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TRI Box 567 

Prepped by Ryan Dugan 

Document Number: 

6DE1-003 

Docket Number: 

400119 

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UNITED STATES ENVIRONMENTAL PROTECTION AS^Gto t 

WASHINGTON, D.C. 20460 

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OGT 6 1997 OFFICE OF 

PREVENTION. PESTICIDES AND 

TOXIC SUBSTANCES 

MEMORANDUM 

Subject: 

From: 

To: 

Review of the Interactive Effects of Methyl Ethyl Ketone 

(MEK) with Neurotoxic Solvents: Response to OSHA/NIOSH 

Comments 

Lois Dicker, Ph.D., Chief .y^cExisting Chemicals Assessment Branch 

Risk Assessment Division (7403) 

Maria Doa, Ph. 

Toxic Release 

Environmental 

D., Chief 

Inventory Branch 

Assistance Division !7408) 

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Per your request (memorandum dated September 4, 1997), RAD 

has reviewed the letters, references, and other materials sent to 

EAD by NIOSH and OSHA concerning the interactive effects of MEK 

with neurotoxic solvents (RAD reviews attached). Epidemiological 

data involving acute exposures at low doses report no adverse 

effects related to co-exposure of MEK with MIBK, toluene, or 

acetone. There were no epidemiological data involving chronic 

exposures. Animal studies indicate that MEK alone produces only 

transient neurological effects at high vapor concentrations with 

no evidence of permanent damage to the nervous system. However, 

MEK in the presence of other neurotoxic solvents such as, nhexane and methyl-n-butyl ketone, appears to potentiate 

neurotoxicity. 

While the animal data support the potentiation of the 

neurotoxicity of other solvents by MEK, the data are inadequate 

to fully characterize the mechanism of action. While it is 

prudent to consider the potentiation of MEK in the workplace 

setting as pointed out by OSHA and NIOSH, RAD does not believe an 

accurate evaluation of effects due to MEK potentiation is 

possible under the TRI statute at this time. Lack of information 

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concerning human exposure scenarios and the composition of 

chemical mixtures at facility fencelines, as well as lack of 

information on the mechanism of action of MEK with other solvents 

all contribute to this. 

We v/ill however, in the future discuss when appropriate, the 

possibility of synergistic effects of a chemical in RAD 

hazard/risk assessments prepared for TRI listing/delisting 

requests. 

Attachments (2) 

cc: Vanessa Vu 

Oscar Hernandez 

Andrea Pfahles-Hutchens 

Deborah Norris 

Katherine Anitole 

Dan Bushman (7408) 

Carol Christensen (7408) 
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^

e0S * * . 

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY 

WASHINGTON, D.C. 20460 

OFFICE OF 

PREVENTION. PESTICIDES AND 

TOXIC SUBSTANCES 

September 17, 1997 

MEMORANDUM 

SUBJECT: Response to OSHA/NIOSH comments on MEK 

FROM: Andrea Pfahles-Hutchens f-^V\ 

TO: Oscar Hernandez 

THRU: Lois Dicke^^• r ^ 

I reviewed the package of materials from Maria Doa, dated September 4, 1997, on OSHA and 

NIOSH comments on MEK toxicity. The following are the conclusions that I have drawn based 

on the review of this package and its referenced material. 

Conclusions 

1. The epidemiological data on the potentiation of neurotoxic effects created by coexposure of 

MEK and other chemicals is very limited. However, the data that are available report no adverse 

effects related to exposure of MEK with MIBK, toluene, or acetone after acute, short-duration 

exposure. 

2. None ofthe reliable epidemiological data on MEK coexposure and another substance refer to 

chronic exposures. 

3. The occupational studies on MEK coexposure described in the OSHA and NIOSH letters 

involve workplace exposures to solvents which may be neurotoxins alone. 

4. The epidemiological studies either have not been performed, are inconclusive, or do not 

support the "significant" acute or "serious or irreversible" chronic health effects criteria needed to 

list MEK on the TRI List. 

5. NIOSH and OSHA are involved in studying and regulating the occupational environment, 

where it seems more appropriate to evaluate toxicity based on actual exposures in the workplace 

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(and thus cumulative or synergistic effects of chemicals). However, for the purposes of TRI, it is 

my opinion that this same approach cannot be applied to releases to the ambient air. 

Basis for conclusions 

The occupational studies that I reviewed did not report neurological effects associated with 

exposure to 200 ppm MEK or 100 ppm MEK + 50 ppm MIBK for 4-hours duration (Dick, et al., 

1992). Dick et al. also studied human subjects for interaction effects of MEK+toluene (1984) and 

MEK+acetone (1989) and reported no neuropotentiation effects related to short-term exposures. 

Hjelm et al., (1990) examined the neurotoxic effects of MIBK+toluene in a small number of 

human subjects but reported only sensory irritation. Smith and Mayers (1944) report on 2 case 

reports that involve coexposure to acetone and MEK; however, it is difficult to draw conclusions 

from these reports since the exposures are so high (combined of almost 1000 ppm) and it is not 

clear whether other substances were present in the workplace. 

I didn't review the studies on glue sniffing (Altenkirch, et al, 1977, and others) for several 

reasons: some of them were not in English, the constituents ofthe glue are not known and 

therefore the polyneuropathies reported cannot be attributed to any one substance or combination 

of specific substances, the exposures are abnormal and cannot be measured, the subjects are not 

reliable since it is difficult to determine their other exposures and life style factors that may have 

influenced the onset ofthe neuropathies. 

Van Engelen, et al. (1997) reported in a toxicokinetics study in humans that there is little effect of 

MEK coexposure with n-hexane after short-term, acute exposure and that interaction of MEK 

and n-hexane actually led to a decrease in concentration of 2,5 hexane-dione (the neurotoxic 

metabolite) as compared to n-hexane alone. This contradicts the supposed mechanism of action 

that has been described in the animal data. 

References 

Dick RB, Krieg EF, Setzer J, Taylor B. (1992). Neurobehavioral effects from acute exposures to 

methyl isobutyl ketone and methyl ethyl ketone. Fund Appl Toxicol 19:453-473. 

Dick RB, Setzer JV, Wait R, Hayden MB, Taylor BJ, Tolos B, Putz-Anderson V. (1984). Effects 

of acute exposure of toluene and methyl ethyl ketone on psychomotor performance. Int Arch 

Occup Environ Health 54:91-109. 

Dick RB, Setzer JV, Taylor BJ, Shukla R. (1989). Neurobehavioral effects of short duration 

exposures to methyl ethyl ketone. Br J Ind Med 46:111-121. 

Hjelm EW, Hagberg M, Iregren A, Lof A. (1990). Exposure to methyl isobutyl ketone: 

Toxicokinetics and occurrence of irritative CNS symptoms in man. Int Arch Occup Environ 

Health 62:19-22. 

Smith AR, Mayers MR. (1944). Poisoning and fire hazards of butanone and acetone. Ind Bull of 

NY23:S, 174-176. 

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 - Altenkirch H, Mager J, Stoltenburg G, et al. (1977). Toxic polyneuropathies after sniffing glue 

thinner. J Neurol 214:137-152. 

•> 

i:. van Engelen JG, Rebel-de Haan W, Opdam JJ, Mulder GJ. (1997). Effect of coexposure to 

methyl ethyl ketone (MEK) on n-hexane toxicokinetics in human volunteers. Toxicol Appl 

Pharmacol 144:2, 385-395. 

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UNITED STATES ENVIRONMENTAL PROTECTION AGENCY 

WASHINGTON, D.C. 20460 

SEP I 8 .'337 

OFFICE OF 

PREVENTION, PESTICIDES AND 

TOXIC SUBSTANCES 

MEMORANDUM 

SUBJECT: 

FROM: 

THROUGH: 

TO: 

> 6 o 

TRI Delisting of Methyl Ethyl Ketone 

Deborah Norris, Ph.D. 

Neurotoxicologist 

Science Support Branch 

Risk Assessment Division (7403 

Tom McClintock, Chief 

Science Support Branch 

Risk Assessment Divisio 

Oscar Hernandez, Deputy Division Director 

Risk Assessment Division (7403) 

««S>- ro*o ..'mJm 

CONCLUSION 

I have reviewed the memorandum of September 4, 1997 from 

Maria Doa regarding the toxicity of methyl ethyl ketone (MEK) and 

the letters and references attached. These documents support the 

conclusion that the neurotoxicity of MEK alone is not a 

significant concern. However, exposure to MEK at the same time 

as other solvents such as n-hexane may cause serious neurotoxic 

effects. Chemical mixtures can produce far different 

neurochemical effects, with different potencies from their 

individual components. This is the case for numerous chemicals. 

In the case of solvents such.as MEK, n-hexane, acetone, ethanol, 

methyl iso-butyl ketone (MiBk), methyl-n-butyl ketone (MnBK) and 

ethyl-n-butyl ketone (EBK), a metabolic mechanism of potentiation 

is postulated. 

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BASIS FOR CONCLUSION 

According to the ATSDR, 10,000 ppm MEK caused incoordination 

and narcosis in guinea pigs acutely exposed in a study by Patty 

et al. (1935). OSHA submitted two reports on the neurotoxic 

effects of MEK. A study by Ytakeuchi et al. (1983) showed slight 

increases in motor nerve conduction velocity and mixed nerve 

conduction velocity and a decrease in distal motor latency in 

rats exposed to 200 ppm MEK for 12 hours/day, 7 days/week. 

However, this slight effect was seen only at 4 weeks of exposure 

and did not occur again over 24 weeks of exposure. Studies of 

human occupational exposure submitted by OSHA are difficult to 

interpret. In one study, people were exposed to a mixture of 

solvents including MEK. In another study, people reported 

disabling dermatoses with numbness at exposures of 300 ppm to 600 

ppm. It is not clear if the numbness was due to contact 

dermatitis or other factors. 

The letter from NIOSH concurs with the EPA health assessment 

that "MEK alone does not cause peripheral neuropathy. 

The issue of concern is the synergism of MEK and other 

solvents such as n-hexane and MnBK. As stated in the ATSDR "the 

potentiation of the neurotoxicity of n-hexane and methyl-n-butyl 

ketone by. 2-butanone (MEK) is well-documented in animals". 

Evidence submitted by OSHA also indicates the potentially 

enhanced toxicity of solvents such as acetone, in the presence of 

MEK, in humans. In this report, women concurrently exposed to 

398-561 ppm MEK and 330-495 ppm acetone suffered from headache, 

confusion, loss of consciousness and convulsion. 

ATSDR and NIOSH propose a metabolic mechanism for these 

synergistic effects. Specifically, it is postulated that MEK 

enhances the production of the active metabolite of 2,5-

hexanedione in solvents such as n-hexane, ethanol, methyl-n-butyl 

ketone and ethyl-n-butyl ketone. 2,5-hexanedione is the most 

potent neurotoxic metabolite of n-hexane and other solvents. 

This is the same mechanism postulated to effect the enhanced 

neurotoxic actions of mixtures of MiBk with n-hexane, and MnBK 

with 0-ethyl 0-4-nitrophenyl phenylphosphonothioate (Abou-Donia, 

1992). While strong evidence exists for a metabolic mechanism of 

potentiation, the evidence is not definitive that metabolic 

activation is the only mechanism enhancing neurotoxicity. 

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REFERENCE 

Abou-Donia, Mohammed "Principles and Methods for Evaluating 

Neurotoxicity", in Neurotoxicology. Ed. M. Abou-Donia, CRC Press, 

Boca Raton, FL, 1992. 

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v>>^^ " % UN I T E D STATES ENVIRONMENTAL PROTECTION AGENCY 

WASHINGTON, D.C. 20460 i" *.-* \ 

SEP r 4 1997 

OFFICE OF 

PREVENTION. PESTICIDES AND 

TOXIC SUBSTANCES 

MEMORANDUM 

SUBJECT: Review of Toxicity of Methyl Ethyl Ketone (MEK) 

FROM: Maria Doa/ChiefV L 

Toxics Release Inventory Branch 

Environmental Assistance Division (7408) 

TO: Vanessa Vu, Director 

Risk Assessment Division (7403) 

Several weeks ago, Lynn Goldman asked us to contact OSHA to see whether that agency 

had information that could be helpful in our consideration of the petition for removing methyl 

ethyl ketone (MEK) from the Toxics Release Inventory (TRI). We requested assistance from 

both OSHA and NIOSH on the question raised by Lynn concerning possible neurotoxic effects of 

MEK and provided both agencies with copies of EPA's health assessment. 

As you will note from the attachments, both OSHA and NIOSH toxicologists expressed 

concern about interactive effects of MEK with neurotoxic solvents such as n-hexane and n-methyl 

butyl ketone (MnBK). Information on this is also found in the attached pages from the ATSDR 

on MEK. The information received indicates that MEK can interact with n-hexane and MnBK to 

increase those chemicals' release of 2,5-hexanedione, a metabolite which has been identified with 

neurotoxic effects. It would seem that the identification of this mechanism of action can be used 

to distinguish between this situation and a situation where the cause of potentiation of toxic 

effects of a chemical (or group of chemicals) is not known. 

The letter we received from NIOSH in reply to our request for review of EPA's hazard 

assessment states that: ^ 

As EPA has noted in this assessment, research has documented that MEK alone does not 

cause peripheral neuropathy. However, in combination with other chemicals that produce 

the reactive metabolite 2,5-hexanedione (2,5-HD), MEK potentiates the neuropathic 

effects of this metabolite, increasing the production of 2,5-HD. Two solvents [MnBK and 

n-hexane] have demonstrated this effect with MEK....No detailed mention of this 

potentiation appears in the [EPA health assessment] other than a brief statement on page 4 

of the Hazard Assessment of MEK, "Prior concerns were based on enhancement by MEK 

of neurotoxicity seen with other solvents." If neither MnBK or n-hexane are present in 

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the atmosphere with MEK, then the peripheral neurotoxic potential of MEK is minimal. 

We would appreciate RAD's review of the letters (including references and other 

materials) sent to us by NIOSH and OSHA and revision of the MEK health assessment as 

appropriate in light of the comments made by those agencies. Please let me know when your staff 

will have their review and possible revisions completed, as we are trying to issue a denial of this 

petition as soon as possible. Also, I believe that you indicated at the MEK briefing that you 

would provide information on MEK's neurotoxicity to Dr. Goldman, please forward a copy of 

what ever you provide to Dr. Goldman to Dan Bushman of my staff. Thanks. 

