OECD SIDS 2

- BUTOXYETHANOL

UNEP PUBLICATIONS 

### FOREWORD INTRODUCTION



# 2

- BUTOXYETHANOL CAS N°: 111

- 76

- 2OECD SIDS 2 -BUTOXYETHANOL

UNEP Publications 149 

## COVER PAGE

SIDS Initial Assessment Report for 6 th 

## SIAM

(Paris, 9-11 June 1997)

Chemical Name: 2-Butoxyethanol

CAS No.: 111-76-2

Sponsor Country: Australia

National SIDS Contact Point in Sponsor Country:

Ms. Lesley Onyon

HISTORY:

The SIDS Dossier was sent to members on 13 August 1996. No furt her testing has been recommended.

no testing (X) testing ( )

COMMENTS:

For discussion at SIAM 6.

The SIAR is based on a national assessment conducted under the Industrial Chemicals (Notification & Assessment) Act 1989 of 2-butoxyethanol in cleaning products and additional exposure information from Member countries.

Deadline for circulation:

Date of circulation: 28 February 1997 (To all National SIDS Contact Poin ts and the OECD Secretariat)OECD SIDS 2 -BUTOXYETHANOL

UNEP Publications 150 SIDS INITIAL ASSESSMENT PROFILE

CAS NO. 111 - 76 - 2

CHEMICAL NAME 2-BUTOXYETHANOL

STRUCTURAL

FORMULA CH 3 CH 2 CH 2 CH 2 OCH 2 CH 2 OH

RECOMMENDATION OF THE SPONSOR COUNTRY

2-Butoxyethanol is considered of low priority for further work.

SHORT SUMMARY OF THE REASONS WHICH SUPPORT THE RECOMMENDATION

The main use is for 2-butoxyethanol is in paints and surface coatings, followed by cleaning products and inks. Other products which contain 2-BE include acry lic resin formulations, asphalt release agents, firefighting foam, leather protec tors, oil spill dispersants and photographic strip solutions.

The principal health effects foll owing acute exposure to 2-butoxyethan ol are irritati on of the eyes and respiratory tract. The crit ical effect identified in rep eated dose animal studies is haematotoxicity. The lowest relia ble NOAEL for haemolysis in the mo st sensitive species, the rat, is 24.6 ppm (22.5 mg/kg/day). The haematological e ffects are transient at lower doses and there are large species differences in the haematological response to 2-butoxyethanol exposure, with evidence to show that humans are less sensitive th an rats. 2-Butoxyethanol is readily absorbed through the skin.

Taking into account the nature of the critical e ffect and the species difference, a comparison of estimated occupational exposures with the NOAEL for haemolytic effects indicates that the potential risk is generally low. However, for printing and cleaning, where there is prolonged exposure to high concentrations of 2-butoxyethanol, there are some concerns and adequate control measures are needed.

Due to low and intermittent exposure, the public h ealth risk from the use of products containing 2- butoxyethanol is low. 2-Butoxye thanol is relatively non-volatile , miscible in water, readily biodegradable and non-bioaccumulative. There is no apparent risk to any of the environmental compartments.

IF FURTHER WORK IS RECOMMENDED, SUMMARISE ITS NATURE

No further testing is recommended in the context of SIDS. An NTP 2-year inhalation study in rats and mice and an epidemiological study in Fran ce are currently being conducted. Given the potential for risk to human health in some s ituations, further work on the extent of dermal absorption would be useful.OECD SIDS 2 -BUTOXYETHANOL

UNEP Publications 151 FULL SIDS SUMMARY

CAS NO: 111-76-2 SPECIES PROTOCO L RESULTS

PHYSICAL-CHEMICAL

2.1 Melting Point - 77°C

2.2 Boiling Point 170.8°C

2.3 Density 0.90 kg/m 3

2.4 Vapour Pressure 1.17 hPa at 25°C

2.5 Partition Coefficient (Log Pow) 0.81

2.6 A Water Solubility miscible

B pH 7

2.7 Flash Point 62°C (closed cup)

2.8 Autoignition temperature 230-245°C

2.9 Flammability limits 1.10-12.7% ENVIRONMENTAL FATE/BIODEGRADATION

3.1. 1 Photodegradation Not expected to undergo direct photolysis

3.1. 2 Stability in Water Not expected to undergo hydrolysis

3.1. 3 Stability in Soil K oc of 67 indicates high mobility in soil

3.2 Monitoring Data In air: 1-8 μg/m 3 ; In ground water: 23 μg/L; In surface water: 1.3-5.7 ppm (contam. site)

3.3 Transport and Distribution Calculated (Fugacity Level 1 type) In water 84%, air 16%, sediment/soil 0.1% No significant transport expected from water to organic matter in sediments and suspended solids.OECD SIDS 2 -BUTOXYETHANOL

UNEP Publications 152 3.5 Biodegradation OECD 301 Readily biodegradable

ECOTOXICOLOGY

4.1 Acute/Prolonged Toxicity to Fish Fath’d min. Sh’ph’d m. Oyster W. shrimp 4d LC 50 = 2137 mg/L 4d LC 50 = 116 mg/L 4d LC 50 = 89 mg/L 4d LC 50 = 130 mg/L

4.2 Acute Toxicity to Aquatic Invertebrates ( Daphnia ) D. magna 2d LC 50 = 835 mg/L

4.3 Toxicity to Aquatic Plants e.g Algae Sel.caprico

rnutum 7d EC 50 > 1000 mg/L

4.5. 1 Chronic Toxicity to Fish Fathead minnow 32d MATC = 135 mg/L (QSAR result)

4.5. 2 Chronic Toxicity to Aquatic Invertebrates (Daphnia) TOXICOLOGY

5.1. 1 Acute Oral Toxicity rat

mouse guinea-pig rabbit OECD 401 LD 50 = 530-3000 mg/kg LD 50 = 1230 mg/kg LD 50 = 950-1414 mg/kg LD 50 = 320-370 mg/kg

5.1. 2 Acute Inhalation Toxicity rat

mouse guinea-pig OECD 403 LC 50 = 450-486ppm(2.2-2.4 mg/L) (4h) LC 50 = 700 ppm (3.4 mg/L) (7h) LC 50 = > 690 ppm (3.4 mg/L) (1h)

5.1. 3 Acute Dermal Toxicity rabbit guinea-pig OECD 402 LD 50 = 100-610 mg/kg LD 50 = 210-> 3000 mg/kg

5.2. 1 Skin Irritation rabbit guinea-pig OECD404 Moderate irritant Irritant

5.2. 2 Eye Irritation rabbit OECD405 Irritant

5.2. 3 Respiratory Irritation mouse Alarie test Weak irritant

5.3 Sensitisation guinea-pig Maximisati

on Non-sensitising

5.4 Repeat Dose Tox. - oral (d/w)

- oral rat

rat 90d NOAEL (m) = 129 mg/kg/d; LOAEL (f) = 82 mg/kg/d (haematotox.) 6 wk LOAEL (m) = 222 mg/kg/dOECD SIDS 2 -BUTOXYETHANOL

UNEP Publications 153 (gav)

- inhalation

- dermal rat

rabbit (haematotox.) 9d NOAEL = 20 ppm (haematotox.); 90d NOAEL = 24.6 ppm (haematotox.) 2 wk NOAEL = 90 mg/kg/d (haematotox.); 90d NOAEL = 150 mg/kg/d (haematotox.)

5.5 Genetic Toxicity In Vitro

A Bacterial Test (Gene Mutation) S. typhimur

E. coli Ch.hamster

V79 cells OECD 471 TA100, 1535, 1537, 97, 98 negative with and without metabolic activation Negative Negative (with and without m. activation) Positive at high doses

B Non-Bacterial In Vitro Test - Chromosomal aberrations

- Sister chromatid exchange

- Unscheduled DNA synthesis Ch.hamster

Ch.hamster

V79 cells

rat liver Negative (with and without m. activation)

Negative (with and without m. activation) Weakly positive at high doses

Inconclusive

5.6 Genetic Toxicity In Vivo - Mouse micronucleus

- DNA binding mouse

rat, mouse Negative

Negative

5.8 Toxicity to Reproduction - oral (d/w) rat (m)

mouse 60d NOAEL (parental) = 443 mg/kg/d NOAEL (parental) = 720 mg/kg/d 5.9 Developmental Toxicity/ Teratogenicity - oral (gav)

- inhalation

- dermal rat

rat rabbit

rat NOAEL = 350 mg/kg/d (maternal tox.); 650 mg/kg/d (embryo-, foetotoxicity) NOAEL = 200 ppm NOAEL = 100 ppm (maternal tox., embryotox.); 200 ppm (foetotoxicity NOAEL = 1760 mg/kg/d

5.11 Experience with Human Irritation of the eyes, nose andOECD SIDS 2 -BUTOXYETHANOL

UNEP Publications 154 Exposure throat. Headache and nausea.OECD SIDS 2 -BUTOXYETHANOL

UNEP Publications 155 SIDS INITIAL ASSESSMENT REPORT

1. IDENTITY

Name : 2-Butoxyethanol

CAS number : 111-76-2

IUPAC name : Ethylene glycol butyl ether

EINECS number : 203-905-0

Molecular formula : C 6 H 14 O 2.

Structural formula : CH 3 CH 2 CH 2 CH 2 OCH 2 CH 2 OH.

Synonyms : 2-BE, Butoxyethanol, n-Butoxyetha nol, 2-Butoxy-1-ethanol, Butyl ethoxol, O-Butyl ethylene glycol, Butyl glyc ol, Butyl monoether glycol, EGBE, Ethylene glycol butyl ether, Ethylene glycol n-butyl ether, Ethylene glycol monobutyl ether, Ethylene gl ycol mono-n-butyl ether, Glycol butyl ether, Glycol monobutyl ether, Monobutyl glycol ethe r, 3-Oxa-1-heptanol.

2-Butoxyethanol is known commer cially under the following trade names. Butyl Cellosolve ® , Butyl Icinol ® , Butyl Oxitol ® , Dowanol EB ® , Eastman ® EB Solvent, Gafcol EB ® , Glycol ether EB ® , Jeffersol EB ® , Poly-Solv EB ®

. Purity : When 2-butoxyethanol (2-BE) is ma nufactured from ethylene oxide and nbutanol, other glycol ethers such as the di- and triethylene glycol ethers are produced. Consequently, commerc ial 2-BE may contain small concentrations of other glycol ethers, n-butanol and ethylene glycol. A stabiliser, 2,6-bis(1,1-dimethylethyl)- 4-methylphenol, is often added at approximately 0.01% to prevent the formation of peroxides.

Physical and chemical properties : These properties are summarised in the table in the Full SIDS Summary. 2-BE is relatively non-v olatile and miscible in water.

Hazard classification : The current European Union (EU) cla ssification is R20/21/22 (Harmful by inhalation, in contact with skin, and if swallowed) and R37 (Irritating to respiratory system). Based on this assessment, risk phrase R36 (Irritating to eyes) is appropriate. The following con centration cut-offs apply: 12.5% for R20/21/22 and 20% for R36 and R37.

EEC classification number is 603-014-00-0.

2. GENERAL INFORMATION ON EXPOSURE

2-Butoxyethanol (2-BE) is used in many different applications. The main use is in paints and surface coatings, followed by cleaning products a nd inks. Other products which contain 2-BE include acrylic resin formulations , asphalt release agents, firefighti ng foam, leather protectors, oilOECD SIDS 2 -BUTOXYETHANOL

UNEP Publications 156 spill dispersants and photographic strip solutions. 2-BE is also used as a feedstock in the manufacture of other chemicals, for example, butyl glycol acetate (BGA).

In international databases, 2-BE is also list ed as a solvent for greases, oils, dyestuffs and nitrocellulose resins and enamels. It has been us ed as an ingredient in agricultural chemicals, cosmetics and brake oils, and as a raw materi al in the production of phthalate and stearate plasticisers.

In Europe, the total EU production of all butyl glyc ol ethers is given in CEFIC statistics as 181,000 tonnes. Process chemistry predic ts that approximately 50% of this will be 2-BE, that is approximately 90,000 tonnes. Virtually no 2-BE is believed to be imported into the EU (CEFIC, 1995).

The best estimates available for s upplies of 2-BE to EU markets ar e presented in Table 1 (in tonnes per year). The final column gives the typical ma ximum 2-BE concentration in formulated products.

Table 1 - Volume* of 2-BE in the EU (by Product Type)

Product Type Total Industrial Public Typical Max % Surface Coatings - Anticorrosion coatings - Can coating - Coil coating - Decorative retail (water based) - Decorative trade (water based) - General industrial (water based) - Auto OEM (solvent based) - Auto OEM (water based) - Wood coating (water based) 70000 2600 9000 6500 10400 15500 16800 1300 6500 1300 59600 2600 9000 6500

15500 16800 1300 6500 1300 10400

10400 1 7 7 1.5 1.5 3 2 8 2

Detergents and Cleaners 4000 3000 1000 10

Inks 5000 5000 0 20

Feedstock for BGA Production 11000 11000

TOTALS 90000 78600 11400

* tonnes per year

In an analysis of the use patterns of glycol ethers in Sweden over the period 1986-1993, the usage of 2-BE in 1993 was 2100 tonnes, of which 1680 tonne s were imported as 2-BE and the remainder imported in chemical products, main ly paints (Johanson and Rick 1996) . In data from the Products Register, 666 products containing 2- BE were listed, with the use pa ttern (in terms of tonnes 2-BE) being 68% as solvent, 23% in pain ts and lacquers, 3% in binders, 3% in cleaning agents, and 3% in other uses.OECD SIDS 2 -BUTOXYETHANOL

UNEP Publications 157 An analysis of the uses of th e 434 cleaning products identified during the national assessment in Australia revealed a wide variety of applications (as stated on the Material Safety Data Sheet and/or the label for each product). The main uses are tabled below.

Table 2 - Main Types of 2-BE Cleaning Products in Use in Australia

Use Number % of total 2-BE min. %

max. surface cleaner floor stripper glass/window cleaner carpet cleaner laundry detergent

rust remover oven cleaner ink/resin remover others 214 49 47 40 15 11 11 9 38 49 11 10 9 4 3 3 2 9 0.57 < 1 < 1 < 1 < 1.5 < 10 < 1 1 < 10 71 30.5 40 10-30 10-30 30-60 10-30 10-93 94

Information from Europe indicates that usage of 2-BE in cosmetics is lo w. It is used as a solvent in hair products such as hair dyes.

