GreenScreen Assessment for Methyl Ethyl Ketone (MEK… · GreenScreen™ Assessment for Methyl...

Copyright 2011 © Clean Production Action

Green Screen Assessment Prepared By: Quality Control Performed By:

Name: Brian Penttila, Ph. D. Name: Alex Stone, Sc. D.

Title: Chemical Engineer Title: Safer Chemical Alternative Chemist

Organization: PNW Pollution Prevention Resource Center Organization: WA Department of Ecology

Date: 30 June 2012 Date: 15 April 2013

GreenScreen™ Version 1.2 Reporting Template - Oct 2011 1

GreenScreen™ Assessment for Methyl Ethyl Ketone (MEK) (CAS #78-93-3)

GreenScreen™ Version 1.2 Draft Assessment

Note: Validation Has Not Been Performed on this Green Screen Assessment

Chemical Name: Methyl ethyl ketone (MEK)

Confirm application of the de minimus rule1: (if no, what de minimus did you use?) Yes.

Chemical Name (CAS #): Methyl ethyl ketone (CAS#78-93-3)

Also Called: 2-Butanone; 3-Butanone; Acetone, methyl- (US EPA, ACToR database, actor.epa.gov/)

Chemical Surrogates, analogs or moieties used in this assessment (CASs #): 2-butanol (CAS #78-92-2)

Chemical Structure(s):

Identify Applications/Functional Uses: (e.g. cleaning product, TV casing)

MEK is used primarily as a solvent in the application of protective coatings (paints and varnishes) and adhesives

(glues and cements) and in paint removers and cleaning fluids. (Additional details in Substance Background).

GreenScreen Rating2: MEK was assigned a Benchmark Score of 2 based on:

o Did not fail any Benchmark 1 criteria.

o Failed Benchmark 2c (very high persistence and moderate developmental and neuro-toxicity), 2e

(moderate developmental toxicity), and 2g (high flammability)

GreenScreen Hazard Ratings: Methyl Ethyl Ketone

Group I Human Group II and II* Human Ecotox Fate Physical

C M R D E AT ST N SnS* SnR* IrS IrE AA CA P B Rx F

single repeat* single repeat*

L L L M DG L L L M DG L DG DG H L L vH vL L H

Note: Hazard levels [Very High (vH), High (H), Moderate (M), Low (L), Very Low (vL)] in italics reflect estimated values and lower

confidence. Hazard levels in BOLD font reflect values based on test data (See Guidance). NE indicates no determination was made (conflicting

data) and DG indicates insufficient data for assigning hazard level.

Transformation Products and Ratings: Identify relevant fate and transformation products (i.e., dissociation

products, transformation products, valence states) and/or moieties of concern3

1 Every chemical in a material or formulation should be assessed if it is:

1. Intentionally added and/or 2. Present at greater than or equal to 100 ppm.

2 For inorganic chemicals with low human and ecotoxicity across all hazard endpoints and low bioaccumulation potential, persistence alone will not be deemed problematic. Inorganic chemicals that are only persistent will be evaluated under the criteria for Benchmark 4. 3 A moiety is a discrete chemical entity that is a constituent part or component of a substance. A moiety of concern is often the parent substance

itself for organic compounds. For inorganic compounds, the moiety of concern is typically a dissociated component of the substance or a transformation product.








Functional

Use

Life Cycle

Stage

Transformation

Pathway

Transformation

Products CAS #

On CPA Red

List4?

Green Screen

Rating5

N/A

No fate or transformation products relevant to toxicity were identified.

Substance Background

2-Butanone, also known as methyl ethyl ketone (MEK) is a clear, colorless, volatile liquid. MEK is soluble in water

and miscible with a wide variety of organic solvents. Major uses of MEK include use as a solvent in the application

of protective coatings (varnishes) and adhesives (glues and cements), vinyl plastic coatings and film manufacture,

paint removers, and cleaning fluids. MEK is also used in production of pharmaceuticals, synthetic resins and

printing inks. Other applications may include use as an extraction medium for fats, oils, waxes and resins, and as an

intermediate in the production of antioxidants, perfumes and catalysts. Applications in consumer products may

include: aerosol paints, architectural coatings, automobile and machinery paints and primers, household surface

cleaners, household dyes and tints, inks, insecticides for yard and garden, laundry starches, lubricating greases and

oils, automotive chemicals, markers, nail polish and polish remover, paints, varnish and paint and varnish removers

and thinners, shoe polish, interior clear finishes, undercoats, and primers, waterproofing compounds, particleboard,

and adhesives used to join PVC pipes. In many applications MEK is used as part of a mixture of organic solvents.

Approximately 80% of MEK use in the US is attributed to protective coatings and adhesives. (ATSDR 1992)

OECD reports that MEK is manufactured in a totally enclosed continuous process that converts butenes into MEK.

Mixed butenes react with a circulating sulfuric acid-water mixture. Sufficient water is added to the olefin-acid-water

mixture to form secondary butyl alcohol (SBA). SBA is heated in a furnace and dehydrogenated to MEK and

hydrogen. The MEK is purified to remove water and heavy ketones. MEK can also be produced by the oxidation of

n-butane, either as the main product or as a by-product in the manufacture of acetic acid. The OECD assessment lists

sec-butyl alcohol and acetone as impurities. A technical brochure from Sigma-Aldrich identifies a variety of other

impurities found in “commercial grade” MEK, including: methanol, ethanol, acetone, isopropanol, t-butanol, n-

propanol, n-butanol, ethyl acetate, diethoxymethane, sec-butanol, methyl isobutyl ketone, isopropyl acetate,

isobutanol, toluene, and 4-methyl-2-pentanone. No information was found on additives used in commercial MEK.

(OECD 1997)

Exposure to MEK is likely most often via inhalation due to solvent evaporation from coated surfaces or adhesive

use. Industrial exposure to moderate levels of MEK is widespread and ventilation is critical in applications such as

shoe factories, printing plants and painting operations. Solvents are often used in mixtures and MEK can exacerbate

the health impact of exposure to other solvents. US EPA reports that in rodents, orally administered MEK is

absorbed from the gastrointestinal tract and rapidly eliminated. Data from both humans and rats suggest that MEK is

well absorbed during inhalation exposure due to its high blood/air solubility ratio. Absorption through the skin also

appears to be rapid. (US EPA 2003)

The metabolism of MEK is similar in humans and experimental animals. MEK is metabolized to 3-hydroxy- 2-

butanone, which is then metabolized to 2,3-butanediol (in the liver), however, a small amount is reversibly

converted to 2-butanol. For humans inhaling MEK vapor, 2-butanol and 2,3-butanediol have been identified as

metabolites in serum, while 3-hydroxy-2-butanone and 2,3-butanediol have been identified metabolites in urine.

From a study of inhalation exposure to MEK in human volunteers (200 ppm for 4 hours), it was estimated that 3%

of the absorbed dose was exhaled as MEK, 2% of the absorbed dose was excreted in urine as 2,3-butanediol, and the

remainder of the absorbed dose entered into mainstream metabolism and ultimately converted to simple compounds

such as carbon dioxide and water. MEK has been identified as a minor, normal constituent of urine, a constituent in

4 The CPA “Red List” refers to chemicals 1) flagged as Benchmark 1 using the GreenScreen™ List Translator or 2) flagged as Benchmark 1 or 2

using the GreenScreen™ List Translator and further assessed and assigned as Benchmark 1. The most recent version of the GreenScreen™ List

Translator should be used. 5 The way you conduct assessments for transformation products depends on the Benchmark Score of the parent chemical (See Guidance).








serum and urine of diabetics, and in expired air. Its production in the body has been attributed to isoleucine

catabolism. MEK increases microsomal cytochrome P-450 enzyme activity. This enhanced enzyme activity may

explain how MEK potentiates the toxicity of some solvents (haloalkane and aliphatic hexacarbon solvents). For

hazard assessment, 2-butanol is sometimes used as a surrogate when data is not available for MEK. The US EPA

reports: “Because of the similarity in the effects of exposure to MEK and 2-butanol, as well as the finding that 2-

butanol is rapidly converted to MEK in rats, 2-butanol is considered to be an appropriate surrogate for assessing

MEK-associated toxicity.” (US EPA 2003)

As MEK evaporates readily and is very soluble in water, it is highly mobile in the environment. In water containing

free halogens or hypohalites, it reacts to form a haloform that is more toxic than the original compound. MEK is

distributed by both air and water, but does not accumulate in any individual compartment, and does not persist long

where there is microbial activity. In air MEK is subject to photochemical decomposition and is also synthesized by

photochemical processes. (IPCS 1993)

References:

1. IPCS (International Program on Chemical Safety) 1993, Environmental Health Criteria Monograph on MEK,

available at: http://www.inchem.org/documents/ehc/ehc/ehc143.htm, accessed May 2012.