Attachments (3) 

cc:, Dan Bushman 

-^Carol Christensen 

Myra Karstadt 

Fred Metz (7406) 

Katherine Anitole (7403) 

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2-BUTANONE 

U.S. DEPARTMENT OF HEALTH & HUMAN SERVICES 

Public Health Service 

Agency for Toxic Substances and Disease Registry 

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34 

2. HEALTH EFFECTS 

Hepatic Effects. No studies were located regarding hepatic effects in • 

humfffTT after inhalation, oral, or dermal exposure to 2-butahone. Animal daca 

indicate that hepatic effects after high-level exposure to 2-butanone would be 

minimal in humans. Liver congestion was found in guinea pigs exposed acutely 

by inhalation to 10,000 ppm or more (Patty et al. 1935). Serum concentrations 

of hepatic enzymes were not changed in rats after 2-butanone exposures of 

300-5,000 ppm for 1-12 weeks (Cavender et al. 1983; Li et al. 1986; Schwetz 

et al. 1974). No lesions that could be linked to 2-butanone exposure were 

found following histological examination, although a slight increase in 

absolute and relative liver weight was noted (Cavender* et al. 1983). After 

exposure of rats to 800 ppm 2-butanone for 5 weeks, no changes were observed 

in the content of hepatic cytochrome P-450 or in the cytochrome P-450 isozyme 

profile (Toftgard et al. 1981). 2-Butanone, however, .altered the metabolism 

of androscenedione by increasing the formation of two metabolites and 

decreasing the formation of two other metabolites. Furthermore, liver weighc 

was increased in the 2-butanone-exposed rats (Toftgard et al. 1981). While no 

induction of microsomal enzymes was found in rats exposed to 2-butanone by 

inhalation, several studies have shown that 2-butanone has the ability co 

induce microsomal liver enzymes in rats after acute oral exposure (Brady ec 

al. 1989; Raunio ec al. 1990; Robertson et al. 1989; Traiger et al. 1989). 

These scudies also suggested that 2-butanone potentiates the toxicity of ocher 

chemicals, such as, carbon tetrachloride, n-hexane, m-xylene, and chloroform, 

by increasing their metabolism to toxic metabolites. While enzvme induction 

by icself represents a normal physiological response to a xenobiotic rather 

rhiin nn nl i i ,i i ffi i r. thr p^yi)*? induction by 2-bUCanon6 tian be viewed as" an 

.adverse effect if coexposure to other chemicals tor which 2-bUCanOrie 

potentiates toxicity by this mechanism occurs. Tneretore, humans working or 

1'iving nfifir ri-iTpr*-*"1"- "•"••'•'•* ni m where these chemicals are present along with 

2-butanone may be ac greater risk of adverse hepatic* e~tfeces, 

Renal Effects. Renal effects of 2-butanone exposure in humans would 

probably be minimal based on animal data. Kidney congestion was found irt 

guinea pigs exposed acutely by inhalation to 10,000 ppm or more (Patty ec al. 

1935). Cavender et al. (1983) assessed kidney function with measurements of 

blood urea nitrogen, urine volume, urine specific gravity, and pH after a 

90-day exposure co 5,000'ppm 2-butanone. All values were within normal 

ranges, and no histopathological lesions attributable to. 2-butanone exposure 

were found. Oral exposure of rats tp 1,080 mg 2-butanone/kg caused mild renal 

tubule necrosis but had no effect on renal organic ion transport or plasma 

creacinine; therefore, in spite of mild necrosis, normal kidney functions were 

not impaired. Exposure of humans to 2-butanone at hazardous waste sices is, 

therefore, not likely to result in severe kidney effects. _ 

Neurological Effects. The main neurological complaints of humans exposed 

occupationally to 2-butanone are headaches, dizziness! nausea, and fatigue 

(Lee and Frederick 1981; Lee and Parkinson 1982). However, chese symptoms 

were noc reporced in several inhalacion studies in which humans were exposed 

to 200 ppm of 2-butanone for 4 hours (Dick et al. 1984, 1988, 1989; Liira 

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35 

HEALTH EFFECTS 

ec al. 1988a, 1988b). In the occupational exposures cited, 2-butanone was 

combined with several other solvents; therefore, a neurological effect 

exclusive to 2-butanone cannot be inferred. Dick et al. (1984, 1988, 1989) 

found that exposure to 2-butanone had no effect on any neurobehavioral 

measurement. Nevertheless, early signs of narcosis and incoordination based 

on a battery of neurobehavioral tests were described in juvenile baboons after 

continuous exposure to 100 ppm 2-butanone for 7 days (Geller et al. 1979). It 

is also possible that the baboons were distracted during testing by the 

irritant effects of 2-butanone on the respiratory tract and were not, as the 

investigators concluded, in a state of narcosis. 

Narcosis and incoordination were also observed in guinea pigs exposed to 

10,000 ppm or more 2-butanone in air for a few hours (Patty et al. 1935). 

2-Butanone was not neurotoxic at lower concentrations in longer duration 

studies in animals. Rats continuously exposed to 1,125 ppm for 5 months 

showed no signs of peripheral neuropathy on histological examination (Saida 

et al. 1976). Altenkirch et al. (1978a) observed no clinical signs of 

neuropathy in rats exposed for 7 weeks to 6,000 ppm. No neurological effects 

were observed in rats exposed by inhalation to 5,000 ppm for 90 days (Cavender 

et al. 1983).. Alterations in nerve conduction velocity were seen in rats 

exposed by inhalation for 4 weeks to 200 ppm 2-butanone (Takeuchi et al. 

1983). The toxicological significance of this observation is questionable 

because normal nerve conduction velocities were observed at all time points 

beyond 4 weeks. No neurological effects were observed in rats after oral 

exposure to 1,725 mg/kg for 90 days (Ralston et al. 1985). Therefore, 

exposure of humans to 2-butanone alone in the workplace or at hazardous waste 

sices is not likely to result in serious neurological effects. 

e- Although exposure to 2-butanone appears relatively innocuous, this ketone 

is very hazaraous in comoxnation with other solvents. 2-Butanone markedly 

•potenciaces- the neurotoxicity of qthanol. n-hexane. methyl-n-butyl ketone^and 

ethyl-n-butyl kecone (Altenkirch et al. 1977; Cunningham et al. 1989; King •• 

ec al. 1985; Ralston et al. 1985; Robertson et al. 1989; Vallat et al. 1981). 

Glue formulations containing both 2-butanone and n-hexane caused."glue 

sniffers' neuropathy" (Altenkirch ec al. 1977; King et al. 1985; Vallat et al. 

1981). This neuropathy is characterized by motor nerve dysfunction, paresis, 

paralysis, muscular atrophy, and neural tissue morphology changes including 

paranodal axon swelling! neurofilamentous hyperplasia, and demyelination (see 

Section 2.6). Therefore,, humans working or living near hazardous waste sices. 

where methyl-n-butyl ketone, eChyl-n-butyL ketone. or n-hexane~is presenc or 

who Ittfqufei,Uly_use alcohol may be ar grsat-or ri cW fr>r npurnl ngi a.\ effects "if 

2-Sutanpne is also presenc. 

Developmental Effects. No studies were located regarding developmental 

effeces in humans following inhalation, oral, or dermal exposure to 

2-butanone. Inhalation exposure of rats and mice to 3,000 ppm during 

gestation resulted in fetotoxic effects, such as reduced fetal weight, 

skeletal variations, and delayed ossification (Deacon et al. -1981; Mast et al; 

<rm'! 

I'll. 

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40 

2. HEALTH EFFECTS 

identified that would be useful as biomarkers to characterize effects of 

2-butanone. 

2.6 INTERACTIONS WITH OTHER CHEMICALS 

The neurological and hepatic effects of 2-butanone alone are minimal. 

For certain applications, 2-butanone is combined with other chemicals that 

have serious neurotoxic or hepatotoxic effects. Clinical reports and animal 

studies have clearly shown that 2-butanone potentiates both the neurotoxicity 

of ethanol, n-hexane, and methyl-n-butyl ketone and.the hepatotoxicity of 

carbon tetrachloride and chloroform. 

Altenkirch et al. (1977) investigated a large outbreak of toxic 

polyneuropathies in a group of West Berlin "glue sniffers." The development 

of neuropathies (muscular atrophy, paresthesia, paresis, quadriplegia) 

coincided with a change in the composition of a glue that was popular for 

sniffing. Until the fall of 1975, the major constituents of the glue were 

n-hexane, toluene, ethyl acetate, and benzene.. At this, time, 2-butanone was 

added to the mixture and the sudden appearance of the toxic neuropathies 

began. 

A 39-year-old woman who had worked for several years gluing shoes 

developed polyneuropathy after a few weeks of work in a poorly ventilated shop 

(Vallat et al. 1981). The glue she was using contained 20X 2-butanone and 8%* 

n-hexane. 

"Glue sniffing neuropathy" was also described in a clinical case report 

of three men who had similar symptoms (King et al. 1985). All had been 

sniffing the same brand of glue containing light, volatile hydrocarbons 

(C6-C8), toluene, and 2-butanone; 2-Butanone had recently been added to the 

glue formulation, and the authors suggested that this may have increased the 

neurotoxicity. A change in the formulation of a solvent compound also 

precipitated a sudden outbreak of peripheral neuropathy in a coated fabrics 

plant (Allen et al. 1975; Billmaier et al. 1974). Methyl-n-butyl ketone 

introduced into a solvent used at the plant was implicated as the causative 

agent; however, the solvent also contained high concentrations of 2-butanone. 

Combined exposure to 2-butanone and methyl-n-butyl ketone has not been studied 

epidemiologically in humans; therefore, whether 2-butanone potentiates 

methyl-n-butyl ketone neurotoxicity in humans is not known (Katz 1985). 

The potentiation of the neurotoxicity of n-hexane and methyl-n-butyl 

ketone by 2-butanone is well-documented ih animals (Altenkirch et al. 1978a, *j 

1978b, 1982a, 1982b; Saida et al. 1976; Takeuchi et al. 1983). Altenkirch 

et al. (1978a) exposed rats to either 10,000 ppm n-hexane or a combination of 

1,000 ppm 2-butanone and 9,000 ppm n-hexane. A summary of three experiments 

under'these conditions showed that rats exposed to the combination of n-hexane 

and 2-butanone developed paresis more rapidly and in greater numbers than rats 

exposed to n-hexane only. In the same study, rats exposed to 6,000 ppm 

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41 

HEALTH EFFECTS 

2-butanone only showed no signs of neurotoxicity up to 7 weeks, when all the 

rats in this group died suddenly of bronchopneumonia. These results were 

confirmed in a second study; mixtures of 500 ppm n-hexane and 2-butanone (4:1 

or 3:2) or 700 ppm (5:2) caused clinical signs of neuropathy 1-5 weeks earlier 

than 500 ppm n-hexane alone (Altenkirch et al. 1982a). Histological 

examination revealed morphological changes in the rats similar to those found 

in youths suffering fro*** glue sniffing neuropathy, including paranodal axon 

swelling, accumulation of neurofilaments in the cytoplasm, and demyelination. 

Takeuchi et al. (1983) observed a significant decrease in motor nerve 

conduction velocity in rats exposed to 300 ppm n-hexane:2-butanone (1:2). In 

this study, motor nerve conduction velocity increased in rats exposed to 

200 ppm 2-butanone alone and did not change in rats exposed to 100 ppm 

n-hexane alone. Male Wistar rats exposed to n-hexane or a coipbination of 

n-hexane and 2-butanone developed ultrastructural changes in the 

intrapulmonary nerves characteristic of hexacarbon neurotoxicity (Schmidt 

et al. 1984). Concomitant exposure to n-hexane and 2-butanone decreased the 

onset of observable neuropatholpgical changes. 

Saida et al. (1976) reported a marked potentiation of peripheral 

neurotoxicity when rats were exposed*to methyl-n-butyl ketone*,2-butanone 

(225:1,125 ppm). Rats exposed to methyl-n-butyl ketone-only-developed-' 

paralysis by 66 days. The combination caused paralysis in 25 days, while 

2-butanone alone had no effect up to 5 months. Histological examination of 

neurons revealed morphological changes similar to those reported by Altenkirch 

et al. (1982a), which included paranodal axon swelling, accumulation of 

neurofilaments, and demyelination. Subcutaneous injection.of methyl-rn-butyl 

ketone with or without 2-butanone increased distal motor latency and decreased 

motor fiber conduction velocity in male Donryu strain rats (Misurai and Nagano 

1985). The combination of the. two ketones enhanced these effects. 

In vitro studies support the hypothesis that 2-butanone potentiates 

n-hexane and methyl-n-butyl ketone neurotoxicity. Veronesi et al. (1984)-

observed that, in tissues cultured from fetal mouse spinal cord,, dorsal' root 

ganglia, and muscle, the combination of 2-butanone and n-hexane produced giant 

axonal swellings more rapidly than cultures treated with n-hexane alone. 

Furthermore, cultures exposed tk nontoxic concentrations of n-hexane also 

developed giant axo'nal swellings when 2-butanone was administered 

concomitantly. 

•__ Biotransformation of both n-hexane and methyl-n-butyl ketone can produce 

"~2,5-hexanedione (Couri et al. 1978; DiVincenzo et al. ly/b; "Robertson et ai." 

l'uxmi Thic r*-.tr1pr.iimd_ is the most potent neurotoxic metabolite of n-hexane and. 

,-methyl-n-butyl ketone" known (Katz 1985~ ?-5utanone mav potentiate n-hexane^ 

and methyl-n-b-iifyl ketone neurotoxicity by enhancing their metabolic 

conversion to 2^j-hexanedione. Combined administration of metnyT^nPbutyl 

£—kettmS~"and 2-butanone produced mnr*? 7 ,5-hrirnnrrH nnr fhnn irlmini --rration of 

^---ffigtttyi-n-butyl ketone alone (Couri et al. 1978). The concentrations of the 

n-hexane metabolites 2,5-nexanedione and 2,5-dimethylfuran were significantly 

15 
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42 ' 

2. HEALTH EFFECTS 

higher in the blood and-sciatic nerve of rats pretreated by gavage with 

2-butanone followed by inhalation exposure to n-hexane compared with rats 

exposed to n-hexane alone (Robertson et al. 1989). In addition, concomitant 

oral administration of 2-butanone and 2,5-hexanedione in rats reduced blood 

2,5-hexanedione clearance (Ralston et al. 1985). 

Ethyl-n-butyl ketone is a weak neurotoxin (O'Dohoghue et al. 1984). Oral 

administration in rats for several weeks caused the paranodal axon swelling 

and neurofilamentous hyperplasia characteristic of n-hexane and methyl-n-butyl 

ketone neurotoxicity. Biotransformation of ethyl-n-butyl ketone produced two 

neurotoxic metabolites, 2,5-hexanedione and 2,5-heptanedione. 