3. ENVIRONMENT

3.1 Environmental Exposure

3.1.1 General Discussion

2-BE will enter the environment via effluent at site s where it is formulated into products and via the disposal of any wash water used in cleaning, prin ting and surface treatment pr ocesses. It will also enter the atmospheric compartmen t due to evaporation. Release to water is the predominant pathway for cleaning processes, whereas evaporation is the main pathway for the other major use, paints/surface coatings.

Biodegradation studies indicate that 2-BE will be readily degraded by micro-organisms present at sewage treatment plants. Ready biodegradability tests showed that 2-BE achieved a biodegradation rate of greater than 77% after 3 days and 100% after 7 days . A 20-day biochemical oxygen demand test and an Organisation for Economic Cooperati on and Development (OECD) 28-day closed bottle test gave 2-BE degradation rates of 75% and 88% respectively. Literature data confirm these results.

Any 2-BE that passes through sewage treatment plan ts and enters receiving waters is likely to remain in the water column until biodegraded by micro-organisms present in the water. Accordingly 2-BE half-lives in surface water range from 4 weeks to 7 days. The complete miscibility of 2-BE in water suggests that vola tilisation, adsorption and bioconcentration are not important fate processes. 2-BE is expected to have a short residence time in the atmosphere.

Disposal of waste 2-BE to landfill may re sult in contamination of groundwater. A K oc of 67 for 2- BE indicates that it will be highly mobile in soil, and unlikely to partition from the water column toOECD SIDS 2 -BUTOXYETHANOL

UNEP Publications 158 organic matter contained in sedime nts and suspended solids. 2-BE has been detected in aquifers underlying a municipal landfill and a h azardous waste site in the USA.

2-Butoxyethanol was detected at 8 ug/m 3 in 1 of 6 samples selected for GC-MS from indoor air samples collected from 14 homes and 1 small o ffice in Italy (De Bortoli et al., 1986). The Environmental Protection Agency’s volatile organi c compounds national ambient database includes data on indoor air showing an average for 14 samples of 0.214 ppb (Shah & Singh, 1988) 2-Butoxyethanol is listed as a contaminant in drinking water samples analysed between September 1974 and January 1980 in a survey of US cities (Lucas, 1984). In Kentucky, USA, 2-BE was detected in ground water at a concentration of 23 ug/L in 1/7 samples collected in February 1974 near the Valley of Drums (S tonebreaker & Smith, 1980)

In Japan, 2-BE was detected in surface water at a concentration of 1310 and 5680 ppb in the water of the Hayashida River as a contaminant from l eather industry effluents. The values represent levels after steam and vacuum distilla tion respectively (Yasuhura et al., 1981).

3.1.2 Predicted Environmental Concentration

The predicted environmental concentrations (PECs) were calculated on the ba sis of data available for the national Australian assessment, that is, a total volume of approxi mately 2500 tonnes, with 40% into cleaning products, approximately 50% in paints and surface coatings, and the remainder in inks and other applications. A daily output of 250 million litres from the sewage treatment plant was assumed.

In other countries, the use and release patterns may differ. For example, data from Europe indicates that the greater per centage of 2-BE goes into paints/surface co atings (see Table 1) and that the daily output from a sewage treatment plant may be 2 million litres. In these circumstances, the PECs may be different from the following concen trations calculated for a large metropolis.

In the following estimates, the PEC of 2-BE in water was calculated according to the methods in the Technical Guidance Document and formula from the USES model.

The assumptions used for calculating the PECs included:

. All 2-BE used is released to the environment.

. When used in cleaning products, 90% is released to water, with 10% to the atmosphere. All release to water is via the sewage treatment plant.

. When used in paints/surface coatings; inks; a nd other uses, 10% is released to sewer, with 90% to the atmosphere due to evaporation.

. 300 days per year of 2-BE handling.

. Manufacture of 2-BE occurs on 300 days per ye ar (at one site only), with 1% released to sewer, that is, a daily release of 67 kg.

. In the absence of data, 40% use of 2-BE will be assumed to occur in the Sydney metropolitan area, for which the PEC local is calculated.OECD SIDS 2 -BUTOXYETHANOL

UNEP Publications 159 Based on these assumptions, the following daily release figures through end use have been calculated.OECD SIDS 2 -BUTOXYETHANOL

UNEP Publications 160 Table 3 - Estimated Daily Release of 2-BE for End Use

Cleaning products Paints/surface coatings Inks and other

Use per day (continental) 3.33 te 4.17 te 0.83 te

Amount to sewer (continental) 3000 kg 416.7 kg 83.3 kg

Amount to sewer (local) 1200 kg 166.7 kg 33.3 kg

PEC (local)

The PEC (local) for water can be calculated using the equation:

PEC local(water) = C eff /((1+K p(susp) . C (susp) ) . D)

C eff = the concentration of the chemical in the sewage treatment plant;

K

p(susp) = suspended matter-water adsorption coefficient;

C susp = concentration of suspended matter in re ceiving waters (default value 15 mg/L); D = dilution factor (= 10).

C eff = W.(100 - P)/(100.Q) where W = emission rate (see values in Table 4); Q = volume of waste wa ter (= 250 million litres/day); P = % removal in the sewage treatment plant (= 91%).

K

p(susp) = Foc (susp) .Koc, Koc = a.P ow (a = 0.411) where Foc (susp) = fraction organic carbon in su spended matter (= 100 mg/L);

P ow = octanol-water partition coefficient (= 6.46).

For the Australian case, PEC (local) is based in Sydney, where the Se wage Treatment Plant is assumed to carry a daily outpu t of 250 million litres.

Because of the biodegradability of 2-BE, a high percentage could reasonably be expected to be removed from the Sewage Plant prior to rele ase to receiving waters. According to the SIMPLETREAT model, 91% is eliminated in the Sewage Plant.

These equations have been used to calculate PEC local for the water compartment based on release of 2-BE through its use as cleaning agents, in paints/surface coatings, and in inks and other applications. The PECs calculated are given in Table 4. The PEC value calc ulated for production is probably conservative as a release of 1% is used. Production is carried out in a closed system, with product being recovered during pur ging processes being recycled.OECD SIDS 2 -BUTOXYETHANOL

UNEP Publications 161 The PEC effluent is equivalent to the PEC local(surface water) before dilution. A dilution rate of 10 is used so values for PEC effluent have also been calcula ted and are in Table 4.

Table 4 - Local PECs Calculat ed for the Aquatic Environment

Process Emission rate to

sewer (kg/day) PEC local (μg/L) PEC effluent (μg/L)

Production 67 2.4 24

Total use 1400 50.4 504

- in cleaning products 1200 43.2 432

- in paints/surface coatings 166.7 6 60

- in inks/other 33.3 1.2 12 NB: Figures are based on a total annual use of 2500 tonnes of 2-BE.

PEC (continental)

A continental PEC has been calculated based on an Australian population of 18 million people, with a total sewer output of 2700 million litres per day (150 L per person).

Assuming all 2-BE used is released, the daily con tinental release is 8.3 tonnes. Of this, 3.5 tonnes is released to sewer through en d use activities. Ba sed on these estimates, the continental concentration of 2-BE in receiving waters was estimated to be 12 μg/L.

Atmosphere

It has been estimated that 10% of 2-BE used in cleaning agents is released to the atmosphere, while 90% used in paints; inks; and othe r applications is rele ased to the atmosphere through volatilisation.

A PEC (local) for air release of 2-BE from end uses can be calculated. The following equation can be used to calculate the concentrat ion in air at 100 m from the site.

C air = Emission x Cstd air

where C air = concentration in air at 100 m from a point source (kg/m 3 ); Emission = emission ra te to air (kg/sec); and Cstd air = standard concentr ation in air at source stre ngth of 1 kg/sec (= 24 x 10 -6 ).

Table 5 - Local PECs Calculated for the Atmospheric Environment

Process Emission to air (kg/day) PEC local ( μ g/m 3 )

Use in cleaning products 133.3 37 Use in paints/surface coatings 1500 417OECD SIDS 2 -BUTOXYETHANOL

UNEP Publications 162 Use in inks/other 300 83

Total 1933 537

These are conservative estimates as they assu me all release is from a single point source.

2-BE is expected to have a shor t half-life in air through reaction w ith hydroxyl radicals, with a halflife of less than 1 day. The level 1 Mackay fugac ity model indicates that, at equilibrium, 84% of 2- BE will partition to water, a nd 16% will partition to air.

3.2 Effects on the Environment

3.2.1 Aquatic Effects

The results of aquatic toxicity st udies are summarised in table 6.

Table 6 - Aquatic Toxicity Results

Test Species Result (mg/L) Reference

Acute Fish toxicity Fathead minnow (F) 4d LC 50 = 2137 Dow Chemical (1979) Sheepshead minnow (S) 4d LC 50 = 116 US EPA (1984) Inland silverside (F) 4d LC 50 = 1250 AQUIRE Invertebrates Oyster (S) 4d LC 50 = 89 US EPA (1984) White shrimp (S) 4d LC 50 = 130 US EPA (1984) Brine shrimp (S) 24h LC 50 = 1000 AQUIRE Daphnia magna (F) 2d LC 50 = 835 Dow Chemical (1979) 24h EC 50 = 1815 AQUIRE Growth Algae inhibition Green algae 7d EC 50 > 1000 Dow Chemical USA (1988) Blue-green algae EC 50 > 35 AQUIRE Micro-organisms Sewage bacteria 16h IC 50 > 1000 Union Carbide Chemicals and Plastics Co. Inc. (1989) F=Freshwater species; S=Saltwater species

The lowest definitive LC 50 result was for the oyster ( Crassotera virginicas ) and was 89.4 mg/L. This was chosen over the result obtained for testing on blue green algae, as th is result is a toxicity threshold and was therefore considered inapprop riate to base a PNEC on. A good range of test results are available. Even so, an assessment factor of 1000 was used. While this is very conservative, it will demonstrate the potential hazar d of 2-BE in a worst case situation. Applying the assessment factor of 1000, the PNEC is 89.4 μ g.L -1

.

3.2.2 Terrestrial Effects

No data available.OECD SIDS 2 -BUTOXYETHANOL

UNEP Publications 163 3.3 Initial Assessment for the Environment

Aquatic Compartment

PEC/PNEC ratios for the aquatic compartment can be calculated using the worst-case local scenario, in this instance, the PEC (local) of 52.8 μg/L. This was based on a worst case emission factor from 40% of all 2-BE being re leased in the Sydney metropolitan area.

The PEC/PNEC ratio has been ca lculated for local and continental compartments as follows:

PEC/PNEC local = 0.59

PEC/PNEC continental = 0.13

These ratios suggest that 2-BE is unlikely to ca use adverse effects in th e aquatic environment.

The risk of 2-BE to sewage micro-organisms is considered to be minimal as the PEC effluent figure of approximately 528 μg/L (Table 4) is several orders of magnitude below the only available test result of 16h IC 50 > 1000 mg/L.

4. HUMAN HEALTH

4.1 Human Exposure

4.1.1 Occupational Exposure

The major routes of exposure to 2-BE are inhalati on and skin absorption. 2- BE is a liquid which is miscible with water. It is readily absorbed through the skin, including absorption from aqueous solution, and in vapour and aerosol form. The tota l exposure of workers to 2-BE must take into account the inhalation uptake of va pours and aerosols and the dermal absorption of 2-BE in liquid, vapour and aerosol form.

Exposure estimates were calculated from the available monitoring data and by modelling. Measured data were limited, particularly for derm al exposure. The worst-case estimates generated in this exposure assessment are considered to be ‘feasible’ worst-case estimates, as they describe high end or maximum exposures in ‘feasible but not unre alistic’ situations. The estimates are not intended to account for extreme or unusual use s cenarios which are unlikely to occur in the workplace. The vast majority of occupational exposures are expected to be well below these estimates.

For occupational exposure to vapour s, a respiratory rate of 1.3 m 3 /h and a bioavailability of 0.75 were assumed. Based on toxicological data, it wa s assumed that an additional 20% of the vapour uptake was due to dermal absorpti on. For the dermal absorption of 2-BE liquid, a skin absorption rate of 0.2 mg/cm 2 /h and a skin surface area of 1000 cm 2 were assumed. Fo r all occupational exposure estimates, a body weight of 70 kg was assumed. Details of o ccupational exposure estimates are given in Appendix 1.

4.1.1.1 Exposure during manufactureOECD SIDS 2 -BUTOXYETHANOL

UNEP Publications 164 2-BE is manufactured by the reacti on of n-butanol and ethylene oxide . The process is enclosed as extensive precautions are taken to prevent and mini mise exposure to workers in the production area, due to the toxicity of the ethylene oxide feedstock.

2-BE is stored in sealed tanks wh ich are bunded to contain any spills.

Exposure during manufacture is low as the process is sealed. Exposur e during transfer to tankers or drums is generally minimised by the use of automa ted filling, where the operator is segregated from the area during transfer, and the use of local e xhaust ventilation. Incide ntal exposure may occur when the process is breached or when spills occur. Exposure may occur during maintenance activities, however, the purgi ng of plant and equipment is ge nerally standard practice.

Atmospheric monitoring for 2-BE is usually c onducted regularly by manuf acturers in their plant areas (see table 7).

Table 7 - Measured Inhalation Data for Manufacture

Manufacturer Monitoring Area No. of readings Mean ppm Maximum

ppm BASF (EU) Production Filling Technical unit Laboratory Various 97 66 9 14 8 0.09 1.3 0.25 1.3 0.5 1.2 5.3* 1.2 11* 2.7

BP (EU) All 311 < 0.1 1.6

Eastman (US) Production Tanker loading 16 11 < 0.25 < 0.04 1.8

Huls (EU) Production Filling Laboratory/Sampling 30 10 20 < 0.14 < 0.14 < 0.38 0.31 0.22 1.1

ICI (Australia) All (personal monitoring) Maintenance (area) 0.1 1.8

* These values are reported as outliers by th e department of Work Safety (Germany).

The above results are supporte d by monitoring data av ailable for a US plant. For a similar process, where the manufacturing operation is also enclose d, the highest results were obtained during drum filling, with a time-weighted average (TWA) reading of 1.7 ppm ( 8.3 mg/m 3 ) obtained in area monitoring. The highest personal m onitoring reading was 0.1 ppm (0.5 mg/m 3 ). During drum filling, local exhaust ventilation wa s in place to minimise inhalation exposure in case of spills.

Taking 3 ppm (14.7 mg/m 3 ) as a maximum atmospheric concentration (taken from Table 7, where highest maximum reading was 2.7 ppm), the estim ated daily dose for exposure to 2-BE vapours (inhalation and dermal) during manufacture is 2.0 mg/kg/day.OECD SIDS 2 -BUTOXYETHANOL

UNEP Publications 165 For dermal exposure to 2-BE liquid during manufactur e, it is assumed that skin contact will be incidental, that is, for 1% of the work period. The estimated dermal exposure is 0.2 mg/kg/day.