2. US EPA 2003, Toxicological Review of MEK, available at: http://www.epa.gov/iris/toxreviews/0071tr.pdf,

accessed May 2012.

3. National Pollutant Inventory (Australia), fact sheet on MEK, available at:

http://www.npi.gov.au/substances/methyl-ethyl-ketone/source.html, accessed May 2012.

4. OECD 1997 SIDS Initial Assessment Report available at:

http://webnet.oecd.org/Hpv/UI/SIDS_Details.aspx?id=31C513F8-2B0D-4DE8-9A14-8463CD709ADD,

accessed May 2012.

5. ATSDR 1992 Toxicological Profile for 2-Butanone, available at:

http://www.atsdr.cdc.gov/toxprofiles/tp.asp?id=343&tid=60, accessed May 2012.

6. Sigma-Aldrich, fact sheet on MEK impurities, available at:

http://www.sigmaaldrich.com/Graphics/Supelco/objects/11800/11745.pdf, accessed May 2012.

http://www.inchem.org/documents/ehc/ehc/ehc143.htm

http://www.epa.gov/iris/toxreviews/0071tr.pdf

http://www.npi.gov.au/substances/methyl-ethyl-ketone/source.html

http://webnet.oecd.org/Hpv/UI/SIDS_Details.aspx?id=31C513F8-2B0D-4DE8-9A14-8463CD709ADD

http://www.atsdr.cdc.gov/toxprofiles/tp.asp?id=343&tid=60

http://www.sigmaaldrich.com/Graphics/Supelco/objects/11800/11745.pdf








Hazard Classification Summary Section:

Group I Human Health Effects (Group I Human)

Carcinogenicity (C) Score (H, M or L): L

MEK was assigned a score of L based on information found. However, authoritative bodies such as IRIS have

indicated there is insufficient data for classification of carcinogenicity. The decision to assign this endpoint a value

of ‘L’ is based upon professional judgment of an Ecology Toxicologist and should be revisited regularly to see if

additional data changes the initial score of L.

European Commission IUCLID datasheet states: ‘MEK was used as the solvent for the investigation of the

contribution of elemental sulfur and of organic sulfur compounds to dermal carcinogenesis in male C3H mice.

There are no other chronic/carcinogenicity studies available for MEK. After 50 mg of a 17% MEK solution

was applied to each mouse topically twice a week for one year, no skin tumors were observed.’, available at:

http://esis.jrc.ec.europa.eu/doc/IUCLID/data_sheets/78933.pdf, accessed April 2013.

EPA’s Hazardous Substances Database states: ‘Experimental animal studies are limited, but are generally

negative, and agents in this group have little mutagenic activity.’, available at: http://toxnet.nlm.nih.gov/cgi-

bin/sis/search/r?dbs+hsdb:@term+@na+METHYL ETHYL KETONE, accessed April 2013.

Woo et al.6 assigned a low level of carcinogenicity concern for Butanone (Table 3: List of DBPs under

evaluation, page 78) based upon their structure activity relationship (SAR) analysis.

US EPA 2003 IRIS assessment reports that the hazard descriptor “data are inadequate for an assessment of

human carcinogenic potential” is appropriate for MEK because cancer studies of humans chronically exposed to

MEK are inconclusive, MEK has not been tested for carcinogenicity in animals by the oral or inhalation routes,

and the majority of short-term genotoxicity testing of MEK has demonstrated no activity. [References are

internal to the IRIS assessment.] US EPA 2003, Toxicological Review of MEK, p. 55, available at:

http://www.epa.gov/iris/toxreviews/0071tr.pdf, accessed May 2012.

US EPA also reports that “SAR analysis suggests that MEK is unlikely to be carcinogenic based on the absence

of any structural alerts indicative of carcinogenic potential (Woo et al., 2002).” IRIS website information for

MEK at: http://www.epa.gov/iris/subst/0071.htm, accessed May 2012. [References are internal to the IRIS

assessment.]

Not listed as a known carcinogen by CA Prop 65, IARC, ISSCAN, NIOSH, or NTP.

Mutagenicity/Genotoxicity (M) Score (H, M or L): L

MEK was assigned a score of Low for mutagenicity based on GHS-Japan listing as “Not Classified” (GreenScreen

Screening A list) and negative results summarized in the 2003 IRIS toxicological review.

NITE/Japan 2006 reports that MEK is “Not Classified” due to negative results reported for micronucleus tests

using mammalian erythrocytes. Japanese NITE ID618 in the Microsoft Excel workbook found at

http://www.safe.nite.go.jp/english/files/ghs_xls/classification_result_e%28ID566-666%29.xls, accessed May

2012.

US EPA 2003 reports that “MEK is not mutagenic as indicated by a number of conventional short-term assays

for genotoxic potential.” In vitro tests reviewed include: Salmonella (Ames) assay with or without metabolic

activation, the L5178/TK+/-mouse lymphoma assay, and the BALB/3T3 cell transformation assay. “MEK did

not induce unscheduled DNA synthesis in rat primary hepatocytes (O’Donoghue et al., 1988). MEK also tested

negative in a battery of in vitro tests (Salmonella, chromosome aberration, and sister chromatic exchange)

conducted by the National Toxicology Program (NTP, undated). MEK was not mutagenic in Salmonella

typhimurium strains TA98, TA100, TA1535, or TA1537 in the presence or absence of rat hepatic homogenates

(Florin et al., 1980; Douglas et al., 1980; Zeiger et al., 1992). No induction of micronuclei was found in the

erythrocytes of mice (O’Donoghue et al., 1988) or hamsters (WHO, 1992) after intraperitoneal injection with

6 Woo, Yin-Tak, David Lai, Jennifer L. McLain, Mary Ko Manibusan and Vicki Dellarco, Use of Mechanism-Based Structure-Activity

Relationships Analysis in Carcinogenic Potential Ranking for Drinking Water Disinfection By-Products, Envir. Health Persp., Vol. 110, Suppl. 1, Feb. 2002, pages 75-87.

http://esis.jrc.ec.europa.eu/doc/IUCLID/data_sheets/78933.pdf


http://www.epa.gov/iris/subst/0071.htm

http://www.safe.nite.go.jp/english/files/ghs_xls/classification_result_e%28ID566-666%29.xls








MEK. The only evidence of mutagenicity was mitotic chromosome loss at a high concentration in a study on

aneuploidy in the diploid D61, M strain of the yeast Saccharomyces cerevisiae (Zimmermann et al., 1985); the

relevance of this positive result to humans is unknown. Low levels of MEK combined with low levels of

nocodazole (another inducer of aneuploidy) have also produced significantly elevated levels of aneuploidy in

the S. cerevisiae test system (Mayer and Goin, 1987).” [References are internal to the IRIS assessment.] US

EPA 2003, Toxicological Review of MEK, p. 47-48, available at:

http://www.epa.gov/iris/toxreviews/0071tr.pdf, accessed May 2012.

REACH registration dossier report on several key studies (reliability 1 and 2, non-GLP-compliant) that were

negative for genotoxicity, including: In vitro Mammalian Chromosome Aberration Test equivalent to OECD

Guideline 473, in vitro Mammalian Cell Gene Mutation Test equivalent to OECD Guideline 476, Bacterial

Reverse Mutation Assay equivalent to OECD Guideline 471, etc. Additional details available in the European

Chemicals Agency REACH registration dossier for 2-butanone, available at:

http://apps.echa.europa.eu/registered/data/dossiers/DISS-9d91195a-65f3-618d-e044-00144f67d249/AGGR-

4d0fe03b-37be-4b2d-b996-cac20c64c2aa_DISS-9d91195a-65f3-618d-e044-00144f67d249.html, accessed May

2012.

Reproductive Toxicity (R) Score (H, M, or L): L

MEK was assigned a score of Low for reproductive toxicity based on weight of evidence from animal studies.

Effects were described by reviewers as “minimal” (NITE and OECD) responses and occurred at high doses in both

inhalation (MEK) and oral exposure (2-butanol) studies. The database relies on studies with 2-butanol as a

surrogate, however, 2-butanol is suitable as it is rapidly converted to MEK in rats. A rating of Data Gap may be

warranted given that US EPA recommends negative studies with two species. The database also lacks a full set of

modern reproductive endpoint determinations (estrous cyclicity, sperm parameters, and uterine weight).

NITE/Japan lists as not classified. NITE considered IRIS 2003 [US EPA 2003] and ATSDR 1999 sources

among other data "judging to be minimum influence…" Japanese NITE worksheet ID618 in the Microsoft

Excel workbook available at: http://www.safe.nite.go.jp/english/files/ghs_xls/classification_result_e%28ID566-

666%29.xls, accessed May 2012.

US EPA 2003 reports (US EPA 2003, Toxicological Review of 2-Butanone for IRIS available at:

http://www.epa.gov/iris/toxreviews/0071tr.pdf, accessed May 2012):

o p. 86: “In experimental animals, the longest exposure study available for characterizing the health effects of

repeated exposure to MEK is the 90-day inhalation study by Cavender et al. (1983), wherein no toxicity

could be attributed to MEK at concentrations as high as 2,518 ppm (7,430 mg/m³).”

