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1. Exposure Data

1.1 Chemical and physical data

From IPCS (1990, 1997), oxicological Index

(2005), and HSDB (2008) unless otherwisespecified.

1.1.1 Nomenclature

Chem. Abstr. Services Reg. No.: 108-10-1Chem. Abstr. Name: 4-Methylpentan-2-oneSynonyms: Hexone; isobutyl methylketone; isopropylacetone; ketone, isobutylmethyl; methyl i-butyl ketone; methyl-2-oxopentane; methylpentan-2-one;

2-methyl-4-pentanone; 4-methyl-2-pen-tanone; 4-methylpentan-2-one; 2-meth-ylpropyl methyl ketone; MIBK; MIK;2-pentanone, 4-methyl-RTECS No.: SA9275000EINECS No.: 203-550-1United Nations TDG number : 1245

1.1.2 Structural and molecular formulae andrelative molecular mass

C CH 2

O

CH CH3

CH 3

H3 C

C6H

12O

Relative molecular mass: 100.16

1.1.3 Chemical and physical properties of the pure substance

Description: Colourless liquid with a sweetodourBoiling-point: 117–118 °C

Melting-point : -84 °C (Lide, 2005);-80.26 °CRelative density (water = 1): 0.80 at 20 °C(Lewis, 2001)Vapour pressure: 19.9 mm Hg at 25 °CSolubility : Soluble in water (1.91 g/100mL at 20 °C); miscible with most organicsolvents; soluble in chloroormRelative vapour density (air = 1): 3.45Flash-point : 14 °C

Autoignition: 460 °COctanol/water partition coefficient : log P,1.31 (LOGKOW, 2010)Water/air partition coefficient : 79 (Sato &Nakajima, 1979)Blood/air partition coefficient : 90 (Sato &Nakajima, 1979)Oil/air partition coefficient : 926 (Sato &Nakajima, 1979)Henry’s law constant :1.38 × 10-4 atm.m3/mol at 25 °C

Conversion factor at 25°C and 760 mm/Hg :1 ppm = 4.09 mg/m3; 1 mg/m3 = 0.245 ppm

1.1.4 Technical products and impurities

No data were available to the Working Group.

METHYL ISOBUTYL KETONE

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1.1.5 Analysis

More than 15 methods to measure methylisobutyl ketone in different environmentsare available. Although sampling and extrac-

tion techniques differ, all methods involve gaschromatography.

Te Environmental Protection Agency o theUnited States o America (US EPA) has publishedat least three different methods or the analysiso waste material (EPA methods 8015, 8015Aand 8240A), two methods or water (EPA-NERL524.2 and EPA-OSW 8015C) and one methodor different environmental matrices (EPA-OSW8260B).

Te National Institute o Occupational Saetyand Health (NIOSH) has also developed methodsor the analysis o methyl isobutyl ketone in air.Both methods (1300, Issue 2 and 2555, Issue 1)use gas chromatography with a flame ionizationdetector. Te American Society or esting andMaterials (ASM D5790) uses gas chromato-graphy/mass spectrometry to measure methylisobutyl ketone in water (HSDB, 2008).

1.2 Production and use

1.2.1 Production

More than 60% o methyl isobutyl ketone isproduced by aldol condensation o acetone andits derivative intermediates, diacetone alcoholand mesityl oxide. Acetone is treated with bariumhydroxide to yield diacetone alcohol, which isdehydrated to mesityl oxide, which in turn ishydrogenated to saturate the double bond andproduce methyl isobutyl ketone. Another method

is the hydrogenation o mesityl oxide over nickelat 160–190 °C. Methyl isobutyl ketone can alsobe prepared by reacting sodium acetoacetic esterwith isopropyl bromide and treating the resulting2-isopropyl acetoacetic ester with diluted acid tosaponiy the ester and decarboxylate the resultingketo acid (NP, 2007).

In 1995 and 1996, the USA produced 80 000tonnes o methyl isobutyl ketone (NP, 2007). In2003, the industrial production capacity in theUSA was 195 million pounds [88 000 tonnes]per year (HSDB, 2008). Sources indicate thatmethyl isobutyl ketone was produced by threecompanies in the USA (HSDB, 2008). Accordingto IUCLID (2000), nine companies in Europeproduced methyl isobutyl ketone in 2002: threein France, two in the Netherlands, and one eachin Belgium, Germany, Denmark, and the UnitedKingdom.

1.2.2 Use

Methyl isobutyl ketone is used primarily asa denaturant and solvent in cosmetic products,in denatured alcohol, and as an excipient indrugs. It is also used as a component o syntheticflavouring substances and adjuvants, and as acomponent o adhesives that are present in arti-cles intended or use in packaging, transportingor holding ood (HSDB, 2008).

Methyl isobutyl ketone is also consideredto be an excellent solvent or resins used in theproduction o surace coating and is widely used

in rubber chemicals or the production o tyres.(HSDB, 2008). Methyl isobutyl ketone is alsoused as a solvent in paint and lacquers (IPCS, 1990).

1.3 Occurrence and exposure

1.3.1 Natural occurrence

Methyl isobutyl ketone occurs naturally inood (see Section 1.3.3).

1.3.2 Occupational exposure

Te most probable routes o exposure inthe workplace are by inhalation o vapours andby skin and eye contact during the productionand use o methyl isobutyl ketone and productsin which it is a constituent. In the National

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Methyl isobutyl ketone

Occupational Exposure Survey (NIOSH, 1990)conducted rom 1981 to 1983, the number oworkers potentially exposed to methyl isobutylketone in the USA was estimated as 48 000.

Exposure to methyl isobutyl ketone duringspray painting was ound to be 0.6 ppm (time-weighted average; WA) (Whitehead et al., 1984). Concentrations o methyl isobutyl ketoneat three locations in a poly(vinyl) chloride plasticwaste recycling plant in aiwan, China, rangedrom 1517 to 11 324 μg/m3. In the same study,concentrations at nine locations in polyethylene-polypropylene recycling plants ranged rom 12 to72 μg/m3 (sai et al., 2009). In a study o workersin two actories in aipei, mean concentrations

o methyl isobutyl ketone in the air samples osolvent-exposed workers were 2 ppm (range,0–68 ppm), while the mean exposure o spraypainters in painting booths was 76 ppm (range,8–369 ppm) (Chen et al., 1991). In a study amongsolvent-exposed workers, a mean exposure o16.7 ppm was noted in an unidentified actory(Ogata et al., 1995). Among a group o 27 urni-ture-makers exposed to a mixture o methylisobutyl ketone, methyl ethyl ketone, acetone,toluene, xylene, ethylbenzene, butyl acetate,

and isobutyl acetate, the WA concentrationo each solvent was below the correspondingoccupational exposure limit. Arithmetic meanexposure to methyl isobutyl ketone was 1.8 ppm(range, 0.1–15.1 ppm). A linear relationshipbetween exposure and urinary concentrationwas ound (Kawai et al., 2003). Hänninen et al. (1976) reported a mean WA concentration o7 mg/m3 (range, 4–160 mg/m3) [1.7 ppm; range,1–39 ppm] in the breathing zone o spray painters

in car repair shops.Methyl isobutyl ketone may occur as acontaminant in environments near spacecraf,where it has been detected at levels o < 0.005–0.02 mg/m3 (IPCS, 1990). It has been identifiedas a volatile degradation product o polypro-pylene at temperatures o 220–280 °C and underreduced pressure (Frostling et al., 1984).

