Page 2 of 19

Drug Administration (FDA) as Generally Recognized as Safe (GRAS) when used as a food 

ingredient and an earlier review considered it safe for use in cosmetics. 

Isobutane is an asphyxiant and acute exposure may cause tachypnea and tachycardia. While direct 

contact with the liquid may cause burns, the vapor has no effects on the skin and eyes. Sudden 

death has also been reported from abusive “sniffing” of products containing isobutane, especially 

lighter refills. In a safety assessment of isobutane as a cosmetic ingredient (1982), dermal 

irritation in humans was very slight and transient erythema occurred randomly. Repeated 

inhalation exposure did not result in any changes in electroencephalograms, adrenocortical 

function, pulmonary function, neurological 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 route 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 was reported for two species of monkeys and one 

species of rabbits exposed for 90 days to various formulations containing isobutane. 

No effects on survival, body weight, hematology, clinical 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 exposure groups. There were no clinical signs of 

toxicity observed and no gross or microscopic lesions seen in Sprague-Dawley 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 combined with reproduction/developmental toxicity 

screening and neurotoxicity screening study, Sprague Dawley CD rats were treated with isobutane 

(purity 99.0%) to assess the repeated dose, reproductive and developmental toxicity potential of 

this material when administered by whole body inhalation exposure. A no-observed-adverse effect 

level (NOAEL) of 9000 ppm (equivalent 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 fertility 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 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% isobutane was lethal in 

dogs, while 41-52% isobutane was lethal to mice 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 measuring the cardiopulmonary toxicity of isobutane. No effects were 

seen at in anesthetized Rhesus monkeys exposed for 5 minutes to 5% isobutane through a tracheal 

cannula. Effects on the heart were shown in the dog with concentration-related decreased 

contractility, pressure, and output measured between 2-10% isobutane. Mongrel dogs were also 

anesthetized and exposed to isobutane through a tracheal cannula. Blood pressure and heart rate 

were not affected by exposure. All concentrations significantly increased pulmonary resistance 

and decreased pulmonary compliance. Similarly, anesthetized male Osburn-Mendel rats exposed 

to 27% isobutane showed apnea after 8.7 minutes of exposure followed by cardiac arrest; 

decreased respiratory rate, tidal volume, and pulmonary compliance and increased airway 

resistance were also found. In another test with anesthetized male Swiss mice, 20-40% isobutane 

did not induce cardiac arrhythmia, but did sensitize the heart to epinephrine-induced arrhythmia. 

No evidence of an increase in mutation frequency 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 and potential exposure is adequately characterized 

given the low toxicity of the chemical. In terms 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 infants and children to isobutane when used as an 

inert ingredient in pesticide formulations and a safety 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 dietary exposure (food and drinking water) or for 

residential exposure from the use of isobutane for the proposed use pattern as an inert ingredient in 

pesticide products. EPA expects aggregate exposure to isobutane to pose no appreciable dietary 

risk given that the data on isobutane show a lack of any systemic toxicity via inhalation at doses of 

up 3,000 ppm (equivalent to 1867 mg/kg/day) and a lack of any apparent developmental effects. 

If released to the environment, isobutane is expected to exist in the atmosphere as a gas and 

volatilize rapidly from surface water and soil. Estimated volatilization half-lives from a river and 

lake are 2 hours and 3 days, respectively. Neither hydrolysis, nor direct photolysis, is an important 

fate process. Data on potential toxicity to aquatic organisms were not found in the available 

literature. 

Taking into consideration all available information on isobutane, EPA concludes that there is a 

reasonable certainty that no harm will result to the general public or to infants and children from 

aggregate exposure to isobutane when used as an inert ingredient in pesticide formulations. 