PPRC: The Cavender study included histological examination of the testes, epididymides, seminal

vesicles, vagina, cervix, uterus, oviducts, ovaries, and mammary glands. No exposure-related lesions

were identified. See ATSDR 1992 bullet below.

o p. 86: “A two-generation reproductive and developmental toxicity study of Wistar rats exposed to 2-

butanol, a metabolic precursor of MEK, in drinking water, reported no clear reproductive effects, but found

body weight deficits in offspring and kidney histopathologic lesions in adult male rats at estimated dose

levels of approximately 3,000 mg/kg-day (Cox et al., 1975).”

o p. 87: For the Cox study mentioned above: “Furthermore, certain parameters routinely evaluated in studies

of more current design (e.g., estrous cyclicity, sperm parameters, and uterine weight) were not measured in

Cox et al. (1975).”

o p. 86: “In the absence of chronic toxicity information for MEK by any route of exposure, the effects of

lifetime exposure to MEK must necessarily remain somewhat uncertain… It is therefore reasonable and

prudent to state that MEK is a possible health hazard to humans who are repeatedly exposed to relatively

high levels of MEK.”

REACH registration dossier provides details of the Cox et al. 1975 study discussed above:

o “Secondary butyl alcohol, administered in drinking water to rats over two generations did not affect

reproductive performance or cause developmental toxicity up to a concentration of 1.0% (1644 mg/kg/day).

Adult rats exposed to 2.0% SBA (3122 mg/kg/day) showed significant kidney histopathology in the form

of renal tubular degeneration/ regeneration, renal tubular casts, microcysts on the tip of the papilla. Pup


http://apps.echa.europa.eu/registered/data/dossiers/DISS-9d91195a-65f3-618d-e044-00144f67d249/AGGR-4d0fe03b-37be-4b2d-b996-cac20c64c2aa_DISS-9d91195a-65f3-618d-e044-00144f67d249.html

http://apps.echa.europa.eu/registered/data/dossiers/DISS-9d91195a-65f3-618d-e044-00144f67d249/AGGR-4d0fe03b-37be-4b2d-b996-cac20c64c2aa_DISS-9d91195a-65f3-618d-e044-00144f67d249.html











viability was reduced at 3.0% (4571 mg/kg/day). Fetal body weights were slightly lower at 2.0%. The

NOAEL in the study for general systemic, reproductive, and fetotoxic effects was 10000 mg/L (1644

mg/kg/day).”

o European Chemicals Agency, registration dossier found at:

http://apps.echa.europa.eu/registered/data/dossiers/DISS-9d91195a-65f3-618d-e044-

00144f67d249/AGGR-4d0fe03b-37be-4b2d-b996-cac20c64c2aa_DISS-9d91195a-65f3-618d-e044-

00144f67d249.html#section_1.1, accessed May 2012.

ATSDR 1992 reports: p. 50: “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.” ATSDR Toxicological Profile for 2-Butanone, found at:


OECD 1997 reports (regarding the Cox et al. 1975 study above): “The F1 generation animals were raised to

maturity, mated to produce one set of litters, and then sacrificed for gross and microscopic evaluation. Gross

and microscopic pathologic findings were negative for the two lower dose levels, being limited to those

frequently seen in untreated rat colonies. The 2.0% level resulted in a series of mild changes in the rat kidney

which, while not suggestive of overt toxicity, appeared to represent responses to stress. No other findings of

note were seen. 2-butanol produced no effects when administered to rats in the drinking water up to the level of

1% (equivalent to approximately 1500 mg/kg/day). The 2% dose level caused effects suggesting mild toxicity

and/or stress reactions. There was no observed reproductive toxicity in parental animals. The 2.0% group

offspring had a significant depression in growth of weaning rats. 2-Butanol was somewhat fetotoxic at the 2.0%

dose level, as shown by decreased mean pup weights. This was a minimal response as shown by the fact that

none of the other parameters (nidation, early or late fetal deaths) were detectably affected.” [Section 3.3] OECD

SIDS Initial Assessment Report available at: http://webnet.oecd.org/Hpv/UI/SIDS_Details.aspx?id=31C513F8-

2B0D-4DE8-9A14-8463CD709ADD, accessed May 2012.

Developmental Toxicity incl. Developmental Neurotoxicity (D) Score (H, M or L): M

MEK was assigned a score of Moderate for developmental toxicity based on data from animal experiments

consistent with GHS Category 2. While effects are modest and occur at high dose, they appear consistently in a

number of studies employing multiple species.

NITE/Japan 2006 lists as “Not classified.” NITE considered IRIS 2003 and ATSDR 1999 among other data

concluding that "all were judged to be minimum influence…" Japanese NITE worksheet ID618 in the Microsoft



US EPA 2003 reports (US EPA 2003 Toxicological Review of 2-Butanone for IRIS available at:


o p. 86 : “A two-generation reproductive and developmental toxicity study of Wistar rats exposed to 2-

butanol, a metabolic precursor of MEK, in drinking water, reported no clear reproductive effects, but found

body weight deficits in offspring and kidney histopathologic lesions in adult male rats at estimated dose

levels of approximately 3,000 mg/kg-day (Cox et al., 1975). In addition, several developmental toxicity

studies of rodents (exposed by inhalation 6–7 hours/day during gestation) reported reduced fetal weight and

increased skeletal variations at exposure levels of approximately 1,000 ppm (3,000 mg/m³) MEK (Schwetz

et al., 1974, 1991; Deacon et al., 1981).”

o p. 86: “In the absence of chronic toxicity information for MEK by any route of exposure, the effects of

lifetime exposure to MEK must necessarily remain somewhat uncertain. Available animal data consistently

identify developmental effects in animals exposed to relatively high levels of MEK. It is therefore

reasonable and prudent to state that MEK is a possible health hazard to humans who are repeatedly exposed

to relatively high levels of MEK.”

o pp. 82-3: “The MEK data base does not, however, specifically include a developmental neurotoxicity

study.”

REACH registration dossier provides details of several studies (European Chemicals Agency, registration

dossier found at: http://apps.echa.europa.eu/registered/data/dossiers/DISS-9d91195a-65f3-618d-e044-

http://apps.echa.europa.eu/registered/data/dossiers/DISS-9d91195a-65f3-618d-e044-00144f67d249/AGGR-4d0fe03b-37be-4b2d-b996-cac20c64c2aa_DISS-9d91195a-65f3-618d-e044-00144f67d249.html#section_1.1


















00144f67d249.html#section_1.1, accessed May 2012):

o Regarding Cox et al. 1975 study discussed above: “Secondary butyl alcohol, administered in drinking water

to rats over two generations did not affect reproductive performance or cause developmental toxicity up to

a concentration of 1.0% (1644 mg/kg/day)...Pup viability was reduced at 3.0% (4571 mg/kg/day). Fetal

body weights were slightly lower at 2.0%. The NOAEL in the study for general systemic, reproductive, and

fetotoxic effects was 10000 mg/L (1644 mg/kg/day).”

o Regarding Deacon et al. 1981 study discussed above (inhalation exposures to MEK at 400, 1000, and 3000

ppm, Sprague-Dawley rats). Summary notes: “Significant decrease in delayed ossification of interparietal

bones and significant increase in the incidence of extra lumbar ribs at 3000 ppm.”

o Reporting on a 2005 study (litter-based statistical analysis): “Sprague-Dawley rats were exposed via whole-

body inhalation to vapour concentrations of 0, 1000, or 3000 ppm methyl ethyl ketone (MEK) for 6

hours/day, through gestation days GD6 - GD20. Test groups (nine in total), included MEK alone, and also

MEK in combination with ethylbenzene (EB) at either 250 or 1000 ppm. Maternal weight gain and food

consumption was significantly affected at 3000 ppm MEK alone or in combination with EB. Fetal body

weights were lower in the 3000 ppm MEK treatment groups. There was no effect of treatment on

embryolethality, or in[c]reases in skeletal or visceral variations or malformations.

ATSDR 2010 reports (ATSDR Addendum to the Toxicological Profile For 2-Butanone, found at:

http://www.atsdr.cdc.gov/toxprofiles/2-butanone_addendum.pdf, accessed May 2012):

o p. 5-6, regarding Schwetz et al. 1991: “No significant alterations in the number of fetuses or litters with

malformations were found; however, a significant trend for increased incidence of misaligned sternebrae

was observed at doses >400 ppm.”

o p. 6, regarding Saillenfait et al. 2006: “Groups of 19 to 23 pregnant Sprague-Dawley rats were exposed to

0, 1,000, 2,000, 4,000, or 6,000 ppm 2-butanone 6 hours per day on gestation days 6–20 (Saillenfait et al.