1.3.3 Occurrence in food and dietaryexposure

Te most probable routes o exposure tomethyl isobutyl ketone by the general population

are ingestion o contaminated drinking-waterand dermal contact with consumer products owhich it is a constituent (Johnson, 2004).

Dietary sources o exposure are: naturaloccurrence in ood, addition to ood as aflavouring, and migration into ood rom oodpackaging. Methyl isobutyl ketone has also beendetected in human breast milk (Pellizzari et al.,1982), and traces have also been detected in tap-water in the USA (IPCS, 1990).

(a) Natural occurrence in food

Methyl isobutyl ketone was reported tooccur naturally in orange and lemon juice,grapes, vinegar, baked potatoes, papaya, ginger,wheat bread, cheeses, milk, cooked eggs, roastchicken, cooked bee, lamb at, pork liver, hopoil, beer, cognac, coffee, tea, plumcot, plumbrandy, mushrooms, trassi, sesame seed, buck-wheat, wort, elder flowers, Bourbon vanilla, claryand red sage, crabs, clams, and Chinese quince

(Burdock, 2005). Te ollowing levels have beenreported (IPCS, 1990): papaya, 8 µg/kg; beer,10–120 µg/kg; and coffee, 6.5 mg/kg.

(b) Flavouring agent

Methyl isobutyl ketone is permitted as aflavouring agent in the USA, where it is consid-ered as sae at current levels o intake. Usualreported levels ranged rom 2.6 mg/kg in meatproducts to 12.3 mg/kg in sof candy; maximumreported levels were 25 mg/kg in rozen dairyand non-alcoholic beverages; other reporteduses are in baked goods, gelatines and puddings(Burdock, 2005).

Te Council o Europe reported maximumlevels o 11 mg/kg in beverages and 1 mg/kgoods in general (Council o Europe, 2000).

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Per-capita exposure to methyl isobutyl ketone,estimated by the FAO/WHO Expert Committeeon Food Additives based on poundage dataprovided by industry, is 7 µg per capita perday in Europe (based on a reported volume o50 kg/year) and 2 µg per capita per day in the

USA (based on a reported production volumeo 8 kg/year) (FAO/WHO, 1999). More recently,individual intake was estimated at 0.02 μg/kg perday (Burdock, 2005).

(c) Migration from food packaging

Methyl isobutyl ketone is used in packagingmaterials that come into contact with ood.Levels reported in oods rom packaging are:baked goods, 10.9 mg/kg; rozen dairy products,

11.5 mg/kg; meat products, 2.6 mg/kg; sof candy,12.3 mg/kg; gelatins and puddings, 10.9 mg/kg;and beverages, 10.2 mg/kg (IPCS, 1990).

308

Table 1.1 International limit values for methyl isobutyl ketone

Limit value –8 h Limit value – short-term

ppm mg/m3 ppm mg/m3

Austria 20 83 50 208

Belgium 20 83 50 208

Canada – Québec 50 205 75 307

Denmark 20 83 40 166

European Union 20 83 50 208

France 20 83 50 208

Germany (AGS) 20 83 40 (1) 166 (1)

Germany (DFG) 20 83 40 166

Hungary 83 208

Italy 20 83 50 208

Japan 50

the Netherlands 104 208

Poland 83 200Spain 20 83 50 208

Sweden 25 100 50 200

Switzerland 20 82 40 164

USA – NIOSH 50 205 75 (1) 300 (1)

USA – OSHA 100 410

United Kingdom 50 208 100 416

Remarks

European Union Bold type: indicative occupational exposure limit values and limit values or occupational exposure

France Bold type: restrictive statutory limit values

Germany (AGS) (1) 15 min average value

Germany (DFG) 15 min average value

USA – NIOSH (1) 15 min average valueAGS, German Committee on Hazardous Substances (Ausschuss ür Geahrstoffe); DFG, German Research Foundation (Deutsche

Forschungsgemeinschaf); h, hour or hours; NIOSH, National Institute o Occupational Saety and Health; OSHA, Occupational Saety and

Health Administration

From GESIS (2011)

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1.3.4 Environmental occurrence

Methyl isobutyl ketone may be releasedinto the environment in effluent and emissionsrom its manuacture and use, in exhaust gas

rom motor vehicles (Hoshika & akata, 1976)and rom land disposal o waste that containsthis compound (Verschueren, 2009). Release omethyl isobutyl ketone into the atmosphere mayoccur during its production through ugitiveemissions and incomplete removal o vapoursrom reaction gases beore they are vented ordisposed o in a scrubber. In addition, methylisobutyl ketone has requently been identifiedin leakages rom landfills and could potentiallycontaminate groundwater (Francis et al., 1980;IPCS, 1990). Another source o environmentalcontamination is the release o methyl isobutylketone during the discharge o spent scrubbingwater rom industrial production processes(IPCS, 1990).

1.4 Regulations and guidelines

Methyl isobutyl ketone has been listed bythe Council o Europe in category B (flavouring

substances or which urther inormation isrequired beore the Committee o Experts isable to offer a firm opinion on the saety o theiruse; these substances can be used provisionallyin oodstuff) (Council o Europe, 2000). Methylisobutyl ketone is listed in the European register ochemically defined flavourings (FLAVIS number07.017), and no urther evaluation is needed roma legal point o view according to the EuropeanUnion (EU) evaluation programme (European Comission, 2009). Methyl isobutyl ketone is listedin the EU database or cosmetic ingredients withthe ollowing unctions: denaturant, solvent andperume (European Commission, online). Basedon the Commission Regulation (EC) No 3199/93,methyl isobutyl ketone is permitted or use todenature alcohol in all EU countries (European Commission, 1993).

Short-term and 8-hour limit values ormethyl isobutyl ketone are given in able 1.1.Both the American Conerence o GovernmentalIndustrial Hygienists (ACGIH) in the USA andthe Maximale Arbeitsplatz-KonzentrationsCommission in Germany provide guidelines ormethyl isobutyl ketone in the workplace envi-ronment (able 1.1).

2. Studies in Humans

No data were available to the Working Group

3. Cancer in Experimental Animals

Te carcinogenicity studies reviewed beloware limited to those o inhalation exposure omice and rats to methyl isobutyl ketone that wereadequately conducted by the National oxicologyProgram (NP, 2007; Stout et al., 2008), theresults o which are summarized in able 3.1.

3.1 Inhalation

3.1.1 Mouse

Groups o 50 male and 50 emale B6C3F1

mice were exposed by whole-body inhalation tomethyl isobutyl ketone (> 99% pure) at concen-trations o 0, 450, 900 and 1800 ppm or 6 hoursplus

90 (time required to reach 90% o the target

concentration within the exposure chamber; 12minutes) per day on 5 days a week or 105 weeks.reatment-related increases in the incidence

o liver tumours (hepatocellular adenoma andcarcinoma combined) were observed in malesand emales, together with concurrent treatment-related increases in the incidence o eosinophilicoci in the liver.