2,5-Hepcanedione can be further metabolized to 2,5-hexanedione. Concomitant 

inhalation exposure to 700 ppm ethyl-n-butyl ketone and 700 ppm 2-butanone for 

4 consecutive days caused a 2.6-fold increase in the serum' concentration of 

2,5-heptanedione. Qral-adm-intstration of 2-butanone potentiated the 

development of p/l i,n*•*•'** 1 anri h. cr-plnf-Hr-al gift-rig of ethyl-n-butyl neurotoxicity,*^—*" 

2-Butanone- has also heart found to potentiate tha neurotoxicity of ethanol 

(Cunningham et al. 1989).Mice pretreated intraperitoneally witn i-butanone 

followed by intraperitoneal injection of ethanol 30 minutes later showed 

prolonged loss of righting reflex induced by ethanol. 2-Butanone also 

decreased the rate of ethanol elimination in mice in vivo and inhibited the in 

-vitro activity of alcohol dehydrogenase, the main mechanism for ethanol 

elimination. These results suggest that 2-butanone potentiated the • 

neurotoxicity of ethanol by inhibiting its metabolism by- alcohol . 

dehydrogenase. 

2-Butanone is not a universal potentiator of hydrocarbon- and aliphatic 

ketone-induced neuropathies (O'Donoghue et.al. 1982). Concomitant, oral 

administration of 2-butanone and 5-nonanone did not potentiate the . 

neurotoxicity of 5-nonanone»- ' .. 

[^Butanone alone is minimally neurotoxic (Altenkirch etal. 1978a; Saida 

et al. 1976). This, compound, however, is frequently mixed with n-hexane and 

methyl-n-butyl ketone-for various commercial and industrial applications. The 

previous discussion emphasizes the public health hazard of mixed solvent 

exposure to 2-butanone. Exposure to a mixed solvent is more likely to occur 

in an occupational setting or at a hazardous waste site, than exposure to 

2-butanone alone. 

2-Butanone alone is not highly hepatotoxic (see the discussion of Heggtic 

Effects in Section 2.2.1.2) but has a well-documented role in potentiating 

haloalkane-Induced hepatotoxicity (Brown and Hewitt 1984; Dietz and Tralger 

1979; HeVlLL ei al. 1963, 1986, 19&7; , Tanii et al. 1986). Intraperitoneal 

injection of chloroform (0.5 mL/kg) caused a nine-fold increase in rat SGPT 

activity (Brown and Hewitt 1984). In contrast, chloroform injection caused a 

195-fold increase in rat SGPT activity if administered 18 hours after oral 

administracion of 2-butanone. Similarly, intraperitoneal injection of 

<eJ I, 
P.18 

43 

2. HEALTH EFFECTS 

chloroform increased rat plasma ornithine carbamyl transferase activity 

215-fold if given 18 hours after oral administration of 2-butanone (Hewitt 

et al. 1983). In addition to the doses administered, the length of time 

between administration of 2-butanone and the chloroform injection determined 

the severity of hepatotoxicity (Hewitt et al. 1987). Measurements of SGPT and 

plasma ornithine carbamyl transferase revealed that 2-butanone is most 

efficacious for potentiation of chloroform-induced hepatotoxicity if 

administered 18 hours before chloroform. 

2-Butanone also potentiates carbon tetrachloride-induced'hepatotoxicity 

(Dietz and Traiger 1979; Traiger et al. 1989). Measurement of SGPT activity 

and hepatic triglyceride content showed that administration of 2-butanone 

16 hours before intraperitoneal injection of carbon tetrachloride 

significantly enhanced liver damage. The mechanism of 2-butanone potentiation 

of chloroform and carbon tetrachloride hepatotoxicity may be related to 

biotransformation of the ketone to its metabolite, 2,3-butanediol. Carbon 

tetrachloride increased rat SGPT 164-fold when injected 16 hours after oral 

administration of. 2,3-butanediol. Replacement of 2,3-butanediol with,. .... 

2-butanone increased the transaminase 66-fold. Hepatic triglyceride contentwas potentiated to a similar degree by both 2-butanone and 2,3-butanediol. 

However, the maximal potentiation of carbon tetrachloride-induced hepatic 

injury by pretreatment with 2-butanone coincided with increased microsomal 

enzyme activity within the same time frame following exposure to 2-butanone, 

alone (Traiger et al. 1.989). This strongly suggests that 2-butanone 

potentiates the hepatotoxicity of carbon tetrachloride by enhancing its 

metabolism to toxic intermediates. The mechanism of 2-butanone potentiation, 

of chloroform-induced hepatotoxicity apparently does not involve, 

biotransformation of chloroform to a reactive intermediate, an alteration of 

the cytochrome P-450 system, or depletion of liver glutathione (Hewitt etal. 

1987). It is possible that 2,3-butanediol also contributes to the toxicity of 

chloroform. 

Pretreatment of ddY mice with carbon tetrachloride 24 hours before oral 

administration of 2-butanone reduced the 2-butanone LD50 about 20X (Tanii 

et al. 1986). The mechanism of this effect was not investigated. 

Exposure of pregnant rats continuously to n-hexane alone 

(1,000-1,500 ppm) or n-hexane and 2-butanone (1,200 ppm n-hexane, 300 ppm 

2-butanone) throughout gestation and/or during the postnatal period resulted 

in reduced birth weight of pups, and weight gain reduction persisted during 

the postnatal exposure period (Stoltenburg-Didinger et al. 1990). The effect 

was more pronounced with the mixture of solvents. In addition, hindlimb 

weakness in. one dam during the gestational exposure period progressing to 

quadriplegia in all dams during the postpartum exposure period was for the 

solvent mixture, while only hindlimb weakness was observed in the dams exposed 

to n-hexane alone. 

)7 
P.19 

44 

2. HEALTH EFFECTS 

Coexposure of ?, cerevisiae to 2-butanone, ethyl acetate, and propionitrile 

enhanced the induction of chromosome loss caused by 2-butanone (Zimmermahn et al. 

1989). Coexposure of S. cerevisiae to 2-butanone and nocodazole enhanced the 

induction of aneuploidy caused by 2-butanone alone (Mayer and Goin 1987). 

2.7 POPULATIONS THAT ARE UNUSUALLY SUSCEPTIBLE 

No studies were located that identified populations that are unusually 

susceptible to adverse health effects after exposure to 2-butanone. The very young 

and the very old are typically more susceptible to chemicaL toxicity than are older 

children, adolescents, and healthy adults. Individuals that are alcoholics and 

those with existing liver disease would be expected to metabolize 2-butanone 

differently than the general population. Persons with existing.neuropathies may 

also be more susceptible. Exposure to both 2-butanone and n-hexane or 

methyl-n-butyl ketone is possible in occupational settings and at hazardous waste 

sites; thus, neurological effects of n-hexane and methyl-n-butyl ketone may be 

greater with coexposure to 2-butanone. Likewise, occupational exposure or exposure 

at hazardous waste sites to a combination of 2-butanone and the haloalkanes, carbon 

tetrachloride, or chloroform, presents a greater risk for liver damage. 

2.8 MITIGATION OP EFFECTS 

This section will describe clinical practice and research concerning methods for 

reducing toxic effects of exposure to 2-butanone. This section is intended to 

inform the public of existing clinical practice and the status of research 

concerning such methods. However, because some of the treatments discussed may be 

experimental and unproven, this section should not be used as a guide for treatment 

of exposures to 2-butanone. When specific exposures have occurred, poison control 

centers and medical toxicologists should be consulted for medical advice. 

2-Butanone has a low order of systemic toxicity. The main.effects in humans are 

irritation of respiratory tissues and eyes and nonspecific neurological effects, 

such as headache, dizziness, nausea, and fatigue. Such effects are characteristic 

of solvent exposure and are mitigated primarily by removing affected individuals, 

from exposure conditions and decontaminating exposed areas (Bronstein "and: Currance 

1988; Stutz and Janusz 1988). > For exampleP,contaminated clothing is removed and 

skin washed. If the eyes were exposed, they are flushed with water. For ingestion 

of 2-butanone, there, is controversy as to whether or not to administer emetics. The 

controversy centers around the risk of aspiration of vomitus into the lungs during 

emesis. Administration of activated charcoal has been suggested to reduce 

gastrointestinal absorption. Please refer to Bronstein and Currance (1988) and 

Stutz and Janusz (1988) for more complete information. — 

\ . AT though 2 butauuu" "•»"«•• jg nr»r. highly neurotoxic or hepatotoxic, it potentiates 

i__Ehe neurotoxicity of n-hexane and methyT-n-butyi ketone, and the hepatotoxicity of~ 

chloroform and carbon tetrachloride (see Section z.bj. Exposure to 2-butanone with 

other solvents isjftrp lik^y rhan exposure to 2-butanone alone in occupational and^ 

environmental settings. Since both n-hexane artd in-aLliylMi-tJuEyl ketone can be 

It 
45 

HEALTH EFFECTS 

P.20 

metabolized to 2,5-hexanedione (Couri et al. 1978; DiVincenzo et al 1976), a potent 

neurotoxic agent (Katz 1985), 2-butanone may potentiate the neurotoxicity of the 

other chemicals by enhancing the biotransformation of n-hexane and methyl-n-butyl 

ketone to 2,5-hexanedione by inducing microsomal enzymes. The potentiation of the 

hepatotoxicity of carbon tetrachloride and chloroform by 2-butanone may be related 

to the biotransformation of 2-butanone to 2,3-butanediol, a metabolite that 

potentiates the hepatotoxicity of carbon tetrachloride to a greater extent than does 

2-butanone (Dietz and Traiger 1979). Alternatively, the induction of microsomal 

enzymes by 2-butanone may enhance the biotransformation of chloroform and-carbon " 

tetrachloride to toxic intermediates (Brady et al. 1989; Traiger et al. 1989). If. 

carbon tetrachloride or chloroform shift metabolic pathways of 2-butanone in favor 

of greater formation of 2,3-butanediol, administration of an agent that blocks this 

shift could mitigate the potentiation. 2-Butanone is reduced to 2-butanol and 

oxidized to 3-hydroxy-2-butanone, which is further reduced to 2,3-butanediol 

(DiVincenzo et al. 1976). However, the enzyme systems involved in the 

biotransformation of 2-butanone have not been characterized. Similarly, if 

2-butanone enhances the metabolism of chloroform and carbon tetrachloride by 

inducing microsomal enzymes, agents that block this induction could mitigate this 

potentiation. 

2.9 ADEQUACY OF THE DATABASE 

Section 104(i)(5) of CERCLA as amended directs the Administrator of ATSDR (in 

consultation with the Administrator of EPA and agencies and programs of the Public 

Health Service) to assess whether adequate information on the health effects of 

2-butanone is available. Where adequate information is not available, ATSDR, in 

conjunction with the National Toxicology Program (NTP), is required to assure the 

initiation of a program of research designed to determine the health effects (and 

techniques for developing methods to determine such health effects) of 2-butanone. 

. The following categories of possible data needs have been identified by a joint 

team of scientists from ATSDR, NTP, and EPA. They are defined as substance-specific 

informational needs that, if met, would reduce or eliminate the uncertainties of 

human health assessment. In the future, the identified data needs will be evaluated 

and prioritized, and a substance-specific research agenda, will be proposed. .. 

2.9.1 Existing Information on Health Effects of 2-Butanone 

The existing data on health effects of inhalation, oral, and dermal exposure of 

humans and animals to 2-butanone are summarized in Figure 2-4. The purpose of this 

figure is to illustrate the existing information concerning the health effects of 

2-butanone. Each dot in the figure indicates that one or more studies provide 

information associated with that particular effect. The dot does not imply anything 

about the quality of the study or studies. Gaps in, this figure should not be . 

interpreted as "data needs" information. 

Studies regarding the adverse health effects of exposure to 2-butanone in humans 

is limited (Figure 2-4). No reports exist regarding death in humans 

n 
P.21 

46 

2 . HEALTH EFFECTS 

^IGURE 2-4. Existing Information on Health Effects of 

2-Butanone 

Inhalation 

Oral 

Dermal 

HUMAN 

3JP 
HEALTH EFFECTS 

following exposure to 2-butanone by any route. Existing information regarding . 

systemic effects of 2-butanone exposure have come primarily from two clinical 

reports involving accidental poisoning: one by oral exposure and one by 

inhalation (Berg 1971; Kopelman and Kalfayan 1983). A clinical study reported 

contact urticaria triggered by dermal exposure to 2-butanone in a 48-year-old 

male painter (Varigos and Nurse 1986). Intermediate dermal exposure to 

2-butanone had no effect on humans (Wahlberg 1984). Acute inhalation studies 

in humans showed no adverse neurological effects (Dick et al. 1984, 1988, 

1989). However, 2-butanone produced nose, throat, and eye irritation in 

humans (Nelson et al. 1943). Epidemiological studies showed no clear 

relationship between occupational exposure to 2-butanone and the development 

of neoplasms (Alderson and Rattan 1980; Wen et al. 1985). 

Animal studies regarding death after acute and intermediate exposure to 

2-butanone by inhalation, oral, dermal, and other routes are available. 

Several studies are also available that show that acute and intermediate 

inhalation exposures have minimal or no systemic.effects. Minimal effects 

were limited to small increases in organ weight (Cavender et al. 1983; 

Toftgard et al. 1981). Inhalation, oral, and dermal studies showed that 

2-butanone is minimally neurotoxic in most species. Guinea pigs exposed 

acutely to high concentrations (10,000 ppm) developed incoordination and 

narcosis (Patty et al. 1935). Juvenile baboons exposed to 100 ppm 2-butanone 

also appeared to show early signs of incoordination and narcosis in a complex 

discriminant neurobehavioral test (Geller et al. 1979). Histological 

examination of reproductive organs of male and female rats exposed by 

inhalation to 5,000 ppm revealed no effects (Cavender and Casey 1981; Cavender 

et al. 1983). Studies of acute oral exposure showed that 2-butanone caused 

renal tubular necrosis (Brown and Hewitt 1984; Hewitt et al. 1983) and induced 

hepatic microsomal enzymes (Brady et al. 1989; Raunio et al. 199.0, Robertson 

et al. 1989; Traiger et al. 1989). One intermediate oral exposure showed that 

2-butanone was not neurotoxic (Ralston et al. 1985). Acute and intermediate 

dermal exposures to 2-butanone were mildly irritating to the skin of rabbits, 

rats, and guinea pigs (Hazleton Laboratories 1963a; Wahlberg 1984). No 

reports of systemic toxicity are available for dermal exposure. Several 

studies demonstrating that 2-butanone is moderately irritating to the eyes of 

rabbits are available. 2-Butanone was fetotoxic, causing delayed development 

in fetuses of rats (Deacon et al. 1981; Schwetz et al. 1974) and mice (Mast 

et al. 1989) exposed by inhalation. 

