cont ain isobutane, including various cleaning products and air fresheners. Another common type of products containing isobutane are personal care products. These products include shaving creams, deodorants, and hair care products. (MRID 47727606)Page 5 of 19 Isobutane is blended with motor fuel to control vo latility, used as a react ant in the production of propylene oxide, and used as an aerosol prope llant in a variety of products (MRID 47727602). The chemical is designated by FDA as Generally R ecognized as Safe (GRAS) when used as a food ingredient and an earlier review considered it safe for use in co smetics (Expert Panel, 1982). In the current petition for exemption from tolerance, the proposed use for isobutane is as an inert aerosol propellant in pesticide formulations us ed pre- and post-harves t and when applied to animals (MRID 47727601).

IV. Physical and Chemical Properties

Table 2. Physicochemical Properties of Isobutane

Parameter Value Source Appearance Colorless gas

Molecular wt. 58.12

Melting pt. -138.3 °C Boiling pt. -11.7 °C Vapor pressure 2611 mmHg at 25 °C MRID 47727602

Autoingnition point 462.2 °C Expert Panel, 1982 Octanol/water partition

coefficient 2.76

Water solubility 48.9 mg/L at 25 °C MRID 47727602

Explosive limits in air 1.8-8.4% Reactivity Relatively stable; generally

inert Expert Panel, 1982

V. Human Health Assessment

Toxicological Discussion Isobutane is toxic only at levels that exceed th e lower explosive limit in air which is 1.8%, or 18,000 ppm. None of the toxic eff ects reported in experimental an imal studies occur below this concentration. Asphyxiation, tachyc ardia, and anesthesia can occu r at higher concentrations.

Administered alone, isobutane di d not induce cardiac arrhythmia but sensitization to epinephrine was demonstrated in the dog and mouse following exposures to 5% and 20%, respectively. Cardiopulmonary toxicity has been shown in the dog and monkey at a concentration of 10% isobutane administered through a tracheal cannula.

The chemical is essentially non-ir ritating to the skin and eyes a nd upper airway irritation was not seen in mice. Repeated inhalation exposure of laboratory animals to up to 4500 ppm or to aerosol spray bursts was without toxic e ffects. The chemical did not induce hydrocarbon nephropathy in

male rats.Page 6 of 19 Toxicological Data

A. Effects in Humans

Isobutane is an asphyxiant and acute exposure may cau se tachypnea and tachycar dia. While direct contact with the liquid may cause burns, the va por has no effects on the skin and eyes (Carreón, 2001). Case reports described lif e-threatening ventri cular tachycardia af ter intentional or accidental inhalation of products, such as air fre shener and aerosol deodorant, containing isobutane (LoVecchio and Fulton, 2001; Wason et al., 1986). Sudden death has also been reported from abusive “sniffing” of products containing isobutane, especially lighter refills (Pfeiffer et al., 2006; Rohrig, 1997).

In a safety assessment of isobutane as a cosmetic ingredient, an Expert Panel (1982) reviewed

dermal and inhalation effects in humans. Produc ts containing 64.5-70% of a mixture of isobutane and propane were tested for skin irritation by applic ation twice a day for 12 weeks; very slight and transient erythema occurred randomly and the reactio ns were reported to be negligible. Repeated inhalation exposure to 500 ppm isobutane, up to 8 hours/day, 5 days/week for 2-4 weeks did not result in any changes in electroencephalogr ams, adrenocortical function, pulmonary function, neurological response, subjective response, cardi ac function or cognitive re sponse (Expert Panel, 1982). Another review noted that up to 1000 ppm isobutane for 8 hours was without adverse effect (Galvin and Bond, 1999).Page 7 of 19 B. Acute Toxicity

Table 3. Acute Toxicity Studies with Isobutane (CAS No. 75-28-5)

Study Type Species/strain Results Tox. Category MRID No.