Therefore, the establishment of an exemption from tolerance under 40 CFR 180.910 and 40 CFR 

180.930 for residues of isobutane when used as an inert ingredients in pre- 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 isobutane when used as an inert ingredient (aerosol 

propellant) in pesticide formulations applied pre- and post-harvest under 40 CFR 180.910 and 

applied to animals under 40 CFR 180.930. EPA published the Notice of Filing for this petition in 

the Federal Register on October 7, 2009 (74 FR 51597). No comments were received in response 

to this notice. This document provides an assessment of the risk to human health and the 

environment for isobutane when used as an inert ingredient in pesticide formulations and was 

based on information provided by the submitter and information 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-dimethylethane; 2-methylpropane 

PC Code 800015 

Chemical formula C4H10

Chemical structure 

III. Use Information 

A. Pesticide Uses 

Currently, isobutane is listed on “Inert Ingredients Permitted for Use in Nonfood Use Pesticide 

Products.” It is widely used in nonfood use insecticide products, including repellents, foggers and 

pet care products. (MRID 47727606) 

B. Other Uses 

Isobutane is also widely used in other products as a propellant. It is used in auto products, such as 

tire inflators, battery cleaners and home maintenance products, such as spray paints and sealants. 

Several products used inside the home also contain 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 volatility, used as a reactant in the production of 

propylene oxide, and used as an aerosol propellant in a variety of products (MRID 47727602). 

The chemical is designated by FDA as Generally Recognized as Safe (GRAS) when used as a food 

ingredient and an earlier review considered it safe for use in cosmetics (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 used pre- and post-harvest 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 the lower explosive limit in air which is 1.8%, or 

18,000 ppm. None of the toxic effects reported in experimental animal studies occur below this 

concentration. Asphyxiation, tachycardia, and anesthesia can occur at higher concentrations. 

Administered alone, isobutane did 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-irritating to the skin and eyes and 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 effects. 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 cause tachypnea and tachycardia. While direct 

contact with the liquid may cause burns, the vapor has no effects on the skin and eyes (Carreón, 

2001). Case reports described life-threatening ventricular tachycardia after intentional or 

accidental inhalation of products, such as air freshener 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. Products containing 64.5-70% of a mixture of isobutane 

and propane were tested for skin irritation by application twice a day for 12 weeks; very slight and 

transient erythema occurred randomly and the reactions 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 electroencephalograms, adrenocortical function, pulmonary function, 

neurological response, subjective response, cardiac function or cognitive response (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 LC50 = 570,000 

ppm (15 min) 

IV MRID 47727602, 

MRID 47727604 

Acute 

inhalation 

mouse LC50 = 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 system (CNS) stimulation; all survivors 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 was instilled into one eye of male rabbits and 

rinsed after 4 seconds (MRID 47727604). Rabbits exposed in a closed setting to aerosol bursts of 

the 22% isobutane hair spray formulation showed no clinical effects, changes 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 exposed to formulations or to mixtures. 

No toxicity was reported for cynomolgus monkeys exposed for 90 days to a hair spray formulation 

containing isobutane (Expert Panel, 1982). Similarly, no adverse effects were seen in stump-tail 

monkeys exposed for 90 days to an aerosol spray deodorant containing a mixture of isobutane and 

propane; exposures were for 6 hours/day during which 1- or 5-second sprays into the chamber 

occurred at 42- or 21-minute intervals, 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 sprayed 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 chemistry, 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 effects on survival, body weight, hematology, clinical 

pathology, or liver and kidney weights were observed. Clinical signs included hunched posture 

and lethargy in 3 males at 4500 ppm and 2 males at 1000 ppm and crusted eyes in males and 

females of both exposure groups. At interim sacrifice after 4 weeks of exposure, males in both 

exposure groups showed a slight increase in severity, but not incidence, of mild hydrocarbon 

nephropathy. No differences in incidence or severity of kidney lesions were evident at terminal 

sacrifice (Aranyi et al., 1986; API, 1985). 