Several studies are available regarding 2-butanone potentiation of 

n-hexane and methyl-n-butyl ketone neurotoxicity and 2-butanone potentiation 

of haloalkane hepatotoxicity. 

2.9.2 Data Needs 

Acute-Duration Exposure. Several studies are available that report the 

results of acute duration exposure to 2-butanone by inhalation, oral, and 

dermal routes in both humans and animals. In acute inhalation studies, an 

£' 
48 

HEALTH EFFECTS 

LC50 value in rats (LaBelle and Brieger 1955) and other exposures that caused 

death in rats (Klemisch 1988; Smyth et al. 1962), mice (LaBelle and Brieger 

1955),. and guinea pigs (Patty et al. 1935) were identified. The target organs 

identified in guinea pigs after acute inhalation exposure to high 

concentrations of 2-butanone are the respiratory system, liver, kidney, eye, 

and central nervous system Patty et al. 1935. Slight neurotoxicity was also 

seen in mice and baboons exposed to low concentrations (DeCeaurriz et al. 

1983; Geller et al. 1979). Narcosis and incoordination were observed, in 

guinea pigs exposed acutely to high concentrations of 2-butanone (Patty et al. 

1935). An acute-duration inhalation MRL was not derived'because target organs 

of rats and mice have not been sufficiently investigated. Although target 

organs of acute inhalation exposure of rats and mice have not been 

sufficiently investigated, intermediate duration studies indicate that effects 

on the liver, kidney, respiratory system, and nervous system of rats are 

minimal. In acute oral studies, LDS0 values for rats (Kimura et al. 1971; 

Smyth et al. 1962) and mice (Tanii et al. 1986) were available, and the kidney 

was identified as a target (Brown and Hewitt 1984). No acute oral MRL was 

derived because target organs have not been sufficiently investigated. 

Furthermore, inhalation studies indicate that 2-butanone is a developmental 

toxicant, but developmental effects after oral exposure were not studied. 

Acute dermal studies have shown that 2-butanone is a skin and eye irritant in 

rabbits (Hazleton Laboratories 1963a, 1963b) and guinea pigs (Anderson et al. 

1986; Wahlberg 1984), but the systemic toxicity of acute dermal exposure has 

not been investigated. The available pharmacokinetic data are not sufficient 

to predict whether target organs would be similar by the various routes of 

exposure. Acute exposure of humans near a toxic waste site to 2-butanone 

alone would probably not have serious clinical consequences. 2-Butanone is 

detectable by humans at concentrations far below its OSHA and NIOSH 

permissible levels because of its odor. Further acute exposure studies with 

2-butanone alone would probably not be useful. In contrast, further acute 

exposure studies by oral, inhalation, and dermal routes of 2-butanone combined 

with such hepatotoxins as chloroform and carbon tetrachloride, or with such 

neurotoxins as n-hexane and methyl-n-butyl ketone would yield valuable 

information on the potentiation of the hepatotoxicity and neurotoxicity, 

respectively, of the other chemicals by 2-butanone. These chemicals are often 

found together in formulations used occupationally and they'might be stored 

together at toxic waste sites. Therefore, workers and populations surrounding 

hazardous waste sites might be exposed to these substances for acute 

durations; 

Intermediate-Duration Exposure. A comprehensive 90-day inhalation study 

in rats showed that 2-butanone did not have adverse effects ih the 

respiratory, cardiovascular, gastrointestinal, musculoskeletal, hematological, 

hepatic, renal, or dermal/ocular systems (Cavender and Casey 1981; Cavender 

et al. 1983). The most serious effect was slightly increased liver weight at 

the highest concentration tested, 5,000 ppm. Occupational exposures to 

concentrations this high are unlikely since humans find* 350 ppm 2-butanone 

intolerable (Nelson et al. 1943). No signs of neurotoxicity, either clinical 

msA— *J* 
49 

HEALTH EFFECTS 

or histological, were observed in several studies of intermediate exposures to 

high concentrations of 2-butanone up to 6,000 ppm (Altenkirch et al. 1978a, 

1978b; Cavender and Casey 1981; Cavender et al. 1983). Therefore, most organs 

and tissues in humans probably would not be adversely affected by intermediate 

2-butanone exposures either occupationally or near toxic waste sites. An 

intermediate duration inhalation MRL was not derived because nose and throat 

irritation occurred in humans at acute inhalation exposure levels lower than 

the NOAEL values for intermediate duration inhalation exposure in animals. No. 

intermediate oral or dermal studies investigated the systemic toxicity of 

2-butanone by these routes, and the available pharmacokinetic data are not 

sufficient to predict whether target organs would be similar by the various 

routes of exposure. 2-Butanone has been detected in air,, water, food, and 

soil (see Section 5.4); therefore, exposures by the inhalation, oral,, and 

dermal routes are possible. From a public health perspective, exposure to 

solvent mixtures is more likely than exposure to a single pure chemical. 

Therefore, intermediate exposure studies of 2-butanone mixed with other 

solvents (hexacarbons and haloalkanes), the toxicity of which is potentiated 

by 2-butanone, would provide valuable information on neurotoxicity and 

systemic toxicity. This information is important since these chemicals are 

often found together in solvents used occupationally, and they might be stored 

together at hazardous waste sites where surrounding populations could be 

exposed for intermediate durations. 

Chronic-Duration Exposure and Cancer. flo studies were \qrftt-i-i. r^^arding 

, the health effects of chronic, exposure to 2-butanone by any route in humans -t£r<^"""" 

animals, but acute and intermediate dura*-*"" '•|,^

i-1 af, ',u_" viudles indicated that ^~ 

^-by—ttSelf, 2-butanone is minimally toxic. Pharmacokinetic data are 

'" insurticient to predict Llie uusbibly target organs of chronic exposure by any 

route. Since 2-butanone has been detected in air, water, food, and soil (see 

Section 5.4), exposures by the inhalation, oral, and dermal routes are 

possible. 2-Butanone is often found in formulations with other chemicals, 

such as chloroform, carbon tetrachloride, n-hexane, and methyl-n-butyl ketone, 

the toxicities of which 2-butanone potentiates. These chemicals may be stored 

together at hazardous waste sites. Chronic inhalation, oral,, and dermal 

studies in which animals are administered these chemicals in combination with 

2-butanone may provide dose-response information for the potentiation of the 

neurotoxicity and hepatotoxicity of these chemicals by 2-butanone. This 

information is important because there are populations surrounding hazardous 

waste sites that might by exposed tQ these chemicals for similar durations. 

Although no cancer bioassays were available, preliminary epidemiological — ^..i_., 

studies suggesc thac occupational exposure to 2-butanone does not increase the 

development of neoplasms. Furthermore, 2-butanone was not genotoxic, either 

with or without metabolic activation, in several microorganisms and cultured 

mammalian cells (O'Donoghue et al. 1988; Thorpe 1982). Furthermore, no 

induction of micronuclei was found in the erythrocytes of hamsters (Basler 

1986) or mice (O'Donoghue et al. 1988) after intraperitoneal injection with 

• j 

2.3 

 
50 

HEALTH EFFECTS 

2-butanone. On the basis of this information, 2-butanone does not appear to 

be carcinogenic. 

Genotoxicity. No induction of micronuclei was found in the erythrocytes 

of hamsters (Basler 1986) or mice (O'Donoghue et al. 1988) after 

intraperitoneal injection with 2-butanone. A comprehensive battery of in 

vitro, tests showed that 2-butanone was not mutagenic in two prokaryotic 

organisms and two eukaryotic organisms, did not transform mammalian cells in 

culture, and did not induce unscheduled DNA synthesis in rat primary 

hepatocytes (O'Donoghue et al. 1988; Thorpe 1982). 2-Butanone did not cause 

gene mutations in S. cerevisiae (Thorpe 1982), but caused mitotic chromosome 

loss (Whittaker et al. 1990; Zimmerraann et al. 1989) and aneuploidy in S, 

cerevisiae (Mayer and Goin 1987) at high concentrations. The positive 

induction of chromosome loss in the yeast cells was enhanced by coexposure to 

2-butanone, ethyl acetate, and propionitrile (Zimmermann et al. 1989). The 

positive induction of aneuploidy was enhanced by coexposure to 2-butanone and 

nocodazole (Mayer and Goin 1987).. Although 2-butanone contains an 

electrophilic center at the carbonyl carbon, further testing for genotoxicity 

does not seem warranted, except in combination with other solvents. 

Reproductive Toxicity. No studies were located regarding effects on 

reproductive capacity or reproductive organs and tissues in humans following 

exposure to 2-butanone. The authors of a health hazard evaluation report for 

NIOSH concluded that a perceived increase in the number of spontaneous 

abortions among female workers believed to result from exposure to 2-butanone 

and several other volatile chemicals at a shoe factory was not related to 

exposure (Tharr et al. 1982). No histopathological lesions were found in male 

or female reproductive organs of rats exposed to 5,000 ppm 2-butanone for 

90 days (Cavender and Casey 1981; Cavender et al. 1983), but reproductive 

function was not assessed. Further studies of the reproductive function of 

2-butanone by all durations and routes would provide valuable information 

particularly if the studies include histological examination of the organs and 

tissues of the reproductive system. If reproductive organs were identified as 

targets of 2-butanone toxicity,'single or multigeneration reproductive studies 

probably would be warranted. Since 2-butanone potentiates the neurotoxicity 

or hepatotoxicity of certain chemicals, it would be valuable to investigate 

the reproductive effects of mixed solvent exposures that include 2-butanone. 

This investigation would be useful because 2-butanone is often found in 

mixtures of other solvents in occupational settings, and these mixtures may be 

found together at or near hazardous waste sites. 

Developmental Toxicity. Information regarding developmental toxicity of 

2-butanone in humans was not located. 2-Butanone was slightly fetotoxic in 

rats (Deacon et al. 1981; Schwetz et al. 1979) and mice (Mast et al. 1989) 

following inhalation exposure of pregnant rats and mice to 3,000 ppm. The 

fetotoxicity was related to delayed development. Furthermore, five of eight 

pregnant rats exposed continuously to 800 ppm throughout gestation failed to 

deliver litters (Stoltenburg-Didinger et al. 1990). In addition, 

ab 
• *ltt VS- . 

1

19/97 TUE 16:1 9 i-Al 202 213 "<" 1 ii5 OShA rii? P.26 

FAX COVER SHEET 

DIRECTORATE OE HEALTH STANDARDS PROGRAMS 

OCCUPATIONAL SAFETY AND HEALTH ADMINISTRATION 

ROOMN-3718 

200 CONSTITUTION AVENUE, NW 

WASHINGTON DC 20210 

August 19,1997 

Pagelofl7„, 

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Organization;; 

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Telephone Number: 

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Cdihmenis on tbe EPA tepiort: 

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— • P?7 

OJ/19/97 TUE 16:20 FAl 202 219 7125 GSH.V-K3P • UL, . 

U S DeoartmOflt Of Labor Occupational Safety and Health Administration 

K

 Washington, O.C. 20210 

Reply to the Attention of*. 

Myra Karstadt, Ph.D. 

Office of Prevention, Pesticides 

& Toxic Substances 

U.S. EPA 

Washington, D.C. 20460 

Dear Dr. Karstadt: 

This is in reference to your letter dated August 1 to Dr. Finkel. In that letter you^ asked ustb " " 

review the Environmental Protection Agency's (EPA) report on asstssnier^6.f the jiealth effects.... 

of methyl ethyl ketone (MEK). Youspecifically wanted ui to'Joaisits cpmmer&Q&:: .;-?-:-

neurotoxicity. I would like to thankyou for giving us this opportunity tOHpreseifrourjyiewott-Pp 

thismatterv / --•-••.-•*.- ;.--•-- -y ,w:;-,.,p , P::> '-•'.- -^,.A :-

After reviewing the document sferif to us by you, we found it diffi ^ .', 

the original articles were submitted with the report. The EPApr6vided~H$ own.summarie^.ef P -

various documents it had used iii its regulatory process. These: summ&ies bynhemselves"(without 

the original articles) are inadequate to make any indqpendent judgemei^ld^etr^it ftbii wfial th^.7; 

EPA had concluded. "'''" -"I'

t

--

J:

 '-•-••- y-•••• >••"• --'- •'-'-

Occupational Safety.and HeahhAdihrms^^ 

describes tfie neurotoxicity of MEK alone. During the last proposed* rale making process on June"-

12,1992, OSHA..considered 2 studiesJhat dealt wiAjieuiotoxiceilect^MEK^-Wtaie^: -

presenting the conchmon of tl*^ ~-

In one ofthe studies,jrat^exposed tp a 200-ppm concentration of 2-butanone for 12 hours/days, 7 

days/week for 24 wetfcj^jK^ed slight and reversible neurological effects after 4 weeks of 

exposure (Takeuchi et aT; 1985)t A slight increase in motor nerve conduction velocity and mixed 

nerve conduction velocity and a decrease in distal motor latency.was observed at 4 weeks of 

exposure. However, no difference was observed after 4 weeks. It is not jpossible to determine thel 

significance of this increase?ui; motor nerve conduction velocity. 

In another studies, workers exposed to 2-butanone via inhalation and skin contact have been 

reported to experience dermatitis and numbness ofthe extremities (STmith and Mayers, 1944). 

Also, two young women exposed concurrently to 2-butanone at concentrations of 298 to 560 

ppm and„to acetonieat concentiations^f 3JO to 495 ppm exhibitedsignsefsevere intoxication,-

including convulsions andloss of Consciousness (Smith; 1944),,;This study only dealt with acute*: 

effects. 

:,\r 
'3*10-9 7 H E 16 : .10 FA-L '~'0~ -l a fl--"* vjon.i. M I P.28 

Based on the EPA's summaries ofthe literature, I agree mat there is no convincing evidence that. 

MEK is neurotoxic in either experimental animals or humans. However, there is also no 

eyidence presented by the EPA that rules out the MEK's neurotoxicity. 

We agree with the EPA that no peripheral neuropathy of sciatic nerve and intrinsic foot muscles 

was observed in rats continuously exposed to MEK (1125 ppm) for 16-55 days in a study by 

Saida et al. (1976). This study demonstrated that MEK exposure up to 5041 ppm did not 

produce any neuro-histopathological changes. Also, no evidence of peripheral 

neurohistopathological changes was seen in rats continuously exposed to 1125 ppm MEK for up 

to 5 months. Other studies have found no treatment-related central or peripheral 

neurohistopathology in rats exposed for 90 days (6 h/days, 5 d/wk) to MEK concentrations up to 

5041 ppm (Toxigenics, 1981; Cavender etal., 1983). ? 