Acute oral NS NS NS NS

Acute dermal NS NS NS NS

Acute

inhalation rat LC 50 = 570,000 ppm (15 min) IV MRID 47727602,

MRID 47727604

Acute

inhalation mouse LC 50 = 520,000

ppm (2 hour) IV MRID 47727604; Expert Panel, 1982

Eye irritation rabbit Transient iritis and mild conjunctivitis

at a concentration

of 22% Non-irritating MRID 47727604

Skin irritation rabbit No to moderate erythema and

edema at concentrations up to 89.55%; indices 0.29-2.025 (scale 0- 8) Non-irritating MRID 47727604

Skin

sensitization NS NS NS NS

NS= no study available

Acute toxicity data on isobutane were limited to inhalation exposure and eye and skin irritation. The LC50 was 570,000 ppm for 15 minutes in the rat and 520,000 ppm for 2 hours in the mouse (MRID 47727604). In the rat study, it was noted that all deaths occurred during exposure and were due to central nervous sy stem (CNS) stimulation; all su rvivors recovered quickly and appeared normal within 10 minutes after removal from exposure (MRID 47727604).

Upper airway irritation was not seen in male CD-1 mice exposed head-only to 12,460 ppm. Animals were exposed for 1 minute, allowed to breathe room air for 10 minutes followed by exposure for 1 minute and room air for 5 minutes. No changes in respiratory patterns were found (Galvin and Bond, 1999).

The chemical was basically non-irritating to the skin and eye of rabbits. In the eye irritation test, a hair spray formulation containing 22% isobutane wa s instilled into one eye of male rabbits and rinsed after 4 seconds (MRID 47727604). Rabbits expos ed in a closed setti ng to aerosol bursts of the 22% isobutane hair spray formulation showed no clinical effects, cha nges in body weight, or pathological lesions (Expert Panel, 1982).Page 8 of 19 C. Subchronic Toxicity

No subchronic studies testing isobutane alone were found but several studies were found in which monkeys, rabbits, and rats were expose d to formulations or to mixtures.

No toxicity was reported for cyno molgus monkeys exposed for 90 days to a hair spray formulation containing isobutane (Expert Panel, 1982). Similarly, no adverse eff ects were seen in stump-tail monkeys exposed for 90 days to an aerosol spra y deodorant containing a mi xture of isobutane and propane; exposures were for 6 hour s/day during which 1- or 5-s econd sprays into the chamber

occurred at 42- or 21-minute interv als, respectively (Expert Panel, 1982). No other details of these

studies were included.

New Zealand rabbits were exposed to a hair spray containing 22% isobutane twice daily, 5 days/week, for 90 days; the aerosol was spraye d for 30-second bursts and the animals remained in the chamber for 15 minutes after each discharge. No clinical signs of toxicity were observed; no changes in body weight, hematology, clinical ch emistry, and urinalysis were found, and no gross or microscopic lesions were seen in exposed animals (Expert Panel, 1982).

Groups of 20 male and 10 female Fischer 344 rats were exposed to 0, 1000, or 4500 ppm (equivalent to 0, 623 or 2803 mg/kg/day) of a 50:50 mixture of isobutane: isopentane for 6 hours/day, 5 days/week, for 13 weeks. No effect s on survival, body weight, hematology, clinical pathology, or liver and kidney we ights were observed. Clinical signs included hunched posture and lethargy in 3 males at 4500 ppm and 2 male s at 1000 ppm and crusted eyes in males and females of both exposure groups. At interim sacr ifice after 4 weeks of exposure, males in both exposure groups showed a slight increase in se verity, but not incidence, of mild hydrocarbon nephropathy. No differences in incidence or seve rity of kidney lesions we re evident at terminal sacrifice (Aranyi et al., 1986; API, 1985).

Ten male and 10 female Sprague-Dawley rats we re exposed to 0, 44, 432, or 4437 ppm (equivalent to 0, 27, 269 or 2763 mg/kg/day) of a mixture co ntaining 25% each of n-butane, isobutane, npentane, and isopentane for 6 hours/day, 5 days/week, for 3 weeks. No clinical signs of toxicity were observed and no effects on body weight, hema tology, and clinical pathology were found. No gross or microscopic lesions were seen, especi ally in the kidney (Hal der et al., 1986; MRIDs 47727602, 47727604).