Therefore, the combined dermal and inhalation exposure during ma nufacture would not be expected to exceed 2.2 mg/kg/day.

4.1.1.2 Exposure during formulation

During the formulation of products containing 2-BE, workers may be exposed to 2-BE during preweighing before mixing, during transfer to th e mixing tank, during mixing and during the filling of containers with product. The whole operation is generally carried out at room temperature.

The potential exposure of workers to 2-BE during mixing is variable as the process may be enclosed or relatively open. When the transf er of 2-BE to the mixing vessel is carried out in a sealed system, potential exposure will be minimal, but when the operator adds the raw materials directly by drum to the mixing tank, exposure may be greater due to possible splashing a nd vapour and/or aerosol generation. Information obtained from the national a ssessment of 2-BE in Australia indicated that a number of formulators of clean ing products containing 2-BE use the latter procedure and that approximately 50% of formulators carry out mixi ng in open top tanks, w ith greater potential for

exposure.

There is potential for worker exposure during the pr oduct filling operation. Th e design of the filling operation will influence exposure, for example, if the packing line is enclosed at the point of filling, then inhalation exposure will be reduced. If f illing is an automatic operation with containers pneumatically filled, then exposure is likely to be lower.

Little measured data were available for exposur e during the formulation of products containing 2- BE. In exposure data supplied by one large UK fo rmulator, Holden (part of the ICI group), 2-BE was detected in 15 cases out of 89 personal mon itoring samples, with the mean 0.7 ppm and the maximum 1.5 ppm. In personal monitoring data from Germany, 2-BE was generally below the analytical detection limit, with and without me chanical ventilation. In 204 measurements during weighing and filling operations (bead mills), 95% of samples were below 2.5 ppm (12 mg/m 3 ).

In the scientific literature, in the only data available for formulation, the maximum TWA air concentration for workers in a varn ish production plant was 8.1 ppm (39.7 mg/m 3 ), the 2-BE content in the product( s) not being stated.

Occupational exposures were calcu lated for a range of 2-BE con centrations. As operators are generally involved in both mixing and filling, the estimates of exposure are for the formulation process as a whole. Considering the process an d the tasks during formulation where exposure may occur, inhalation exposure is assumed to be c ontinuous and dermal exposure intermittent (skin contact for 20% of the work time) . Inhalation estimates were based on the available monitoring data for formulation and clean ing operations. The following co mbined inhalation and dermal estimates (in mg/kg/day) were calculate d for an 8-hour work period (Table 8).

Table 8 - Exposure Estimates for Formulation*

% 2-BE Max. 2-BE in air (ppm) Max. daily dose (est.) (mg/kg/d) 10 2 1.9OECD SIDS 2 -BUTOXYETHANOL

UNEP Publications 166 30 10 8.2 60 10 9.5 * See Appendix 1

4.1.1.3 Exposure during use of products containing 2-BE

A considerable amount of atmospheric monitoring data for 2-BE is available for exposure during use of the various products contai ning the chemical. In some cases , biological monitoring (for the major metabolite of 2-BE, 2-butoxyacetic acid (BAA) , has also been conducted. The available atmospheric monitoring data for 2- BE is summarised in table 9.

Table 9 - Atmospheric Monitoring Data for 2-BE during Product Use

Operation % 2-BE Mean ppm Max. ppm Reference

Cleaning Car window cleaning Office cleaning Floor scrubbing Cleaning of floors General window cleaning Schoolroom cleaning Cleaning print machines Cleaning printing press rollers Surface cleaning 5.7-21.2 0.9-9.8 0.3

0.25 10-50 1.8 0.3

n.d < 0.2 < 0.7 5.2 0.3 n.d 7.3 0.7 1.6 <9.6 1

9.7 0.5 <4.9 1 Vincent (1993) Vincent (1993) NIOSH (1979) BGAA (1996) NIOSH (1983) NICNAS (1996) NIOSH (May 1987) NIOSH (1990) BGAA (1996)

Printing General printing Printing (various)

Silk screening 100 100 to 45%

n/a 0.6 0.8 0.2 4 25 2

63 2

6.8 0.2 n.d 0.8

0.7 5 36 169

1.6 <1.6 3 Sakai et al (1993) Veulemans et al (1987) Vincent et al (1996) NIOSH (1986) NIOSH (Dec 1987) NIOSH (Dec 1987) NIOSH (1985) Vincent et al (1996) BGAA (1996)OECD SIDS 2 -BUTOXYETHANOL

UNEP Publications 167 Painting/Surface treatment General painting House painting Painting (various) Fabrication of paints Cataphoresis Staining/varnishing

Floor making Spray painting Spray painting (manual) Surface coating (manual) Car repair Car coating to 55% 4 0.01 0.1 0.4 0.8 5 0.2 2.6 0.4 n.d. n.d. 1.2 0.1 0.015 0.8 45 6.2 71 2.4

<3.1 1

<8.4 1

0.1 Veulemans et al (1987) Norback et al (1996) Vincent et al (1996) Vincent et al (1996) Vincent et al (1996) Denkhaus et al (1986) Vincent et al (1996) NIOSH (1985) Winder & Turner (1992) BGAA (1996) BGAA (1996) Veulemans et al (1987) Vincent et al (1996)

All uses < 25 Guirguis et al (1994)

n.d. non-detectable n/a not available 1 95% samples below this value 2 In this study, only 2 samples for both pers onal monitoring and area monitoring were analysed. 3 90% samples below this value Biological monitoring wa s also conducted in seve ral studies by Vincent and Sakai. Post-shift readings for BAA in urine (expressed as mg/g creatinine) are listed in Table 10.

Table 10 - Biological Monitoring Data for 2-BE during Product Use

Operation % 2-BE Mean BAA Max. BAA Reference

Cleaning Car window cleaning Office cleaning 5.7-21.2 0.9-9.8 96.5 < 2 371 3.3 Vincent (1993, June) Vincent (1993, June)

Printing General printing Printing (various) Silk screening 3.9 2.2 n.d. 9.9 7.1 n.d. Sakai et al (1993) Vincent et al (1996) Vincent et al (1996)

Painting/Surface treatment Painting (various) Fabrication of paints Cataphoresis Staining/varnishing Car coating 4 3.9 17.9 4 2.3 63 60 210 34 28 Vincent et al (1996) Vincent et al (1996) Vincent et al (1996) Vincent et al (1996) Vincent et al (1996)

Cosmetics < 0.5-5 n.d. n.d. Vincent et al (1996)OECD SIDS 2 -BUTOXYETHANOL

UNEP Publications 168 Use of cutting oils 1-5 3.2 8.3 Vincent et al (1996)

n.d. non-detectable

Cleaning

A large number of cleaning produ cts contain 2-BE, so a large num ber of workers are potentially exposed to the chemical. Exposure to 2-BE during cleaning is extremely variable, due to differences in frequency and duration of use, st rength of solution used, me thod of application and precautions taken during use.

The strength of solution used in the cleaning pr ocess is generally low as the product is usually diluted substantially before use, for example, mo st surface cleaners specify a dilution ratio in the range 1:3 to 1:100, depending on the application and the soil loading. A large proportion of cleaning products contain less than 10% 2-BE, so the fina l strength of solution is often less than 1%. In the national Australian assessment, a rand om survey of 20 general surface cleaning products containing < 10% 2-BE indicated th at the dilution ratio ranged from 1:1 to 1:250, with most ratios in the 1:5 to 1:100 range. Some products are sold as high level concentrat es (> 50% 2-BE) which must be diluted with large vol umes of water before use.

A number of different methods are used to apply the cleaning solution, for example, washing, wiping, mopping and spraying. In the national Austra lian assessment, approxi mately half of the cleaning products were used in sp ray form, with a small number mark eted in aerosol spray cans or trigger packs.

Occupational exposures were calcul ated for a range of 2-BE concen trations. Both inhalation and dermal exposure were assumed to be continuous over the whole work peri od. Inhalation estimates were based on the available monitoring data for cleaning activities (see Table 9). Dermal estimates assumed continuous skin contact over the work period. The following combined inhalation and dermal exposure dose estimates (in mg/kg/day) were obtained for an 8-hour work period (table 11).

Table 11 - Exposure Estimates for Use of Cleaning Products*

% 2-BE Max. 2-BE in air (ppm) Max. daily dose (mg/kg/d) 0.1 2 1.4 1.0 2 1.6 10 4 5.0 30 10 13.7 *See Appendix 1

Printing

2-BE is used as a coupling solvent in a range of specialist inks in cluding silk screen inks used by professional trades. The inks contain high levels of solids an d up to approximately 20% 2-BE.

Some monitoring data are availabl e for exposure during the use of inks containing 2-BE (see Table 9). However, some of the data are not representa tive of typical work scenarios in printing, for example, in the NIOSH (1987) study , the workers were exposed to ne at 2-BE in open spray troughs and wash table areas. Consequently, the other da ta were used in calculating exposure during silkOECD SIDS 2 -BUTOXYETHANOL

UNEP Publications 169 screening and general printing tasks using inks containing 2- BE. Dermal estimates assumed continuous skin contact over the work period. The following combined inhalation and dermal exposure estimates (in mg/kg/day) were obtained for an 8-hour work period.

Table 12 - Exposure Estimates for Use of 2-BE in Printing*

Activity % 2-BE Max. 2-BE in air (ppm) Max. daily dose (mg/kg/d) Silk screening 50 10 18.2

General printing 20 2 6.0

* See Appendix 1

Paints/Surface coatings

2-BE is used in a wide variety of paints and su rface coatings, particularly in water-based type. The concentration of 2-BE varies from one product to another, with European exposure data indicating that up to 8% 2-BE is used in the various formul ations (see Table 1). Du e to high volume use, a large number of workers are potentially exposed to 2-BE.

Exposure to 2-BE during painting is extremely va riable, due to differences in frequency and duration of use, concentration of 2-BE in the paint, method of application and precautions taken during use. This variation is re flected in the atmospheric monitori ng data available for 2-BE during painting and surface treatment (see Table 9).

Assuming a maximum atmospheric c oncentration of 10 ppm (49 mg/m 3 ) TWA for use of a paint/surface coating containing 10% 2-BE, an estimate for exposure to vapours is 6.8 mg/kg/day.

Dermal estimates assumed continuous skin contact over the work period (8 hours). This resulted in an estimate for dermal exposure to liquid 2-BE of 2.3 mg/kg/day.

Therefore, the combined inhalation and dermal da ily dose of 2-BE during an 8 hour work period would not be expected to exceed 9.1 mg/kg/day.

4.1.1.4 Exposure during use as feedstock

2-BE is used as a chemical intermediate to produ ce butyl glycol acetate (BGA) . As the transfer to reaction vessels is via a sealed system, exposure is negligible.

4.1.2 Consumer Exposure

Cleaning

Consumers are potentially exposed to 2-BE during the use of cleaning products containing the chemical, for example, during general surface clea ning. Cleaning products for consumer use which contain 2-BE generally contain less than 10% 2- BE are diluted substantially before use. Some trigger packs containing low concentrations of 2- BE are available to consumers. Inhalation and dermal exposure may arise during use. Details of consumer exposure estimates are given in Appendix 1.OECD SIDS 2 -BUTOXYETHANOL

UNEP Publications 170 Assuming a maximum atmospheric c oncentration of 4 ppm (19.6 mg/m 3 ), a respiratory rate of 0.8

m 3 /h and a body weight of 60 kg, the estimate for exposure to vapours for a cleaning time of one hour is 0.25 mg/kg/event.

For dermal exposure, assuming a sk in absorption rate of 0.2 mg/cm 2 /h, a skin surface area of 1000

cm 2 , and continuous skin contact over a one hour cleaning period, the estimate for dermal exposure to a 10% solution is 0.33 mg/kg/even t. Therefore, the combined inhalation and dermal exposure for use of a 10% cleaning solution for one hour woul d not be expected to exceed 0.58 mg/kg/event.

Paints/Surface coatings

Consumers are potentially exposed to 2-BE during the use of paints containing the chemical. European exposure data indicates that paints available for consumer use which contain 2-BE typically contain less than 1.5% 2-BE (see Table 1). Inhalation and dermal exposure may arise during use.

Assuming a maximum atmospheric c oncentration of 2 ppm (9.8 mg/m 3 ), a respiratory rate of 0.8

m 3 /h and a body weight of 60 kg, the estimate for e xposure to vapours for a painting time of 6 h/day is 0.75 mg/kg/day.

For dermal exposure, assuming a sk in absorption rate of 0.2 mg/cm 2 /h, a skin surface area of 1000

cm 2 , and continuous skin contact ov er a 6 hour painting period, the es timate for dermal exposure to a paint containing 1.5% 2-BE is 0.3 mg/kg/day. Therefore, the combined inhalation and dermal exposure for use of a paint containing 1.5% 2-BE for 6 hours would not be expected to exceed 1.05 mg/kg/day.

Cosmetics

2-BE is listed as being used as a solvent in cosme tics, although EU data indi cates that usage may be very low in Europe. According to the Cosmetic Ingredient Dictionary, it is used in hair dyes. Solvents in hair dye formulations can be present at concentrations up to 10%.

The EU Scientific Committee on Cosmetology (SCC) advi se that the quantity of hair dye used is likely to be approximately 100 mL (= g) once a month for permanent dyes and 35 mL once a week for semi-permanent dyes. The amount of 2-BE applied would therefore be 10/28 = 0.36 g/day for permanent dyes and 3.5/7 = 0.5 g/day for semi-permanent dyes.

It is estimated that 10% of the product remains on the head after rinsing, of which 10% is available for absorption through the scalp (the other 90% rema ins with the hair), that is, 1% of the amount applied may be absorbed. Therefore, exposure ma y be up to 3.6 mg/day for permanent dyes and up to 5 mg/day for semi-permanent dyes.

4.1.3 Indirect Exposure via the Environment

Indirect exposure of the public at large to 2-BE via the environment is restricted to the use of products containing 2-BE in public places, for ex ample, paints and cleaning agents in public buildings. Due to the low concentration of 2-BE in paints and cleaning solutions (generally less than 10%), the low volatility of 2-BE and its rea dy biodegradability in the environment, indirect exposure is likely to be minimal.OECD SIDS 2 -BUTOXYETHANOL

UNEP Publications 171 4.2 Effects on Human Health

4.2.1 Kinetics and Metabolism

The toxicokinetics of 2-BE have been well investigat ed in laboratory animals, particularly the F344 rat, and some studies have been conducted on huma n volunteers. The results of many of the studies have been reported in the open literature. In orde r to optimise the extrapol ation of data from one species to another, pharmacokinetic models have been developed.