However, I disagree with the report's conclusion on the significance of the study by Geller et al^ 

(1979) Geller et al. conducted Operant conditionings behavior test in baboons during exposure 

to 100 ppm MEK continuously for 7 days and compared it pre-exposure test scores. The operant 

behavior selected was a match-to-sample discrimination task and experimental protocol allowed 

the performance bf each baboon during exposure to be comparedtil^ during a.:. • 

clean air exposure in the same chamber immediately prior tt> each exposure. A decrease in mean 

response time and response during delay. But no significant^ectwas observed on accuracy. ' 

We agree with authors that this could be an early manifestation of incooVtinatiOT an*f rtait^sisv^ ' 

However, this conclusion is clouded by the fact these animals were p^rtbusly!exposed foother 

chemicals. This study may not be as inconclusive as the EPA has* stated;-We agree that it is notclear whether the observed.effect was produced by MEK alone or by MEK*sinteraction with--* 

other chemical. However, it is clear that MEK's had a sigmfieaBfrrbte in maiuiestationOf this '•'• 

effect either alone or by exacerbation ofthe effectsof other chemicals since&e;te$t scores were 

compared.with preexposure test scores. It is^urpris^thaitfiis study, was not repeated withv • 

MEK alone to ascertain the effect* of MEK»~. ••;-"-_; •-.-.•*•*.' :*•. : •••- y-•••-•••. A.A 

A similar study was conducted in male^ta^ et"i|F.;:1988). TheseP 

volunteers were exposed to 186 ppm for ^ Kburs. No* statistically sigmfi^t chafes in, *,.. 

neurobehavioral performance were observed. Sm^Uiis was'only aotAe exposure study-; it .ianofc- • 

possible to extrapolateto situations where^orkersmay be chronically exposed to MEK. ^ • • P 

•*•*•;-c?r> ZK -

The time weighted av^ge concentration of MEK in a group of :C*6rkerS in a printing, factory has-"-

been reported to ra$ge Jroni 1.43 to 223.7 ppjri, with a mean concentra.tion,Qf 47;.6 ppm" v* -.-.. :... 

(Yoshikawa et alv i995)i : Iathis'sttidy, personal exposure jgr^toring^wasricarried out ^*J,ftK .•impassive samplers during the work shift*.- Althoughthis isa Ja^anese^studyv-similar 

American workers.is quite poissible since OSHA's PEL is 200 pprn: An'aftefed operant^'; 

conditioning behavior test in baboons at 100 ppm in astudy by.GelfeT et'al.(W*9) mse^ncerns.r. 

at OSHA about workers health since this-is far below the currehtPEL. ^r--:-;.- ; • 

21 
J8/19/97 TUE 16:20 FAl 202 219 7125 Ciu,. 

The role of MEK in potentiating peripheral neuropathies caused by potent neurotoxins such as. 

hexane and methyl-n-butylketohe is well documented. MEK by itself may or may not have any 

neurotoxic effect, but its potentiating effects on other neurotoxin are unquestionable. 

Van Engelen et al. (1997) exposed volunteers to n-hexane (60 ppm) with or without 

simultaneous inhalatory coexposure to MEK (200 or 300 ppm) for 15.5 minutes. No effect of 

MEK was observed on the concentration-time course of exhaled n-hexane. The conentration-time 

course ofthe neurotoxic metabolite, 2,5-hexanedione, revealed a decrease in the rate of formation 

of 2,5-hexanedione (about threefold) after coexposure to MEK indicating that interaction of nhexane and MEK leads to a decreased concentration ofthe neurotoxic metabolite. Furthermore, 

the time to reach the peak concentration was increased from 18 to 30 minutes after the start of 

exposure. ..*•„ . ' 

Yasui et al (1995) injected rats subcutaneously with 2,5-hexanedione (2,5-HD 2.6 mmol/kg) 

alone or.with methyl ethyl ketone (2.6 or 13.0 m mol/kg) and dtferminedthe concentration of 

2,5-HD in serum and in the sciatic nerve 0.5,1,2,4,8 and 16 h after administration. They found 

that the concentration of 2,5-HD inthe serum, the sciatic nerve, and the urine was increased 

significantly in a dose-related manner in the co-administered groups: Also, tile clearance of 2,5-

HD from both serum and the sciatic nerve was delayed in the co-administration. The study by 

Van Engelen et al. (1985) observed that MEK reduced the production of a neurotoxic metabolite 

which would suggest a decrease in n-haxene toxicity in the presence of MEK. However, a study 

by Yasui et al. (1995) demonstrated that the MEK increases the availability of a neurotoxic 

metabolite at the target site(s). Since we know that MEK increase n-hexane induced 

neurotoxicity, later may be more critical steps in interaction between MEK and n-hexane. 

Under many occupational settings, n-hexane and MEK is likely to be present in a same mixture. 

Therefore, it would be more appropriate to consider the toxicity of n-hexane and MEK in a 

mixture than either of these chemicals individually. 

Thank you again for giving us the opportunity to provide comments. If you have any additional 

questions, please feel free to call me at (202) 219-7157. 

Sincerely 

s\>v«t~<9^-r^rt-< * * 

Surender Ahir, PhD 

Office of Risk Assessent 

enclosures 

3-1 
Copyrighted page/s removed. 

Please contact the EPA Docket Center, Public 

Reading Room to view this document. 

Address: 

1301 Constitution Ave, NW 

Room 3334 

Washington, DC 20004 

Telephone: 

202-566-1744 

Fax: 

202-566- 9744 

Email: 

docket-customerservice@epa.gov
'0$. 19. 97 TIE 16:23 FM 202 Hi Ti. 

welding fume 

fume dense to thi 

•Jon of 30 mg. m 

ily accepted max* 

ding fume Whe 

limit, visibility ' 

ution not presently 

jlaintj from work 

nit for total furn 

uards from nne 

rata oxide, oaon 

j . It is, therefore 

:never dense <*<ld 

lar 

rt ecently de 

fien. 

misting of a .. 

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ume laden air 

The size of pvunj 

\ so chosen that 

• produced by on 

ion of fume is 3( 

in 

rncasuremen mtc 

' - -rnal lineH> 

h 

'* 

Spaces 

meets in the pro 

velopment of sup 

liffer from air Hm 

uire the workmei 

-id mouth. Air i 

nets either aroun 

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wards, or in fron 

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mosphere of fresl 

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o aid in 

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it other forms 

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'•* continu***! 

INDUSTRIAL HYGIENE 

DIVISION OF INDUSTRIAL HYGIENE, NEW YORK STATE 

DEPARTMENT OF LABOR 

LEONARD GREENHJRG. M. O. EXECUTIVE pmtCTOE 

Aaprfeifad Jrom Thm Industrial Ouilrin UJIM-J uoch month oe Altai* by tho 

Industrial Commissioner of tha State of Sow York. Vol. 23; Wo. 3; May, IUi 

BONING AND FIRE HAZARDS OF BUT.VMONE 

AND ACETONE" 

A0U.AIOC ROSS SMITH, MO.. aa* MAY K. MAYtU. M.O. 

utaoonc, or meJiyi ethyl ketone (CH- CO C-H.), u 

effective solvent [or certain gums and resins, al^o 

cellulose acetate. As such it haa found consider. 

e use in industry, very often as a substitute to.-

n toxic solvents such as benzol. Animal expertnts with butanone, conducted by Patty, Schrenk. 

i Yam1, showed that its action is as a narcotic 

mucous membrane irritant, and that ic has a 

tuively low degree of toxicity. They found that 

concentration ot I per cent by volume in air 

,000 P.P.M.) could be tolerated for several houn 

experimental animals without serious disturbance, 

t-monem changes, in animals after exposure to 

concentrations were found to be: Marked contion of the brain, systemic organs and lungs, 

itation of the eyes and nasal passages was promit among the noted effects. No repons have been 

Ide of any harmful effects of butanone on humans. 

^fUttooe, or dimethyl ketone (CH.COCH.), also 

"efficient solvent for many organic compounds, has 

eived considerably more study than butanone-. It, 

has a narcotic action in high concentrations and 

an irritant to mucous membranes of the eye and 

piratory tract, but no acute cases of poisoning have 

reported' from industrial exposure. A fewcases have been described, characterized by 

eye and throat irritation with coughing, 

erate depression of the central nervous system 

headache. * 

Plant I—Exposure in Raincoat Manufaaure 

Recently a situation in which there was exposure 

both of these solvents simultaneously without exist ventilation of any kind was investigated by 

Division of Industrial Hygiene. Two cases of 

ite intoxication had developed under these circumaces. Since, so far as is known, acute industrial 

oxication due to these solvents has not been retted, it seems worthwhile to describe these cases 

a contribution to knowledge of die toxic potenualiof two commonly used solvents which arc geny considered to be relatively harmless, 

rhe exposure referred to occurred in the process 

waterproofing the seams of raincoats for the Army, 

iterials used for the purpose were two vinylite 

^in* one dissolved in butanone and the other in . 

tone. 

I*he compounds were applied with a brush to all 

in an operation known as brushing, - Each, 

received three brushing? at interval* of two, 

. In the tint two, acetone was the'solvent*, in 

_ third, butanone. . __ 

The room in which the operation of brushing was' 

rried on was approximately 30'x85' with a 12' 

fit aaaWita u d chtaucal ie»u' *••)•* atati* >y wiltUia >wkt. 

Mtato*vitt. »i%rl $. Tri*** nf *H. Divi.tA* nl TMiMfritt Ht^itnc 

„f. A. P»uv, oi fidtlir* »«4 U-MUiliy ta»w«Kt UITIMI A 

; • ' • * 

ceiling. It was done at tables 10" long with one or 

two brushen at each uble. Each brusher had before 

her an open eight-ounce jar containing the compound 

she was using. There were 59 table ia the room 

altogether, and 82 operator!. After brushing, the 

coats were hung up to dry on clothes racks located 

between the tables. Two thousand coats were ordinarily in the room at one time. 

Although there were windows on three sides of the 

room, in cooi weather only a few were opened. Air 

tests disclosed concentrations' of butanone ranging 

from 398 to 561 P.P.M. and for acetone from 330 to 

495 P.P.M. Since- vapon of both solvents were 

present in the air at the same time the accumulated 

concentration of both together was in the vicinity of 

1,000 P.P.M. Evidence of the toxic effect of such 

concentrations was, seen in the two acute episodes 

herewith reported. 

Two Cases of Acute Poisoning 

Case 1—I. H., a girt brusher, 18 yean of age, 

complained of gastric distress one ninrning ia January 

while at work. Her tablemate also noticed that her 

eyes were watering. In the afternoon she fdt wone 

and went to the rest room where, she was found 

unconscious a short time later. 

An ambulance was called and she was taken to 

a nearby hospital about 4:30 r. M. She was admitted 

in coma with a strong odor of acetone 6a the breath. 

This caused the admitting physician to suspect diabeta, but the urine was negative. Physical exaaina* 

tion was also negative except for occasional twitching 

of the face and extremities and hyperactive reflexes. 

Pulse 112. Temperature 98°. B.P. 128/70. Spinal 

up showed fluid under pressure—190 nun. mg. 

She was given a 6c c of conmin intravenously 

within an hour of admission and responded immediately. Her only complaint thereafter was severe 

headache. On the day after admission there were no 

objective signs. The headache subsided. She was 

discharged two days later. 

Case 2—M. M., likewise a girl brusher, aged 

19 years, fainted while at work the day following the. 

episode described above. The fainting was followed by 

a convulsion, after which she regained consciousness. 

She was taken to the same, hospital where the 

admitting physician found her mentally confused 

and complaining of headache. No evidence was 

found in either history or physical examination of 

any pre-existing condition which might have been 

responsible for the convulsion. After an hour's observation, she was allowed to go home and two diys 

"

 :T*teFsheijreturned to work. 

'?'. * • Fire Hazard 

One cannot omit mention of the serious fire hazard 

' which"H. associated with this type of work since these 

divans arc highly iiiAammAblc. 

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'08-19/9 7 Tl'E 16:2 4 FM 20J Hi '12 3 'JirtA HiP 

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In the plant under discussion, thousands ol coata, 

were found hung up to dry all over the mom—ail 

dose together; and all giving off solvent vapon. 

The workroom was also crowded with small tables 

on which, the solvent was applied to the raincoats. 

Any spark from a cigarette could have started a 

catastrophic fire in this room; and, once started, 

the fire would have swept rapidly from coat to coat. 

Any attempt on the part of the workers to flee the 

fire would have caused large numbers of the raincoats to drop off their hangars on top of them. The 

stage was perfect for a serious panic and great loss 

of life, despite the presence of fire exits at both ends 

of the room. 

Discussion 

Since vapors of both butanone and acetone were 

freely present in the air of the workroom, it is of 

coune impossible to ascribe the above effects solely 

to the action of one or the other. It must logically 

be assumed that they were the result of the cooabination of both. Both solvents act as narcotics, and 

both cases reported were characterized by central 

nervous system Involvement. 

This incident brings up the question of permissable 

concentrations of butanone and acetone vapors in 

the air of workrooms. No standards for butanone 

have as yet been published. Whether or not it is 

more, toxic than acetone cannot be detennined without further experience, but on the basis of is chemi. 

cal similarity to acetone (butanone being methyl ethyl 

ketone while acetone is dimethyl ketone) it seems 

likely that the two are of approximately the same 

order of toxicity and diat the same permissable limia 

for air concentration would be suitable for both.. 

Investigation bf suggested standards for safe concentrations for acetone in this country reveals a 

surprisingly wide variation, one which ranges from 

200 to 1,500 parts per million. If we assume that 

• butanone and acetone are of the same order of 

toxicity, the experience indicates that concentrates 

of either in the neighborhood of 1,000 P.P.M. are 

too-high. 

It may, of course, be that the combination of the 

two different vapon produces a synergistic effect 

which makes the two together more toxic than either 

one alone in equal concentrations. The possibility 

must be taken into consideration wherever there is 

exposure to two or more potentially tone substances 

at the same tune. 

Plant II—Exposure to Butanone in the Manufacture 

of Raincoat Material 

In the manufacture of the waterproof material 

from which these raincoats are made, there may be 

exposure to high concentrations of butanone (methyl 

ethyl ketone) unless proper precautions are observed. 

This process involves machine spreading, on a fabric 

base, of a jelly-like resin dissolved in this solvent. In 

the preparation of the jelly, and in the spreading 

operations, workers are exposed to varying amounts 

of the solvent, which is highly volatile and permeates 

the air of the workroom. Workers also tend to wash 

their hands, in the solvent. They also dip a wiping 

cloth into it with which they clean the spreading 

blades of their machines. These practices gready 

increase their exposure—in terms of direct skin contact and an opportunity to inhale high concentrations 

of the vapor*. 