D. Chronic Toxicity and Carcinogenicity

No chronic toxicity or carcinogenicity studies with isobutane were identified. However, the concern for carcinogenicity is low based on rapid metabolism, lack of mutagenicity and lack of systemic toxicity at doses up to 1867 mg/kg/ day. In addition, the Agency used a qualitative structure activity relationship (S AR) database, DEREK11, to determ ine if there were structural alerts suggestive of carcinoge nicity. No structural al erts were identified.Page 9 of 19 E. Subchronic Toxicity Study Combined wi th Reproduction/Developmental Toxicity Screening and Neurotoxicity Screening Study

In a four week subchronic toxicity study comb ined with reproduction/developmental toxicity screening and neurotoxicity sc reening study, Sprague Dawley CD rats (12/sex/main study group and 12 females/satellite group) were treated with isobutan e (purity 99.0%) to assess the repeated dose, reproductive and developmental toxicity pote ntial of this material when administered by whole body inhalation exposure. The subchroni c portion (main study) in cluded neurotoxicity assessment for behavioral and motor activity toxic ity potential. The re productive/developmental portion of this study was referre d to as the satellite study.

The test substance was administ ered as a gas at target con centrations of 900, 3000 and 9000 ppm (equivalent to 560, 1867, and 5600 mg/kg/day ) for 6 hours/day, 7 days/week for 2 weeks prior to mating initiation. Main study male rats were e xposed for a minimum of 28 days during mating and pre-mating periods. Main study female ra ts were exposed for once daily, 6 hours/day, 7 days/week for 28 days. For the reproduction stu dy, satellite female rats were exposed for 6 hours/day, 7 days/week for 2 weeks prior to mating initiation. Satellite female rats were then exposed once daily (6 hours/day) during mating and continued to be treated once daily (6 hours/day) during gestation (Days 0-19).

Observations for mortality and general condi tion were completed at least once during each exposure. Clinical observations were made weekly for male and female rats in the main study. Satellite females were observed weekly duri ng premating and on gestation days 0, 7, 14, 20 and lactation day 0. Blood was collected for clinical chemistry studies and for hematology studies.

Body weights were recorded on the first day of treatment and once weekly for the main study group males and females. Satellite female rats were weighed on the first day of treatment and twice weekly until evidence of copulation was obse rved. Mated satellite females were weighed on gestation days 0, 7, 14, 20 and lactation days 1-4. Satellite females w ithout evidence of mating were weighed twice weekly during the mating and post-mating period.

Food consumption for main study male and female rats was recorded pretest and weekly during the treatment period. For satellite female rats, f ood consumption was recorded pretest and weekly during pre-mating period and if not mated, during the post-mati ng period. For pregnant or confirmed mated satellite females, food consum ption was measured on gestation days 0-7, 7-14 and 14-20. It was also recorded on lactation days 1-4. After 7 days (pre -mating), 6 or 7 days (gestation) or 3 days (lactation), the feeders we re reweighed to obtain the total amount consumed over the 7, 6 or 3-day period. Feed consumption was measured weekly beginning one week prior

to treatment.

Observations included in the functional obs ervational battery (FOB) included, sensory, neuromuscular, physiological, motor activity, clinical pathology (ter mination), and organ weights. Macroscopic postmortem observations were performed on all main study male and female rats and all satellite female rats. Microscopic pathology for a wide range of organs were obtained at necropsy for all study animals.Page 10 of 19 F1 pup evaluations included physical examinat ions, body weights, sexing and macroscopic observations. Physical examina tions were done on lactation days 0 and 4. Body weights were recorded on lactation days 1 and 4. Pups were sexed on lactation day 0 and sex was verified on lactation day 4. Macroscopic postmortem examina tions (internal and exte rnal) were done on F1 pups found dead during lactation an d on all F1 pups on lactation day 4 for pups surviving to that

interval.