2006). Significant decreases in maternal body weight gain (recorded on gestation day 0, 6, 13 and 21) and

food consumption (measured across gestation days 6-13 and 13-21) were observe at exposure levels of

4,000 and 6,000 ppm. Decreases in fetal body weight were observed at ≥2,000 ppm; fetal body weights

were 4.4, 15, and 20% lower than the weights of controls in the 2,000, 4,000, and 6,000 ppm groups,

respectively. No significant alterations in the total number of external, visceral, or skeletal variations were

observed at any level of 2-butanone exposure. However, the study reported statistically significant

increases in the incidence of incomplete sternebrae ossification in the 4,000 and 6,000 ppm groups.” [pp. 5-

6; references internal to the assessment.]

o PPRC: 2000, 4000, and 6000 ppm correspond to 5.9, 11.8, and 17.7 mg/L respectively.

ATSDR 1992 reports: “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.” [pp. 50-1; references internal to the report.] ATSDR Toxicological Profile for 2-Butanone, found

at: http://www.atsdr.cdc.gov/toxprofiles/tp.asp?id=343&tid=60, accessed May 2012.

NTP 1989 abstract of the Mast et al. 1989 study discussed above: “Four groups of Swiss (CD-1®) mice were

exposed to 0, 400, 1000 or 3000 ppm MEK vapors, 7 hours per day, 7 days per week…Mild developmental

toxicity was evident at 3000-ppm as a reduction in mean fetal body weight. This reduction was statistically

significant for the males only, although the relative decrease in mean fetal body weight was the same for both

sexes…In summary, pregnant Swiss (CD-1®) mice appear to be relatively insensitive to the toxic effects of

MEK at the exposure levels employed in this study. However, the offspring of the mice exhibited significant

signs of toxicity at the 3000-ppm exposure level. Neither maternal nor developmental toxicity were observed at

1000 ppm MEK or below.” National Toxicology Program abstract for “Inhalation Developmental Toxicology

Studies: Teratology Study of Methyl Ethyl Ketone (CAS No. 78-93-3) in Mice,” available at:

http://ntp.niehs.nih.gov/index.cfm?objectid=07304AE2-B845-E4FD-32521A5B2FC1C848, accessed May

2012.

OECD 1997 reports: “MEK and its metabolic surrogate, 2 butanol, do not appear to present significant risk of

adverse reproductive or developmental effects.” [Section 3.3] OECD SIDS Initial Assessment Report available

http://www.atsdr.cdc.gov/toxprofiles/2-butanone_addendum.pdf


http://ntp.niehs.nih.gov/index.cfm?objectid=07304AE2-B845-E4FD-32521A5B2FC1C848








at: http://webnet.oecd.org/Hpv/UI/SIDS_Details.aspx?id=31C513F8-2B0D-4DE8-9A14-8463CD709ADD,

accessed May 2012.

Endocrine Activity (E) Score (H, M or L): DG

MEK was assigned a score of DG for endocrine activity based on lack of data.

MEK is not listed as an endocrine disruptor in the following lists:

o European Union Priority List of suspected endocrine disruptors.

o OSPAR Convention for The Protection of the Marine Environment of the North-East Atlantic, List of

Chemicals for Priority Action and List of Substances of Possible Concern

o International Chemical Secretariat (ChemSec) Substitute it Now (SIN) List 2.0

o The Endocrine Disruptor Exchange (TEDX) List of Potential Endocrine Disruptors

No specific test data excluding endocrine activity was identified.

Group II and II* Human Health Effects (Group II and II* Human)

Note: Group II and Group II* endpoints are distinguished in the v 1.2 Benchmark system. For Systemic

Toxicity and Neurotoxicity, Group II and II* are considered sub-endpoints and test data for single or repeated

exposures may be used. If data exist for single OR repeated exposures, then the endpoint is not considered a data

gap. If data are available for both single and repeated exposures, then the more conservative value is used.

Acute Mammalian Toxicity (AT) Group II Score (vH, H, M or L): L

MEK was assigned a score of Low for acute mammalian toxicity based on lethal dose/concentration data in animal

studies consistent with a low level-of-concern by all exposure pathways.

NITE/Japan 2006: Category 5 for vapor inhalation and for oral toxicity. Not classified for dermal exposure.

GHS-Country Screening A list; translates to Low level-of-concern. Japanese NITE, worksheet ID618 in the

Microsoft Excel workbook available at:


2012.

US EPA 2003, Toxicological Review of 2-Butanone for IRIS, available at

http://www.epa.gov/iris/toxreviews/0071tr.pdf, accessed May 2012 reports that:

o p. 52: LD50 values for adult mice and rats are 2–6 g/kg body weight, with death occurring within 1–14 days

following a single oral dose (Tanii et al., 1986; Kimura et al., 1971; Smyth et al., 1962).

o p. 54: A few animal studies involving a single or limited number of inhalation exposures reported

behavioral effects and narcosis (Nelson et al., 1989, 1990; Glowa and Dews, 1987). Several well-conducted

studies in experimental animals, however, provide no convincing evidence that repeated exposure to MEK,

by itself, is capable of producing persistent neurological effects.

OECD 1997 reports that: “MEK has a low order of toxicity following single oral, dermal, or inhalation

exposure. In rats, oral LD50 values range from 2.6 to 5.4 g/kg and inhalation LC50 values are greater than 5000

ppm [14.7 mg/L], and the dermal LD50 in rabbits was reported to be 6.4-8.0 g/kg (Krasavage et al., 1982;

Cavender et al., 1983)...In a publication to determine the relationship between acute toxicities (oral and

inhalation) of 108 chemicals in the rat, MEK was ranked as “slightly toxic” based upon a summary of acute

lethality studies (Kennedy and Graepel, 1991).” [Section 3.1, p.7; references internal to dossier.] OECD SIAR

found at: http://webnet.oecd.org/Hpv/UI/SIDS_Details.aspx?id=31C513F8-2B0D-4DE8-9A14-

8463CD709ADD, accessed May 2012.

ATSDR 1992 reports that 4 hr inhalation exposure to rats gave an LC50 11,700 ppm [34.5 mg/L]. Data for

inhalation exposures are listed in Table 2, p. 8 of the ATSDR Toxicological Profile for 2-Butanone, found at:


HSDB reports: “Acute Exposure/ Exposure /of rats/ to 2000 ppm /for 2 hr/ showed no apparent toxicity.

Exposure to 8000 ppm killed 3 of 6 rats in 8 hr, while 16,000 ppm for 1 hr caused death of all the animals.”

[PPRC conversions: 2000 ppm = 5.9 mg/L; 8000 ppm = 23.6 mg/L; 16,000 ppm = 47.2 mg/L.]













Systemic Toxicity/Organ Effects incl. Immunotoxicity (ST)

Group II Score (single dose: vH, H, M or L): L

MEK was assigned a score of Low for systemic toxicity/organ effects based on weight-of-evidence from human and

animal studies.

PPRC: While NITE/Japan reports Category 2 (target organ: kidney), the ATSDR assessment suggests that

normal kidney function was not impaired, which would not meet the GHS requirements for Category 2.

Similarly, NITE/Japan reports classification as Category 3 (target organ: respiratory system), however the data

reviewed by ATSDR and US EPA provide little support for respiratory irritation.

NITE/Japan 2006 reports in worksheet ID618 in the Microsoft Excel workbook available at:


2012):

o Category 2, single-exposure kidneys; “…Moreover, based on the description that effects were observed in

kidney by a moderate dosage of the oral administration to rats (DFGOTvol.12 (1999), IRIS (2003), and

ATSDR (1992)), kidney was also judged to be the target organ and was set as Category 2.”

o Category 3, for single-exposure respiratory irritation.

US EPA 2003 reports (US EPA 2003, Toxicological Review of 2-Butanone for IRIS available at:


o p. 45: The study cited by NITE/Japan is described: “A single gavage dose of 15 mmol/kg MEK (1,082

mg/kg) in corn oil produced no deaths or histological alterations in the livers of male Fischer 344 rats, but

produced tubular necrosis in the kidneys (Brown and Hewitt, 1984).” No further analysis provided.

o p. 55: Regarding inhalation exposures: “The available data provide no evidence for portal-of-entry effects

following inhalation exposure to MEK.”

ATSDR 1992 reports (ATSDR Toxicological Profile for 2-Butanone, found at

http://www.atsdr.cdc.gov/toxprofiles/tp.asp?id=343&tid=60, accessed May 2012):

o Regarding the 1984 Brown & Hewitt study: p. 34 - “Oral exposure of rats to 1,080 mg 2butanone/kg

caused mild renal tubule necrosis but had no effect on renal organic ion transport or plasma creatinine;

therefore, in spite of mild necrosis, normal kidney functions were not impaired.”

o p. 33: “Since 2-butanone exposure is not tolerable to humans at concentrations of 350 ppm (Nelson et al.