•*5 

la one such plant, where air analyses 

concentrations of methy ethyl ketone rantinc 

300 P.P.M. to 600 P.P.M., workers developed 

abling dermatoses and several workers compl. 

of numbness of the fingers and arms. One v . 

described one shoulder as feeling "as though it 

made of dough, and did not belong to him" so 

he could not lie on it at night. Another *« 

complained of numbness in the legs and a ten 

for them to suddenly give way under him. _ • 

men who merely worked in the rooms where 3^ ? 

solvent was present in the air, but had no occai goto touch it, developed a dermatitis which origin* *)f* * 

on the face and was confined to that area: <•» -5 

Discussion Bperat 

The experience in this plant, where the expo* ^b^°. 

was to butanone alone in concentrations ranging fi *w''f ' 

300 to 600 P.P.M. when considered in the lighi

 tom*t

* 

Plant I, would seem to indicate very definitely i . *n<i 

these concentrations are too high. 

The complaints of numbness which might, otl '. 

wise have been, difficult of interpretation would » M*». 

to acquire significance in the light of. the n UL 

severe poisoning in the girls in Plant. I. In k ^ 

Instances, the nervous system was primarily invoh i 

Dermatitis venenata developing in workers fi ,' 

handling butanone is not uncommon. It is . IEFFT 

always necessary, however, for a worker to actu .- j; 

work with and touch a volatile solvent with his ha t 

in order to develop* a dermatitis. As in die cast -

the two workers above mentioned, a dermatitis of ' 

face or other exposed surfaces of the skin may den Ventil 

solely as a result of expoaure of the skin tb vap pden 

or finely atomized droplets in the air. Here vest jaibtc 

tion provides die solution to the dermatitis probl itilatk 

Control Measures * [j j Jj 

Ventilation—Adequate local exhaust ventilatsc- ^ p( 

a basic safety measure in exposure to these solve 4 ya( J 

In considering maximum allowable concentrati. n 

the occurrence of periodic surges in which there 1 . } pa o 

be brief exposures at specific points in the workit j 4^c a 

to much higher concentrations than are to be f 01 ^y- , 

in the room as a whole must be taken into acco* _ *t 

The maintenance of solvent vapon in the air be 4^' 0_ 

toxic limits, automatically prevents concentrati -^ 

which are explosive. , ope r 

Attention to stoppage of leaks from raachinn, < •jr.mf. 

ing rooms, and the like, is extremely important; 1 ;m• a 

also the dissemination of vapon into the workrc po f L 

from uncovered barrels or other solvent contain _ c c 

whether full or empty. m m 

The importance of ventilation in the control ^ngCC 

dermatitis has already been discussed. . *^n. 

Skin Protection—Aside from cleanliness of the s x ^ 

protective measures include the use of (1) gloves ^ ^^ 

sleeves; (2) protective water-soluble creama app j £-»,„ 

in advance of exposure and re-applied periodic jfortu 

during the day; (3) soothing creams and lotion ^j ^ 

be appUed after washing at the end of the day •„ * 

replace the fatty elements in the skin removed by [y *„, 

solvents in the course of the day's work; (4) disc t j w j 

tinuance of the practice of immersing uncovc ^ ^ 

hands in the solvent for any purpose whatever, inc! •eraj_ 

ing its use as a cleansing agent for the skin. TK*-— 

important not merely as a means of protecting CP.* 

skin, but also as a IHMW of p-dunn*; inhibitor ^_ 

35 1?5 

/ > : 
•)%• 19-9 7 TIE 16 : FAI.2 0 2 

naiyse* 

he ranging 

i developed 

ken eompl 

-s. One 

though it 

to him" so t 

at vapon. 

will 

Socae workers, once they have become 

__, never again be able to work with 

chemicals; othen may become "hardened" by 

mous exposure. 

Summary and Condusions 

,w >u_ — i_Evidence is presented of an acutely toxic effect 

Another wot m 4 combination of acetone and butanone vapon 

-s and a tende ^y i ethyl ketone) which together reached ap* 

J w:

- T oatimately 1,000 P.P.M. 

w .5 2—Evidence is also presented of low grade intoxihad no occas ,jon md dermatitis from exposure to butanone 

which origina i0t m concentrations ranging from 300-600 P.P.M. 

• 3—The inflammability of these solvents at room 

nperature suggests extreme caution in their use.. 

^ ^ 4—Concentrations of these solvent vapors, suffihere the expos ^ , o w t o prowc t

 ^ e health of workers, will 

^^ itomatically provide safe concentrations from the 

e and explosion standpoint. 

tions ranging 

td in the light 

i erf definitely 

-hich might ©ti aaraumcas 

•tation would s« •?"•

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 ,

W B r " *" M>* Mr* to tpe n <*H »• « ov* coMmraal •rtw itrht of the m m. !•»••»••. th*. *»»«••. a.**, w i, i m 

PI nt I I n b *mi*

m

'

 AUc*: u<,

»

u W T«n«oto*|*f. Hupn , IS<H. 

primarily involv , 0 . 

i in worken fr 

mmon. It is EFFECTIVE CONTROLS OF HAZARDS 

worker to acta IN WELDING, FLAME CUTTING 

vent with his ha AN D METALLIZING* 

As in the case , •»,.„ . ' 

, a dermatitis of »T Arthur C Stem 

he skin may deve Ventilation of confined spaces requires special 

the skin to vap uideration. Respiratory protection of the types 

! *ir. Here* vent Bribed is the best method of control. General 

uatitis probh ablation of spaces under 5,000 cubic foot should 

t be left tb natural ventilation, even in part, but 

^ .. . juld have the entire ventilation load handled by 

xhaust ventilanoi ^ Fo r ^ ^ jpac o ^ {o r ^ mtex\or of tan ks 

« to these solve a ^ veruiiation of the order of from 750 to 1,500 

able concentrati' n ^ wdde r ^p^ent, good practice. The smaller 

vn which there B E jpaCft die gn^cx is the hazard from fume and 

nts in the *TM**° s accumulation. Notwithstanding any minimizing 

han are to be tot voiding hazards that may seem apparent in this 

taken into accov _ ^ it mm t -^ j^d ^ d m gases such as nitrous 

on us the air be [^ otCM u d c^jton monoxide which offer little 

-ents concentrau ^ d « die low dilutions encountered in work in 

, . e open room may become highly concentrated and 

from machines, a ,,0 ^ dangerous to a man welding inside a tank 

aely important; a ; M ^ ima|1> improperly ventilated room. 

1

 tnto the workro FoT ^ ventilation of enclosed or small spaces in 

:t solvent contain jp construction- work, several special fans and 

• . , . swen have appeared on the market. They are 

QnTM * e

 "Otrol ^^ d with multiple inlet or outlet connections 

u

f

se^;. , . , r three, four, six or any number of flexible hoses. 

cleanliness of the sl le mump-dots is that the various welden will 

USe Of (I) glOVeS S rK * m n » . h*. ~ — fl^rrW- k« » fnr KM * wntiliMnri 

(I) gloves s ch «tange his own flexible hose for best ventilation 

oluble crcama appl d thus a number of workmen may bc protected, 

re-applied periodic ,fortunately each welder and foreman is not a 

creams and lotton**! n,y»tion engineer so that the usual result U that 

he end of the^day tui wWc n WM originally overrated, becomes woeie skin removed by ^ madequatc as additions and bends are added 

ay's work; (4) disc d« hose, kinks and leaks develop, and sections of 

unmening uncove K ^ m cnuhed and otherwise obstructed. In 

ipose whatever, mcl ^ die means of ventilation should either be 

it the skin. Th i > 

.«. jf protecting C»»«ta«*** froa p*«« l«a. Ap*U ISM ina* of Turn Imam* , 

reducing inhalation J"""* 

* 176 

properly engineered and permanently installed or, 

it permanent installation is impossible, for -f*k 

temporary setup, the choice of fan, nuinber of 

hoses pex fan, hose diameter and length, and type 

and placement of hood should be delegated to the 

care of a trained ventilation man. This man should 

be supplied with sufficient accurate dau about each 

fan, hood and size of hose employed so that he can 

make aecurrate on-the-spot estimates of the performance of each such temporary setup. Workmen 

should not be allowed to start work until the ventilating man completes his setup and gives the go-ahead 

signal to the welders. Shipyard experience points 

:o the value of using both supply sod exhaust air 

to double-bottona and similar spaces rather than 

exhaust alone. The supply air should, of course, 

be taken from out-of-dctors, rather than from some 

other pan of the ship, and, where possible, semi, 

permanent solid metal supply ducts should be extended tb plenum chamben strategically located 

about the ship, from, which local supply may be 

taken as needed. 

Ventilation ia Factories 

For ordinary factory work exhaust alone will 

suffice, since windows, doon and kxtvered will 

openings can supply sufficient make-up air without 

excessive pressure drop. Where exhaust only is 

used, it may take the form of either beal exhaust, 

as near as possible the point of weld, or of general 

room ventilation. Local exhaust n generally feasible 

only when welding is done on a production baas oa 

bencha. It is sometimes attempted oo productioa 

work of more extensive character, by having* the 

welder move the exhaust hood as he mova about. 

the work, but. this is not usually very satisfactory 

insofar as the welder is prone to weld too far 

from his hood before moving it, or to neglect to 

move it at aL Tables have been prepared and, 

even, incorporated in codes specifying the relation 

between air quantity to be exhausted and distance 

from hood to weld. However, for the reasons above 

noted, it is preferable to base all local exhaust for 

welding on the more fundamental basu of the maintenance of an air velocity at the point of weld of 

100 lineal feet per minute away from the breathing 

tone of the welder and towards the hood, booth or 

enclosure provided. 

Standards for general room ventilation are very 

difficult to formulate in the abstract. One reasonable criterion is to require not less than four air 

changes per hour, supplied either by natural ventilation, mechanical venulation or both. The recently 

issued New Jersey Department of Labor Welding 

Protection Standards also recommend that welding 

bays should not be structurally blocked thereby 

obstructing cross ventilation and that there should 

be provided either a space, allowance of 15,000 cubic 

feet per welder or ventilation of at least 350 cfm 

per welder. 

The general conclusions concerning welding hazards and their control are, therefore, that by wearing 

of oroper protective clothing, goggles and helmets 

and providing adequate ventilation, welding, cutting 

and metallizing can be undertaken in industry without hazard to the workmen involved. 

>-•*—« ^ * ^ •3(e 

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0 3-19 , 97 TUE 16:2 5 FM 102 Hi 71 US 

document http*.'/se«rch t heaM>^»ie.c0ra/cgij,jtv af.totrnut.cgi 

| leSH Heading (Major) 

Alcohol, Ethylj*BL; Alcohols, Butyl|*; Carcinogensl*; Chromatography, Gas|*MT/ST 

leSH Heading 

Butanones; Forensic Medicine; Human; Postmortem Changes 

I 'ublication Type 

JOURNAL ARTICLE 

SSN' 

0379-0738 

Country of Publication 

IRELAND 

CAS Registry/EC Number 

0 (Alcohols,'Butyl); 0 (Butanones); 0 (Carcinogens); 64-17-5 (Alcohol, Ethyl); 75-65-0 (tert-butyl 

alcohol); 78-93-3 (methylethyl ketone) 

Record 3 from database: MEDLINE 

Order full text for this document 

Title 

Biological monitoring of occupational exposure to methyl ethyl ketone in Japanese workers. 

Author 

Yoshikawa M; Kawamoto T; Murata K; Arashidani K; Katoh T; Kodama Y 

Address 

Division of Occupational Hygiene, School pf Nursing and Medical Technology, University of 

Occupational and Environmental Health, Kitakyushu, Japan. 

Source 

Arch Environ Contam Toxicol 1995 JuL 29:1, 135-9 

Abstract 

The relationship between occupational exposure to methyl ethyl ketone (MEK) and its concentration 

in urine and blood was studied in a group of 72 workers in a printingjactory. Personal exposure 

monitoring was carried out with passive samplers during the"workshifts. The time weighted average 

(TWA) concentration of MEK ranged from 1.3 to 223.7 ppm-, with a mean concentration of 47.6 

ppm. In addition to MEK, toluene, xylene, isopropyl alcohol, and ethyUcetatewere detected as the 

maSnTcontaroinants in all samples. At the end ofthe workshift, urine samples were collected to ,. 

determine the urinary MEK, hippuric acid (HA), and creatinine, and blood samples were also 

collected at the same time for determination of MEK. The concentrations of urinary MEK ranged 

from 0 20 to 8.08 mg/L with a mean of 1.19 mg/L and significantly correlated with TWA 

concentrations of MEK in the air with a correlation coefficient of 0.889 for uncorrected urine 

samples. The concentration of MEK in the blood was also significantly correlated with the TWA 

concentration of MEK with a correlation coefficient of 0.820. From these relationships, MEK 

concentrations in urine and blood corresponding to the threshold limit value-TWA (200 ppm; 

3 7 

8/7'97 2:33 PM 
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ACGIH 1992) were calculated to be 5.1 mg/L and 3.8 mg/L as a biological exposure index (BEI), 

respectively. Although the BEI for urinary MEK obtained from the present study was higher than 

that of previous reports and ACGEHTs recommendation (2.0 mg/L), the BEI agreed well with a 

previous study in Japaa(ABSTRACT TRUNCATED AT 250 WORDS) 

Language of Publication 

English 

Unique Identifier 

9S3143S2 

Order full text for this document 

MeSH Heading (Major) 

Butanones!* AE/AN; Environmental Monitoringl*; Occupational Exposure|* 

MeSH Heading 

Adult; Aged; CreatininelUR; Female; Hippurates|UR; Human; Japan; Male; Middle Age;'Reference 

Standards; Solvents|AN/ME 

Publication Type 

JOURNAL ARTICLE 

ISSN 

.0090-4341 

Country of Publication 

UNITED STATES 

CAS Registry/EC Number 

0 (Butanones); 0 (Hippurates); 0 (Solvents); 495-69-2 (hippuric acid); 60-27-5 (Creatinine); 78-93-3 

(methylethyl ketone) 

Record 4 from database: MEDLINE 

Order lull text for this document ' 

Title 

Effect of coexposure to methyl ethyl ketone (MEK) on n-hexane toxicokinetics in human volunteers. 

Author 

van Engelen JG; Rebel-de Haan W; Opdam JJ; Mulder GJ 

Address 

Division of Human Toxicology, University of Amsterdam, Academic Medical Centre, The 

Netherlands. 