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310

T a b l e 3 . 1

C a r c i n o g e n i c i t y s t u d i e s o f i n h a l a t i o n e x p

o s u r e t o m e t h y l i s o b u t y l k e t o n

e ( > 9 9 % p

u r e ) i n e x p e r i m e n t a l a n i m a l s

S p e c

i e s ,

s t r a

i n ( s e x

)

D u r a t i o n

D o s i n g r e g

i m e n

A n

i m a

l s / g r o u p a t s t a r t

I n c

i d e n c e o

f t u m

o u r s

S i g n

i fi c a n c e

( p o l y - 3

t e s t

)

C o m m e n t s

M o u s e ,

B 6 C 3 F 1

( M )

1 0 5 w k

0 , 4 5 0 , 9 0 0 o r 1 8 0 0 p p m , 6 h

p l u s T 9 0

( 1 2

m i n ) / d , 5 d / w k

5 0 a n i m a l s / g r o u p

L i v e r ( h e p a t o c e l l u

l a r a d e n o m a o r

c a r c i n o m a ) a :

2 7 / 5 0 , 3 4 / 5 0 , 2 8 / 5

0 , 3 7 / 5 0


l a r a d e n o m a ) a :

1 7 / 5 0 , 2 5 / 5 0 , 2 3 / 5 0 , 3 4 / 5 0


l a r c a r c i n o m a ) a :

1 2 / 5 0 , 1 2 / 5 0 , 1 0 / 5

0 , 9 / 5 0

P = 0 . 0 1 9 ( h i g h d o

s e )

P = 0 . 0 2 8 ( t r e n d )

P < 0 . 0 0 1 ( h i g h d o

s e )

P < 0 . 0 0 1 ( t r e n d )

N S

S u r v i v a l : 4 0 / 5 0 , 4 2 / 5 0 , 3 5 / 5 0 , 3 7 / 5 0

L i v e r ( e o s i n o p h i l i c f o c i ) : 3 / 5 0 , 4 / 5 0 , 5 / 5 0 , 8 / 5 0

M o u s e ,

B 6 C 3 F 1

( F )

1 0 5 w k

0 , 4 5 0 , 9 0 0 o r 1 8 0 0 p p m , 6 h

p l u s T 9 0

( 1 2

m i n ) / d , 5 d / w k



l a r a d e n o m a o r

c a r c i n o m a )

b :

1 7 / 5 0 , 1 7 / 5 0 , 2 2 / 5 0 , 2 7 / 5 0


l a r a d e n o m a )

b :

1 3 / 5 0 , 1 5 / 5 0 , 2 0 / 5

0 , 2 3 / 5 0


l a r c a r c i n o m a )

b :

6 / 5 0 , 5 / 5 0 , 6 / 5 0 , 1

1 / 5 0

P = 0 . 0 3 5 ( h i g h d o

s e )

P = 0 . 0 1 3 ( t r e n d )

P = 0 . 0 3 3 ( h i g h d o

s e )

P = 0 . 0 1 6 ( t r e n d )

N S

S u r v i v a l : 3 5 / 5 0 , 3 7 / 5 0 , 3 9 / 5 0 , 3 8 / 5 0

L i v e r ( e o s i n o p h i l i c f o c i ) : 4 / 5 0 , 1 1 / 5 0 g 1

0 / 5 0 , 1 4 / 5 0 f

R a t , F 3 4 4 / N

( M )

1 0 4 w k

0 , 4 5 0 , 9 0 0 o r 1 8 0 0 p p m , 6 h

p l u s T 9 0

( 1 2

m i n ) / d , 5 d / w k


K i d n e y ( r e n a l t u b

u l e a d e n o m a o r

c a r c i n o m a ) c ,

d : 2 / 5

0 , 4 / 5 0 , 3 / 5 0 , 1 1 / 5 0


u l e a d e n o m a )

d :

2 / 5 0 , 3 / 5 0 , 3 / 5 0 , 1

0 / 5 0


u l e c a r c i n o m a ) c , d :

0 / 5 0 , 1 / 5 0 , 0 / 5 0 , 2

/ 5 0

S i n g

l e s e c t i o n a

l o n

e


u l e a d e n o m a ) :

0 / 5 0 , 0 / 5 0 , 2 / 5 0 , 3

/ 5 0


u l e c a r c i n o m a ) :

0 / 5 0 , 1 / 5 0 , 0 / 5 0 , 2

/ 5 0

S t e p s e c t i o n e v a

l u

a t i o n a

l o n e

( 3 – 4

s e c t i o n s p e r

k i d n e

y ) :


u l e a d e n o m a ) : 2 / 5 0 ,

3 / 5 0 , 1 / 5 0 , 7 / 5 0

P = 0 . 0 0 4 ( h i g h d o

s e )

P < 0 . 0 0 1 ( t r e n d )

P = 0 . 0 0 9 ( h i g h d o

s e )

P = 0 . 0 0 2 ( t r e n d )

N S

S u r v i v a l : 3 2 / 5 0 , 2 8 / 5 0 , 2 5 / 5 0 , 1 9 / 5 0

K i d n e y ( r e n a l t u b u l e h y p e r p l a s i a

) e : 1 / 5 0 ( 2 . 0

) ,

1 4 / 5 0 f ( 2 . 9

) , 7 / 5 0 f ( 2 . 0

) , 2 1 / 5 0 g (

2 . 5 ) h

K i d n e y ( n e p h r o p a t h y ) : 4 2 / 5 0 ( 2 . 0

) , 4 5 / 5 0 ( 2 . 6

) ,

4 7 / 5 0 ( 2 . 4

) , 5 0 / 5 0 f ( 3 . 1

)

K i d n e y ( p a p i l l a , m i n e r a l i z a t i o n ) : 1 / 5 0 ( 1 . 0

) , 6 / 5 0 f

( 1 . 2

) , 2 2 / 5 0 g (

1 . 6

) , 2 9 / 5 0 g (

1 . 5

)

K i d n e y ( p e l v i s , t r a n s i t i o n a l e p i t h

e l i u m

h y p e r p l a s i a ) : 1 / 5 0 ( 1 . 0

) , 5 / 5 0 ( 1 . 8 )

, 6 / 5 0 f ( 1 . 2

) ,

1 9 / 5 0 g (

1 . 4

)

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311

S p e c

i e s ,

s t r a

i n ( s e x

)

D u r a t i o n

D o s i n g r e g

i m e n

A n

i m a

l s / g r o u p a t s t a r t

I n c

i d e n c e o

f t u m

o u r s

S i g n

i fi c a n c e

( p o l y - 3

t e s t

)

C o m m e n t s

R a t , F 3 4 4 / N

( F )

1 0 4 w k

0 , 4 5 0 , 9 0 0 o r 1 8 0 0 p p m , 6 h

p l u s T 9 0

( 1 2

m i n ) / d , 5 d / w k


K i d n e y ( m a l i g n a n t m e s e n c h y m a l

t u m o u r i ) :

0 / 5 0 , 0 / 5 0 , 0 / 5 0 , 2

/ 5 0

P = 0 . 0 4 3 ( t r e n d )