2-BE is well absorbed via the inhalation, oral and dermal routes . Absorption studies in various species, including humans, have shown that 2-BE is rapidly absorbed through the skin, including absorption from aqueous solution. There is some ev idence to indicate that 2-BE in aqueous solution is more readily absorbed than fr om neat liquid (Bartnik et al., 1987; Johanson & Fernstrom, 1988). Dermal studies in humans and human skin specimen s indicate that the derm al absorption rate is most likely in the order of 0.2 mg/cm 2 /h (Dugard et al., 1984). From the results of several inhalation studies in volunteers, the respiratory uptake was approxi mately 57-78% of the inspired amount (Johanson et al., 1986; Johanson & Boman, 1991). Recent human studies and predictions from the physiologically-based pharmacokinetic (PBPK) model of Corley et al (1994) indicate that the dermal absorption of vapour may contribute up to approximately 20% of the total vapour uptake.

Animal studies have shown that 2-BE is rapidly distributed to all ti ssues via the blood stream. In a gavage study in F344 rats with 14 C-labelled 2-BE, the highest levels of radioactivity were found in the forestomach, then the liver, ki dneys, spleen and glandular stom ach (Ghanayem et al., 1987 (b)). In a dermal study in male Wistar rats, 14 C-labelled 2-BE was distributed widely to all tissues, with the greatest level of radioactivity in the spleen and thymus, followed by the liver (Bartnik et al., 1987).

Studies in animals and humans ha ve indicated that the major me tabolic pathways of 2-BE are similar in various species. In the different species , 2-BE is efficiently metabolised, mainly to BAA, which is formed by oxidation by alcohol/aldehyde dehydrogenase. In animals, smaller amounts of the glucuronide and sulfate conjugates and ethyl ene glycol can be formed by other metabolic pathways, following exposure at high doses. In human studies, the glutamine conjugate of BAA has been detected in urine following exposure to 2-BE, and suggests an a dditional detoxification pathway in humans (Rettenmeier et al., 1993). 2-BE is re moved from the blood, with an elimination half-life of approximately 40 to 80 minutes in humans (Johanson et al., 1986). The major metabolite BAA is rapidly excreted in urine in animals and humans with an urinary excretion half-life of approximately 3-6 hours in humans (Johanson et al., 1986). In human studies, wide variations in absorption a nd excretion rates between subjects have been found.

A number of different PBPK models have been propos ed for 2-BE to enable the extrapolation of the effects observed in one species to an other, in particular the effects in the rat to humans. Johanson et al (1986) proposed a PBPK model for the inhalation of 2-BE in humans, but recent developments of the model by Shyr et al (1993) an d Corley et al (1994) have incorporated more data, including that from rat studies and other routes of exposure. The Corley model is a dual 2-BE-BAA model developed to incorporate more physiological and biochemical information on BAA, the principal metabolite of 2-BE. The model also incorporat es the other metabolic pathways identified in metabolism studies. In validation wo rk against a wide variety of test results, including data from rat and human studies and data from different exposure routes, values predicted by the model generally agreed well with experimental data. The phys iologically-based pharmac okinetic model developed by Corley et al (1994), successfully estimated the disposition of 2-butoxye thanol and BAA under aOECD SIDS 2 -BUTOXYETHANOL

UNEP Publications 172 variety of exposure scenarios. Based on data from absorption studies indicating that 2- butoxyethanol was more readily absorbed from aqueous solution, and assuming that 10% of body area was exposed (approximately 2000 cm 2 ), Corley et al’s model predicted as a worst-case scenario that the skin absorp tion of undiluted 2-butoxyethanol ove r 6h would lead to a BAA blood concentration of 0.37 mM, and that absorption of a 40% solution would result in 1.3 mM BAA.

4.2.2 Human Health Effects

Exposure to 2-BE vapour may result in irritation of the eyes, nose a nd throat, headache and nausea. In controlled studies in volunt eers, nose and eye irritation were observed at 113 ppm, nausea and headache at 100 ppm (Carpenter et al., 1956), but no adverse effects were noted at 20 or 50 ppm (Johanson et al., 1956; Johanson & Boman, 1991). Workers using 2-BE cleaning products have reported respiratory irritant e ffects, nausea, headaches and ti redness, however the atmospheric levels were unknown. Isolated ca ses of skin reddening and dermatitis have been reported in workers using cleaning products on a regular basis, however, as the products contain many ingredients, the irritant effect s cannot be solely attributed to 2-butoxyethanol. In general, occupational case studies have not identified skin irritancy as a significant effect in exposed persons. In a patch test in vol unteers, 2-BE was not a skin sens itiser (TKL Research Inc.,1992) .

In a study conducted in human vol unteers (2 men, 1 woman) th e red blood cell fragility was unaffected. Exposure was to 195 ppm for two four-hour periods. BAA was excreted in the urine of the woman and 1 male but only a trace was detect ed in the second male. Symptoms included irritation of the eyes, nose and throat, unpleasan t taste and headache (C arpenter et al., 1956).

Haemolytic effects have only been observed in hu mans who have ingested large quantities (30-60g) of 2-BE (Rambourg-Schepens et al., 1988; Gijse nbergh et al., 1989). Th e ingestion of large quantities of 2-BE (30-106g) may also result in coma, metabolic acidosis, shock and respiratory distress (Rambourg-Schepens et al., 1988; Gijsenbergh et al., 1989; Bauer et al., 1992). Respiratory distress was observed in one case re port and may have occurred as a result of aspiration of refluxed stomach contents rather than bei ng directly attributable to exposure to 2-BE (Bauer et al., 1992).

4.2.3 Effects in Experimental Animals and In Vitro Test Systems

The large number of good quality studies conducted in animals and in vitro test systems have enabled the health effects of 2-BE to be well char acterised. The main effect observed in both acute and repeated dose animal toxicity studies is haem atotoxicity, with the prin cipal haemolytic agent being BAA. The species differences in susceptibility to this effect are considerable, with rats and mice the most susceptible, rabbits less susceptible and humans and guinea-pigs the least susceptible

. In vitro studies indicate that there is an order of ma gnitude difference in the susceptibility to BAA of rat red blood cells compared to huma ns, with rats being more susceptible.

Acute toxicity

The acute toxicity of 2-BE is mode rate by all routes of exposure and is , in general, higher than other glycol ethers. The oral LD 50 (rat) is 530-3000 mg/kg, dermal LD 50 (rabbit) is 100-610 mg/kg, and inhalation 4h LC 50 (rat) is 2.2-2.4 mg/L (450-486 ppm) (ECETOC, 1994). The dermal LD 50 of 100 mg/kg (Duprat and Gradski, 1979) is lower than ( no observable adverse effect level) NOAELs and (lowest observable adverse effect level) LOAELs of short-term repeated dose studies and is therefore considered questionable. Death was ge nerally caused by narcosis or respiratory failure and congestion and damage to the kidney, liver, lungs and spleen were often observed at necropsy.OECD SIDS 2 -BUTOXYETHANOL

UNEP Publications 173 Haemolytic effects were observed in most acute studies. Acute derm al studies show that 2-BE is readily absorbed through the skin.

Irritant effects

2-BE is a severe eye irritant (Bushy Run Research Centre, 1980 ; Carreon, 1981; Kennah et al., 1989; Jacobs, 1992). Results of skin irritation studi es are conflicting, however, 2-BE is considered to be a mild to moderate skin irritant in te st animals (Tyler, 1984; Gingell et al., 1994; ECETOC ,1994). The results of one sensory irritation st udy in mice indicate that 2-BE vapour may be irritating to the nose and throat (Kane et al., 1980). Skin sensi tisation studies were negative (Unilever Research, 1989; Zissu 1995), and immunotoxic ity studies in the rat and guinea pig did not result in any significant effect on the immune response (Grant et al 1985; Bartnik et al., 1987; Ghanayem et al., 1987 (b); Crevel et al., 1990).

Repeated dose toxicity

Several short-term and subchronic repeated dose st udies in animals by all routes of exposure have been performed. The critical effect seen in re peated dose studies is h aematotoxicity. The main signs of toxicity at high doses include anaemia (decreased red blood cell count and haematocrit, decreased mean cell haemoglobin concentra tion and increased mean cell volume) and haemoglobinuria due to haemolysis of the red blood cells. At lo w doses, haemolytic effects are transient, generally occurring duri ng the first days of exposure only (Werner et al., 1943; Carpenter et al., 1956; Dodd et al., 1983). There is some evidence of haemopoiesis occurring as a compensatory mechanism, such as spleen hyperplasi a. In addition, this tr ansience could be due in part to the replacement of older red blood cel ls with younger more resistant ones, as i n vitro test results indicate that younger red blood cells are more resistant to haemolysis than older ones. Haematotoxicity in rats appears to be age-relate d, with the effects more severe in older rats.

The repeated dose studies also indicate that th ere are significant species differences in the susceptibility to the haemolytic effects of 2-BE. Rats appear to be the most sensitive species (Carpenter et al., 1956). The most relevant inhalation studies and the haemolytic effects observed are summarised in table 13.

In a 90-day inhalation study in rats, the NOAEL wa s 24.6 ppm. In this study 16 male and 16 female Fischer 344 rats were exposed (whole body) to 2-BE vapours at 0, 5.0, 24.6 or 77 ppm. Ten animals/sex/dose were exposed for 6 hrs/day for 13 weeks while the other 6 rats/sex/dose were sacrificed after 6 weeks for blood analysis. Haem atological effects were obs erved in rats exposed to 77 ppm, particularly the females. After 6 week s of exposure statistical ly significant decreases were observed in haemoglobin, re d blood cell count and haematocr it and an increase in mean corpuscular (or cell) volume (MCH). These effects were noted only in the females. At the end of 13 weeks statistically significant de crease in the red blood cell count was seen in male and female rats and an increase in MCH in female rats. A small but not statistically significant decrease in haemoglobin and haematocrit and an increase in white blood cells was observed in male rats. There was no sign of blood in the urine of the animals. No effect on red blood cell osmotic fragility was observed. No significant gross or microscopic lesions were observed at necropsy and there were no significant effects on the lungs, liver, kidney or testes (Snellin gs et al., 1981).

Table 13 - Summary of In Vivo Haematological Studies (Inhalation)

Study Species Dose/Duration Haemolytic EffectOECD SIDS 2 -BUTOXYETHANOL

UNEP Publications 174 Carpenter et al (1956) rat 62 ppm/4h Increased RBC fragility

54-432 ppm/7h, 30d Increased fragility (all doses) Haemoglobinuria (> 203 ppm) 113 ppm/4h Increased fragility mouse 112-400 ppm/7h, 30- 90d Increased fragility (all doses) Haemoglobinuria (> 200 ppm) rabbit 125, 197 ppm/7h Increased fragility (both doses) guinea pig 665 ppm/8h No effect human 113 ppm/4h No effect 195 ppm/8h No effect Longo & Dodd (1981) rat 20 ppm/6h, 9d No effect

86 ppm/6h, 9d Haemolysis Snellings et al (1981) rat 25 ppm/6h, 90d No effect

77 ppm/6h, 90d Haemolysis

Johanson (1994) rat 20 ppm/12d No haemolysis

100 ppm/12d No haemolysis

In a 90-day dermal study in rabbits, the NOAEL was 150 mg/kg/day (WIL Research Laboratories Inc., 1983). In a 90-day drinki ng water rat study conducted by the US National Toxicology Program (NTP), the NOAEL was 129 mg/kg/day for male rats, but no NOAEL could be established for the females as slight anaemia was observe d at the lowest dose ( 82 mg/kg/day) (NTP,1993).

Effects other than haemolysis which have been observed in repeated-dose studies include changes to the liver, kidney, spleen and thymus, with these effects considered secondary to haemolysis as they are seen at levels at or above haematotoxic doses.

Fertility and reproductive toxicity

In fertility studies, minor changes in sperm concen tration and the oestrous cycle were noted in a drinking water rat study but adve rse effects have been observed onl y at or above doses which are toxic in other respects (NTP, 1993). In a con tinuous breeding study in mi ce, significant adverse effects were observed onl y at very high dose levels whic h caused severe maternal toxicity (Morrissey et al., 1989; Heindel et al., 1990). These results for 2-BE are in contrast to the lower molecular weight homologues, 2-methoxyethanol a nd 2-ethoxyethanol, which both cause testicular degeneration (Nagano et al., 1984; Morrissey et al., 1989; Exon et al., 1991). In other reproductive studies, developmental effects were observed only at maternally toxic doses. No evidence of teratogenicity was observed in any studies, ag ain in contrast to 2-methoxyethanol and 2- ethoxyethanol (Tesh, 1976; Bushy Run Research Center, 1984; Wier et al., 1987; Sleet et al., 1989; Working & Mattison, 1993).OECD SIDS 2 -BUTOXYETHANOL

UNEP Publications 175 Genotoxicity

2-BE has tested negative in a wide variety of well-conducted in vitro assays, including gene mutation (Chiewchanwit & Au, 1995), chromosomal aberration (Villalabos-P ietrini et al., 1989); and DNA effect assays. These as says were generally conducted at both cytotoxic and non-cytotoxic doses. In a recent study, 2-BE was a weakly positiv e inducer of gene mutations, sister chromatid exchanges and aneuploidy in V79 cells at high doses (Elias et al., 1996). 2-BE was negative in an in vivo mouse micronucleus assay (Elias et al., 1996). Based on the available data, 2-BE is unlikely to be genotoxic.

Carcinogenicity

No 2-year carcinogenicity studies were available but an NTP inhalation study in rats and mice is under way.

In vitro Haematological Studies

In vitro studies have confirmed the species differences observed in in vivo studies (see Table 14). In particular, the studies have s hown that human red bloods cells are at least ten times less sensitive than rat red blood cells to the haemolytic effect s of BAA (Bartnik et al., 1987; Ghanayem, 1989). Studies demonstrated that haemolysis is preced ed by swelling, increased osmotic fragility and decreased cell deformability of red blood cells. Therefore, the evidence indicates that the haemolytic effects are a result of changes to the cell membrane, rather than effects on the bone marrow (Ghanayem et al., 1990; Udden & Patton, 1994). The haemolytic resistance of red blood cells from potentially susceptible humans was studied. The red blood cel ls from healthy young adults, aged persons, patients with sickle cell di sease and persons with hereditary spherocytosis were treated with 2mM BAA for 4 hrs. Haemolysis in treated cel ls was higher than controls for aged adults, but the difference was not statistically significant. The deformability of red cells from persons with sickle cell diseas e or hereditary spherocytosis was reduced, but BAA had no added effect (Udden, 1994).