Source 

Toxicol Appl Pharmacol, 1997 Jun, 144:2, 385-95 

Abstract 

In order to study the effects of methyl ethyl ketone (MEK) on the toxicokinetics of n-hexane and, in 

particular, the fonnation of 2,5-hexanedione from n-hexane in humans, volunteers were exposed to 

3$ 

8/7/97 2:33 PM 
oS< 1-9 -'97 TUE 1 6:26 FAI 202 219 7125 OSHA H5P 

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n-hexane (approx, 60 ppm, 2.4 microM in the inhaled air) with or without simultaneous inhalatory 

coexposure to MEK for 15.5 min. The concentration-time course of n-hexane (in exhaled alveolar 

air) and its neurotoxic metabolite, 2,5-hexanedione (in serum), were studied. The concentration-time 

courses obtained after exposure to n-hexane alone were compared with those obtained after 

coexposure to 200 or 300 ppm MEK in the same volunteer on the same day. No effect of MEK was 

observed on the concentration-time course of exhaled n-hexane. The concentration-time course of 

the metabolite, i.ii-hexanedione, revealed a decrease in therate of formation of 2,5-hexanedione 

(about three-fold) after coexposure to MEK. Furthermore, the time to reach the peak concentration 

waMncreased from 18* to~3^Tmmafter the start of exposure. These changes in the concentration-time 

course of 2,5-hexanedione caused by MEK are most likely the result of inhibition ofthe 

biotransformation of one ofthe mtermediate steps in the conversion of n-hexane to 2,5-hexanedione. 

These results indicate that the interaction of n-hexane and MEK leads to a decreased concentration 

ofthe neurotoxic metabolite 2,5-hexanedione (after short-term, acute exposure). 

anguage of Publication ' 

English 

nique Identifier 

•97337729 ' 

Order full text for this document 

vleSH Heading (Major) 

Butanones|AD/*PD;Hexanes|AD/*PK/*TO 

VleSH Reading 

Administration, Inhalation; Adult; Biotransformation|DE; Blood Chemical Analysis; Breath Tests; 

Drug Interactions'; Female; Human; Male; Maximum Permissible Exposure Level; Models, 

Biological 

c-ublication Type 

JOURNAL ARTICLE 

iSSN 

0041-008X . 

Country of Publication 

UNITED STATES 

CAS Registry/EC Number 

0 (Butanones); 0 (Hexanes); 110-54-3 (n-hexane); 78-93-3 (methylethyl ketone) 

Record 5 from database: MEDLINE 

Order full text for this document 

Title 

Influence of different doses of methyl ethyl ketone on 2,5-hexanedione concentrations in the sciatic 

nerve, serum, and urine of rats. 

39 

8/7/97 2:33 Pt 
08-'19-97 TIE 16:26 FAX 202 219 "125 OSHA-iiSF *~. " ~

£AL 

t ' ? 

Jocyment

 hnP;/^se«cKI.hcslth'jate.com/egi.bin/>torm*it.cgi 

athor 

Yasui T; Zhao W; Misumi J; Aoki K; Sbimaoka A; Kudo M 

ddress 

Department of Public Health and Hygiene, Oita Medical University, Japan. 

)urce 

Sangyo Eiseigaku Zasshi, 1995 Jan, 37:1, 19-24 

bstract 

Rats were injected subcutaneously with 2,5-hexanedione (2,5-HD 2.6 m mol/kg) alone (HD group) 

or with 2,5-HD and methyl ethyl ketone (MEK) (2.6 in mol/kg of each agent, HD&MEK group) or 

with 2,5-HD 2.6 m mol/kg and 5 times that dose (13.0 m mol/kg) of MEK (HD&5MEK group). 

The concentration of 2,5-HD in serum and inthe sciatic nerve was determined 0.5, I, 2, 4, 8, and 16 

h after administration. Urinary 2,5-HD concentration was detennined from the beginning of " 

administration up to* 16 h afterward. 1) The concentration of 2.5-HP. in the.serunL.the. sciatic nerve, 

and the urine was increased significantly (p < 0.05) inthe co-administered groups; the higher the 

MEjtjfoses were^thcjieater was the increase. 2) The clearance of 2,5-HD from both the serum and 

the sciatic nerve was delayed in the cn-administered groups. The highest concentration in serum and 

the sciatic nerve appeared at I and 2 h respectively. After administration, the biological halflife (tl/2) 

of 2,5-HD from 1 to 8 h in serum was 6.5, 5.8 and 12.0 h for the HD, HD&MEK, and HD&5 MEK 

groups respectively. From 8 to 16 h, the tl/2 in serum was 1.2, 3.2 and 16.6 h for the HD, 

HD&MEK, and HD&SMEK groups, respectively. In nerve tissue, the prolongation of clearance in 

the co-administered groups was greater than that in serum, the tl/2 from 2 to 8 hbeing 5.2, 9.6 and 

19.9 h for the HD, HD&MEK, and HD&5MEK groups, respectively.(ABSTRACT TRUNCATED 

AT 250 WORDS) 

Language of Publication 

English 

Unique Identifier 

95299994 

Order full text for this document 

vleSH Heading (Major) 

Butanones|*AD; Glycols|*AN/BL/UR; Sciatic Nerve|*CH 

VleSH Heading 

Animal; Half-Life; Male; Rats; Rats, Wistar; Support, Non-U.S. Gov't 

Publication Type 

JOURNAL ARTICLE 

ISSN 

1341-0725 

Country of Publication 

JAPAN 

CAS Registry/EC Number 

0 (Butanones); 0 (Glycols); 2935-44-6 (2,5-hexanediol); 78-93-3 (methylethyl ketone) 

4° 8/7/97 233 PM 
:

 — . P.42 

03.19-'9' 7 TL'E 16:2 6 FM 20 2 21 9 712 5 OSHA-HSP _ ^01 7 

, - Document ^•//M,ucl*

,

-

1,caJthgate.com/c*ji-bi*Vq-fonnatet5i 

English 

Unique Identifier 

36323389 

Order full text for this document 

MeSH Heading (Major) 

Gases|*PD; Ion Transport|*PH; Tight Junctions|*PH; Trachea|*ME 

MeSH Heading 

Alcohol, Ethyl|ME; Animal; Calcium|ME; Diffusion; Dogs; Female; Magnesium|ME; Male; Support, 

U.S. Gov't, P.H.S. 

Publication Type 

JOURNAL ARTICLE 

ISSN 

8750-7587 

Country of Publication 

UNITED STATES 

CAS Registry/EC Number 

0 (Gases); 64-17-5 (Alcohol, Ethyl); 7439-95-4 (Magnesium); 7440-70-2 (Calcium) 

Record 10 from database. MEDLINE 

Order full text for this document 

Title 

Reversible myoclonus, tremor, and ataxia in a patient exposed to methyl ethyl ketone. 

Author 

Orti-Pareja M; Jimenez-Jimenez FJ; Miquel J; Montero E; Cabrera-Valdivia F; Benito A; 

Garcia-Albea E ' 

Address 

Department of Neurology, Hospital Universitario Principe de Asturias, Madrid, Spain. 

Source 

. Neurology, 1996 Jan, 46:1, 272 

Abstract 

Abstract unavailable online. 

Language of Publication 

English 

Unique Identifier 

96143212 

Order full text for this document 

4i 

(t/7/97 2:33 PM 
P.43 

C 0 V E R 

SHEE T 

To: Dr. Myra Karstadt 

Fax#: 202/401-8142 

Subject: NIOSH comments on MEK assessment 

Dater August 21,1997 

Pages: 6, including this cover sheet 

COMMENTS:-*-".- ':/•-T.b^':"';' 

From David Votaw. 

FAX 

i 

4^ 

From tho dealt of... 

Dian* Manning 

Docket Office Manager 

NIOSH 

467S Columbia Partway 

Cincinnati. OH 46226 

913/533-8450 

Fax:513/533-a2B%_ 
P.44 

«"*•.* DEPARTMENT OF HEALTH AND HUMAN SERVICES - Public Health Service 

National Institute for Occupational 

Safety and Health 

Robert A. Taft Laboratorlea 

4676 Columbia Parkway 

Cincinnati OH 45226-1 BBS 

August 21,1997 

Myra Karstadt, Ph.D. 

U.S. Environmental Protection ' 

Agency 

OPPT/EAD/TRIB 

Mailstop 7408 

401 M Street, S.W. 

Washington, DC. 20460 

Dear Dr. Karstadt 

The National Institute for Occupational Safety and Health (NIOSH) has reviewed the 

U.S. Environmental Protection Agency's (EPA) Hazard and Risk Assessment of Methyl 

Ethyl Ketone (MEK), focusing on the neurotoxic effects of MEK. With regard to your 

principal question as to whether NIOSH has identified any data that ascribe neurotoxic 

effects to MEK alone rather than to MEK as part of a mixture, we have not NIOSH is, 

however, providing the two additional comments noted below from our review of EPA's 

MEK documents. 

As EPA has noted in this assessment, research has documented that MEK alone does 

not cause peripheral neuropathy. However, in combination with other chemicals that 

produce the reactive metabolite 2,5-hexanedione (2,5-HD), MEK potentiates the 

neuropathic effects of this metabolite, increasing the production of 2,5-HD. Two 

solvents, methyl normal butyl ketone (MnBK) and n-hexane, have demonstrated this 

effect with MEK [Abdel-Rahman et al. 1976; Couri et al. 1977; Spencer et al. 1980]. No 

detailed mention of this potentiation appears in the documents reviewed other than a 

brief statement on page 4 of the Hazard Assessment of MEK, "Prior concerns were 

based on enhancement by MEK of neurotoxicity seen with other solvents." If neither 

MnBK or n-hexane are present in the atmosphere with MEK, then the peripheral 

neurotoxic potential of MEK is minimal. 

Documentation in this assessment is weak regarding the acute toxic effects of 

exposures to MEK in humans, especially the dose-response ranges for occurrence of 

effects. EPA has described animal studies that used dose response ranges that could 

not be tolerated by humans. The Hazard Assessment states on page 2, "In humans, 

Inhalation of high doses produces irritation ofthe eyes and upper and lower respiratory 

system, effects characteristic of solvent exposure." Research conducted by NIOSH 

[Dick et al. 1992] indicates that sensory and irritant effects were present in human 
P.45 

Page 2 - Myra Karstadt 

volunteers at 200 ppm, not a high dose when compared to the dose ranges cited in the 

animal studies (>3000 ppm). Additionally, the primary basis for the Occupational Safety 

and Health Administration (OSHA) Permissible Exposure Limit (PEL) of 200 ppm for 

MEK Is the prevention of sensory Irritation [54 Federal Register 2452, January 19, 

1989]. The discussion issue regarding sensory or Irritant effects, if deemed an 

important nervous system effect by EPA, should be the potential for the release of MEK 

into the atmosphere at concentrations that could produce sensory and irritant effects in 

humans. Judging by the data presented in Table 4, page 8 ofthe Hazard Assessment 

the stack release exposure conditions would not produce such exposures. Only fugitive 

releases under the maximum conditions might have the potential to cause some 

debilitating Bensory and irritant effects in humans. 

Thank you for the opportunity to review EPA's Hazard and Risk Assessment of MEK. If 

you have any questions regarding these comments, please call me at (513) 533-8327. 

Sincerely yours, 

IbuVi 

David M. votaw 

Toxicologist 

Education and Information Division 

Enclosure 

44 
P.46 

REFERENCES 

1. Abdel-Rahman MS, Hetland LB, Couri D [1976]. Toxicity and metabolism of methyl 

n-butyl ketone. Am Ind Hyg Assoc J 37:95-102. 

2. Couri D, Hetland LB, Abdel-Rahman MS, Weiss H [1077]. The influence of Inhaled 

ketone solvent vapors on hepatic microsomal biotransformation activities. Toxicol 

Appl Pharmacol 41:285-289. 

3. Dick RB, Krieg EF, Setzer J, Taylor B [1992]. Neurobehavioral effects from acute 

exposures to methyl Isobutyl ketone and methyl ethyl ketone. Fund Appl Toxicol 

18:453-473. 

4. Spencer P, Schaumberg HH, Sabri M, Veronesi B [1980]. The enlarging view of 

hexacarbon neurotoxicity. CRC Crit Rev Toxicol 7:279-356. 

5. 54 Fed. Reg. 2453 [1989]. Occupational Safety and Health Administration: air 

contaminants; final rule. 

45 
2452 Federal Register / Vol. 54, No. 12 / Thursday, January 19, 19&9 / Rules and Regulations 

n •' 

study group. According to Dr. Smith, 

whan lha data are reanalyzed using 

arithmetic meant, the observed health 

effects would be associated with 

9xpoa\irea to much higher dust levels 

than those presented in the report {Ex. 

3-744. Attachment 3. p. 13). 

Because the raw exposure data from 

the study ware not available to Or. 

Smith, he based his reanalysis of lha 

exposure data on an assumption that all 

individuals In a job category had 

exposures equal to the mean exposure 

level for the lob category as a whole. For 

example, according to Dr. Smith, If "four 

laborers In the fusing building had 

average exposures of 49.2 mg/m' * * " 

[it was assumed] that all four had the 

soma exposure" (Ex. 3-744. Attachment 

3. p. 8). OSHA believes that Or. Smith's 

approach provides less information 

about the actual exposures of the 

members of tha cohort than doea Dr. 

Garabraiit's because Dr. Garabrant took 

two factors (representative data by Job 

category aa well as subjective selfreporting of exposure levels by 

employees) into account while Dr. 

Smith only considered a single factor 

(job category). That le. Dr. Smith 

assumes that all workers In a job 

. category have the same exposure, while 

Dr. Garabranfs approach recognizes the 

impact of such factors as Individual 

differences in work practices, 

differences in control effectiveness at. 

different workstations, etc, on the 

exposures of individuals in the same job 

category. OSHA is therefore 

unparsuaded by Dr. Smith's reanalysis: 

the Agency finds Dr. Garabrant'a 

analysis convincing and believes that it 

more accurately reflects the true 

exposures of members of this cohort. 

Largely because of questions raised 

concerning the dose-response 

relationship for tetraborates. U.S. Borax 

has been conducting a large 

epidemiologic Study al its facility. This 

study, deecribed at the informal hearing 

by Mr. Mlddleton (Tr. pp. 9-114 to 9-115, 

Ex. 120), will spaira three- to foiir-year 

period and will obtain about 400 

measurements of workplace tetraborate 

dust. The test protocols have been 

reviewed by representatives of OSHA. 

the U.S. Bureau of Mines. NIOSH. the 

ACGIH TLV Committee, and the Mine 

Safety and Health Administration. The 

Hnal report Is expected to ba released in 

mld-1988. At the hearing. Mr. Middleton 

stated the position of U.S. Borax: 

Baiad on the feat thai the prsaent data 

does ooi support lha establiih'mcnt) of PEL'S 

for these compounda snd that U.S. Borax I*. 

presently collecting dala thai could ba 

meaningful in establishing PEL'S, we request 

that OSHA delay action nn these compounds 

until -has* data are available and can ba 

analyzed by OSHA and MSHA (Tr. pp. &-

113).' 