For main study animal observations, there was no effect of treatment on survival. All animals

survived until the term ination of the study. There were no exposure-related differences in body weights and weight changes or feed consumption in the exposed male animals as compared to the

air control animals. There was no treatment-related effect on FOB parameters or motor activity for either sex in this study.

“There were no meaningful differences in hemato logy or coagulation values in test substance exposed male animals as compared to the air controls. Statistically significant increases in hemoglobin and mean corpuscular hemoglobin co ncentration in the 9000 ppm test substance exposed males, decreases in platelets in 3000 and 9000 ppm test substance exposed males and decreases in monocytes in 3000 and 9000 ppm test substance exposed females were seen in exposure-related patterns but there were no ac companying changes in the other hematology parameters, nor were there any similar differences in the other sex. In isol ation, these minor intergroup differences were not considered to indicate an effect of the exposures and were generally within the normal range of these values for a rat.” (The Petroleum HPV Testing Group, 2009)

“There were no meaningful differen ces in clinical chemistry values in the test substance exposed animals as compared to the air control animals. Statistically significant increases in sodium concentration in the 9000 ppm test substan ce exposed males and decreases in phosphorus concentration in all test substance exposed female s were seen but the absolute differences were relatively small, were not in an exposure level re lated pattern and there we re no similar differences in the other sex. In isolation, thes e minor inter-group differences were not considered to indicate an effect of the exposures.” (The Petroleum HPV Te sting Group, 2009)

“There were no meaningful inter- group differences in organ weight s in the test substance exposed animals as compared with air control animal s. The 900 and 3000 ppm exposed males showed an increase in spleen weights (a bsolute and/or relative to body or brain weight) but no similar difference was seen in the 9000 ppm exposed males or any of the exposed females. In isolation, this minor inter-group difference wa s not considered to indicate an effect of the exposures.” (The Petroleum HPV Testing Group, 2009)

“There were no exposure-related differences in macroscopic or microscopic postmortem evaluations in the test substance exposed animals compared to the air control animals. The testes were examined qualitatively with an awareness of the stages of the spermatogenic cycle to detect any disturbances in spermatogenesis, and with empha sis on the interstitial (L eydig) cells to detect any changes in cellular size or structure. No te st article related findings were present.” (The Petroleum HPV Testing Group, 2009)Page 11 of 19 For satellite female animal observations, there wa s no effect of treatment on survival. All animals

survived until the term ination of the study. The animals were generally unremarkable during the exposure and the non-exposure periods. There were no exposure-related differences in body weights or weight changes in the test substance exposed animals as compared to the air control animals. There were no exposure-related differen ces in feed consumption and no exposure-related differences in macroscopic postmortem evaluations or organ weights in the test substance exposed animals compared to the air control animals. A st atistically significant increase in heart to brain weight ratio in 9000 ppm exposed females was seen but, in the absence of any macroscopic and microscopic abnormalities in the main study animals, this difference was considered to have been

incidental.

In terms of mating, fertility and gestation paramete rs, no parental systemic toxicity was observed. In the 9000 ppm group, 25% of the mated female s did not become pregnant. Although not statistically significant, the reduction in male a nd female fertility indices (75%) was considered exposure related since it was below the concurrent control (100%) and the testing facility historical control values (mean 96.4%; rang e 87.5%-100%). A statistically significant (p < 0.05) exposurerelated increase in post-impla ntation loss was also observed for the 9000 ppm group of exposed female rats; mean losses of 0.8+ 0.9 and 1.8 + 0.8 for control and high exposure groups respectively.

In the OECD 422 study, no adverse effects on Func tional Observation Battery (FOB) or motor activity were observed following inhalation exposure to isobutane in rats at doses up to and including 9000 ppm (5600 mg /kg/day). Based on decreased male a nd female fertility and increased post-implantation loss in the 9000 ppm group, the fe rtility and reproductive toxicity NOAEL was determined to be 3000 ppm (equivalent to 1867 mg /kg/day). There were no effects on offspring survival, body weight and development up to post-natal day 4. A NOAEL of 9000 ppm was concluded for developmental effects.”