S u r v i v a l : 3 5 / 5 0 , 3 4 / 5 0 , 2 6 / 5 0 , 3 2 / 5 0

K i d n e y ( n e p h r o p a t h y ) : 1 9 / 5 0 ( 1 . 4

) , 3 5 / 5 0 f ( 1 . 5

) ,

3 8 / 5 0 f ( 1 . 5

) , 4 4 / 5 0 f ( 1 . 9

)

a H

i s t o r i c a l i n c i d e n c e i n m a l e

B 6 C 3 F 1 m i c e f o r 2 - y e a r i n h a l a t i o n s t u d i e s w i

t h c h a m b e r c o n t r o l s g i v e n N T P - 2 0 0 0 d i e t ( m e a n ± s t a n d a r d d e v i a t i o n ) : h e p a t o c e l l u l a r a d e n o m a o r c a r c i n o m a ,

1 9 6 / 3 5 0 ( 5 6 . 0 ± 6 . 2 % ) , r a n g e 5 0 – 6 8 % ; h e p a t o c e l l u l a r a d e n o m a , 1 3 4 / 3 5 0 ( 3 8 . 3 ± 6 . 3 % ) , r a n g e 3 0 – 4 6 % ; h e p a t o c e l l u l a r c a r c

i n o m a , 8 5 / 3 5 0 ( 2 4 . 3 ± 4 . 8 % ) , r a n g e 1 8 – 3 2 %

b H

i s t o r i c a l i n c i d e n c e i n f e m a

l e B 6 C 3 F 1 m i c e f o r 2 - y e a r i n h a l a t i o n s t u d i e s w i t h c h a m b e r c o n t r o l s g i v e n N T P - 2 0 0 0 d i e t (

m e a n ± s t a n d a r d d e v i a t i o n ) : h e p a t o c e l l u l a r a d e n o m a o r

c a r c i n o m a , 1 0 8 / 3 4 7 ( 3 1 . 1 ± 6 . 8

% ) , r a n g e 2 2 – 3 9 % ; h e p a t o c e l l u l a r a d e n o m a , 7 8 / 3 4 7 ( 2 2 . 5 ± 8 . 1 % ) , r a n g e 1 2 – 3 5 % ; h e p a t o c e l l u l a r c a r c i n o m a , 3 7 / 3 4 7 ( 1 0 . 7 ± 1 . 8 % ) , r a n g e 8 – 1 2 %

c N o a d d i t i o n a l r e n a l t u b u l e c

a r c i n o m a s w e r e i d e n t i fi e d i n t h e s t e p s e c t i o n

e v a l u a t i o n .

d H

i s t o r i c a l i n c i d e n c e i n m a l e

F 3 4 4 / N r a t s f o r 2 - y e a r i n h a l a t i o n s t u d i e s w i t h c h a m b e r c o n t r o l s g i v e n N T P - 2 0 0 0 d i e t f o r

s i n g l e s e c t i o n e v a l u a t i o n s ( m e a n ± s t a n d a r d d e v i a t i o n ) : r e n a l

t u b u l e a d e n o m a , 3 / 3 9 9 ( 0 . 8 ± 1 . 0 % ) , r a n g e 0 – 2 % ; r e n a l t u b u l e c a r c i n o m a , 1 / 3 9 9 ( 0 . 3 ± 0 . 7 % ) , r a n g e 0 – 2 % ; r e n a l t u b u l e a d

e n o m a o r c a r c i n o m a , 4 / 3 9 9 ( 1 . 0 ± 1 . 1 % ) , r a n g

e 0 – 2 %

e B a s e d o n c o m b i n e d s i n g l e s e

c t i o n a n d s t e p s e c t i o n e v a l u a t i o n s . S i n g l e s e c

t i o n s a l o n e : 1 / 5 0 ( 2 . 0

) , 1 1 / 5 0 f ( 3 . 2

) , 3 / 5 0 ( 2 . 0 ) ,

1 8 / 5 0 f ( 2 . 7

) ; S t e p s e c t i o n e v a l u a t i o n a l o n e : 0 / 5 0 , 3 / 5 0 ( 2 . 0

) , 4 / 5 0

( 2 . 0

) , 6 / 5 0 g (

2 . 3

)

f

S i g n i fi c a n t l y d i ff e r e n t ( P ≤ 0

. 0 5 ) f r o m t h e c h a m b e r c o n t r o l g r o u p b y t h e p

o l y - 3 t e s t

g P

≤ 0 . 0 1

h N u m b e r s i n p a r e n t h e s e s i n d

i c a t e a v e r a g e g r a d e o f s e v e r i t y o f l e s i o n s i n a ff

e c t e d a n i m a l s : 1 = m i n i m a l , 2 = m i l d , 3 = m o

d e r a t e , 4 = m a r k e d

i

H i s t o r i c a l i n c i d e n c e i n f e m a

l e F 3 4 4 / N r a t s f o r 2 - y e a r i n h a l a t i o n s t u d i e s w

i t h c h a m b e r c o n t r o l s g i v e n N T P - 2 0 0 0 d i e t : 0

/ 3 9 6

d ,

d a y o r d a y s ; F ,

f e m a l e ; h , h o

u r o r h o u r s ; M , m a l e ; m i n , m i n u t e o r m i n u t e s ; N S , n o t s i g n i fi c a n t ; w k , w e e k o r w e e k s

F r o m N T P ( 2 0 0 7 ) , S t o u t e t a

l .

( 2 0 0 8 )

T a b l e 3 . 1

( c o n t i n u e d

)

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3.1.2 Rat

Groups o 50 male and 50 emale F344/Nrats were exposed by whole-body inhalation tomethyl isobutyl ketone (> 99% pure) at concen-

trations o 0, 450, 900 and 1800 ppm or 6 hoursplus

90 (12 minutes) per day on 5 days a week

or 104 weeks. reatment-related increases inthe incidence o kidney tumours were observedin males and emales (renal tubule adenomaand carcinoma combined in males and twomalignant mesenchymal tumours in high-doseemales), together with concurrent treatment-related increases in the incidence o renal tubulehyperplasia and papillary mineralization (whichhad a linear pattern) in males.

[Te Working Group noted that kidneytumours are rare spontaneous neoplasms inexperimental animals.]

4. Other Relevant Data

4.1 Absorption, distribution,metabolism and excretion

4.1.1 Humans

Johnson (2004) reviewed the available phar-macokinetic data or methyl isobutyl ketone.Primary data in humans were described or eightmale volunteers (18–35 years o age) exposed to2.4, 24.4 or 48.8 ppm (10, 100 or 200 mg/m3) or2 hours on three different occasions during lightphysical exercise (Hjelm et al., 1990). Te relativepulmonary uptake was ~60%, which increasedwith increasing dose (0.2 mmol at 10 mg/m3, 1.7

mmol at 100 mg/m3 and 3.2 mmol at 200 mg/m3).Levels in the blood rose rapidly afer the onset oexposure, levelled off and did not reach a plateauor 2 hours. At the end o the exposure, bloodconcentrations increased linearly with dose, withno tendency or saturation kinetics. Te terminalelimination hal-lie was increased with dose,

but exposure concentration did not impact theapparent rate o blood clearance (1.6 L/h/kg).Blood concentrations measured at the end othe exposures indicated linear kinetics (dose-proportional blood concentration) o methylisobutyl ketone at the three doses tested. Only0.04% o the total dose was eliminated unchangedin the urine within 3 hours afer dosing, but theconcentration in the urine was higher than thatin arterial blood at 0.5 and 3 hours afer the endo exposure.