OSHA commends U.S. Borax for . 

undertaking this effort to study the 

relationship between exposure to 

tetraborates and respiratory effects. 

OSHA believes that such dels are 

essential to Inform employees properly 

ebout hazards present in their 

workplaces and to guide employers In 

the development of effective 

occupational health programs. However. 

OSHA doea not agree that the evidence 

currently available Is Inadequate to 

oerve as a basis for establishing a PEL 

for the tetraborates at the present time. 

The study by Carabrent at al. (1985) 

does demonstrate e dose-response 

relationship for respiratory symptoms 

and exposure to sodium borates. OSHA 

finds that employees should be 

protected from experiencing tha 

symptoms that have been reported. 

These symptoms, which hava been 

reported ln the more recent Garabrant et 

al. (1065) and NIOSH (1978©; 1960b) 

studies, as well aa in the older literature. 

Include nosebleeds, upper respiratory 

tract irritation, dermatitis, and dyapnat. 

OSHA believes thet thia evidence 

clearly Indicates that tha tetraborate! -

act aa primary respiratory and akin 

irritants, and that a 10-mg/m'PEL Is 

clearly warranted. In light of the 

research currently being conducted by 

U.S. Borax, however. OSHA notes that 

the Agency will consider naw evidence 

aa it becomes available and will revise 

its limits if such action appears to be 

appropriate. 

OSHA agrees with U.S. Borax that at 

this time, there are insufficient data 

upon which lo establish different PELs 

for the different hydrated forms of 

tetraborate. OSHA believes that currant 

sampling and analytical procedures 

cannot distinguish among the various 

hydrated form* nf tetraborate (Ex. 3-744, 

Attachment 3, pp. 4-5) and therefore 

thst separate standards of 5 mg/m1 end 

1 mg/m' are not feasible al this time. 

OSHA concludes that an 8-hour TWA 

of 10 mg/m5 is appropriate for the 

tetraborates, and the final rule 

establishes this limit. OSHA finds that, 

in the absence of any limit oh exposure, 

employees are at significant risk of 

experiencing antle aye, skin, and 

respiratory irritation effects, and thet e 

10-mg/m* PEL will substantially reduce 

these risks. The Agency considers the 

eye. skin, and upper respiratory tract 

Irritation caused by exposure to all 

forms of sodium tetraborates to be 

material impairments of health. 

BROMINE 

CAS: 772B-9S-0: Choniical Formula: Bi*» 

H.S. No. 10*2 

OSHA's previous exposure limit for 

bromine was 0,1 ppm as an 8-hour TWA. 

OSHA proposed to supplement this 

TWA limit with a STEL of 0.3 ppm. the 

same limit recommended by the ACGIH. 

and NIOSH (Ex. 8-47. Table Nl) 

concurred with this proposal. In tha final 

rule, the Agency Is establishing a 0.1-

ppm TWA limit and a 0.3-ppm STEL for 

bromine. Bromine is a.derk, reddishbrown, noncombustible, diatomic liquid 

that has irritating vapors. 

Early studies of bromine exposure 

indicated that workers exposed to 0.75 

ppm for 8 hours exhibited no symptoms 

(Flury and Zemik 193ia, as cited in 

ACC1H 1988/Ex. 1-3. p. 65). Later 

studies reported physiological responses 

to difforant concentrations of bromine 

and used these findings to make the 

following recommendations: The 

maximum allowable concentration for 

prolonged exposures should be 0.1 to 

0.15 ppm. and the maximum allowable 

concentration for short-term exposures 

(i.e. 30 minutes to one hour) should bt 4 

ppm (Henderson and Haggard 1843b, aa 

cilad tn ACGIH 1968/Ex. 1-3, p. 85). 

These investigators found levels of 40 to 

80 ppm dangerous for short-term 

exposures, and a level of 1000 ppm 

proved rapidly fatal even during short 

exposures. These authors reported thet 

the effects of exposure to bromine 

include respiratory irritation and lung 

edema. Elklna (1859a/Ex. 1106) reported 

that worksrs exposed to 1 ppm in a 

plant handling liquid bromine found this 

level excessively irritating. 

OSHA received no comments on its 

proposed STEL for bromine, other than 

the NIOSH concurrence statement The 

Agency finds that both the TWA and the 

short-term limits are necessary to 

substantially reduce the risk of 

respiratory irritation and lung damage 

that could occur following short-term 

exposures to concentrations of bromine 

that would be permitted by the b hour 

TWA limit alone. OSHA considers the 

effects related to bromine exposure 

ma terial impairments of health. 

Therefore, OSHA is revising the limit for 

bromine to 0.1 ppm aa an 8-hour TWA 

and 0.3 ppm as a 15-minute STEL 

2-DUTANONE (METHYL ETHYL KETONE) 

CAS: 79-93-3; Chamiral formula: 

CH.COCH1CH, — •«-

U.S No. 1048 

OSHA's former exposure limit for 2-

bu t anone was 200 ppm TWA. OSHA 

proposed to supplement this limit with a 

STEL of 300 ppm. based on tha ACGIH ' 

(1988/Ex. 1-3) recommendation. NIOSH 

[Ex. 8-»7. Table Nl) concurred wtih thia 

proposal. The final rule establishes a 

200-ppm TWA limit and a SOO-ppm 5TEI* 

46 A 
•i 

Federal Register / Vol, 54, No. 12 / Thursday, January 19. 1989 / Rules and Regulations 2453 

1 

,.: 2-butanone. 2-Butanone it a 

jolorless. flammable liquid with an 

objectionable odor. 

2-8utanone is an ocular and upper 

respiratory tract irritant. One study 

kelson. Enge. Ross et al. 1943/Ex 1-68) 

Sported that exposures lo 200 ppm for 3 

to 8 minutes caused mild eye Irritation 

ID tome subjects and that others 

experienced slight nose and throat 

Irritation at concentrations of 100 ppm. 

Exposure to 350 ppm caused eye and 

nassl Irritation ln a majority of subjects 

tested. Studies conduded in the 1940s 

noted low-grade intoxication resulting 

from exposure to 300 to 600 ppm (Smith 

and Mayers 1044. aa cited ln ACGIH 

1986/Ex.i-3. p. 395), Later studies have 

shown that approximately 60 percent of. 

trained panelists experienced.eye and 

nose Irritation at 200 ppm (es reported in 

ACGIH 1986/Ex. 1-3. p. 305): 

ln the pceamble discussion on 2-

butanone. OSHA noted that a number ol 

studiee indicate thai the proposed limits 

may not be sufficient lo fully protect 

workers from the irritant effects pf this 

substance (ACGIH 1986/Ex. 1-3; kelson, 

Enge. Ross at aL 1943/Ex. 1-68). tha 

ACGIH also cited a manufacturer's "*," 

publication that stated thdr 200 PPt|l was 

ihe highest concentration judged by "*' 

human subjects to ba "satlsfdctpry" for 

eight hours. In addition, another study 

cited by the ACGIH (1986/EX. 1-3} -;Ai 

reported that expoaure' to ZOO ppm Wa* v. 

associated with a 50-percent response7> 

rate for eye and nasal irriution (the*. 

300-ppm 15-minule STEL for 2-hutanonc 

to proteel employees from the 

significant risk of sensory irritation: 

OSHA considers the irritation caused by 

2-butenone to be a material impairment 

of health dr functional capacity. 

n-BUTYLACETATB 

CAS No.'123-88-4: Chemleel Formula: 

CHiCOO(CU,).CH. 

H.S.No.1017 

The previous OSHA exposure limit for 

n-butyl acetate waa 150 ppm, measured 

as an 8-hour TWA. OSHA proposed the 

adoption of a 15-minute STEL of 200 

ppm to supplement the TWA limit, 

NIOSH (Ex. &-47. Table Nl) concurred 

with this proposal. The final rule 

establishes limits of 150 ppm as an 8-

hour TWA and 200 ppm as a 15-minute 

STEL for this substance; these are tha 

same limits as those recommended by 

the ACGIH (1986/Ex. 1-3). n-Butyl 

acetate is a colorlasa liquid with a fruity 

odor. ' 

n-Butyl acetate la an Irritant to the 

ayes. akin, and respiratory system, in a 

study involving cats exposed for six 

hours to OlOOppm, slight narcotic effects 

were noted (Fairy and Wirth 1883. aa 

cited in: ACGIH 1568/Ex. 1-9, p. 72). 

When exposed to 4200 ppm n-butyl 

aceute for six days at six hours per day, 

data experienced alight irritation pf the 

respiratory passage: at 3100 ppm, //, 

changes ftp blood call morphology yiewe •.. 

recorded. At exposures of 1600 ppicu.«... 

;.!: thejke;cats. t^xhi^d slight Irritation of 

degree of Irritation waa Wot Bpet^fledk >• * e^

e

» fnd tB^tueAukn^mm.^ 

OSHA-ipetlflcnUyteqaestad W* ii-jtfr*!** *«*•» W^ae-tlMi in AtJO^UfliaB/**.; 

comment oa^\to.U9*MpWWfr&&*'* P^ZkAi/cdmwntreMona^ e y 

for 2-butsttiofte were *ufflctent)yv 1' 'Ji ^ P *. W.000 ppm;&-btityl acetate proved fa la)**» 

protective. The New Jersey bepiHnjSntV-^! to rata aftet eight hours; four hours of c A 

of PnbUc Heahh '(Exa-,144,144AfiiJ^t^r"'V^,nK'»ur»atrfhe eame level produced no -

OSHA to set Its limits for 2-but*hoi«

 v v • •; datfli* (Smyth 18M/Ex. 1-759). A paper.,. 

based on EPA's IRJS data; The use of**' ' by Sayew, Schrenk, and Patty (1868/Ex. '• 

such an approach Is discussed ii) ' ' " 1-802) reported thai guinea pigs 

Section V1;A of the preamble. The AFL-i' demonstrated eye lrritetlon effects at 

" --•-* • 3300 ppm, became unconscious after 

hint hours of exposure to 7000 ppm. and 

died after four hours of exposure to 

14,000 ppm. • 

Human volunteers complained that 

throat Irritation, which began at an 

exposure level of 200 ppm n-butyl' 

acetate, worsened and became quite 

severe al 300 ppm (Nelson. Enge, Ross el 

al. 1943/Ex. 1-66). NIOSH was the only 

commenter to the record ln response lo 

OSHA'S proposed STEL for n-butyl 

acetate. 

OSHA finds that workers are al 

significant risk of experiencing severe 

eye, skin, and respiratory irritation. In 

addition to narcotic offects, that are 

associated with short-term exposures to 

this aubstence al levels above the 8-hour 

limit. The Agency considers the Irritant. 

and narcotic effocts resulting from 

CIO (Ex. 194) supported the 

establishment of a STEL for butanone. * 

OSHA has determined that Its : 

previous 8-hour TWA limit of200 ppm 

was not sufficient to protect workers--

from experiencing the Significant. . 

irritation and narcotic effects that are 

associated with short-term exposures to' 

high concentrations of 2-butanone. After 

reviewing the available reports 

describing human sensory response** to 

short-term exposures to 2-butanone. the 

Agency concludes that a 300-ppm STEI. 

• la Also necessary to reduce the 

. significant risk of sensory irritation: 

exposure to 350 ppm for three to five • 

• minutes waa reported to cause eye, -

nose, end throat Irritation In a mejorily 

of subjects (Nelson. Engo, Ross et al. 

1843/Bx. 1-66). Accordingly. OSHA is 

establishing o 2uO-ppm TWA limit and a 

exposure to n-butyl acetate to be 

malerial impairments of health and 

functional capacity. OSHA concludes 

that a STEL Is necessary to reduce this 

risk, and the Agency is therefore 

revising Its limit for n-butyl acetate to 

150 ppm as an 8-hour TWA land 200 ppm 

as a 15-minute STEL 

n-BUTYL LACTATE 

CAS: 136-22-?; Chemical Formula: C,HHQi 

H.S. No. 1053 

OSHA previously had no limit for ftbutyl lactate but proposed a 5-ppm 8-

hour TWA limit, based on the ACGIH 

recommendation. NIOSH* (Ex. 8-47, 

Table Nl) concurred with tlie proposed 

5-ppm TWA limit, and thia limit Is 

established in the final rule. Butyl 

lactate Is a colorless liquid ester of 

lactic acid. 

ln humans, prolonged exposures to nbutyl lactate at approximately 7 ppm, 

with brief peak excursions to l l ppm, 

caused headache. Irritallon of the 

pharyngeal and laryngeal mucosa, and 

coughing ln all workers, end occasional 

nausea, vprnitlng. and sleeplnessh insome (Zutdeme and Pel 1968. as cited in 

ACGIH 1986/Ex 1-3, p. 82). Headache, 

coughing, and irritation of tha pharynx 

were someUmes related Von-butyl 

lactate concentrationsipf 4 ppm: 

"however, no adverse effects* were , 

observed at a concentj-ftlonif^.4 pjr*m.. 

Studiesemploying impWfd san^png •,. 

and analytic method* J«ve subeequenlly 

cdncluded that. ilffioiinJheJJdoY.AI •&*.','; 

bfltyl lactate Is dlei*«niltiJ#«l the y-ppm,7 

level this concentraKohidoae oot.7.'• •'••„ .,•' 

produce objectionable ot Injurious-- «•. 

effects (Tuinpriqn/aa cited in ACGIH .*• 

*1886/Ex.vi-3,p.82)P ;*.* . ... 

In the preamble'discussion of the 

proposed limit for this substance, OSHA . 

rioted that some studies reported acute 

adverse affects associated with 

exposure leveis below the proposed 5-

ppm TWA limit. This was also pointed 

out by Or. Grace Zlem. an independent 

physician (Ex. 46). Based on the study 

by Turner (1972. aa cited in ACGIH 

1986/Ex, 1-3, p. 82). which' employed. 

Improved sampling and analytical 

techniques as compared to earlier 

studies, OSHA judges that promulgation 

of e 5-ppm 8-liour TWA limit Will 

effectively protect workers from the 

significant risks of irritation, headache, 

and nausea caused by exposure to 

higher conentrations of n-butyl lactate. 

OSHA considers these adverse effects . 

to represent material impairments of 

health. Therefore. OSHA Is establishing 

a 5-ppm 8-hour TWA limit for n-butyl 

lactate. 

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