Table 14 - Summary of In Vitro Haematological Studies

Study Species Exposure Duration Dose (mM BAA) Effect

Bartnik et al (1987) rat 1h 7.5 Haemolysis

human 1h 15 No effect rat 3h 3.75 Haemolysis

human 3h 5 No effect Ghanayem (1989) rat 4h 0.5 Haemolysis

human 4h 2 No effect 4 Slight swelling 8 Slight haemolysisOECD SIDS 2 -BUTOXYETHANOL

UNEP Publications 176 Ghanayem & Sullivan (1993) rat 4h 2 Haemolysis

rabbit 2 Swelling

human 2 No effect

Udden & Patton (1994) rat 6h 0.2 Slight haemolysis preceded by swelling 4h 2 Significant haemolysis preceded by swelling

4.3 Initial Assessmen t for Human Health

4.3.1 General Aspects

The critical effects identified for acute exposure to 2-BE are eye and respiratory irritation, with irritation observed in controlled studies at 113 ppm but not at 100 ppm. In most work situations, the risk of irritant effects is low as the concentration of 2-BE is low in most products and 2-BE has a low volatility. However, the risk may be increase d where aerosols are generated, heat is used, or where products are used in spray form. Based on hu man evidence, 2-BE is not classified as a skin irritant, but slight irritation may occur after repeated skin contact. It has been demonstrated that skin absorption can occur in the absence of irritation.

The critical effect (that is, the most sensitive endpoint) identified in animal st udies for repeated or prolonged exposure to 2-BE is ha ematotoxicity. As the haematol ogical effects are transient at lower doses and 2-BE does not bioaccumulate, they are considered more of an acute than a chronic nature. The lowest reliable NOAEL for haemolysis in the most sensitive speci es (the rat) is 24.6 ppm (22.5 mg/kg/day) from a 90-da y inhalation rat study. The NOAE L in mg/kg/day is derived by assuming 100% absorption, the aver age weight of rat of 215g and rat respiratory rate of 0.16

m 3 /day. The NOAEL, 24.6 ppm (121 mg/m 3 ), represents an absorbed dose of:

121mg/m 3 x 0.16 m 3 /day x 6h

------------------ --------------- ---------- = 22.5 mg/kg/day 0.215 kg x 24h

From the results of controlled a nd case studies in humans, animal in vivo studies, and in vitro studies using animal and human red blood cells, hum ans may be less sensitiv e to the haemolytic effect of 2-BE than rats. For example, increa sed red blood cell fragility was observed in rats exposed to 54 ppm 2-BE for 7 hours, however, no effect was observed in human volunteers exposed to 195 ppm for 8 hours. In vitro studies indicate that human red blood cells are at least ten times less sensitive than rat re d blood cells to the haemolytic effects of BAA, and that the red blood cells of the aged and persons with hereditary blood di sorders are not significantly more sensitive to the effects of BAA than red blood cells fr om humans not similarly afflicted.

The conclusion that humans may be c onsiderably less sensitive than rats to the haemolytic effects of 2-BE is supported by Corley’s PBPK model, which successfully estimated the disposition of 2-BEOECD SIDS 2 -BUTOXYETHANOL

UNEP Publications 177 and BAA under a variety of exposur e scenarios. Corley’s model pred icted as a worst-case scenario that the skin absorption of undilu ted 2-BE over 6h would lead to a BAA blood concentration of 0.37 mM, and that absorption of a 40% solution would result in 1.3 mM BAA. These values are below the BAA concentration (2 mM) at which no haemolysis was observed in human cells in vitro and well below the concentration at which haemolysis was observed (8 mM BAA).

The risk of haemolytic effects in humans wa s determined for each scenario by comparing the estimated human daily dose with the rat NOAEL (22.5 mg/kg/day), and then taking into account the following parameters: the human population exposed, th e nature and severity of the effect, interand intraspecies variability, and unc ertainties in the risk assessment process such as the quality and completeness of the database. A knowledge of th e mechanism of action of BAA on red blood cells in different species (including hum ans) may allow for a refinement in intraspecies extrapolations.

4.3.2 Occupational

The risk to human health from exposure to 2-BE ha s been characterised by estimating the margin of safety (MOS). The MOS is derived by compari ng the NOAEL (for the criti cal effect) with the estimated human dose. The most reliable NOAEL for the critical effect (haemolysis) is 24.6 ppm (22.5 mg/kg/d) in a 90 day inhalation rat study. In deciding whether a MOS is considered sufficient, a number of parameters are taken into account, including the human population exposed, the nature and severity of the effect, interspecies and intraspecies variability, and completeness and quality of the database

Manufacture

The manufacture of 2-BE is an enclosed process so typical worker exposure is very low. Single exposures may occur during activities such as plan t maintenance, drum filling off and transference from storage vessels to road tankers, however, as inhalation exposure is low (maximum reading 11 ppm, most readings below 3 ppm TWA) and effective control measures are in place, the risk of acute effects, such as irritant effects, are low.

The calculated MOS for haemolytic effects is 22.5 mg/kg/d/2.2 mg/kg/d = 10, with a high degree of confidence in the estimate due to sufficient re liable data. Taking into account the lower susceptibility of humans to haemolysis by 2-BE co mpared with rats, there is no cause for concern regarding the risk of haemoly tic effects in workers exposed to 2-BE during manufacture.

Formulation

In most work situations, vapour and aerosol conc entrations are unlikely to be high enough to result in acute effects such as respiratory and eye i rritation, headache and naus ea. However, eye and respiratory irritation may occur in certain work situations where aerosols are generated or where high vapour concentrations occur, for example, dur ing the handling of spill s, during maintenance, or if heat is applied.

Based on the exposure estimates in Table 8, the MOS for haemolytic effects is 12 for exposure during the formulation of a produc t containing 10% 2-BE, 2.7 for a 30% formulation and 2.4 for a 60% product. Taking into account the lower sus ceptibility of humans to haemolysis by 2-BE compared with rats, there is little cause for con cern regarding the risk of haemolytic effects in workers exposed to 2-BE during the formula tion of products contai ning up to 60% 2-BE.

CleaningOECD SIDS 2 -BUTOXYETHANOL

UNEP Publications 178 In well-controlled work situations, the risk of acute effects in cleaners is of low concern. However, cleaning products containing 2-BE may be used in workplaces where control measures are poor, for example, without adequate ventil ation and personal protective eq uipment, and therefore exposure may be greater. Also, many of th e cleaning products are deliberately used in spray form and, in some cases, users are advised to apply heat during dilution of the product. The resultant periodic generation of vapour and/or aerosols may lead to a greater risk of respir atory and eye irritation, particularly in workplaces with inad equate ventilation. Most of the reports of irritation in cleaners have been associated with the use of cleaning products in spray form.

Based on the exposure estimates in Table 11, the MO S for haemolytic effects is 16 for exposure during the use of a cleaning solution containi ng 0.1% 2-BE, 14 for a 1% solution, 4.5 for a 10% solution, and 1.6 for a 30% solution. Taking into account the lower susceptibility of humans to haemolysis by 2-BE compared with rats, there is little cause for concern regarding the risk of haemolytic effects in workers exposed to 2-BE du ring the use of cleaning so lutions containing up to 30% 2-BE. However, there may be a concern in situations where there is prolonged exposure (particularly dermal exposure) to solutions containing high concentr ations (30% or more) of 2-BE.

Printing

In most work situations where 2-BE is used in printing in diluted form, vapour concentrations are unlikely to be high enough to result in acute effect s such as respiratory a nd eye irritation (see Table 9). However, eye and respiratory irritation may o ccur in certain work situations where aerosols are generated or where high vapour co ncentrations occur. Acute eff ects may also arise during the use of high concentrations of 2-BE. In monitoring data available for exposure to 2-BE during silk screening, very high vapour c oncentrations (up to 169 ppm) were obtained during the use of 100% 2-BE.

Based on the exposure estimates in Table 12, the MOS for haemolytic effects is 3.7 for general printing (for use of a 20% 2-BE formulation). Taking into account the lower susceptibility of humans to haemolysis by 2-BE compared with ra ts, there is little cause for concern regarding the risk of haemolytic effects in workers exposed to 2-BE during general printing tasks using formulations contai ning up to 20% 2-BE.

The MOS for haemolytic effects is 1.2 for silk screening (for use as a 50% 2-BE formulation). Other much lower readings have been obtained du ring silkscreening (see Ta ble 9). Where workers are exposed to high concentrations of 2-BE during silkscreening, the MOS of 1.2 indicates that there may be some concern regarding the risk of haemolytic effects.

Paints/Surface Coatings

In well-controlled work situations, the risk of acute effects during painting and surface treatment is of low concern. However, paints and surface testament products containing 2-BE may be used in workplaces where control measures are poor, for example, without adequate ventilation and personal protective equipment, and therefore expos ure may be greater. Also, some products are applied in spray form. The resultant periodic ge neration of vapour and/or aerosols may lead to a greater risk of respiratory and eye irritation, particularly in workplac es with inadequate ventilation.

The calculated margin of safety (MOS) for haem olytic effects is 22.5/9.1 = 2.5, based on European data that paints and surface coatings contain less than 10% 2-BE (see Table 1). Taking into account the lower susceptibility of humans to haemolysis by 2-BE compared with rats, there is little causeOECD SIDS 2 -BUTOXYETHANOL

UNEP Publications 179 for concern regarding the risk of haemolytic effects in workers exposed to 2-BE during painting and surface treatment.

Use as a Feedstock

As exposure is negligible during the use of 2-BE as a feedstock for BGA, there is no risk to human health.

4.3.3 Consumers

In most situations concerning consumers, vapour a nd aerosol concentrations are unlikely to be high enough to result in acute effects such as respir atory and eye irritation, headache and nausea. However, eye and respiratory irritation may occur in certain situations where aerosols are generated or where high vapour concentrations occur, for ex ample, during spray painting or during the use of cleaning solutions containing hi gh concentrations of 2-BE.

Comparison of exposure estimates for consumer s for the use of cleaning solutions (MOS = 22.5/0.58) and paints (MOS = 22.5/1.05) with the NOAEL indicates that there is no cause for concern regarding the risk of haemolytic effects.

Similarly, for the minor use of 2-BE in cosmetics, there is no cause for concern regarding the risk to human health.

4.3.4 Indirect Exposure via Environment

As exposure to 2-BE is minimal via the environm ent, there is no cause fo r concern regarding the risk to human health.

5. CONCLUSIONS AND RECOMMENDATIONS

5.1 Conclusions

Human Health

From the risk assessment, there may be concern for the health of workers in some work situations where exposure to 2-BE occurs. There may be a risk of acute effects, eye and respiratory irritant effects in the following situations:

. where formulations or solu tions containing high concentr ations of 2-BE are used;

. where products are used in spray form, pa rticularly without adequate ventilation;

. where heat may be applied, for example, during dilution;

. where aerosols may be generated;

. during the handling of spills; and

. during maintenance procedures if proper precautions are not taken.OECD SIDS 2 -BUTOXYETHANOL

UNEP Publications 180 The risk of adverse health effect s is greater for any of the above situations when accompanied by poor work practices.

For most work situations, the risk of haemolytic effects in workers potentially exposed to 2-BE is minimal. Monitoring data indicated that typical inhalation exposures were well below the estimates used for calculation of MOS. However, it wa s concluded that prolonge d exposure to products containing high 2-BE concentrations (> 30% for products used in cleaning and 50% for products used in printing) should be tr eated with some caution, particul arly where dermal exposure may occur, as there is still conjecture regarding the de gree of dermal absorption for differing strengths of 2-BE solutions.

In general, products available to the public contai n lower concentrations of 2-BE than those used industrially, so the risk to consum ers of haemolytic effects are low. However, there may be a risk of eye and respiratory irritant effects, headache and nausea in situations where 2-BE vapours or aerosols are generated, for example, during spray use.

Environment

2-BE will predominantly enter the environment from the disposal of wash water from cleaning and surface treatment processes and also via effluent at sites where it is formulated into paints, inks and cleaning products. 2-BE will be readily degraded by micro-organisms present at sewage treatment plants and in the receiving waters and is unlikely to bioaccumulate. 2-BE is relatively non-volatile, however, due to the use pattern, some 2-BE will enter the atmospheric compartment.

2-BE disposed to landfill may leach to groundwater due to its expected high mobility in soil and low adsorption potential.

From a considerable body of results, 2-BE can be classified as being prac tically non-toxic to fish, aquatic invertebrates and sewage micro-organisms, slightly to pr actically non-toxic to algae and slightly toxic to oysters.

As noted above, 2-BE will be readily biodegra ded by sewerage micro-organisms and by microorganisms present in receiving waters. With allowance for dilution by waste streams, it is estimated that the concentration of 2-BE in sewage plants w ill be in the order of ppm. Further dilution in the receiving waters is likely to result in sub-ppm concentrations. Such levels do not constitute a significant environmental hazard, and will be further reduced by biodegradation during sewage treatment. In the atmospheric compartm ent, 2-BE has a short residence time.

5.2 Recommendations

No further toxicity testing of 2-BE is recommende d. A 2-year inhalation st udy in rats and mice is currently being conducted under the NTP, and an epidemiological study in workers exposed to glycol ethers, including 2-BE, is under way in France.

Skin absorption is a significant ro ute of exposure and there is a degree of uncer tainty in the estimates of dermal exposure in th is assessment. Therefore, furt her study, includi ng biological and atmospheric monitoring would provide useful in formation and a more thorough understanding of the extent of skin absorption of 2-BE in workers. The establishment of a Biological Exposure Index should be considered.OECD SIDS 2 -BUTOXYETHANOL

UNEP Publications 181 REFERENCES

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UNEP Publications 182 Elias et al., (1996). “Genotoxic and/or epigenetic effects of some glyc ol ethers: Results of different short-term tests.” Occup. Hyg. 2 : 187-212.