F. Cardiopulmonary toxicity

Rhesus monkeys (n = 3) were anesthetized a nd exposed for 5 minutes to 5 or 10% isobutane through a tracheal cannula (Belej et al., 1974; Avia do and Smith, 1975). No effects were seen at 5%. Exposure to 10% resulted in decreased aortic blood pressure, a slight tachycardia, increased pulmonary resistance, decreased pulmonary complia nce, and decreased respiratory minute volume.

Effects on the heart were shown in the dog with concentration-related d ecreased contractility, pressure, and output measured between 2-10% (MRID 47727602). Cardiac sensitization to epinephrine has also been shown in the dog at 50,000 ppm (Aviado and Bele j, 1974) with an EC50 of 70,000 ppm for 5 minutes (MRID 47727604).

Mongrel dogs (n = 3-4) were anesthetized and exposed for 5 minutes to 2.5, 5, or 10% through a tracheal cannula (Belej and Aviado, 1975). Blood pr essure and heart rate were not affected by exposure. All concentrations significantly increased pulmona ry resistance and decreased pulmonary compliance. Respiratory minute volume was decreased at 10%. Similarly,

anesthetized male Osburn-Mende l rats exposed to 27% showed apnea after 8.7 minutes ofPage 12 of 19 exposure followed by cardiac arre st; decreased respiratory rate , tidal volume, and pulmonary compliance and increased airway resistan ce were also found (Friedman et al., 1973).

Anesthetized male Swiss mice were exposed to 10, 20, or 40% isobutane through a face mask for 6 minutes (Aviado and Belej, 1974). Administ ered alone, isobutane di d not induce cardiac arrhythmia, but did sensitize th e heart to epinephrine-induced arrhythmia at 20 and 40%.

G. Neurotoxicity

Acute toxicity studies show eff ects on the CNS with rodents more sensitive than dogs. In the dog, exposure to a concentration of 45% in air resulted in relaxation a nd 55% was lethal (Expert Panel, 1982). In the mouse, CNS depression was obser ved at 15% in 60 minutes and at 23% in 26 minutes, while 22-27% caused anesthesia in 8.7 minutes followed by resp iratory arrest in 15 minutes (MRID 47727602). Similarly, 35% for 25 minut es was an effective anesthetic in mice

while 41-52% was lethal within 2-3 minutes (Expert Panel, 1 982). The 10-minute EC50 for CNS effects was listed as 200,000 ppm for the rat (M RID 47727604). Effects in the rat also include decreases in pulmonary compliance and tidal volume at “high concentrations” (MRIDs 47727602, 47727604).

H. Mutagenicity /Genetic Toxicity

No evidence of an increase in mutation freque ncy was found in five strains of Salmonella typhimurium exposed to up to 50% isobutane in air. Strains TA98, TA100, TA1535, TA1537, and TA1538 were exposed for 6 hours with and without metabolic activation (MRID 47727609).

I. Metabolism and Pharmocokinetics

The uptake of various hydrocarbon vapors was determined in male F344/N rats exposed nose-only for 80 minutes on five consecutive days (Dahl et al., 1988). Uptake was 0.6-1.0 nmol/kg/min/ppm after exposure to 10 or 100 ppm.

Isobutane and the metabolite tert-but anol were detected in the bl ood and several organs of male

ICR mice after a 1-hour whole- body vapor exposure to isobutane. The metabolite was also

detected after isobutane was incubated with isol ated liver microsomes (Tsukamoto et al., 1985; MRID 47727610).

VI. Special Considerations for Infants and Children

Section 408 of the FFDCA provides that EPA shall apply an additional tenfold (10X) margin of safety for infants and children in the case of thre shold effects to account fo r prenatal and postnatal toxicity and the completeness of the database on toxicity and exposure unless EPA determines that a different margin of safety will be safe for infa nts and children. This additional margin of safetyPage 13 of 19 is commonly referred to as the FQPA safety fact or (SF). In applying th is provision, EPA either

retains the default value of 10X or uses a different additional sa fety factor when reliable data to EPA supports the choice of a different factor.