Afer exposure, methyl isobutyl ketone wasreported to be eliminated via a rapid and slowphase. Saghir & Rick (2008) cited another studythat reported biphasic urinary elimination o

methyl isobutyl ketone rom human volunteers(Ogata et al., 1995). However, the major route oelimination was exhalation.

Human volunteers (98 men and women) wereexposed to 100 ppm (410 mg/m3) methyl isobutylketone or 4 hours in an environmental chamber(Dick et al., 1990). Steady-state blood concentra-tions o methyl isobutyl ketone were attained afer2 hours o exposure. Blood and breath samplescollected 90 minutes afer exposure indicatedthat most o the absorbed compound had been

eliminated rom the body.Bellanca et al. (1982) reported that methyl

isobutyl ketone was detected in the brain, liver,lung, vitreous fluid, kidney, and blood in twoworkers who died afer exposure to severalorganic solvents during spray painting. One diedrom a all and the other died o cerebral oedema9 hours later. issue concentrations (mg/100 g)were reported to be: case 1 — brain, 0.25; liver,0.49; lung, 0.43; vitreous fluid, 0.52; kidney, 0.24;

and emoral blood, 0.14; and case 2 — brain, 0.06;liver, 0.22; lung, 0.11; vitreous fluid, 0.02; kidney,0.08; and heart blood, 0.04.

Dowty et al. (1976) reported methyl isobutylketone in human maternal blood samplescollected immediately afer delivery, indicatingthe potential or the compound to enter theumbilical cord and cross the placenta. Methyl

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isobutyl ketone is readily soluble in blood andhas a high affinity or at. In-vitro partition coe-ficients o 70–90 between blood and air and 926between water and oil were reported (Sato & Nakajima, 1979).

Saghir and Rick (2008) used the data o Hjelm et al. (1990) on single-dose inhalation exposureto simulate the repeated-dose kinetics o methylisobutyl ketone in humans. Te physiologicallybased pharmacokinetic model predicted thekinetics and accumulation o methyl isobutylketone afer repeated exposures or 8, 12 and 24hours per day or 7 days to the current ACGIHexposure threshold limit value-WA o 50 ppm,and ollowed a two-compartment model using

inhalation-chamber data. Elimination o methylisobutyl ketone was assumed to occur primarilythrough exhalation, because only 0.04% o thetotal dose was reported to be eliminated throughthe urine (Hjelm et al., 1990). Te model did notaccount or elimination rom the blood/body

via other routes o elimination, e.g. as carbondioxide, or metabolic incorporation into tissues.Measured blood concentrations were used toderive kinetic parameters that were then used topredict blood concentrations ollowing different

exposure scenarios at 50 ppm. [Te model wasnot validated using an independent data set.]Te model output was then used to assess theprobable effects o various conditions o bloodconcentration, potential or accumulation andWA blood concentrations. Kinetic rates werecalculated using the methodology o Hjelm et al. (1990). Berkeley-Madonna modelling sof-ware was used that can simulate a simple one- ortwo-compartment situation. Te model made no

attempt to predict the levels o exhaled methylisobutyl ketone. Tereore, the amount exhaledwas not ed back into the exposure concentrationand the exposure concentration defined in themodel was fixed over a defined exposure period.Te model was optimized by fitting all threeblood concentration time-course concentrationso methyl isobutyl ketone. Te model (Saghir

& Rick, 2008) correctly simulated the experi-mental data measured afer single exposures anddemonstrated a rapid rise in blood concentrationto 1.06 µg/mL within 1 hour, which approachedsteady-state levels o 1.37 μg/mL at 4 hours oexposure and 1.47 μg/mL at the end o expo-sure. Methyl isobutyl ketone was predicted to berapidly eliminated rom blood afer cessation oexposure, reaching 0.53 µg/mL and 0.13 µg/mLwithin 0.5 and 2 hours afer cessation, respec-tively. It was concluded that methyl isobutylketone is not likely to accumulate in workersexposed to 50 ppm.

4.1.2 Experimental systems

Methyl isobutyl ketone was rapidly absorbedollowing oral administration to or inhalationexposure o male Sprague-Dawley rats (Duguay& Plaa, 1995). Te compound was rapidlyabsorbed and was detected in the lung, liver andplasma afer inhalation or within 1 hour aferan oral dose. In CD-1 mice, an intraperitonealinjection was quickly distributed and eliminated(Granvil et al., 1994). Clearance time was 6 hoursand the hal-lie in serum was 66 minutes in

guinea-pigs that received a single intraperito-neal dose o methyl isobutyl ketone (DiVincenzoet al., 1976).

Male Sprague-Dawley rats were exposed tomethyl isobutyl ketone orally (0.5, 3 or 6 mmol/kg body weight (bw)) or by inhalation (200, 400or 600 ppm) (Duguay & Plaa, 1995). Te parentcompound and two products — 4-hydroxymethylisobutyl ketone and 4-methyl-2-pentanol — wereidentified in the plasma, liver and lung ollowinginhalation. Afer oral administration, the parentcompound and the hydroxylated product weredetected in these tissues, but not 4-methyl-2-pentanol. Tese results were consistent with themetabolism o methyl isobutyl ketone via alcoholdehydrogenase and cytochrome P450 (CYP)mono-oxygenases (Vézina et al., 1990). In CD-1mice that received an intraperitoneal injection o

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5 mmol/kg bw methyl isobutyl ketone (Granvil et al., 1994), the major metabolites detected inthe blood and brain were 4-methyl-2-pentanoland 4-hydroxy-4 methyl-2-pentanone.

In a review, Stout et al. (2008) indicated thatthe metabolism o methyl isobutyl ketone inguinea-pigs entails the reduction o the carbonylgroup to a secondary alcohol (4-methyl-2-pen-tanol) and oxidation at the ω-1 carbon atom toorm a hydroxylated ketone (4-hydrodroxyme-thyl isobutyl ketone, also known as diacetonealcohol). 4-Methyl-2-pentanol may be urtherconjugated with sulate or glucuronic acid, mayundergo intermediary metabolism and be elimi-nated as carbon dioxide or may be incorporated

into tissues.

4.2 Genetic and related effects

4.2.1 Humans



Johnson (2004) reviewed the genetic toxi-cology o methyl isobutyl ketone and oundthat it is generally not genotoxic in a variety osystems. An effort was made to test this vola-tile compound in closed systems in some o theassays, including Salmonella and the mouselymphoma thymidine kinase locus Tk+/−, but thecompound still gave either negative or equivocalresults. In studies in Salmonella (Brooks et al., 1988; Zeiger et al., 1992), methyl isobutyl ketonewas not mutagenic in the presence or absence

o metabolic activation in a variety o strains(A98, A100, A1535, A1537 and A1538) inthe pre-incubation assay in closed tubes. Similarnegative results were also observed in the S. typh-imurium assay with A102 and A104 (Zeiger et al., 1992). Equivocal results were ound in theL5178Y mouse lymphoma Tk+/− assay which was

also perormed in closed tubes (O’Donoghue et al., 1988).