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UNEP Publications 186 APPENDIX 1

EXPOSURE ESTIMATES

1. FORMULAE FOR EXPOSURE CALCULATIONS

For 2-butoxyethanol, the total body dose (D) is th e sum of doses resulting from absorption of vapours (D v ) and dermal absorption of liquid (D dl ). That is,

D = D v + D dl (equation 1)

As vapour absorption (D v ) comprises absorptio n across the lungs (D iv ) and dermal absorption of vapours (D dv ), that is, D v = D iv + D dv , where

D = (D iv + D dv ) + D dl (equation 1a)

Exposure to vapours

The daily dose arising from the inhalation of vapours (D iv ) is as follows:

C x R x E x B D iv = ---------------- ------- mg/kg/day (equation 2) BW

where C = concentration of substance in air (mg/m 3 ), R = inhalation rate (m 3 /h), E = exposure duration (h/day), B = bioavailability of vapour s across the lungs (1 = 100%), BW = average body weight of worker/consumer (kg).

In addition, 2-butoxyethanol vapours ar e also absorbed across the ski n. From the results of recent studies in volunteers (Corley et al., 1995) and PBPK modelling (C orley et al., 1994), the dermal absorption of 2-butoxyethanol vapours (D dv ) comprises up to 20% of th e total absorption of vapours (D v ). That is, for 2-butoxyethanol, D iv is approximately 80% of D v . That is, D iv = 0.8 D v , or D v = D iv . (equation 3) 0.8

Therefore, combining equations 2 and 3, th e daily dose arising from vapour exposure (D v ), inhalational plus dermal, is as follows:

D v = C x R x E x B mg/kg/day (equation 4) 0.8 x BW

For vapour exposure, the bioavailability (B) is the proportion of inhaled substance which is absorbed through the lungs, for example, some of the substance is exhaled. In inhalational (breathing zone) tests in volunt eers, 57-78% of the inspired amount of 2-butoxyethanol was absorbed. As these values are similar to the defa ult value of 0.75 (75%) often used in international assessments, a value of 0.75 was used in this report.

For consistency with internationa l assessments, a value of 1.3 m 3 /h was used for the inhalation rate (R) and a value of 70 kg was used for body weight (BW), for occupational exposure during light work activities.OECD SIDS 2 -BUTOXYETHANOL

UNEP Publications 187 Similarly for consumer exposure, values of 0.8 m 3 /h and 60 kg were used for the respiratory rate and the body weight respectively.

Exposure to liquid

The daily total dose arising from liquid exposure (D dl ) is as follows:

D dl = W x S x A x E x F mg/kg/day (equation 5) BW

where: W = weight fraction of substance in product, for example, 0.1 for a 10% solution, S = skin absorption rate (mg/cm 2 /h), A = skin surface area exposed (cm 2 ), E = exposure duration (h/day) F = skin contact time (as fraction of exposur e duration, for example, 0.2 for 20% of time), BW = average body weight of worker/consumer (kg).

For skin absorption rate (S ), the value of 0.2 mg/cm 2 /h, based on human in vitro data, was used.

In this assessment, it was considered that derm al exposure would reasonab ly consist of no more than exposure to both hands (840 cm 2 ) or a hand and a forearm (1000 cm 2 ). For consistency, a value of 1000 cm 2 for was considered appropriate.

For the case of dermal exposure to aerosols, for example, during spray use, exposed parts of the body may include the face, neck, hands and forearms. However, as exposure to aerosols would not be expected to occur simultaneous ly with exposure to liquid 2- butoxyethanol (as a solution), the skin surface area of 1000 cm 2 was considered appropriate.

Liquid 2-butoxyethanol can be in contact with the skin for various fractions (F) of the exposure duration (E), so skin contact w ith liquid can be extensive, intermittent or incidental. For the purposes of this assessment, extensive dermal e xposure is taken as conti nuous contact (F=1) with the skin. Taking into account assumptions made in the UK EASE (Estimation and Assessment of Substance Exposure) model * for dermal exposure, intermittent exposure is taken as being skin contact for 20% of the time (F=0.2) , and incidental exposure as skin contact for 1% of the time (F=0.01).

* The EASE model is the second version of the k nowledge based system developed by the UK Health and Safety Executive (HSE).

2. CALCULATED EXPOSURES FOR VARIOUS SCENARIOS

Using the formulae detailed in Section 1, Occ upational Exposures (Table 1) and Consumer Exposures (Table 2) for various scenarios have been estimated.

Table 1. Occupational Exposure

2- BE (%) W C

ppm mg/m 3 E F Daily Dose

D v D dl D v + D dlOECD SIDS 2 -BUTOXYETHANOL

UNEP Publications 188 Manufacture 100 1 3 14.7 8 0.01 2.0 0.2 2.2 Formulation 10 0.1 2 9.8 8 0.2 1.4 0.5 1.9 3 0.3 10 49 8 0.2 6.8 1.4 8.2 60 0.6 10 49 8 0.2 6.8 2.7 9.5 Cleaning 0.1 0.001 2 9.8 8 1 1.4 0.02 1.4 1 0.01 2 9.8 8 1 1.4 0.2 1.6 10 0.1 4 19.6 8 1 2.7 2.3 5.0 30 0.3 10 49 8 1 6.8 6.9 13.7 Silk Screen Printing 50 0.5 10 49 8 1 6.8 11.4 18.2 General Printing 20 0.2 2 9.8 8 1 1.4 4.6 6 Paints/Surface Coatings 10 0.10 10 49 8 1 6.8 2.3 9.1

Table 2. Consumer Exposure

2-BE (%) W C ppm mg/m 3 E F Daily Dose

D v D dl D v + D dl Cleaning 10 0.1 4 19.6 1 1 0.25 0.33 0.58 Paints/ Surfaces 1.5 0.015 2 9.8 6 1 0.75 0.3 1.05

Key: W = weight fraction of 2-BE in product C = concentration of 2-BE in air (mg/m 3 and ppm) E = duration of exposure (h/day) F = fraction of the exposure duration D v = dose resulting from absorption of vapours D dl = dose resulting from de rmal absorption of liquidOECD SIDS 2 -BUTOXYETHANOL

UNEP Publications 189 

# SIDS DOSSIER

ON THE HPV PHASE 4 CHEMICAL



# 2-BUTOXYETHANOL

CAS No. 111-76-2

Sponsor Country: AUSTRALIA

DATE: 13 August 1996 (revised 1 November 1996)OECD SIDS 2 -BUTOXYETHANOL

UNEP Publications 190 SIDS PROFILE DATE: 13 August 1996

1.01 A CAS No. 111-76-2

1.01 C CHEMICAL NAME (OECD Name) 2-BUTOXYETHANOL

1.01 D CAS DESCRIPTOR

1.01 G STRUCTURAL FORMULA CH 3 CH 2 CH 2 CH 2 OCH 2 CH 2 OH

OTHER CHEMICAL IDENTITY INFORMATION Empirical formula C 6 H 14 O 2 Molecular weight 118.2

1.5 QUANTITY 200 000 - 500 000 tonnes

1.7 USE PATTERN Based on European and Australian data: 70-75% in paints, surface coatings, 5-10% in cleaning products 5-10% in inks 10-15% as feedstock

1.9 SOURCES AND LEVELS OF EXPOSURE Diffuse releases to atmosphere, municipal waste systems, and occasionally ground waters. Indoor air: 0.214 ppb (US EPA), 8 μg/m 3 (Italian study). Ground water: 23 μg/L at US contaminated site. Surface water: 1310-5680 ppb (Japan). Occupational exposure considerable in cleaning services industry, paint, lacquer and varnish industry, hospitality industry, printing. Exposure in other industries and product formulation minor. Some consumer exposure through use of cleaning products, some paints, cosmetics.

. ISSUES FOR DISCUSSION (IDENTIFY, IF ANY) No further SIDS testing required.OECD SIDS 2 -BUTOXYETHANOL

UNEP Publications 191 SIDS SUMMARY

CAS NO: 111-76-2 Information

Available OECD Study GLP Other Study Estimation

Methods Acceptable SIDS Testing Required

STUDY Y/N Y/N Y/N Y/N Y/N Y/N Y/N PHYSICAL-CHEMICAL

2.1

2.2

2.3

2.4

2.5

2.6

2.12 Melting Point Boiling Point Density Vapour Pressure

Partition Coefficient Water Solubility pH and pKa values Oxidation : Reduction potential Y

Y

Y

Y

Y

Y

Y

Y N

N

N

N

Y

N

N

N -

-

-

-

-

-

-

- N

N

N

N

N

N

N

N N

N

N

N

N

N

N

N Y

Y

Y

Y

Y

Y

Y

Y N

N

N

N

N

N

N

N

OTHER P/C STUDIES RECEIVED N - - - - Y N

ENVIRONMENTAL FATE and

PATHWAY

3.1.1

3.1.2

3.2

3.3

3.5 Photodegradation Stability in water Monitoring data Transport and Distribution Biodegradation Y

Y

Y

Y

Y N

N

- N

Y -

-

-

-

- N

-

-

- Y N

Y

- Y

N Y

Y

Y

Y

Y N

N

N

N

N

OTHER ENV FATE STUDIES RECEIVED Y N - Y N Y N

ECOTOXICITY

4.1

4.2

4.3

4.5.2

4.6.1

4.6.2

4.6.3 Acute toxicity to Fish Acute toxicity to Daphnia Toxicity to Algae Chronic toxicity to Daphnia Toxicity to Soil dwelling organisms Toxicity to Terrestrial plants Toxicity to Other non-mammalian terrestrial organisms Y

Y

Y

N

N

N

N N

N

N

-

-

-

- -

- Y

-

-

-

- Y

Y

Y

N

-

-

- N

N

N

-

-

-

- Y

Y

Y

-

-

-

- N

N

N

N

N

N

N

OTHER ECOTOXICITY STUDIES

RECEIVED Y N - Y N Y N

TOXICITY

5.1.1

5.1.2

5.1.3

5.4

5.5

5.6

5.8

5.9

5.11 Acute Oral

Acute Inhalation

Acute Dermal Repeated Dose Genetic Toxicity in in vitro

. Gene Mutation

. Chromosomal aberration Genetic Toxicity in vivo Reproductive Toxicity Development/Teratogenicity Human experience Y

Y

Y

Y

Y

Y

Y

Y

Y

Y Y

Y

Y

Y

Y

N

Y

Y

Y

- -

-

- Y

Y

Y

- Y

Y

- Y

Y

Y

Y

Y

Y

Y

Y

Y

Y N

N

N

N

N

N

N

N

N

N Y

Y

Y

Y

Y

Y

Y

Y

Y

Y N

N

N

N

N

N

N

N

N

N

OTHER TOXICITY STUDIES RECEIVED Y Y Y - - Y NOECD SIDS 2 -BUTOXYETHANOL

UNEP Publications 192 1. GENERAL INFORMATION

1.01 SUBSTANCE INFORMATION

A. CAS number 111-76-2

B. Name (IUPAC name) ETHYLENE GLYCOL BUTYL ETHER.

C. Name (OECD name) . 2-BUTOXYETHANOL

D. CAS Descriptor (where applicable for complex chemicals)

E. EINECS-Number 203-905-0

F. Molecular Formula C 6 H 14 O 2

G. Structural Formula CH 3 CH 2 CH 2 CH 2 OCH 2 CH 2 OH

H

. Substance Group

I. Substance Remark

J. Molecular Weight 118.2

1.02 OECD INFORMATION

A. Sponsor Country: AUSTRALIA

B. Lead Organisation Name of Lead Organisation: Worksafe Australia National Industrial Chemi cals Notification and Assessment Scheme (NICNAS) Contact person: Ms Lesley Onyon Address: Street: 92 Parramatta Road Town: CAMPERDOWN SYDNEY State/Territory: NSW Postcode: 2050

Tel: 61 2 9577 9417 Fax: 61 2 9577 9465

C. Name of responder

Name: ICI Australia Operations Pty Ltd Address : 1 Nicholson St, Melbourne, Victoria Australia 3000

Tel.: 61 3 9665 7227 Fax: 61 3 9665 7929OECD SIDS 2 -BUTOXYETHANOL

UNEP Publications 193 D. Other participating companies

Union Carbide Chemicals (Australia) Pty Ltd Suite 1, 1st floor 1-7 Jordan St Gladesville Sydney, New South Wales Australia, 2111

BP Chemicals Ltd Belgrave House 76 Buckingham Palace Rd SW1 WOSU London United Kingdom

1.1 General Substance Information

Substance type: organic Physical status: liquid Purity: greater than 95%

1.2 Synonyms

beta.-Butoxyethanol 2-BE BG BGE Butilglicole, eteremonobutilico del gl icole monoetilenico, butilcellosolve Butoxyethanol 2-Butoxy-1-ethanol 2-n-Butoxyethanol Butyl Cellosolve® Butyl ethoxol Butyl glycol Butyl glycol ether Butyl Icinol® Butyl monoether glycol Butyl Oxitol® Dowanol EB® Eastman® EB Solvent EGBE Emkanol BG® Ethanol, 2-butoxy Ethylene glycol butyl ether Ethylene glycol mono-n-butyl ether Ethylene glycol monobutyl ether Ethylene glycol n-butyl ether Ethylenglykolmono-n-butylether Glycol butyl ether Glycol monobutyl ether 1-Hydroxy-2-n-butoxyethanOECD SIDS 2 -BUTOXYETHANOL

UNEP Publications 194

Monobutyl glycol ether O-Butyl ethylene glycol 3-Oxa-1-heptanol Solvenon EB

1.3 Impurities Commercial 2-BE may contain sm all concentrati ons of other glyol ethers, n-butanol and ethylene glycol.

1.4 Additives A stabiliser, 2,6-bis(1,1-dime thylethyl)-4-methylphenol, may be added at approx. 0.01% to pr eveent peroxide formation.

1.5 Quantity Based on EU figures, 200 000 - 500 000 tonnes per year produced worldwide (EU 90 000 te/year, Australia 2000 te/year).

1.6 Labelling and Classification

. Type: as in EC Directive 67/548/EEC Labelling: Symbols (classification): Xn (harmful) Category of danger: Harmful, Irritant Specific limits: 12.5% R-Phrases: (20/21/22) Harmful by inhalation, in contact with skin and if swallowed; (37) Irritating to respiratory system; (36) Irritating to eyes S-Phrases: (2) Keep out of reach of children; (24/25) Avoid contact with skin and eyes

1.7 Use Pattern

A. General

Type of use Category

Solvent in surface coatings and paints Wide dispersive use Paints, lacquers and varnishes industry

In cleaning/washing agents Wide dispersive use Public domain Solvent in inks Wide dispersive use Other (printing industry)

Other (feedstock) Used in closed system Chemical industry - in synthesis Other Bead mills (195)

B. Use in Consumer Products

Function Amount present Physical stateOECD SIDS 2 -BUTOXYETHANOL

UNEP Publications 195 Cleaning/washing agents 1-10% liquid

Paints and surface coatings < 1.5% liquid

Cosmetics < 10% liquid

1.8 Occupational Exposure Limit Values

Type of limit: MAC (NL) Limit value: 100 mg/m3 [20 ppm] Short term expos. Limit value: 200 mg/m3 [40 ppm] Schedule: 15 minute (1)

Type of limit: MAK (DE) Limit value: 20 ppm [100 mg/m3] Short term expos. Limit value: 40 ppm [200 mg/m3] Schedule: 30 minute Frequency: 4 times Remark: H = danger of skin absorption; pr egnancy: Group C (no reason to fear risk of damage to the developing embryo when adhering to MAK or BAT values) Reference: Deutsche Forschungsgemeinscha ft, List of MAK and BAT Values 1995, VCH Verlagsges ellschaft, Weinheim, 1995.