1943), it is highly unlikely that inhalation exposure could result in respiratory, dermal, or ocular effects

more serious than minor irritation.”

ATSDR 2010 reviewed a human exposure study: “In a cross-over design study, 19 men were exposed to either

0 or 200 ppm of 2-butanone for 4 hours, then 1 week later exposed to the other dose (Muttray et al. 2002).

Subjects, who were not blinded because of the odorous nature of the substance, were asked to rate the severity

of several symptoms before, then at 2 hours and 4 hours of exposure, with 0 being no effect and 5 being a

severe effect, via the Swedish performance evaluation system (SPES). Although the median score for all

symptoms was 0, a few of the subjects did report a significant increase in the severity of throat irritation after 4

hours of exposure. Significant increases in nasal mucociliary transport time were observed after exposure to 200

ppm of 2-butanone. Non-significant increases in interleukin (IL)-1β and IL-8 levels were measured in nasal

secretions; no alterations in IL-6 levels or tumor necrosis factor-α (TNFα) were found. These findings suggest

subclinical rhinitis.” [References internal to the assessment.] ATSDR Addendum to the Toxicological Profile

For 2-Butanone, found at: http://www.atsdr.cdc.gov/toxprofiles/2-butanone_addendum.pdf, accessed May 2012.

Group II* Score (repeated dose: H, M, L): L

MEK was scored as Low level-of-concern based on lack of significant effects observed in experiments with animals.

PPRC: As described in the bullets below, the US EPA assessment discounts anemia seen with 3-hydroxy-2-

butanone as inconsistent with the full database. Renal lesions reported with oral 2-butanol exposure occurred at

high dose, well above the range considered as Low level-of-concern, i.e., >100 mg/kg-BW/day (GreenScreen

Version 1.2 Criteria).












US EPA 2003 reports (US EPA 2003, Toxicological Review of 2-Butanone for IRIS, available at:


o Inhalation exposure: p. 54: “Available data provide no clear evidence for other systemic effects resulting

from inhalation exposure to MEK. A subchronic inhalation study of MEK found no persistent body weight

changes, gross behavioral changes, or histological changes in major tissues and organs in rats exposed 6

hours/day, 5 days/week for 90 days to concentrations as high as 5,000 ppm (14,750 mg/m3) (Cavender et

al., 1983). Some changes in organ weight (including increased liver weight and decreased brain weight)

and clinical pathology parameters were observed; however, these were not supported by histological

changes.”

o Oral exposure database discussed includes studies with 2-butanol (a metabolic precursor to MEK) and 3-

hydroxy-2-butanone (a metabolite of MEK): p. 53 - “The oral toxicity data base for 3-hydroxy-2-butanone

consists of a 13-week drinking water study in rats (Gaunt et al., 1972). Thirteen weeks of drinking water

exposure to 3-hydroxy-2-butanone in CFE rats (15/sex/dose) did not produce a toxic effect aside from

slight anemia (decreased hemoglobin concentration and red blood cell count) at the high dose (1,286

mg/kg-day) (Gaunt et al., 1972), an effect that has not been reported following exposure to 2-butanol

(orally; Cox et al., 1975) or MEK (by inhalation; Cavender et al., 1983).”

o p. 59: “The only other toxic effect associated with long-term oral exposure to 2-butanol is renal lesions in

male rats at 2% in drinking water (3,384 mg/kg-day) (Cox et al., 1975).”

o pp. 59-60: “While data from the 13-week drinking water study with 3-hydroxy-2-butanone in CFE rats

(Gaunt et al., 1972) suggest adverse hematological effects (decreased hemoglobin concentration and red

blood cell count), the effect was not observed in toxicity studies of 2-butanol (Cox et al., 1975) or MEK

(Cavender et al., 1983). The study concerning exposure to 3-hydroxy-2-butanone in drinking water

provides no information regarding the potential for developmental effects, which are the key effects seen

with oral and inhalation exposure to 2-butanol and inhalation exposure to MEK. Thus, the slight anemia

produced by oral exposure to 3-hydroxy-2-butanone is inconsistent with the effects seen following

inhalation exposure to MEK, or oral or inhalation exposure 2-butanol. Hence, 3-hydroxy-2-butanone does

not appear to be an appropriate surrogate for assessing the toxicity of MEK.”

The REACH dossier for MEK reports on the same 1975 Cox et al. study reviewed above (long-term oral

exposure to 2-butanol): “Kidney pathology in adult rats exposed to the highest doses of 3.0 and 2.0% were

typical of kidney lesions seen in rats with aging.” European Chemicals Agency, registration dossier found at:


4d0fe03b-37be-4b2d-b996-cac20c64c2aa_DISS-9d91195a-65f3-618d-e044-00144f67d249.html#section_1.1,

accessed May 2012.

Neurotoxicity (N)

Group II Score (single dose: vH, H, M or L): M

MEK was assigned a score of Moderate for neurotoxicity-single dose based on reports of effects in humans at low

doses, case studies of occupational exposures and listing as Category 3 in authoritative sources.

PPRC: Regarding CNS effects, the US EPA work casts doubt on the assessment of animal studies cited by

NITE/Japan. While case studies exist for occupational exposures, these are often confounded by co-exposure to

other solvents or show minimal effects. Though other studies with humans show no CNS effects, the doses

studied were low (typically 200 ppm or 0.6 mg/L). EU harmonized classification results are authoritative for the

GreenScreen and weighted more highly than screening list results such as NITE/Japan.

ECHA harmonized classification data shows STOT SE 3 and H336: May cause drowsiness or dizziness,

however these data inform the GreenScreen Neurotoxicity endpoint, but are not used for GreenScreen Systemic

Toxicity/Organ Effects. ECHA C&L Inventory Database, http://clp-

inventory.echa.euroa.eu/SummaryOfClassAndLabelling.aspx?SubstanceID=79649&HarmOnly=no?fc=true&la

ng=en, accessed May 2012.

ATSDR 1992 report that several case studies of occupational exposure to MEK indicate symptoms consistent

with narcosis. ATSDR Toxicological Profile for 2-Butanone, found at:





http://clp-inventory.echa.euroa.eu/SummaryOfClassAndLabelling.aspx?SubstanceID=79649&HarmOnly=no?fc=true&lang=en











ATSDR 2010 reports that: “In an acute-duration study designed to assess potential respiratory effects in 19 men

after a 4-hour exposure to both 0 and 200 ppm 2-butanone, done on different days, significant increases in the

severity of headache and nausea were reported by the subjects 2 hours after exposure began to the 200 ppm

exposure, compared with pre-exposure ratings (Muttray et al. 2002).” [References internal to the assessment.]

ATSDR Addendum to the Toxicological Profile For 2-Butanone, found at:

http://www.atsdr.cdc.gov/toxprofiles/2-butanone_addendum.pdf, accessed May 2012.

US EPA 2003 reports that: “In general, the available human data do not produce a definitive picture of the

possible adverse effects of long-term human exposure to MEK. Short-term inhalation exposure (4 hours) to

MEK under experimental conditions at or near 200 ppm (590 mg/m3) does not appear to pose an increased risk

of neurologic or irritation symptoms (Dick et al., 1984, 1988, 1989, 1992). Although some evidence of

persistent neurotoxicity is available from case reports of repeated exposure (especially when MEK exposure

occurs in combination with other solvents), the case for a persistent neurotoxic effect of MEK exposure is not

well supported in animal studies that have focused on the possible neurotoxicity of MEK, including the

development of peripheral and central nerve fiber degeneration…" [p. 85, references internal to the

assessment.] US EPA 2003, Toxicological Review of 2-Butanone for IRIS, available at

http://www.epa.gov/iris/toxreviews/0071tr.pdf, accessed May 2012

NITE/Japan 2006 reports in worksheet ID618 in the Microsoft Excel workbook available at:


2012. [References internal to the assessment.]):

o Classified as Category 1 (central nervous system, single- and repeat-exposure; peripheral nervous system

with repeat-exposure).

o “There are descriptions that effects on the central nerve system were not observed in the inhalation

exposure test by humans (EHC 143 (1992), DFGOTvol.12 (1999), IRIS (2003), and ATSDR (1992)), and

that there was no statistically significant difference against contrast groups in the result of the time

estimation test (EHC 143 (1992) and PATTY (4th, 1994)). On the other hand, since effects on the central

nerve systems in the inhalation exposure test of the rat or the mouse were identified in comparatively low

concentrations (EHC 143 (1992), PATTY (4th, 1994) and IRIS (2003)), the target organ was judged to be

the central nerve system and it was set as Category 1.”

o GHS Country categorizations are Screening A lists; translates to High level-of-concern.

Grandjean & Landrigan (G&L) (2006): Listed as human neurotoxicant. G&L is a Screening B list and translates

to a very High, High or Medium level-of-concern. Grandjean & Landrigan 2006, Developmental neurotoxicity

of industrial chemicals, Lancet, v. 368: 2167–78.