Methyl isobutyl ketone gave negative resultsor unscheduled DNA synthesis in rat hepato-cytes, or micronuclei in the bone marrow oCD-1 mice (afer intraperitoneal injection), orcell transormation in BALB/33 mouse embryocells (O’Donoghue et al., 1988), or mitotic geneconversion (Brooks et al., 1988) and mitotic chro-mosome loss (Zimmermann et al., 1989) in yeastand or chromosome damage in rat liver cells invitro (Brooks et al., 1988).

4.3 Toxic effects

4.3.1 Humans



(a) Liver and kidney

Methyl isobutyl ketone, its metabolites andother ketones are known to potentiate livernecrosis induced by haloalkanes (e.g. carbontetrachloride and chloroorm (Vézina et al.,

1990)), and cholestasis induced by cholestaticagents (e.g. taurolithocholate (Plaa & Ayotte, 1985; Dahlström-King et al., 1990; Duguay & Plaa, 1997) or manganese-bilirubin (Vézina & Plaa, 1987; Duguay & Plaa, 1997)). Tere is noevidence, however, that methyl isobutyl ketoneor its metabolites have adverse effects on theliver when administered alone either orally (upto 7.5 mmol/kg) or by inhalation (up to 600 ppm)under conditions o a single or repeated (3 days)exposure (Joseph et al., 1992; Duguay & Plaa, 1997).

Although methyl isobutyl ketone showedno toxic effect on the liver in acute or subacuteexposures, it has been shown (Vézina et al., 1990)to increase the total amount o CYP in the ratliver 24 hours afer a single dose (lowest effectivedose tested, 7.5 mmol/kg bw in corn oil vehicle

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by gavage) or afer a 5-day treatment regime(lowest effective dose, 5 mmol/kg bw). While noindividual CYP enzymes were evaluated in thisstudy, the authors tested or the activity o anilinehydroxylase (CYP2E activity), ethoxycoumarinO-deethylase (CYP1A and −2E activity) andaminopyrine N -demethylase (CYP2B activity)and reported increased activity afer treatmentwith methyl isobutyl ketone or all three enzymesat both time-points with minimal effective dosesidentical to that required to increase total CYPcontent.

Te induction o liver CYPs has been asso-ciated with the ‘potentiating’ effect o methylisobutyl ketone on prior hepatotoxic treatments

(Vézina et al., 1990). However, this mechanismdoes not appear to be exclusive because it alsoaffects the toxicity o bile acid, and it has beensuggested that methyl isobutyl ketone may alsoreduce the bile salt pool and/or affect hepaticsecretion o bile acids (Joseph et al., 1992).

A similar effect on the induction o total CYP,as well as aniline hydroxylase (CYP2E activity)and aminopyrine N -demethylase (CYP2Bactivity), was observed in the rat kidney aferoral (3 days; minimal effective dose, 13.6 mmol/

kg bw) administration o methyl isobutyl ketone(Raymond & Plaa, 1995a). Interestingly, whiletotal CYP, CYP2E and −2B activities in the liverwere much greater than those in the kidney, theinduction o total CYP was 2–3 times greater inthe kidney than in the liver. In the same study,covalent binding o [14C]carbon tetrachloride torenal proteins was potentiated by methyl isobutylketone, similarly to the observation in the liver.It was also shown that methyl isobutyl ketone

potentiates chloroorm-induced kidney toxicity,albeit to a lesser degree than that o carbon tetra-chloride (Raymond & Plaa, 1995b). Both studiesconcluded that enzyme induction by methylisobutyl ketone played a major role in the poten-tiation o toxicity o the two nephrotoxicantswhich are known to require metabolic activation.

Subchronic (≥ 90 days) exposure to methylisobutyl ketone by inhalation was shown toincrease liver weights, characterized by hepa-tocellular hypertrophy, in both rats and mice(Phillips et al., 1987; Nemec et al., 2004). Acomparison o the effects o exposure by inha-lation to 410 mg/m3 methyl isobutyl ketone or90 days in male rats, beagle dogs and Macacamulatta monkeys (MacEwen et al., 1971) revealedno pathological effects in dogs or monkeys inany o the major organs examined at necropsy.Statistically significant increases in liver andkidney weights were observed only in male rats.Hyaline droplets were detected in the proximaltubules o all exposed male rats within 15 days

o exposure (some rats were necropsied afer 2, 3,4, 10, or 12 weeks). A study that investigated oraladministration o methyl isobutyl ketone (1.04 g/kg per day in the drinking-water or 120 days) toemale rats ound a significant increase in abso-lute and relative kidney (but not liver or otherorgan) weight, and one o five rats tested had renaltubule-cell hyperplasia (US EPA, 2003). Anothersubchronic toxicity study compared male andemale rats administered methyl isobutyl ketonedaily by oral gavage (59, 250 or 1000 mg/kg bw)

or 13 weeks (IPCS, 1990). Nephrotoxicity andincreased liver and kidney weights were observedin both males and emales at the highest dose.Te no-adverse-effect dose was 50 mg/kg bw.

(b) Other studies of toxicity

Rats, mice, guinea-pigs, cats and dogs werestudied or the acute toxicity o methyl isobutylketone afer oral, dermal, inhalational, intrave-nous or intraperitoneal administration. Tese

studies have been reviewed extensively (Johnson,2004). No species differences in acute toxiceffects were observed. Methyl isobutyl ketonewas shown to be neurotoxic and irritating (tothe upper respiratory tract and lungs afer inha-lation) at the highest concentrations tested. Littleevidence o hepatic or renal toxicity was reportedeven at doses that were lethal.

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wo studies o the reproductive and develop-mental toxicity o methyl isobutyl ketone wereavailable. yl et al. (1987) exposed F344 rats andCD-1 mice to methyl isobutyl ketone (up to 3000ppm) by inhalation on gestational days 6–15.Maternal toxicity (death, increases in absoluteand relative liver weights) were observed in the3000-ppm groups o rats and mice. Fetal toxicity(decrease in body weight, retardation o ossifica-tion) was observed in the offspring o both ratsand mice in the 3000-ppm group. Nemec et al. (2004) exposed Sprague-Dawley rats to up to2000 ppm methyl isobutyl ketone (whole-bodyinhalation) or 70 days beore mating. F0 and F1emales were exposed rom mating to gestational

day 20 and then rom postnatal day 5; F2 litterswere maintained through postnatal day 21. Mostadverse effects were observed only in the 2000-ppm group. Specifically, a sedative effect (centralnervous system depression) was observed in thepups. Increased liver weight was observed inthe F0 and F1 generation males and emales. InF0 generation males, increased kidney (in the500- and 1000-ppm groups) and seminal vesicleweights were observed. In F0 emales, an increasein the weight o ovaries and adrenal glands was

observed. Nephropathy, characterized by baso-philic tubules with variable inflammation andthickening o the tubular basement membrane,was reported in F0 and F1 males exposed to 1000or 2000 ppm methyl isobutyl ketone. No effectson sexual maturation or reproductive end-pointswere observed at any dose tested.