Type of limit: BAT (biological exposure index) Limit value: 100 mg/L Remark: Value expressed as mg 2-BE per litre of urine. Monitoring based on measurement of 2-butoxyacetic acid in urine. Reference: Deutsche Forschungsgemeinscha ft, List of MAK and BAT Values 1996, VCH Verlagsges ellschaft, Weinheim, 1996.

Type of limit: MEL - TWA (UK) Limit value: 120 mg/m3 [25 ppm] Remark: (a) Skin notation; (b) a proposed amendment to COSHH Regulations changes the MEL to an OES - reason: CNS ef fect threshold established.

Type of limit: TLV - TWA (US - ACGIH) Limit value: 121 mg/m3 [25 ppm] Remark: Skin notation (7)

Type of limit: PEL-TWA (US - OSHA): Limit value: 50 ppm [40 mg/m3] Remark: Skin notation (9)

Type of limit: REL - TWA (US - NIOSH)OECD SIDS 2 -BUTOXYETHANOL

UNEP Publications 196

Limit value: 5 ppm [24 mg/m3] Remark: Skin notation (5)

Type of limit: TWA (Australia) Limit value: 25 ppm [121 mg/m3] Remark: Skin notation (8)

1.9 Sources of Exposure

Remark: As the quantities of this subs tance placed on the EU market by Union Carbide Benelux N.V. are normally sourced from the manufacturing facilities of its U.S. parent comp any, no exposure can arise within the EU from the manufacture of these quantities. The comments below on exposure are restricted to uses fo r which Union Carbide believes its customer use this substance.

Major use(s): As solvent in paints and cleaners.

Sources of human exposure: Intermitt ent exposure of general public via inhalation and skin contact. Quantita tive estimates are not available.

Sources of environmental exposure: Diffuse releases to atmosphere, municipal waste systems and occasionally ground waters. Substance is inherently biodegradable and degrad es to carbon dioxide and water. Quantitative estimates of releases to the two compartments are not available. Source: Union Carbide Benelux Antwerpen Source: Eastman Chemical AG Zug

Remark: 1) The majority of BP Chemicals' material is used as a solvent in industrial coatings, inks and adhesive s. All are used industrially and exposure will be controlled by eff ective local exhaust ventilation.

2) Some BP Chemicals' material is used as an intermediate in chemical sythesis. It is is used in closed systems and the only potential for exposure is due to opening of containm ent for filling of transport vessels. This is controlled by effectiv e local exhaust ventilation.

3) Some BP Chemicals' material is used as a minor constituent of waterbased cleaning and washing agents used industrially and possibly by the public. The dilution, circumstances of use, and frequency and duration of potential exposure normally result in insignificant patterns of exposure

to users. Source: BP Chemicals Ltd. London Source: Eastman Chemical (Deutschland) GmbH Koln

Remark: In data from the Products Register in Sweden, 666 products containing 2-BE were listed, with 68% being used as solvent, 23% in paints and lacquers, 3% in binders, 3% in cl eaning agents, and 3% in other uses. Reference: Johanson and Rick, 1996 (169)OECD SIDS 2 -BUTOXYETHANOL

UNEP Publications 197 Remark: In Australia, 434 cleaning products containing 2-BE were identified, with a wide variety of applications. Source: NICNAS 1996 (11)

1.13 Additional Remarks

Remark: TRANSPORT INFORMATION

Delisted by UN as a dangerous good in 1994 Identification Number: NA 1993 Class: Cl (combustible liquid) Packing Group: III Proper Shipping Name: Combustible liquid

Sea (IMO) Class: Cl Packing Group: III Symbol: Harmful Marine Pollutant (Y/N): No

Rail/Road (RID/ADR) Class: Cl Item: 13(c) Symbol: Harmful Kemler Plate: 60/2369

Air (IATA/ICAO) Class: Cl Packing Group: III Symbol: Harmful Source: Shell Nederland Chemie B.V. Hoogvliet-Rotterdam NICNAS 1996 (11)

Remark: Disposal: Incinerate in a furn ace where permitted under national and local regulations. At very low concen trations in water, this product is biodegradable in a biological wastewater treatment plant.

Transport: 2-Buthoxyethanol is shipped in road/rail tankcars, tankcontainers/ISOtanks and sma ller packages (e;g. drums). Source: Union Carbide Benelux Antwerpen

Remark: Transport Road/rail Tankers/isotanks drums Disposal in accordance with local, state or national regulations Source: ICI Chemicals & Polymers Limited Runcorn, Cheshire ICI C&P France SA Chocques

Remark: 2-Butoxyethanol is shipped either in bulk or in steel drums. The bulk shipments are in tank trucks, rail tank cars, or rail tank containers. Our warehouses check that the transporte rs have the necessary papers and equipment available in case of an emergency. Source: Eastman Chemical AG ZugOECD SIDS 2 -BUTOXYETHANOL

UNEP Publications 198

Remark: Transport: 2-Butoxyethanol (2-B E) was listed as a Class 6.1(b) substance in Packaging Group III until late 1994. However, 2-BE was delisted by the UN Committee of Expert s on the Transport of Dangerous Goods at its November 1994 meeting. Source: United Nations (1995) (13)

Remark: 2-Butoxyethanol is shipped either in bulk or in steel drums. The bulk shipments are in tank trucks, rail tank cars, or rail tank containers. Our warehouses check that the transporte rs have the necessary papers and equipment available in case of an emergency. Source: Eastman Chemical (Deutschland) GmbH Ko1n

2. Physico-chemical Data CAS-No.: 111-76-2

2.1 Melting Point

Value: = -75 degree C GLP: no data Source: BP Chemicals Ltd. London (17)

Value: = -70 degree C GLP: no data Source: BP Chemicals Ltd. London (18)

Value: = -77 degree C GLP: no data Source: NIOSH, USA (5)

2.2 Boiling Point

Value: = 167 - 173 degree C at 1013 hPa Method: other: DIN 53171 GLP: no data Remark: Min 95E (v/v) Source: Hoechst AG (15) (21)

Value: = 170.8 degree C Remark: Adapted from values in literature Source: NIOSH, USA (5)

Value: = 170.2 - 172 degree C Remark: Range of values selected from references. Source: BP Chemicals Ltd. London (17) (23)

2.3 Density

Type: density Value: = 0.899 - 0.904 g/cm3 at 20 degree C Method: other: DIN 51757OECD SIDS 2 -BUTOXYETHANOL

UNEP Publications 199 GLP: no data Source: Hoechst AG (15) (21)

Type: relative density Value: = 0.897 at 25 degree C GLP: no Source: Eastman Kodak USA (25)

2.4 Vapour Pressure

Value: = 1.17 hPa at 25 degree C Remark: From selected references. Source: ECETOC, 1994 (122)

Value: = 4 hPa at 40 degree C GLP: no data Source: BASF (27)

2.5 Partition Coefficient

log Pow: = 0.74 Method: other (calculated): using com puter program by CompuDrug Ltd. GLP: no data Source: BASF (28)

log Pow: = 0.81 at 25 degree C Method: OECD Guide-line 107 "Partition Coe fficient (n-octanol/water), Flaskshaking Method" GLP: no data Source: BASF (29)

log Pow: = 0.83 Method: Source: BP Chemicals Ltd. London (30)

2.6 Water SolubilitY

Value: miscible at 20 degree C GLP: no data pH: = 7 Source: Hoechst AG (15)

2.7 Flash Point

Value: = 60 degree C Type: Method: other: DIN 51755 GLP: no data Source: Hoechst AG (21)

Value: = 62 degree COECD SIDS 2 -BUTOXYETHANOL

UNEP Publications 200

Type: closed cup Method: other: ASTM D56 GLP: no Source: Eastman Kodak USA (32)

Value: = 63 degree C Type: closed cup Method: other: ASTM D3278 (Setaflash) GLP: no Source: Eastman Kodak USA (34)

Value: = 65 degree C Type: Method: other: DIN 5178 GLP: no data Source: Hoechst AG (15)

Value: = 70.1 degree C Type: Cleveland open cup Method: Source: Sax and Lewis (19)

Value: = 70 degree C Type: open cup Method: other: ASTM D56 GLP: no Source: Eastman Kodak USA (25)

2.8 Auto FlammabilitY

Value: = 230 degree C Method: other: DIN 51794 GLP: no data Source: BASF (27)

Value: = 235 degree C Method: other: ASTM D2155 GLP: no Source: Eastman Kodak USA (34)

Value: = 238 - 245 degree C Remark: Range of values selected from references. Source: BP Chemicals Ltd. London (35) (36)

2.9 Flammability

Result: other: Lower flammable limit value 1.10% at 93 degree C. Method: other: ASTM E681 GLP: no Source: Eastman Kodak USA (34)OECD SIDS 2 -BUTOXYETHANOL

UNEP Publications 201 Result: other: Upper flammable limit value 12.78% at 135 degree C. Method: other: ASTM E681 GLP: no Source: Eastman Kodak USA (34)

2.10 Explosive Properties

Result: not explosive Method: other: ASTM E537 (Differential Thermal Analysis). GLP: no Source: Eastman Kodak USA (34)

2.11 Oxidizing Properties

2.12 Additional Remarks

Remark: Soluble in mineral oil and most or ganic solvents (The Merck Index). Mixes in all proportions with acetone, benzene, carbon tetrachloride, ethyl ether, n-heptane and water; mi scible in all proportions with many ketones, ethers, alcohols, arom atic paraffins and halogenated hydrocarbons (HSDB). Source: BP Chemicals Ltd. London (23)(18)

Remark: Surface tension = 27.4 mN/m at 25 degreeC. Source: BP Chemicals Ltd. London (18)

Remark: Henry's Law Constant = 2.08 x 10^-7 atm/m^3/mole at 25 degree C. Source: BP Chemicals Ltd. London (39)

Remark: Henry's Law constant - 2.08 x 10^-8 atm/m^3/mole at 25 degree C. Source: BP Chemicals Ltd. London (39)

Remark: Coefficient of cubical expansi on = 9.5 x 10^-4 at 55 degree C. Source: BP Chemicals Ltd. London

Remark: Viscosity = 6.4 cP at 20 degree C. Source: BP Chemicals Ltd. London

Remark: Equilibrium vapour concentration in air is 1300 ppm [6283 mg/m^3] at 20 degree C Source: BP Chemicals Ltd. London

Remark: Combustion with limited access to atmosphere may cause carbon monoxide formation. Source: BP Chemicals Ltd. London

Remark: Refractive index 1.422 at 25 degree C Source : Dow USA (20)

Remark: Forms peroxides.OECD SIDS 2 -BUTOXYETHANOL

UNEP Publications 202

Source : Eastman Kodak USA (34)

Remark: Undergoes reactions typical of glycol ethers Source : Dow USA (20)OECD SIDS 2 -BUTOXYETHANOL

UNEP Publications 203 3. Environmental Fate and Pathways CAS-No.: 111-76-2

3.1.1 Photodegradation

Type: air Light source: other: U.V. fluorescent lights Light spect.: = 345 - 355 nm Conc. of subst.: .00967 mg/l at 30 degree C INDIRECT PHOTOLYSIS Sensitizer: NO3 Conc. of sens.: 1 mg/l Degradation: = 0 % after 6 hour Method: other (measured): Studied in a 12 m^ 3 smog chamber with 55% relative humidity. Analysis by GC/UV. GLP: no data Test substance: other TS Reference: Yanagihara et al, 1977 (40)

Type: air Conc. of subst. at 25 degree C INDIRECT PHOTOLYSIS Sensitizer: OH Conc. of sens.: 500000 molecule/cm3 Rate constant: = 2.3 x 10 -11 cm 3 /(molecule * sec) Method: GLP: no data Test substance: other TS Remark: This rate constant yields an atmo spheric half life of about 17 hours. Reference: Atkinson, 1987 (41)

Type: Method: Test substance: Remark: 2-Butoxyethanol does not absorb light in the environmentally significant range (>290 nm) therefore would not be expected to undergo direct photolysis. Source: BP Chemicals Ltd. London (42)

Type: Method: Test substance: Remark: Based on its vapour pressure, 2-but oxyethanol would be expected to exist entirely in the vapour pha se in air and reactions with photochemicaly produced hydroxyl ra dicals may be important. Source: BP Chemicals Ltd. London (18)

Type: Method: Test substance:OECD SIDS 2 -BUTOXYETHANOL

UNEP Publications 204

Remark: Alcohols and ethers are generally resistant to hydrolysis and do not absorb UV light in the environmenta lly significant range (> 290 nm). Therefore, 2-BE is not expected to undergo hydrolysis or direct photolysis. Source: NICNAS 1996 (11)(22)

3.1.2 Stability in Water

Type: Method: Test substance: Remark: 2-Butoxyethanol does not absorb li ght of wavelength >290 nm and would therefore not be expected to undergo hydrolysis in aquatic environments. Source: BP Chemicals Ltd. London (18)

Type: Method: Test substance: Remark: Because 2-butoxyethanol is miscible in water, and based on an estimated Henry's Law constant of 2.08 x 10^-8 atm/m^3/mole at 25 degree C, volatilisation from natural bodies of water is not expected to be an important fate process. Source: BP Chemicals Ltd. London (18)

3.1.3 Stability in Soil

Type: Radiolabel : Concentration: Cation exch. capacity: Microbial biomass: Method: GLP: Test substance: Remark: Biodegradation is likely to be the most important removal mechanism from aerobic soil. Source: BP Chemicals Ltd. London (18)

Type: Radiolabel: Concentration: Cation exch. capacity: Microbial biomass: Method: GLP: Test substance: Remark: Limited monitoring data has shown that it may leach to ground water. A soil adsorption coefficient of 67 (Syracuse Research Council, 1988) indicates that 2-butoxyethanol will be highly mobile in soil and it should not partition from the water column to organic matter containedOECD SIDS 2 -BUTOXYETHANOL