Group II* Score (repeated dose: H, M, L): DG

MEK was assigned a score of DG for neurotoxicity-repeated dose due to the conflicting or inadequate data

available.

PPRC: NITE/Japan lists as Category 1, but the US EPA assessment casts doubt on the evidence cited. While

some case studies exist showing neurological symptoms for occupational exposures, these are mostly

confounded by co-exposure to other solvents or show minimal effects.

US EPA 2003, Toxicological Review of 2-Butanone for IRIS, available at

http://www.epa.gov/iris/toxreviews/0071tr.pdf, accessed May 2012 reports that:

o p. 54: “Evidence for neurotoxic effects following inhalation exposure to MEK is limited to a small number

of case reports of neurological impairment in occupationally-exposed humans (Welch et al., 1991; Seaton

et al., 1992; Callender, 1995; Orti-Pareja et al., 1996) and in one study of problematic design reporting

increased incidence of subjectively reported neurological symptoms in MEK-exposed workers (Mitran et

al., 1997; Graham, 2000). A few animal studies involving a single or limited number of inhalation

exposures reported behavioral effects and narcosis (Nelson et al., 1989, 1990; Glowa and Dews, 1987).

Several well-conducted studies in experimental animals, however, provide no convincing evidence that

repeated exposure to MEK, by itself, is capable of producing persistent neurological effects. No persistent,

treatment-related central or peripheral neural histopathology was observed in rats exposed for 90 days (6

hours/day, 5 days/week) to MEK at concentrations up to 5,041 ppm (14,870 mg/m3) (Cavender et al.,

1983). Repeated exposure of rats and mice to MEK at approximately 3,000 ppm (8,850mg/m3) (7












hours/day during days 6–15 of gestation) produced no overt neurological effects in the dams (Schwetz et

al., 1974, 1991; Deacon et al., 1981).”

o p 82-3: “Neurotoxicity is adequately addressed by the subchronic inhalation study of Cavender et al.

(1983), in which animals were examined for both neurological function and for central nervous system

lesions with special neuropathological procedures. The results from this study indicate that MEK has little,

if any, neurotoxic potential by itself when tested in adult laboratory animals under conditions of high-level

repeated inhalation exposure. Consistent with this finding is a lack of mechanistic evidence for

neurotoxicity.”

o pp. 85-6: “In general, the available human data do not produce a definitive picture of the possible adverse

effects of long-term human exposure to MEK. Short-term inhalation exposure (4 hours) to MEK under

experimental conditions at or near 200 ppm (590 mg/m3) does not appear to pose an increased risk of

neurologic or irritation symptoms (Dick et al., 1984, 1988, 1989, 1992). Although some evidence of

persistent neurotoxicity is available from case reports of repeated exposure (especially when MEK

exposure occurs in combination with other solvents), the case for a persistent neurotoxic effect of MEK

exposure is not well supported in animal studies that have focused on the possible neurotoxicity of MEK,

including the development of peripheral and central nerve fiber degeneration…” Additional details follow

in the US EPA assessment.

o All indicated references are internal to the assessment.

NITE/Japan 2006 in worksheet ID618 in the Microsoft Excel workbook available at:


2012. [References internal to the assessment.]):

o Classified as Category 1 (central nervous system, single- and repeat-exposure; peripheral nervous system

with repeat-exposure).

o “It was classified all to Category 1considering target organ a central nervous systems and the peripheral

nervous system, according to the description that the sensory paralysis of hand and arm was seen in the

case of human occupation exposure (EHC 143 (1992), DFGOTvol.12 (1999) and IRIS (2003)), the

description suggesting the central nervous systems disorders in the case of occupation exposure

(DFGOTvol.12 (1999) and IRIS (2003)), and the description about three cases in which the effects on the

central nervous systems were seen (IRIS (2003)).

o GHS Country categorizations are Screening A lists; translates to High level-of-concern.

Grandjean & Landrigan (G&L) (2006): Listed as human neurotoxicant. G&L is a Screening B list and translates

to a very High, High or Moderate level-of-concern. Grandjean & Landrigan 2006, Developmental neurotoxicity

of industrial chemicals, Lancet, v. 368: 2167–78.

Skin Sensitization (SnS) Group II* Score (H, M or L): L

MEK was assigned a score Low for skin sensitization based on negative studies with animals.

OECD 1997 reports that “MEK has not been shown to produce skin sensitization in animal studies

(Cannelongo, 1978) or humans (Epstein, 1975).” [References internal to dossier.] OECD SIAR found at:


accessed May 2012.

REACH dossier reports on a 1996, reliability 1, GLP-compliant study according to test method OECD 406

(Buehler test): "Under the conditions of the study, MEK was not considered to be a skin sensitiser in guinea

pigs." European Chemicals Agency, registration dossier found at:


4d0fe03b-37be-4b2d-b996-cac20c64c2aa_DISS-9d91195a-65f3-618d-e044-00144f67d249.html#section_1.1,

accessed May 2012.

American Chemistry Council VCCEP submission reports: “MEK produced no sensitization reactions in human

volunteers exposed to a 20% MEK in petrolatum mixture, and no irritation was seen following a 48-hour

closed-patch test in humans.” Report available at:

http://www.tera.org/peer/vccep/MEK/MEK%20VCCEP%20Submission%20December%202003.pdf, accessed

May 2012.





http://www.tera.org/peer/vccep/MEK/MEK%20VCCEP%20Submission%20December%202003.pdf








Respiratory Sensitization (SnR) Group II* Score (H, M or L): DG

MEK was assigned a score of Data Gap for respiratory sensitization based on lack of data.

American Chemistry Council VCCEP submission reports: "In measuring pulmonary sensitization, the MEK

concentration necessary to produce a 50% decrease in the initial respiration rate (i.e., the RD50) in mice was

10,745 ppm (DeCeaurriz et al.1981). This high concentration indicates a lack of immediate allergenic

sensitizing response. In humans, no sensitization reactions were seen in volunteers exposed to a 20% MEK in

petrolatum mixture (Epstein 1975)." p. 48. Report available at:


May 2012.

ATSDR 2010 reviewed a human exposure study: “In a cross-over design study, 19 men were exposed to either

0 or 200 ppm of 2-butanone for 4 hours, then 1 week later exposed to the other dose (Muttray et al. 2002).

Subjects, who were not blinded because of the odorous nature of the substance, were asked to rate the severity

of several symptoms before, then at 2 hours and 4 hours of exposure, with 0 being no effect and 5 being a

severe effect, via the Swedish performance evaluation system (SPES). Although the median score for all

symptoms was 0, a few of the subjects did report a significant increase in the severity of throat irritation after 4

hours of exposure. Significant increases in nasal mucociliary transport time were observed after exposure to

200ppm of 2-butanone. Non-significant increases in interleukin (IL)-1β and IL-8 levels were measured in nasal

secretions; no alterations in IL-6 levels or tumor necrosis factor-α (TNFα) were found. These findings suggest

subclinical rhinitis.” ATSDR Addendum to the Toxicological Profile For 2-Butanone, found at:

http://www.atsdr.cdc.gov/toxprofiles/2-butanone_addendum.pdf, accessed May 2012.

Skin Irritation/Corrosivity (IrS) Group II Score (vH, H, M or L): DG

MEK was assigned a score of Data Gap for skin irritation/corrosivity. While NITE/Japan classifies as GHS Category

2, the available database is primarily narrative description without sufficient quantifiable data to fulfill GHS

classification requirements.

NITE/Japan 2006 lists as Category 2: “…based on the description that mild to moderate irritation was observed

in the skin application examination on rabbits (EHC 143 (1992), DFGOTvol.12 (1999), PATTY (4th, 1994),

and ATSDR (1992)), it was classified as Category 2.” Japanese NITE in worksheet ID618 in the Microsoft



ATSDR 1992 reports: “Acute and intermediate dermal exposures to 2butanone were mildly irritating to the

skin of rabbits, rats, and guinea pigs (Hazleton Laboratories 1963a; Wahlberg 1984).” ATSDR Toxicological

Profile for 2-Butanone, found at: http://www.atsdr.cdc.gov/toxprofiles/tp.asp?id=343&tid=60, accessed May

2012.

ECHA harmonized classification reports EUH066: May cause cracking and drying. ECHA C&L Inventory

Database, http://clp-



ACC 2003 reports: “MEK produced no sensitization reactions in human volunteers exposed to a 20% MEK in

petrolatum mixture, and no irritation was seen following a 48-hour closed-patch test in humans.” American

Chemistry Council (ACC) Methyl Ethyl Ketone VCCEP Submission 2003, available at:


May 2012.

OECD 1997 dossier reports that skin irritation tests with MEK using rabbits; [method not specified] gave mild

to moderate irritancy (24 hr occluded or un-occluded). Reference: Weil, C.S. and Scala, R. A. (1971). Study of

intra- and inter-laboratory variability in the results of rabbit eye and skin irritation tests. Toxicol. Appl.