4.4 Mechanistic considerations

4.4.1 Tumours of the kidney Te development o kidney tumours in male

rats in association with chemically inducedα2u-globulin nephropathy is mechanism that isnot considered to be a predictor o carcinogenicrisk to humans by the IARC or the US EPA (US EPA, 1991; Swenberg & Lehman-McKeeman,

1999). Te lack o relevance o the α2u-globulinmechanism or the evaluation o carcinogenicrisk is based on the absence o the productiono an analogous protein in humans. Strict scien-tific criteria have been outlined to establish therole o α2u-globulin-associated nephropathy inrenal carcinogenesis in male rats (Swenberg & Lehman-McKeeman, 1999), and were used todetermine the plausibility o an α2u-globulin-associated nephropathy based on a limitednumber o studies that have been carried outwith subchronic and chronic exposures to methylisobutyl ketone.

Criterion 1 is evidence o a lack o genotoxicactivity (agent and/or metabolite) based on an

overall evaluation o in-vitro and in-vivo data.As reviewed in Section 4.2, there was little, i anyevidence that methyl isobutyl ketone was geno-toxic. wo o its metabolites — 4-hydroxymethylisobutyl ketone and 4-methyl-2-pentanol — thatare ound in male Sprague-Dawley rat liver,serum and lung afer exposure to methyl isobutylketone have not been evaluated or genotoxicity.Tus, this criterion appears to be met.

Criterion 2 is the specificity in male rats ornephropathy and renal tumorigenicity; criterion

6 is the induction o sustained increased cellprolieration in the renal cortex; and criterion 7mentions the observed similarities in the dose–response relationship o the tumour outcomewith the histopathological end-points (proteindroplets, α2u-globulin accumulation and cellprolieration). Stout et al. (2008) evaluated thepotential o methyl isobutyl ketone to inducetoxic and carcinogenic effects ollowing chronicexposure. Groups o 50 male and 50 emale F344

rats were exposed to concentrations o 0, 450, 900or 1800 ppm by inhalation or 6 hours per day on5 days a week or 2 years. Survival was decreasedin 1800-ppm males, and body weight gains weredecreased in 900- and 1800-ppm males. In males,but not emales, increased mineralization o therenal papilla was observed at all exposure concen-trations. Te incidence o chronic progressive

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nephropathy was increased at 1800 ppm andits severity was increased in all exposed groupso males. Te incidence o chronic progressivenephropathy was increased in all treated groupso emales, the severity o which was increasedwith the highest dose. In male, but not emales,increases in incidence o renal tubule hyperplasiawere observed at all exposure concentrations, andin that o adenoma and adenoma or carcinoma(combined) at 1800-ppm. α2u-Globulin levelswere not evaluated in this study. Tis chronicstudy provided dose–response consistency andmale specificity o mineralization, sustainedincreases in cell prolieration in the renal cortexand the induction o combined adenomas and

carcinomas in the kidney. However, the studyound that chronic progressive nephropathy wasnot male-specific.

Criterion 3 is the induction o the character-istic sequence o histopathological changes inshorter-term studies, o which protein dropletaccumulation is obligatory. Te Bushy Run Research Center (1982) exposed three groups oF344 rats (six males and six emales) to methylisobutyl ketone at concentrations o 101 ppm[413 mg/m3], 501 ppm [2050 mg/m3] and 1996

ppm [8180 mg/m3] or 6 hours per day or 9 days.A ourth group served as the untreated control.Te first 5 days and the remaining 4 days o expo-sure were separated by a 2-day non-treatmentperiod. In the highest-dose group (1996 ppm), asignificant increase in both absolute and relativekidney weights was noted in male and emalerats. Epithelial regeneration o the proximalconvoluted tubules was also noted at 1996 ppm[male and emale specificity was indicated in

the summary]. In the 501-ppm exposure group,a non-significant increase in kidney weight wasobserved in male but not emale rats. In both501- and 1996-ppm exposure groups, hyalinedroplet ormation was observed in the kidneyso male rats. No microscopic abnormalities werenoted in rats exposed to 101 ppm methyl isobutyl

ketone (Bushy Run Research Center, 1982, citedby US EPA, 2003).

Male and Female F344 rats and B6C3F1 mice

were exposed to 0, 100, 500 or 2000 ppm methylisobutyl ketone or 6 hours per day or 2 weeks.At 2000 ppm, a slight increase in male rat liverweight (absolute and relative)was observed.Te only changes observed histologically wereincreases in regenerative tubular epithelia andhyaline droplets in the kidneys o male but notemale rats exposed to 500 or 2000 ppm Phillipset al. (1987). Exposure levels or a subchronicstudy were 0, 50, 250 or 1000 ppm methyl isobutylketone vapour or 6 hours per day on 5 days aweek or 14 weeks. Te 14-week exposure had no

adverse effect on the clinical health or growth othe rats. Te only microscopic change observedwas an increase in the incidence and extent ohyaline droplets within the proximal tubularcells o the kidneys o male but not emale ratsexposed to 250 and l000 ppm. Tese two studiesindicate the induction o hyaline protein dropletsin shorter-term studies. Protein droplets werealso identified and characterized urther in thestudy described below (Borghoff et al., 2009).

Another criterion is the identification

o protein accumulation in tubule cells asα2u-globulin. Borghoff et al. (2009) adminis-tered corn oil (vehicle control), d -limonene (posi-tive control, 300 mg/kg bw) or methyl isobutylketone (1000 mg/kg bw) to male and corn oil(vehicle control) or methyl isobutyl ketone toemale F344 rats by oral gavage or 10 consecu-tive days. Methyl isobutyl ketone caused anincrease in protein droplets, accumulation oα2u-globulin and renal cell prolieration in male

but not emale rats. It produced histopatholog-ical changes in the male rat kidney identical tothose o d -limonene, an acknowledged inducero α2u-globulin-mediated nephropathy, exceptthat the grade o severity tended to be slightlylower with methyl isobutyl ketone. Methylisobutyl ketone did not induce any effects inemale rats. Te authors ound α2u-globulin

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accumulation in tubule cells afer exposure inmales. However, the experimental design did notallow or the evaluation o a dose–response rela-tionship in the increases in α2u-globulin accu-mulation; moreover, treatment-related increasesin the incidence and average severity o chronicprogressive nephropathy were observed in bothmales and emales, which suggests that an alter-native mechanism may also be involved. Renaltubule neoplasms probably arose via the malerat-specific α2u-globulin-mediated mechanism(NP, 2007).

Te last criterion is the reversible bindingo the chemical or metabolite to α2u-globulin,which was not shown direct in any o the studies.

One study showed reversibility o the adverseeffects in the kidney afer withdrawal o methylisobutyl ketone. Te Wright-Patterson Air ForceBase Aerospace Medical Research Laboratory(MacEwen et al., 1971) conducted a subchronicinhalation toxicity study in male Wistar albinorats that were exposed to 410 mg/m3 methylisobutyl ketone vapour [100 ppm] or 90 days inan altitude chamber. Te untreated control groupwas maintained in a separate altitude chamber.Statistically significant increases in liver and

kidney weights and organ-to-body weight ratiosor these tissues were noted in exposed rats.Microscopic examination o the kidneys revealedhyaline droplet degeneration o the proximaltubules (with occasional oci o tubular necrosis)in all o the exposed rats, including those that wereremoved rom the inhalation chamber afer 15,22, 28, 71 and 85 days. Te authors noted a trendtowards a linear progression o hyaline dropletdegeneration during exposure, but this pattern

was not seen in all treatment groups. Moreover,the hyaline droplets appeared to increase in sizewith time. Tis observation was thought to haveresulted rom the coalescence o smaller drop-lets. Microscopic examination o rat kidneysremoved afer 15 days o exposure indicated agradual reversion o tubular damage with time.Kidney damage was completely reversed in rats

observed up to 60 days afer exposure. Recoveryrom methyl isobutyl ketone-induced kidneylesions was also noted in rats that were seriallykilled to study reversibility afer 90 days o expo-sure. However, recovery was not as rapid as thatnoted in animals exposed or shorter periods.A weakness o the study was the exclusion oemale rats. Te study showed the reversibility oeffects that could be attributed to α2u-globulinnephropathy.