EPA has determined that reliable data show the sa fety of infants and children would be adequately protected if the FQPA SF were reduced to 1X. That decision is based on the following findings:

The toxicity database is sufficient for isobutane an d potential exposure is ad equately characterized given the low toxicity of the chemical. In term s of hazard, there are low concerns and no residual uncertainties regarding prenatal and/or postnatal toxicity. Isobutane has low subchronic toxicity. In a four week subchronic toxicity study combined with reprod uction/developmental toxicity screening and neurotoxicity sc reening study, Sprague Dawley CD rats (12/sex/main study group and 12 females/satellite group) were treated with isobutan e (purity 99.0%) to assess the repeated dose, reproductive and developmental toxicity pote ntial of this material when administered by whole body inhalation exposure. A NOAEL of 9000 ppm (equivalent to 5600 mg/kg/day) was concluded for general systemic/neurotoxic (paren tal) endpoints in this study. Based on decreased male and female fertility and increased post-im plantation loss in the 900 0 ppm group, the fertility and reproductive endpoints NOAEL was determin ed to be 3000 ppm (equivalent to 1867 mg/kg/day). There were no effect s on in offspring survival, body weight and development up to post-natal day 4. A NOAEL of 9000 ppm (equivale nt to 5600 mg/kg/day) was concluded for developmental effects. No acute or subchronic neurotoxicity studies are available, but there were no signs of neurological effects observed in the database at high doses. Therefore, the Agency concluded that the developmental neurotoxicity study is not required. No immunotoxicity study is available, however, no systemic toxicity was obser ved in rats at high doses . In addition, no hazard has been identified following exposure to isobutan e. Based on this information, there is no concern at this time for increased sensitivity to in fants and children to isobutane when used as an inert ingredient in pesticide formulations and a safe ty factor analysis has not been used to assess risk. For the same reason, EPA has determined that an additional safety factor is not needed to protect the safety of infants and children.

VII. Endocrine Disruptors

As required under FFDCA section 408(p), EPA has developed the Endocrine Disruptor Screening Program (EDSP) to determine whether certain su bstances (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 eff ects as the Administrator may designate.” The EDSP employs a two-tiered approach to making the statutorily required dete rminations. Tier 1 consists of a battery of 11 scr eening assays to identify the potential of a chemical substance to interact with the estrogen, androge n, or thyroid (E, A, or T) horm onal systems. Chemicals that go through Tier 1 screening and are foun d to have the potential to inte ract 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 te sting is designed to identify any adverse endocrine related effects caused by th e substance, and esta blish a dose-response relationship between the dose a nd the E, A, or T effect.Page 14 of 19 Between October 2009 and February 2010, EPA issued test orders/data call-ins for the first group of 67 chemicals, which contains 58 pe sticide active ingredients and 9 in ert ingredients. This list of chemicals was selected based on the potential fo r human exposure through pathways such as food and water, residential activity, and certain post-application agricultural scenarios. This list should

not be construed as a list of know n or likely endocrine disruptors.

Isobutane was not among the group of 58 pesticide act ive ingredients on the initial list to be

screened under the EDSP. Under FFDCA sec. 408(p) the Agency must screen all pesticide chemicals. Accordingly, EPA anticipates issuin g future EDSP test orders/data call-ins for all pesticide active ingredients.

For further information on the status of the ED SP, the policies and procedures, the list of 67 chemicals, the test guidelines and the Tier 1 screening battery, pleas e visit our website: http://www.epa.gov/endo/

.

VIII. Exposure Assessment

A. Aggregate Exposure In examining aggregate exposure, the Federa l Food, Drug, and Cosmetic Act (FFDCA) section

408 directs EPA to consider available information concerning exposures from pesticide residue in food and all other non-occupational exposures, including drinking water from ground water or surface water and exposure through pesticide use in gardens, lawns, or buildings (residential and other indoor uses).