Pharmacol. 19, 276; Moreno, O.M. (1975). Report to RIFM, 11 April; cited in Food & Cosmet. Toxicol., 15,

627, 1977.” OECD SIDS Initial Assessment Report available at:


















accessed May 2012.

IPCS 1993 reports: “In skin irritation studies, a small dose (8 mg) applied to clipped skin and covered by an

impervious plastic film for 24 h (which was followed by a 14-day observation period) produced only minor

irritation in male New Zealand albino rabbits (Smyth et al., 1962). A dose of 400 mg applied to the clipped

dorsal skin of restrained albino rabbits in a gauze patch produced mild to moderate irritation in some cases

(Weil & Scala, 1971). Data from this latter study, however, were highly variable and may reflect the fact that its

purpose was intercomparison of laboratories rather than the effects of MEK on test animals. Neat MEK (0.1 ml)

applied to the clipped skin of the flanks of guinea-pigs and rabbits daily for 10 days and left uncovered caused

erythema and oedema after 24-72 h. These effects were more marked in rabbits (Wahlberg, 1984a).” IPCS

(International Program on Chemical Safety) 1993, Environmental Health Criteria Monograph on MEK,

available at: http://www.inchem.org/documents/ehc/ehc/ehc143.htm, accessed May 2012.

Eye Irritation/Corrosivity (IrE) Group II Score (vH, H, M or L): H

MEK was assigned a score of High for eye irritation/corrosivity based on European Union harmonized classification

as Category 2 and H319 (EU H-statements are GreenScreen Authoritative A lists.)

ECHA lists harmonized classification as Eye Irritant Category 2, H319: Causes serious eye irritation. ECHA

C&L Inventory Database, http://clp-

inventory.echa.europa.eu/SummaryOfClassAndLabelling.aspx?SubstanceID=79649&HarmOnly=no?fc=true&l

ang=en, accessed May 2012.

NITE/Japan 2006 lists as Category 2B, Japanese NITE in worksheet ID618 in the Microsoft Excel workbook

found at: http://www.safe.nite.go.jp/english/files/ghs_xls/classification_result_e%28ID566-666%29.xls ,

accessed May 2012.

Ecotoxicity (Ecotox)

Acute Aquatic Toxicity (AA) Score (vH, H, M or L): L

MEK was assigned a score of Low for acute aquatic toxicity based on measured test data (L/EC50 > 100 mg/L).

HSDB lists LC50 > 3000 mg/L, fathead minnows, 96 hr. exposure; results of same order of magnitude for nearly

all other fish data. Data for brine shrimp and daphnia also clearly lead to a low level of concern for this

endpoint. Hazardous Substances Data Bank, available at: http://toxnet.nlm.nih.gov/cgi-bin/sis/htmlgen?HSDB,

accessed May 2012.

Acute aquatic toxicity is low based on data from the European Chemicals Agency REACH registration dossier

found at: http://apps.echa.europa.eu/registered/data/dossiers/DISS-9d91195a-65f3-618d-e044-


00144f67d249.html#section_1.1, accessed May 2012:

o Fish: 1998, reliability 1, GLP-compliant study, according to test guideline OECD 203 reports LC50 = 2993

mg/L for fathead minnows (96 hr. exposure).

o Invertebrates: 1998, reliability 1, GLP-compliant study, according to test guideline OECD 202 reports EC50

= 308 mg/L for Daphnia magna (48 hr. exposure).

o Plants: 1998, reliability 1, GLP-compliant study, according to test guideline OECD 201 reports EC50 =

2029 mg/L for freshwater algae (96 hr. exposure).

NITE/Japan 2006: Not classified. "It carried out the outside of Category from 96-hour LC50>100 mg/L of fishes

(Oryzias latipes) (MOE eco-toxicity tests of chemicals, 1996)." Japanese NITE in worksheet ID618 in the

Microsoft Excel workbook found at:


2012.


http://www.inchem.org/documents/ehc/ehc/ehc143.htm

http://clp-inventory.echa.europa.eu/SummaryOfClassAndLabelling.aspx?SubstanceID=79649&HarmOnly=no?fc=true&lang=en




http://toxnet.nlm.nih.gov/cgi-bin/sis/htmlgen?HSDB












Chronic Aquatic Toxicity (CA) Score (vH, H, M or L): L

MEK was assigned a score of Low for chronic aquatic toxicity based on the low acute toxicity, good aqueous

solubility and low bioaccumulation (consistent with GHS criteria for substances with no chronic toxicity data).

NITE/Japan 2006: "Not classified. [Since not water-insoluble (aqueous solubility =2.23×105 mg/l [PHYSPROP

Database 2005]) and acute toxicity is low.]" Japanese NITE in worksheet ID618 in the Microsoft Excel

workbook found at: http://www.safe.nite.go.jp/english/files/ghs_xls/classification_result_e%28ID566-


US EPA’s ECOSAR v1.11 modeled ChV values for all taxa > 10 mg/L. This is consistent with GreenScreen

Low level-of-concern (see details results in Appendix A).

Environmental Fate (Fate)

Persistence (P) Score (vH, H, M, L, or vL): vH

MEK is volatile and likely to end up in the atmosphere where it is long lived (half-life in air of 12 days). This

translates to a very High level-of-concern. Ignoring the air results would lead to a Moderate level-of-concern based

on the estimated 30 day half-life in soil.

Environment Canada lists MEK as "Yes" for Persistence. The GreenScreen List Translator indicates Very High

or High level-of-concern for this Screening B list. Environment Canada Categorization Decisions for

Substances on the Domestic Substance List (DSL), http://www.ec.gc.ca/lcpe-

cepa/default.asp?lang=En&n=5F213FA8-1&wsdoc=D031CB30-B31B-D54C-0E46-37E32D526A1F, accessed

May 2012.

REACH dossier reports a 1992, reliability 1, GLP-compliant study equivalent to OECD 301D: MEK is “readily

biodegradable.” European Chemicals Agency, registration dossier found at:


8c260306-392b-4cd7-b6c7-3f516d9fcb76_DISS-9d91195a-65f3-618d-e044-00144f67d249.html#AGGR-

8c260306-392b-4cd7-b6c7-3f516d9fcb76, accessed May 2012.

US EPA’s PBT Profiler fate model predicts:

o Medium Halflife (days) % in medium GreenScreen Rank by Medium

o Water 15 days, 44% Low persistence.

o Soil 30 days, 43% Moderate persistence.

o Sediment 140 days, 0% - (Not likely to accumulate in sediment.)

o Air 12 days, 13% very High persistence.

o US EPA’s PBT Profiler available at: http://www.pbtprofiler.net/default.asp (Appendix B).

Bioaccumulation (B) Score (vH, H, M, L, or vL): vL

MEK was assigned a score of very Low for bioaccumulation based on the measured log Kow of 0.3. Log Kow ≤ 4

translates to GreenScreen Low level-of-concern.

A 1992, reliability 1, GLP-compliant study equivalent to test method OECD 117 reports a measured log Pow =

0.3. For details, see the REACH registration dossier available at:


55112edc-f79e-420e-8a85-08534849e6ae_DISS-9d91195a-65f3-618d-e044-00144f67d249.html#AGGR-

55112edc-f79e-420e-8a85-08534849e6ae, accessed May 2012.

OECD 1997 reports QSAR-based BCF values ranged from ~1 to 3. “Metabolic studies in man demonstrate that

concentrations likely to be present in the environment will not lead to accumulation in human tissues. MEK's

high water solubility, rapid degradation by aquatic bacteria, and low octanol-water partition coefficient suggest

that it is unlikely to concentrate in aquatic species.” OECD SIDS Initial Assessment Report available at:

http://webnet.oecd.org/Hpv/UI/handler.axd?id=7cbc8885-fd70-4315-8db8-bd9298141c28, accessed May 2012.

The US EPA PBT Profiler estimates BCF at 3.2; log Kow estimated at 0.29. PBT Profiler found at:

http://www.pbtprofiler.net/default.asp, accessed May 2012. (Appendix B)



http://www.ec.gc.ca/lcpe-cepa/default.asp?lang=En&n=5F213FA8-1&wsdoc=D031CB30-B31B-D54C-0E46-37E32D526A1F

http://www.ec.gc.ca/lcpe-cepa/default.asp?lang=En&n=5F213FA8-1&wsdoc=D031CB30-B31B-D54C-0E46-37E32D526A1F

http://apps.echa.europa.eu/registered/data/dossiers/DISS-9d91195a-65f3-618d-e044-00144f67d249/AGGR-8c260306-392b-4cd7-b6c7-3f516d9fcb76_DISS-9d91195a-65f3-618d-e044-00144f67d249.html#AGGR-8c260306-392b-4cd7-b6c7-3f516d9fcb76



http://www.pbtprofiler.net/default.asp

http://apps.echa.europa.eu/registered/data/dossiers/DISS-9d91195a-65f3-618d-e044-00144f67d249/AGGR-55112edc-f79e-420e-8a85-08534849e6ae_DISS-9d91195a-65f3-618d-e044-00144f67d249.html#AGGR-55112edc-f79e-420e-8a85-08534849e6ae



http://webnet.oecd.org/Hpv/UI/handler.axd?id=7cbc8885-fd70-4315-8db8-bd9298141c28

http://www.pbtprofiler.net/default.asp








Physical Hazards (Physical)

Reactivity (Rx) Score (vH, H, M or L): L

MEK was assigned a score of Low for reactivity based on a chemical structure inconsistent with explosive, reactive

or oxidizing properties as reported by NITE/Japan.