Ten male and 10 female Sprague-Dawley rats were 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, 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, hematology, and clinical pathology were found. No 

gross or microscopic lesions were seen, especially in the kidney (Halder 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 (SAR) database, DEREK11, to determine if there were structural 

alerts suggestive of carcinogenicity. No structural alerts were identified. 
Page 9 of 19

E. Subchronic Toxicity Study Combined with Reproduction/Developmental Toxicity 

Screening and Neurotoxicity Screening Study 

In a four week subchronic toxicity study combined with reproduction/developmental toxicity 

screening and neurotoxicity screening study, Sprague Dawley CD rats (12/sex/main study group 

and 12 females/satellite group) were treated with isobutane (purity 99.0%) to assess the repeated 

dose, reproductive and developmental toxicity potential of this material when administered by 

whole body inhalation exposure. The subchronic portion (main study) included neurotoxicity 

assessment for behavioral and motor activity toxicity potential. The reproductive/developmental 

portion of this study was referred to as the satellite study. 

The test substance was administered as a gas at target concentrations 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 exposed for a minimum of 28 days during mating 

and pre-mating periods. Main study female rats were exposed for once daily, 6 hours/day, 7 

days/week for 28 days. For the reproduction study, 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 condition 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 during 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 observed. Mated satellite females were weighed on 

gestation days 0, 7, 14, 20 and lactation days 1-4. Satellite females without 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, food consumption was recorded pretest and weekly 

during pre-mating period and if not mated, during the post-mating period. For pregnant or 

confirmed mated satellite females, food consumption 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 were 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 observational battery (FOB) included, sensory, 

neuromuscular, physiological, motor activity, clinical pathology (termination), 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 examinations, body weights, sexing and macroscopic 

observations. Physical examinations 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 examinations (internal and external) were done on F1 

pups found dead during lactation and 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 termination 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 hematology or coagulation values in test substance 

exposed male animals as compared to the air controls. Statistically significant increases in 

hemoglobin and mean corpuscular hemoglobin concentration 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 accompanying changes in the other hematology 

parameters, nor were there any similar differences in the other sex. In isolation, 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 differences 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 substance exposed males and decreases in phosphorus 

concentration in all test substance exposed females were seen but the absolute differences were 

relatively small, were not in an exposure level related pattern and there were no similar differences 

in the other sex. In isolation, these minor inter-group differences were not considered to indicate an 

effect of the exposures.” (The Petroleum HPV Testing Group, 2009) 

“There were no meaningful inter-group differences in organ weights in the test substance exposed 

animals as compared with air control animals. The 900 and 3000 ppm exposed males showed an 

increase in spleen weights (absolute 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 was 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 emphasis on the interstitial (Leydig) cells to detect 

any changes in cellular size or structure. No test article related findings were present.” (The 

Petroleum HPV Testing Group, 2009) 
Page 11 of 19

For satellite female animal observations, there was no effect of treatment on survival. All animals 

survived until the termination 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 differences 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 statistically 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 parameters, no parental systemic toxicity was observed. 

In the 9000 ppm group, 25% of the mated females did not become pregnant. Although not 

statistically significant, the reduction in male and 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%; range 87.5%-100%). A statistically significant (p < 0.05) exposurerelated increase in post-implantation 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 Functional 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 and female fertility and increased 

post-implantation loss in the 9000 ppm group, the fertility 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 and exposed for 5 minutes to 5 or 10% isobutane 

through a tracheal cannula (Belej et al., 1974; Aviado 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 compliance, and decreased respiratory minute volume. 

Effects on the heart were shown in the dog with concentration-related decreased 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 Belej, 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 pressure and heart rate were not affected by 

exposure. All concentrations significantly increased pulmonary resistance and decreased 

pulmonary compliance. Respiratory minute volume was decreased at 10%. Similarly, 

anesthetized male Osburn-Mendel rats exposed to 27% showed apnea after 8.7 minutes of 
Page 12 of 19

exposure followed by cardiac arrest; decreased respiratory rate, tidal volume, and pulmonary 

compliance and increased airway resistance 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). Administered alone, isobutane did not induce cardiac 

arrhythmia, but did sensitize the heart to epinephrine-induced arrhythmia at 20 and 40%. 