The primary route of exposure to isobutane from its use as an inert ingredie nt in pesticide products would most likely be through cons umption of food to which pestic ide products containing it have been applied, and possibly through drinking wate r (from runoff). Residential (dermal and inhalation) exposures from home garden uses are possible.

No hazard was identified for the acute and chronic dietary assessment (food and drinking water), or for the short, intermediate, and long term re sidential assessments, and therefore no aggregate risk assessments were performed.

For isobutane, a qualitative assessment for all pa thways of human exposure (food, drinking water, and residential) is appropriate gi ve the lack of human health con cerns associated with exposure to isobutane when used as an inert ingred ient in pesticide formulations.

B. Cumulative Exposure

Cumulative effects from substances with a common mechanism of toxicity. Section 408(b)(2)(D)(v) of FFDCA requires th at, when considering whether to establish, modify, or revoke a tolerance, the Agency consider “available info rmation” concerning the cumulative effects of a particular pesticide's residues and “other substanc es that have a common mechanism of toxicity.”Page 15 of 19 EPA has not found isobutane to share a common mechan ism of toxicity with any other substances, and does not appear to produce a toxic metabolite produced by other substances. For the purposes of this tolerance action, therefore, EPA has assu med that does not have a common mechanism of toxicity with other s ubstances. For information regarding EPA's efforts to determine which chemicals have a common mechanism of toxicity a nd to evaluate the cumulative effects of such chemicals, see EPA's website at ht tp://www.epa.gov/pesticides/cumulative

.

IX. Environmental Justice Statement

Potential areas of environmental ju stice concerns, to the extent possi ble, were considered in this human health risk assessment, in accordance w ith U.S. Executive Order 12898, "Federal Actions

to Address Environmental Just ice in Minority Populations an d Low-Income Populations," http://www.eh.doe.gov/oepa/ guidance/justice/eo12898.pdf

.

X. Environmental Fate and Ecotoxicity

If released to the environment, isobutane is ex pected to exist in the atmosphere as a gas and volatilize rapidly from surface water and soil. Th e chemical reacts with hydroxyl and nitrate radicals in the atmosphere with an estimated ha lf-life of 6.9 and 165 days, respectively. Estimated

volatilization half-liv es from a river and lake are 2 hour s and 3 days, respectively. Neither hydrolysis nor direct photolysis is an important fate process (MRID 47727602).

Data on potential toxicity to aquatic organisms we re not found in the avai lable literature. The toxicity values presented in Ta ble 4, estimated by EPIWIN v. 3.20, i ndicate that the chemical is moderately toxic to aquatic organisms.

TABLE 4. Estimated Toxicity Values to Aquatic Organisms

Species Duration End point Predicted concentration (ppm)

Fish 96-hour LC 50 8.317 Fish 14-day LC 50 16.998 Daphnid 48-hour LC 50 9.392 Green algae 96-hour EC 50 6.134

XI. Risk Characterization

Acute toxicity data on isobutane were limited to inhalation exposure and eye and skin irritation. Isobutane was not acutely toxic via the inhalation r oute and was basically non- irritating to the skin and eye of rabbits.

Several studies were found in which monkeys, rabbits , and rats were exposed to formulations or to mixtures containing isobutane. No toxicity wa s reported for two species of monkeys and one species of rabbits exposed for 90 days to va rious formulations c ontaining isobutane.Page 16 of 19 No effects on survival, body weight, hematology, c linical pathology, or liver and kidney weights were observed in rats were exposed to 0, 1000, or 4500 ppm (equivalent to 0, 623 or 2803 mg/kg/day) of a 50:50 mixture of isobutane: isopentane for 13 weeks, however clinical signs included hunched posture, lethargy and crusted eyes in both exposure groups. There were no clinical signs of toxici ty observed and no gross or microsc opic lesions seen in Sprague-Dawley rats were exposed to 0, 44, 432, or 4437 ppm (e quivalent to 0, 27, 269 or 2763 mg/kg/day) of a mixture containing 25% each of n-butane, isobutane, n-pentane, and isopentane for 3 weeks.

No chronic toxicity or carcinogenicity studies with isobutane were identified.