NITE/Japan 2006 reports “[t]here are no chemical groups associated with explosive properties present in the

molecules.” and “[t]here are no chemical groups associated with explosive or self-reactive properties present in

the molecule.” Japanese NITE in worksheet ID618 in the Microsoft Excel workbook found at:


2012.

US DOT Hazard Class 3 (flammable liquid), but otherwise not classified as explosive. Listed as "ethyl methyl

ketone or methyl ethyl ketone." US DOT Hazardous Materials Table, revised January 2012, available at:

http://www.phmsa.dot.gov/staticfiles/PHMSA/DownloadableFiles/Files/Hazmat/Hazmat%20Table.xls,

accessed May 2012.

Flammability (F) Score (vH, H, M or L): H

MEK was assigned a score of High for flammability based on European Union harmonized classification as H225

(GreenScreen Authoritative A list) and GHS Category 2 flammable liquid.

ECHA lists harmonized classification as Flammable liquid 2; H225: Highly flammable liquid and vapor

(harmonized classification). The GreenScreen List Translator indicates H225 as a High level-of-concern. ECHA

C&L Inventory Database, http://clp-



NITE/Japan 2006 reports Category 2, highly flammable liquid and vapor. Translates to GreenScreen High level-

of-concern (GHS country classifications are GreenScreen Screening A lists). Japanese NITE in worksheet

ID618 in the Microsoft Excel workbook found at


2012.

HSDB reports a flash point of 16 deg F (-9 deg C) (Closed cup) [HSDB references the Fire Protection Guide to

Hazardous Materials. 13 ed. Quincy, MA: National Fire Protection Association, 2002, p. 325-85]. Boiling point

reported as 79.59 deg C. GHS classifies flash point < 23 C and boiling point > 35 deg C as Category 2. HSDB

entry for methyl ethyl ketone available at: http://toxnet.nlm.nih.gov/cgi-bin/sis/htmlgen?HSDB, accessed May

2012.

References

References provided within individual endpoint results.


http://www.phmsa.dot.gov/staticfiles/PHMSA/DownloadableFiles/Files/Hazmat/Hazmat%20Table.xls





http://toxnet.nlm.nih.gov/cgi-bin/sis/htmlgen?HSDB








Abbreviations / Acronyms / Initialisms

ACGIH American Conference of Industrial Hygienists

ASTDR Agency for Toxic Substances and Disease Registry

CAMEO CAMEO Chemicals Database of Hazardous Materials

CEPA-DSL Canadian EPA Domestic Substances List

ChemSec International Chemical Secretariat [prepares the Substitute it Now (SIN) List]

CPA Clean Production Action

ECCSP Environment Canada Chemical Substances Portal

EC-EDD European Commission endocrine disrupting substance database

ECHA C&L ECHA Classification and Labeling Inventory Database

ECHA European Chemicals Agency

EPA HPV US EPA High Production Volume Information System

EPA SRS US EPA Substance Registry System

ESIS European chemical Substances Information System

EU European Union

GHS Globally Harmonized System (of classification and labeling)

HSDB Hazardous Substances Data Bank

IARC International Agency for Research on Cancer

IPCS International Program on Chemical Safety

IRIS Integrated Risk Information System (US EPA)

ISSCAN Chemical carcinogens database (Italy)

J-Check Japan Chemicals Cooperative Knowledge database

KEMI Swedish Chemicals Agency

MSDS Material Safety Data Sheet

NFPA National Fire Protection Association

NIOSH National Institute of Occupational Safety and Health

NITE National Institute of Technology and Evaluation (Japan)

NTP National Toxicology Program

OECD Organization for Economic Co-operation and Development

OSPAR Oslo Paris Commission and convention for protection of the marine environment

PBT Profiler US EPA's PBT Profiler

Prop 65 California Proposition 65 regulation and list of chemicals of concern

REACH European Commission chemicals regulation

RoC Report on Carcinogens (National Toxicology Program)

RTECS Registry of Toxic Effects of Chemical Substances

SIDS Screening Information Data Sets

TEDX The Endocrine Disruptor Exchange

UNEP United Nations Environment Program

US DOT US Department of Transportation Hazardous Materials Regulations

US EPA United States Environmental Protection Agency








Appendix A – ECOSAR Modeling Results

ECOSAR Version 1.11 Results Page

SMILES : O=C(CC)C MOL FOR: C4 H8 O1

CAS Num: 000078-93-3 CHEM : 2-Butanone

ChemID1: Melt Pt: (User Entered for Wat Sol estimate)

MOL WT : 72.11 Wat Sol: 1.112E+005 (mg/L, EPISuite WSKowwin

v1.43 Estimate)

Log Kow: 0.256 (EPISuite Kowwin v1.68 Estimate) Wat Sol: 2.23E+005 (mg/L, PhysProp DB exp value)

Log Kow: 0.29 (PhysProp DB exp value - for

comparison only)

Melt Pt: -86.60 (deg C, PhysProp DB exp value for

Wat Sol est)

Log Kow: (User Entered) Wat Sol: (User Entered)

Values used to Generate ECOSAR Profile

Log Kow: 0.256 (EPISuite Kowwin v1.68 Estimate)

Wat Sol: 2.23E+005 (mg/L, PhysProp DB exp value)

Available Measured Data from ECOSAR Training Set

Measured

CAS No Organism Duration End Pt mg/L (ppm) Ecosar Class Reference

=========== ========== ========== ====== ========== ===========================

000078-93-3 Fish 96-hr LC50 3220 Neutral organics DUL

ECOSAR v1.1 Class-specific Estimations

Neutral Organics

Predicted

ECOSAR Class Organism Duration End Pt mg/L (ppm)

=========================== ================== ======== ====== ==========

Neutral Organics : Fish 96-hr LC50 2181.619

Neutral Organics : Daphnid 48-hr LC50 1054.505

Neutral Organics : Green Algae 96-hr EC50 403.655

Neutral Organics : Fish ChV 176.357

Neutral Organics : Daphnid ChV 65.695

Neutral Organics : Green Algae ChV 73.855

Neutral Organics : Fish (SW) 96-hr LC50 2717.971

Neutral Organics : Mysid 96-hr LC50 6582.640

Neutral Organics : Fish (SW) ChV 101.710

Neutral Organics : Mysid (SW) ChV 953.982

Neutral Organics : Earthworm 14-day LC50 190.119

Note: * = asterisk designates: Chemical may not be soluble enough to measure this predicted effect. If the effect

level exceeds the water solubility by 10X, typically no effects at saturation (NES) are reported.

Class Specific LogKow Cut-Offs

If the log Kow of the chemical is greater than the endpoint specific cut-offs

presented below, then no effects at saturation are expected for those endpoints.

Neutral Organics:

Maximum LogKow: 5.0 (Fish 96-hr LC50; Daphnid LC50, Mysid LC50)

Maximum LogKow: 6.0 (Earthworm LC50)

Maximum LogKow: 6.4 (Green Algae EC50)

Maximum LogKow: 8.0 (ChV)








Appendix B – US EPA’s PBT Profiler Modeling Results

Results

Orange or red highlights indicate that the EPA criteria have been exceeded.

Black-and-white version

Persistence

Bioaccumulation

Toxicity

78-93-3 2-Butanone

PBT Profiler Estimate = PBT

Media

Half-Life (days)

Percent in

Each Medium

BCF

Fish ChV (mg/l)

Water 15 44% 3.2 180

Soil 30 43%

Sediment 140 0%

Air 12 13%

http://www.pbtprofiler.net/criteria.asp

http://www.pbtprofiler.net/Results.asp?BW=T

http://www.pbtprofiler.net/Details.asp#P

http://www.pbtprofiler.net/details.asp#B

http://www.pbtprofiler.net/details.asp#T

http://www.pbtprofiler.net/details.asp#media

http://www.pbtprofiler.net/details.asp#half-life

http://www.pbtprofiler.net/details.asp#percent

http://www.pbtprofiler.net/details.asp#percent

http://www.pbtprofiler.net/details.asp#bcf

http://www.pbtprofiler.net/details.asp#fishchv

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