Kidney tumours were induced in male butnot emale rats. Mechanistic studies provideevidence that some o the criteria that denote anα2u-globulin mode o action were met. [Teseinclude male rat-specific nephropathy, dose–

response associations o end-points and dose-related increases in cell prolieration.] However,in a review o the linkages between end-pointsthat are typically considered to support anα2u-globulin mode o action (Doi et al., 2007),recent NP studies demonstrated inconsisten-cies with this proposed mechanism, including, insome cases, kidney tumour responses that werear weaker than expected based on the extent oα2u-globulin nephropathy. Te review revealedno, or at best weak, associations between tumour

responses and renal α2u-globulin concentra-tions, indices o cell turnover or microscopicevidence o α2u-globulin nephropathy inpre-chronic studies. While tumour responsescorresponded to some extent with a measure ocumulative α2u-globulin nephropathy (linearmineralization o the papilla) at the end o the2-year studies, the severity o chronic nephrop-athy generally correlated best with the pattern otumour response. Tese results suggest that, while

α2u-globulin nephropathy may contribute to therenal tumour response, the critical component(s)o the nephropathy most closely associated withthe development o tumours has not been identi-fied. Tus, the strength o the evidence that malerat kidney tumours arose through a α2u-globulinnephropathy mechanism is weak. Te relevance

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Data rom single-dose inhalation exposurestudies were used to simulate the repeated-dosekinetics o methyl isobutyl ketone in humans.Te two-compartment pharmacologically basedpharmacokinetic model predicted the kineticsand accumulation or repeated exposures.It correctly simulated the experimental datameasured afer single exposures and demon-strated a rapid rise in blood concentrationwithin 1 hour and rapid elimination rom theblood afer cessation o exposure. On the basis othese results, methyl isobutyl ketone is not likelyto accumulate in workers exposed to 50 ppm.Methyl isobutyl ketone was rapidly absorbedafer oral administration to or inhalation expo-

sure o male rats. It was detected in the lung, liverand plasma within 1 hour afer an oral dose. Inmice, methyl isobutyl ketone administered byintravenous injection was quickly distributedand eliminated. A clearance time o 6 hours anda hal-lie in serum o about 1 hour were meas-ured in guinea-pigs afer a single intraperitonealdose o methyl isobutyl ketone.

No data were available on the metabolismo methyl isobutyl ketone in humans. In rats,the parent compound and two metabolites —

4-hydroxymethyl isobutyl ketone and 4-methyl-2-pentanol — were identified in the plasma, liverand lung ollowing inhalation. Afer an oraldose, the parent compound and the hydroxylatedproduct were detected in these tissues, but not4-methyl-2-pentanol. Tese data are consistentwith metabolism that involves alcohol dehydro-genase and cytochrome P450 mono-oxygenases.Similar patterns o metabolism were seen in miceand guinea-pigs.

Methyl isobutyl ketone was generally notgenotoxic in a variety o systems. Also, whenthis volatile compound was tested in closedsystems, no indication o genotoxicity was ound.Methyl isobutyl ketone was not mutagenic inbacterial assays. It did not induce unscheduledDNA synthesis in rat hepatocytes, micronucleimouse bone marrow, cell transormation in

BALB/33 mouse embryo cells, mitotic geneconversion or mitotic chromosome loss in yeastor chromosome damage in rat liver cells invitro. Tere is little, i any, evidence that methyl

isobutyl ketone-induced tumours in rodentsarise through a genotoxic mechanism, althoughits two metabolites (4-hydroxymethyl isobutylketone and 4-methyl-2-pentanol) have not beenevaluated or genotoxicity.

Methyl isobutyl ketone and its metabolitespotentiate liver necrosis induced by haloalkanesand enhance cholestasis induced by cholestaticagents or manganese-bilirubin. Tere is noevidence that acute administration o methylisobutyl ketone or its metabolites has adverse

effects on the liver when given alone, either orallyor via inhalation. It increased the total activity ocytochrome P450s 1A, 2B and 2E in the liver andkidney o rats. Te induction o these isozymesby methyl isobutyl ketone has been associatedwith the potentiating effect mentioned above. Ithas been suggested that methyl isobutyl ketonealso reduces the bile-salt pool and affects thesecretion o bile acids by the liver.

Subchronic inhalation exposure to methylisobutyl ketone was shown in one study to result

in increased liver weight, characterized by hepa-tocellular hypertrophy, in both rats and mice,but statistically significant increases in bothliver and kidney weights were observed onlyin male rats. Hyaline droplets were detected inthe proximal tubules o all exposed male rats.However, another subchronic toxicity study thatcompared male and emale rats demonstratednephrotoxicity and increased liver and kidneyweights in both male and emale rats.

In various animal species, methyl isobutylketone was shown to be neurotoxic and irritatingto the upper respiratory tract and lungs aferinhalation at high concentrations.

Te IARC scientific criteria to determine theplausibility o α2u-globulin-associated neph-ropathy as the underlying mechanism o kidneytumorigenesis were considered based on the

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limited number o studies on subchronic andchronic exposure to methyl isobutyl ketone, andwere not completely ulfilled. Te strength o theevidence that the kidney tumours in male ratsarise through an α2u-nephropathy-associatedmechanism is weak.

Tere is no evidence that liver tumours inmice arise rom a cytotoxic-regenerative cell-prolieration mechanism, because no overt livertoxicity has been demonstrated. Tere is onlyweak evidence that the tumours arise through areceptor-mediated mechanism.

Te relevance o the tumour response in miceand rats to humans cannot be excluded.

6. Evaluation

6.1 Cancer in humans


6.2 Cancer in experimental animals

Tere is sufficient evidence in experimentalanimals or the carcinogenicity o methyl isobutylketone.

6.3 Overall evaluation

Methyl isobutyl ketone is possibly carcinogenic to humans (Group 2B).

References

Bellanca JA, Davis PL, Donnelly B et al. (1982). Detectionand quantitation o multiple volatile compounds intissues by GC and GC/MS. J Anal Toxicol , 6: 238–240.PMID:7176553

Borghoff SJ, Hard GC, Berdasco NM et al. (2009).Methyl isobutyl ketone (MIBK) induction o alpha2u-globulin nephropathy in male, but not emale rats.Toxicology , 258: 131–138. doi:10.1016/j.tox.2009.01.018 PMID:19428932

Brooks M, Meyer AL, Hutson DH (1988). Te genetic toxi-cology o some hydrocarbon and oxygeneated solvents. Mutageneis, 3: 227–232. doi:10.1093/mutage/3.3.227

Burdock GA (2005). Fenaroli’s Handbook of FlavorIngredients, 5th ed. Boca Raton, FL: CRC Press.

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