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Arm UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D .C . 2046 0

'1+1714 PR01 El woo s

OFFICE O F

PESTICIDES AND TO..C SL) .STANCES

DIFMORAN'DU M

SUBJECT :

Delisting Petitions for tletbyl Ethyl Ketone (t,',T7K) and

Ilethy! Isobutyl Ketone (MI -2K) Nutagenicity Ha7ard

FROM : m,ichael C . Cimino, Ph .D .

Biologist

Toxic Effects Section

Toxic Effects Branch

Health and Environmenta l

Review Division (TS-7Q6)

TO : Elbert Dago

Chemical 11anage r

Che-lical Review and F.valuation Branch

Health and Fnvironmental.

Review Division (TS-796)

THRU : Angela Auletta, Ph .D .

Sec t 4 on Chie f

Toxic Effects Section

o x i c Ff-fects Branch

Health and Envi ronmental-' /

Review Division (71S-7961"

I . SUMMARY

The two del isting peti tions sl ightly underrepresei-it the

r

K) a i,utagenLcity hazard presented by methyl ethyl ketone (NF nd

methvl isobutyl ketone (rIIBK) . Although MEK shows little

evi(~ence of mutagenicity, it does induce cell. transformation in

mammalian cells in culture . 111131"' shows slig)itly greater evidence

of mutagenicity, with a weak positive respense in mammalian cells

in culture . It also induces cell transformation in mammalian

cells in culture .

63980000356
p. 5

II . DISCUSSIO N

A . MEK

A HERD review of the TSCA Section 4 nutaqenicitv data on

one of the methyl ethyl ketone (MEK : Cimino 1985) disagrees with

conclusions in the delist -ing petition . HERD assesses the cell

transformation assay as positive, based upon review of the sa-me

industry data referred to in the petition (p .23) . The clelisting

petition cites a manuscript by O'Donoghue et al . which deals with

these same industry data . (This manuscript has recently been

published ; O'Donoghue et al . 1988 .) After re-evaluziting the HERD

review in light of the O'Donoghue i:)aper, no convincing arguments

have been presented to change HERD's conclusions .

Three other papers cited by the petition have been reviewed

(Brooks et al . 1988 ; Perocco et al. 1983 ; Zimmer-mann et al 1985) .

HERD concurs with the data evaluation on these papers .

SUMMARY OF MUTAGENICITY-D/N.TA ON NT' K

Gene mutations : Negative Sal-monella/Ames

Negative Fscherichia

Negative lymphoma

Chromosome mutations : Positive Saccharomyces aneUplo4dv

Negative CHO cells in vitro

Negative RrA cells in vitro

Negative mouse micronucleus in viv o

DNA effects : Negative Saccharomyces recom,,S-in -ation

Negative sister chromatid exchange in

CHO cells in vitr o

Negative rot hepatocyte UI) S

Negative DIIA synthesis in human cells

-i-n- v i tr o

Cell transformation : Positive BALB/c mouse cells in vitro

There are no animal data indicating that may induce

heritable mutations .

p . 2
p. 6

B MIBK

A HERD review of the TSCA Section 4 mutagenicity data on

methyl isobutyl ketone (M19K : Cimino 1985) disagrees with some of

the conclusions in the delisting petition . The mouse lymphoma

assay is assessed as being a positive response (albeit weak), and

the cell transformation assay is assessed as positive . These

assessments are based upon review of the same industry data

referred to in t>e petition (pp .23-28) . As stated above for MFK,

re-consideration of these data in light of the O'Donoghue et al .

.paper does not change HERD's ronclusions .

The OHFA document on MIBK (OHFA 1986, p .11) suffers from the

same deficiencies in interpretation for the lymphoma and cell

transformation assays as the delisting petition .

Another paper cited by the petition has been reviewed

(Brooks et al . 1988) . HERD concurs with the data evaluation on

this paper .

SUMMARY OF NUTAGENICITY DATA ON MIBK

Gene mutations : Negative Salmonella/Ames

Negative Escherichia

Positive lymphom a

Chromosome mutations : Neqative CHO cells in vitro

Negative RL4 cells "T Ttro

Negative mouse micronucleus in vivo

DNA effects : Negative Saccharomyces recombination

Negative rat hepatocyte UD S

Cell transformation : Positive BALB/c mouse cells in vitro

There are no animal data indicating that NIBK may induce

heritable mutations .

III . CONCLUSIONS

The two delisting petitions slightly underrepresent the

mutagenicity hazard presented by MEK and MIBK . MEK shows little

evidence of mutagenicity . However, it induces cell

transformation in mammalian cells in culture .' NIBK shows

slightly greater evidence of mutagenicity, with a weak positive

response in mammalian cells in culture . It also induces cell

transformation in mammalian cells in culture .

p . 3
p. 7

IV . REFERENCE S

Brooks, TM, Meyer AL and Huston, DN . 1908 . The genetic

toxicology of some hydrocarbon and oxygenated solvents .

Mutagenesis 3 : 227-232 .

Cimino, MC . 1985 . U .S . Environmental Protection Agency, Office

of Pesticides and Toxic Substances . Mutagenicity Data Evaluation

on MIBK and MFK . Intradivision memorandum to J . Kariya date d

August 7, 1985 . USTPA . Washington, DC . 20460 .

O'Donoghue, JA, Haworth, SP, Curren, RD, et al . 1988 .

mutagenicity studies on ketone solvents : Methyl ethyl ketone,

methyl isobutyl ketone, and isophorone . Mutat . Res . 206 : 149-

161 .

OHFA . 1987 . U .S . Environmental Protection Agency, Environmental

Criteria and Assessment Office . Health Effects Assessment for

Methyl Isobutyl Ketone . Final Draft ECAO-CIN-HO81 dated April,

1987 . USEPA . Washington, DC . 20460 .

Perocco, P, Bolgnesi, S and Alberghini W . 1983 . Toxic activity

of seventeen industrial solvents and halogenated compounds on

human lymphocytes cultured in vitro . Toxicology Letters 16 : 69-

75 .

Zimmermann, FK, Mayer, VW, Scheel, I and Resnick, MA . 1985 .

Acetone, methyl ethyl ketone, ethyl acetate, acetonitrile and

other polar aprotic solvents are strong inducers of aneuploidy in

Saccharomyces cerevisiae . Mutation Research 149 : 339-351 .

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