In a four week subchronic toxicity study comb ined with reproduction/developmental toxicity screening and neurotoxicity screening study, Sprague Dawley CD rats were treate d with isobutane (purity 99.0%) to assess the repeat ed dose, reproductive and devel opmental toxicity potential of this material when administered by whole body i nhalation exposure. A no-observed-adverse effect level (NOAEL) of 9000 ppm (e quivalent to 5600 mg/kg/day) was concluded for general systemic/neurotoxic (parental) endpoints in this study. Based on decreased male and female fertility and increased post-implantation loss in the 9000 ppm group, the fert ility and reproductive endpoints NOAEL was determined to be 3000 ppm (equivalent to 1867 mg/ kg/day). There were no effects on offspring survival, body weight and development up to post-natal day 4. A NOAEL of 9000 ppm was concluded for developmental effect s. No effects on FOB parameters and motor activity were observed in this study.

In terms of neurotoxicity, acute toxicity studies show effects on the central nervous system (CNS) with rodents more sensitive than dogs. Exposure to a concentration of 55% in was lethal in dogs,

while 41-52% was lethal to mice within 2-3 mi nutes. The 10-minute EC50 for CNS effects was listed as 200,000 ppm (equivalent to 124560 mg/kg/day) for the rat.

Several tests were found measuri ng the cardiopulmonary toxicity of isobutane. No effects were seen at 5% in anesthetized Rhesus exposed for 5 minutes to isobutane thr ough a tracheal cannula. Effects on the heart were shown in the dog with concentration-related d ecreased contractility, pressure, and output measured between 2-10%. Mongr el dogs were also anesthetized and exposed to isobutane through a tracheal cannula. Blood pr essure and heart rate were not affected by exposure. All concentrations significantly increased pulmona ry resistance and decreased pulmonary compliance. Similarly, anesthetized male Osburn-Mendel rats exposed to 27% showed apnea after 8.7 minutes of exposure followed by car diac arrest; decreased respiratory rate, tidal volume, and pulmonary compliance and increased ai rway resistance were also found. In another test with anesthetized male Swiss mice, is obutane did not induce cardi ac arrhythmia, but did sensitize the heart to epinephrine- induced arrhythmia at 20 and 40%.

No evidence of an increase in mutation freque ncy was found in five strains of Salmonella typhimurium exposed to up to 50% isobutane in air. Strains TA98, TA100, TA1535, TA1537, and TA1538 were exposed for 6 hours with and without metabolic activation

The uptake of various hydrocarbon vapors was determined in male F344/N rats exposed nose-only for 80 minutes on five consecutive days. Upta ke was 0.6-1.0 nmol/kg/min/ppm after exposure toPage 17 of 19 10 or 100 ppm. Isobutane and the metabolite tert-but anol were detected in the blood and several organs of male ICR mice after a 1-hour whole- body vapor exposure to isobutane. The metabolite

was also detected after isobutane was incuba ted with isolated liver microsomes.

Residues of concern are not anticipated for di etary exposure (food and drinking water) or for residential exposure from the use of isobutane for th e proposed use pattern as an inert ingredient in pesticide products. EPA expects aggregate exposur e to isobutane to pose no appreciable dietary risk given that the data on isobutane show a lack of any systemic toxicity at doses of up 3,000 ppm (equivalent to 1867 mg/kg/day) and a lack of any appare nt developmental effects.

Taking into consideration all available information on isobutane, EPA has determined that there is a reasonable certainty that no harm to any popula tion subgroup will result from aggregate exposure to isobutane when used as an inert ingredient in pesticide formulations applied during pre-and post-harvest and applied to animals when considering dietary exposure and all other nonoccupational sources of pesticide exposure for whic h there is reliable information. Therefore, the establishment of an exemption from tolerance under 40 CFR 180.910 and 40 CFR 180.930 for residues of isobutane (CAS Reg. No. 72-28-5) when us ed as an inert ingredients in pre- and postharvest and animal applications in pesticide fo rmulations, can be considered assessed as safe under section 408(q) of the FFDCA.

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