G. Neurotoxicity 

Acute toxicity studies show effects on the CNS with rodents more sensitive than dogs. In the dog, 

exposure to a concentration of 45% in air resulted in relaxation and 55% was lethal (Expert Panel, 

1982). In the mouse, CNS depression was observed at 15% in 60 minutes and at 23% in 26 

minutes, while 22-27% caused anesthesia in 8.7 minutes followed by respiratory arrest in 15 

minutes (MRID 47727602). Similarly, 35% for 25 minutes was an effective anesthetic in mice 

while 41-52% was lethal within 2-3 minutes (Expert Panel, 1982). The 10-minute EC50 for CNS 

effects was listed as 200,000 ppm for the rat (MRID 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 frequency 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-butanol 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 incubated with isolated 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 threshold effects to account for 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 infants and children. This additional margin of safety 
Page 13 of 19

is commonly referred to as the FQPA safety factor (SF). In applying this provision, EPA either 

retains the default value of 10X or uses a different additional safety factor when reliable data to 

EPA supports the choice of a different factor. 

EPA has determined that reliable data show the safety 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 and potential exposure is adequately characterized 

given the low toxicity of the chemical. In terms 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 reproduction/developmental toxicity 

screening and neurotoxicity screening study, Sprague Dawley CD rats (12/sex/main study group 

and 12 females/satellite group) were treated with isobutane (purity 99.0%) to assess the repeated 

dose, reproductive and developmental toxicity potential 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 (parental) endpoints in this study. Based on decreased 

male and female fertility and increased post-implantation loss in the 9000 ppm group, the fertility 

and reproductive endpoints NOAEL was determined to be 3000 ppm (equivalent to 1867 

mg/kg/day). There were no effects on in offspring survival, body weight and development up to 

post-natal day 4. A NOAEL of 9000 ppm (equivalent 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 observed in rats at high doses. In addition, no hazard 

has been identified following exposure to isobutane. Based on this information, there is no 

concern at this time for increased sensitivity to infants and children to isobutane when used as an 

inert ingredient in pesticide formulations and a safety 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 substances (including pesticide active and other 

ingredients) may have an effect in humans or wildlife similar to an effect produced by a “naturally 

occurring estrogen, or other such endocrine effects as the Administrator may designate.” The 

EDSP employs a two-tiered approach to making the statutorily required determinations. Tier 1 

consists of a battery of 11 screening assays to identify the potential of a chemical substance to 

interact with the estrogen, androgen, or thyroid (E, A, or T) hormonal systems. Chemicals that go 

through Tier 1 screening and are found to have the potential to interact with E, A, or T hormonal 

systems will proceed to the next stage of the EDSP where EPA will determine which, if any, of the 

Tier 2 tests are necessary based on the available data. Tier 2 testing is designed to identify any 

adverse endocrine related effects caused by the substance, and establish a dose-response 

relationship between the dose and the E, A, or T effect. 

 
Page 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 pesticide active ingredients and 9 inert ingredients. This list of 

chemicals was selected based on the potential for 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 known or likely endocrine disruptors. 

Isobutane was not among the group of 58 pesticide active 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 issuing future EDSP test orders/data call-ins for all 

pesticide active ingredients. 

For further information on the status of the EDSP, the policies and procedures, the list of 67 

chemicals, the test guidelines and the Tier 1 screening battery, please visit our website: 

http://www.epa.gov/endo/. 

VIII. Exposure Assessment 

A. Aggregate Exposure 

In examining aggregate exposure, the Federal 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 ingredient in pesticide products 

would most likely be through consumption of food to which pesticide products containing it have 

been applied, and possibly through drinking water (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 residential assessments, and therefore no aggregate 

risk assessments were performed. 

