el

- .'. p. 4

JED S'%~' //0011 1
~ , Arm UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON, D.C. 20460
'1+1714 PR01 

# El woos

OFFICE O F PESTICIDES AND TO . .C SL) .STANCES DIFMORAN'DUM
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 Dag o

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 xi 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
.

63980000356p. 5

II . DISCUSSION 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 vivo 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 t ro Cell transformation : Positive BALB/c mouse cells in vitro There are no animal data indicating that may induce heritable mutations .

p . 2p. 6

B MIB K 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 lymphoma 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 UDS 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 . 3p. 7

IV . REFERENCES 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 dated 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 .

p . 4