For isobutane, a qualitative assessment for all pathways of human exposure (food, drinking water, 

and residential) is appropriate give the lack of human health concerns associated with exposure to 

isobutane when used as an inert ingredient 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 that, when considering whether to establish, modify, or revoke 

a tolerance, the Agency consider “available information” concerning the cumulative effects of a 

particular pesticide's residues and “other substances that have a common mechanism of toxicity.” 
Page 15 of 19

EPA has not found isobutane to share a common mechanism 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 assumed that does not have a common mechanism of 

toxicity with other substances. For information regarding EPA's efforts to determine which 

chemicals have a common mechanism of toxicity and to evaluate the cumulative effects of such 

chemicals, see EPA's website at http://www.epa.gov/pesticides/cumulative. 

IX. Environmental Justice Statement 

Potential areas of environmental justice concerns, to the extent possible, were considered in this 

human health risk assessment, in accordance with U.S. Executive Order 12898, "Federal Actions 

to Address Environmental Justice in Minority Populations and 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 expected to exist in the atmosphere as a gas and 

volatilize rapidly from surface water and soil. The chemical reacts with hydroxyl and nitrate 

radicals in the atmosphere with an estimated half-life of 6.9 and 165 days, respectively. Estimated 

volatilization half-lives from a river and lake are 2 hours and 3 days, respectively. Neither 

hydrolysis nor direct photolysis is an important fate process (MRID 47727602). 

Data on potential toxicity to aquatic organisms were not found in the available literature. The 

toxicity values presented in Table 4, estimated by EPIWIN v. 3.20, indicate 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 LC50 8.317 

Fish 14-day LC50 16.998 

Daphnid 48-hour LC50 9.392 

Green algae 96-hour EC50 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 route 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 was reported for two species of monkeys and one 

species of rabbits exposed for 90 days to various formulations containing isobutane. 
Page 16 of 19

No effects on survival, body weight, hematology, clinical 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 toxicity observed and no gross or microscopic lesions seen in Sprague-Dawley 

rats were 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 combined with reproduction/developmental toxicity 

screening and neurotoxicity screening study, Sprague Dawley CD rats were treated with isobutane 

(purity 99.0%) to assess the repeated dose, reproductive and developmental toxicity potential of 

this material when administered by whole body inhalation exposure. A no-observed-adverse effect 

level (NOAEL) of 9000 ppm (equivalent 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 fertility 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 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 minutes. 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 measuring the cardiopulmonary toxicity of isobutane. No effects were 

seen at 5% in anesthetized Rhesus exposed for 5 minutes to isobutane through a tracheal cannula. 

Effects on the heart were shown in the dog with concentration-related decreased contractility, 

pressure, and output measured between 2-10%. Mongrel dogs were also anesthetized and exposed 

to isobutane through a tracheal cannula. Blood pressure and heart rate were not affected by 

exposure. All concentrations significantly increased pulmonary resistance and decreased 

pulmonary compliance. Similarly, anesthetized male Osburn-Mendel rats exposed to 27% showed 

apnea after 8.7 minutes of exposure followed by cardiac arrest; decreased respiratory rate, tidal 

volume, and pulmonary compliance and increased airway resistance were also found. In another 

test with anesthetized male Swiss mice, isobutane did not induce cardiac arrhythmia, but did 

sensitize the heart to epinephrine-induced arrhythmia at 20 and 40%. 

No evidence of an increase in mutation frequency 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. Uptake was 0.6-1.0 nmol/kg/min/ppm after exposure to 
Page 17 of 19

10 or 100 ppm. Isobutane and the metabolite tert-butanol 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 incubated with isolated liver microsomes. 

Residues of concern are not anticipated for dietary exposure (food and drinking water) or for 

residential exposure from the use of isobutane for the proposed use pattern as an inert ingredient in 

pesticide products. EPA expects aggregate exposure 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 apparent developmental effects. 

Taking into consideration all available information on isobutane, EPA has determined that there is 

a reasonable certainty that no harm to any population 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 which 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 used as an inert ingredients in pre- and postharvest and animal applications in pesticide formulations, can be considered assessed as safe 

under section 408(q) of the FFDCA. 

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