UNEP Publications 205 in sediments or suspended solids. Source: BP Chemicals Ltd. London (18)

3.2 Monitoring Data (Environment)

Type of measurement: background concentration Medium: air Remark: 2-Butoxyethanol was detected at 8 ug/m^3 in 1 of 6 samples selected for GC-MS from indoor air sample s collected from 14 homes and 1 small office in Italy. Reference: De Bortoli, 1986 (44)

Type of measurement: background concentration Medium: air Remark: The Environmental Protection Agen cy's volatile organic compounds national ambient database includes data on ind oor air (not industrial space) showing an average for 14 samples of 0.214 ppb. Reference: Shah and Singh, 1988 (45)

Type of measurement concentration at contaminated site Medium: drinking water Remark: 2-Butoxyethanol is listed as a c ontaminant in drinking water samples analysed between September 1974 and January 1980 for a survey of US cities including Pomona, Escondido, Lake Tahoe, Orange Co., Dallas, Washington DC, Cincinna ti, Philadelphia, Miami, New Orleans, Ottumwa and Seattle. Values specified in Volume 2. Reference: Lucas, 1984 (46)

Type of measurement: concentration at contaminated site Medium: ground water Remark: 2-Butoxyethanol was detected at a concentration of 23 ug/l in 1/7 samples collected in February 1974 near the Valley of Drums, Kentucky, USA, a contaminated site. Reference: Stonebreaker and Smith, 1980 (47)

Type of measurement: concentration at contaminated site Medium: surface water Remark: 2-Butoxyethanol was detected at concentrations of 1310 and 5680 ppb in the water of the Hayashida Ri ver(Hyogo prefecture, Japan) as a contaminant from leather industry e ffluents. The values represent levels after steam and vacuum distil lation respectively. Date of study: 2 April 1980. Reference: Yasuhara, 1981 (48)

3.3.1 Transport between Environmental Compartments

Type: adsorption Media: soil - air Method: other: calculated by equation 4-8 in Lyman, W.J. et al. (1982), Handbook of chemical prope rty estimation methods. Year: 1982OECD SIDS 2 -BUTOXYETHANOL

UNEP Publications 206

Remark: The soil adsorption coefficient Koc was estimated as 67. Source: BP Chemicals Ltd. London (38)

3.3.2 Distribution

Media: water - air Method: other (measurement): by headspace chromatography. Year: 1988

Remark: Partition coefficient from salt water was 7051 at 37 degree C. Source: BP Chemicals Ltd. London (50)

3.4 Mode of Degradation in Actual Use

3.5 Biodegradation

Type: aerobic Inoculum: activated sludge, domestic, non-adapted Concentration: 10 mg/l related to DOC (Dissolved Organic Carbon) Degradation: = 95% after 28 days Result: readily biodegradable Method: OECD Guideline 301 E "Ready biode gradability: Modified OECD Screening Test" Year: 1981 GLP: no Test substance: other TS: Huels AG Source: BP Chemicals Ltd. London (51)

Type: aerobic Inoculum: activated sludge, domestic, non-adapted Concentration: 500 mg/l related to test substance Degradation: = 100% after 28 days Result: inherently biodegradable Method: OECD Guideline 302 B "Inherent bi odegradability: Modified ZahnWellens Test" Year: 1981 GLP: no Test substance: other TS: Huels AG Source: BP Chemicals Ltd. London (51)

Type: aerobic Inoculum: activated sludge, industrial, non-adapted Concentration: 450 mg/l related to test substance Degradation: = 100% after 5 days Result: inherently biodegradable Kinetic: 1 day = 22% 3 day = 63% 5 day = 100% Method: OECD Guideline 302 B "Inherent biodegradability: Modified ahnWellens Test"OECD SIDS 2 -BUTOXYETHANOL

UNEP Publications 207 Year: 1976 GLP: no Test substance: other TS: Hoechst AG Source: BP Chemicals Ltd. London (52)

Type: aerobic Inoculum: activated sludge Concentration 100 mg/l related to Test substance Degradation = 96% after 14 days Result: inherently biodegradable Method: other: MITI-Test (BOD of ThOD). Year: GLP: no data Test substance: other TS Test condition: Concentration of sludge: 30 mg/l Source: BP Chemicals Ltd. London (53)

Type: aerobic Inoculum: domestic sewage, adapted Degradation: Result: readily biodegradable Method: other : No 219. American Public Hea lth Association Inc. COD determined by ASTM 1974. Year: 1979 GLP: no data Test substance: other TS: as marketed by Shell. Remark: Theoretical Oxygen demand = 2.31 g/g; BOD5 = 0.71 g/g (31% of theoretical oxygen demand); COD = 2.20 g/g. With seeding adapted, BOD = 1.68 g/g (73% of theoretical oxygen demand). Reference: Bridie et al, 1979 (54)

Type: aerobic Inoculum: domestic sewage, adapted Concentration: 10 mg/l related to Test substance Degradation: = 88% after 20 days Result: readily biodegradable Kinetic: 5 day = 26% 10 day = 74% 15 day = 82% 20 day = 88% Method: other: not specified Year: 1974 GLP: no data Test substance: other TS Remark: A 20 day test in fresh water (these results) and salt water (see next record). Butoxyethanol concentr ations were 3, 7 and 10 mg/l. Theoretical Oxygen demand was 2.3 mg/mg and measured chemical oxygen demand (COD) was 2.25 mg/mg. Reference: Price et al, 1974 (55)

Type: aerobicOECD SIDS 2 -BUTOXYETHANOL

UNEP Publications 208

Inoculum: domestic sewage, adapted Concentration: 10 mg/l related to test substance Degradation: = 10- 75% after 20 days Result: readily biodegradable Kinetic: 5 day = 26% 10 day = 74% 15 day = 82% 20 day = 88% Method: other: not specified. Year: 1974 GLP: no data Test substance: other TS Remark: This record for biodegradation in sa lt water complements the previous record for fresh water. Reference: Price et al, 1974 (55)

Type: aerobic Inoculum: mixed activated sludge and secondary effluent Concentration: 0.8 ml/100 ml Degradation: = 77.7% after 3 days, 100% after 7 days Result: readily biodegradable Method: ISO 7827, based on OECD Guidelines 301A and 301E Year: 1984 GLP: no Test substance: Source: ICI Australia Operations (24)

Type: aerobic Inoculum: domestic sewage Concentration: 0.8 ml/100 ml Degradation: = 88% after 28 days Result: readily biodegradable Kinetic: 5 day = 25% 10 day = 60% 20 day = 75% 28 day = 88% Method: OECD TG 301 C, 301 D Year: GLP: Test substance: Source: ICI Australia Operations (31)

3.6 BOD5, COD and BOD5/COD Ratio

B O D 5 Method: other Year: 1979 GLP: no Concentration: 3 μg/l related to Test substance BOD5: = 1300 mgO2/l C O DOECD SIDS 2 -BUTOXYETHANOL

UNEP Publications 209 Method: other Year: 1979 GLP: no COD: = 2180 mg/g substance

R A T I O B O D 5 / C O D BOD5/COD: = 0.6 Result: TOD = 2300 mg 02/ml. BOD 20 = 1800 mg 02 at 3 ul/l. Test condition: Method similar to BOD Method 405 .1, U.S. EPA (EPA-600/4-79-020, 1979) and COD Method 410.1, U.S. EPA(EPA-600/4-79-020, 1979). Concentration units expressed as 3 ul/l, not ug/l. Test medium was activated sludge under aerobic conditions. Source: Eastman Kodak USA (56)

B O D 5 Method: other: fresh water using non-acclimated seed. Year: GLP: no data BOD5: = 598 mgO2/l C O D Method: other: measured value taken from Bridie et al. Year: GLP: no data COD: = 2200 mg/g substance R A T I O B O D 5 / C O D BOD5/COD: <= 0.27

Remark: BOD5 value taken from BP Chemicals Limited source. Source: BP Chemicals Ltd. London

B O D 5 Method: other: not specified; seeding adapted. Year: GLP: no data BOD5: = 0.17 mgO2/l C O D Method: other: not specified. Year: GLP: no data COD: = 2200 mg/g substance R A T I O B O D 5 / C O D BOD5/COD: = 0.76

Reference: Bridie et al, 1979 (54)

B O D 5 Method: other: not specified; seeding not adapted Year: GLP: no data BOD5: = 0.71 mgO2/l C O DOECD SIDS 2 -BUTOXYETHANOL

UNEP Publications 210

Method: other: not specified Year: GLP: no data COD: = 2200 mg/g substance R A T I O B O D 5 / C O D BOD5/COD: = 0.32

Reference: Bridie et al, 1979 (54)

B O D 5 Method: other: salt water using non-acclimated seed. Year: GLP: no data BOD5: = 667 mgO2/l C O D Method: other: measured value from Bridie, A.L. et al. Year: GLP: no data COD: = 2200 mg/g substance R A T I O B O D 5 / C O D BOD5/COD: <= 0.3

Remark: BOD5 value from BP Chemicals Ltd source. Reference: Bridie et al, 1979 (54)

3.7 Bioaccumulation

Species: other: not specified Exposure period: Concentration: BCF: = 2.51 Elimination: Method: other: not specified Year: GLP: no data Test substance: other TS Remark: 2-Butoxyethanol should not bioconc entrate among aquatic organisms. Source: BP Chemicals Ltd. London (18)

Species: other: specified as aquatic species only. Exposure period: Concentration: BCF: = 2.5 Elimination: Method: other: Calculated from log Kow Year: GLP: no data Test substance: other TS Remark: Calculated using equation 5.2 in Lyman, W. J. et al. 1982. Source: BP Chemicals Ltd. London (38)OECD SIDS 2 -BUTOXYETHANOL

UNEP Publications 211 3.8 Additional Remarks

Remark: No data identified from literature searched. Source: BP Chemicals Ltd. London

4. Ecotoxicity CAS-No.: 111-76-2

AQUATIC ORGANISMS

4.1 Acute and Prolonged Toxicity to Fish

Type: other: not specified Species: Poecilia reticulata (Fish, fresh water) Exposure period: Unit: μmol/l Analytical monitoring no data LC50: = 14791 Method: other: guideline followed not recorded. Year: GLP: no data Test substance: other TS Remark: The value was calculated according to Litchfield, J.F. and Wilcoxon, F. (1949). in J. Pharmacol Exp. Th er. 96, 99, or by estimation from a log/probit plot. Source: BP Chemicals Ltd. London (61)

Type: semistatic Species: Poecilia reticulata (Fish, fresh water) Exposure period: 7 day Unit: μmol/l Analytical monitoring no data LC50: = 8318 Method: other: guideline followed was not recorded. Year: 1981 GLP: no data Test substance: other TS: acetone or propan-2-ol we re used as the solvent vehicle. Remark: Groups of 8, 2-3 mth-old fish were exposed to each concentration tested. Water hardness was 25 mg /l as calcium carbonate and oxygen content was >5 mg/l. Temperat ure was 22 (+/-1) degree C. Source: BP Chemicals Ltd. London (61)

Type: static Species: Carassius auratus (Fish, fresh water) Exposure period: 24 hour Unit: mg/l Analytical monitoring: yes LC50: = 1700OECD SIDS 2 -BUTOXYETHANOL

UNEP Publications 212

Method: other: Standard methods for the ex amination of water and wastewater. Method No 231, American Public Health Association Inc., NY. Year: 1971 GLP: no data Test substance: other TS Remark: Test conducted in tap water. Source: BP Chemicals Ltd. London (63)

Type: static Species: Lepomis macrochirus (Fish, fresh water) Exposure period: 96 hour Unit: mg/l Analytical monitoring: no data LC50: = 1490 Method: other: not specified. Year: GLP: no data Test substance: other TS Remark: Tests conducted in potable well wa ter, 23 degreeC with mild aeration applied after 24 hr. It is reported that some test substances in the study were diluted with water or a solvent described as having relatively low toxicity Source: BP Chemicals Ltd. London (64)

Type: static Species: Leuciscus idus (Fish, fresh water) Exposure period: 48 hour Unit: mg/l Analytical monitoring: no LC50: = 1880 Method: other: DIN 38412 part 15 Year: 1982 GLP: no Test substance: other TS: Huels AG. Source: BP Chemicals Ltd. London (65)

Type: static Species: Leuciscus idus melanotus (Fish, fresh water) Exposure period: 48 hour Unit: μmol/l Analytical monitoring: no data LC0: = 1170 - 1350 LC50: = 1395 - 1575 LC100: = 1490 - 1620 Method: other: Deutsche Einheitsverfahr en zur Wasser-, Abwasser - und Schlamm-Untersuchung L15: Fischtest. Year: 1976 GLP: no dataOECD SIDS 2 -BUTOXYETHANOL

UNEP Publications 213 Test substance: other TS Source: BP Chemicals Ltd. London (66)

Type: static Species: Menidia beryllina (Fish, estuary, marine) Exposure period: 96 hour Unit: mg/l Analytical monitoring: no data LC50: = 1250 Method: other: not specified Year: 1975 GLP: no data Test substance: other TS Remark: Tests carried out in potable well wa ter at 20 degreeC with added sea salt mix. It is reported that some test substances evaluated in the study were diluted in water or a solvent described as having relatively low toxicity. Source: BP Chemicals Ltd. London (64)

Type: static Species: Pimephales promelas (minnow, fathead) Exposure period: 96 hour Unit: mg/l Analytical monitoring: no data LC50: 2137 Method: other: Methods for Acute Toxicity Te sts with Fish, Macroinvertebrates and Amphibians. USEPA, Corvallis, Oregon, USA. Year: 1975 GLP: no data Test substance: other TS Remark: Raw lake water dechlorinated with activated carbon used in test aquariums. Reference: Bartlett, 1979 (37) Source: Dow Chemical, USA

Type: static Species: Cyprinodon variegatus (minnow, sheepshead) Exposure period: 96 hour Unit: mg/l Analytical monitoring: no data LC50: 116 Method: other: Methods for Acute Toxicity Te sts with Fish, Macroinvertebrates and Amphibians. USEPA, Corvallis, Oregon, USA. Year: 1975 GLP: no data Test substance: other TS Remark: Dilution water used was syntheti c sea water, 25.0 ppt, pH = 8.3. Source: Amoco Corporation, USA (43)OECD SIDS 2 -BUTOXYETHANOL

UNEP Publications 214

Species: Brine shrimp Exposure period: 24 hour Unit: mg/l Analytical monitoring: no data LC50: 1000 Method: other: Year: GLP: no data Test substance: other TS Remark: Source: AQUIRE (183)

4.2 Acute Toxicity to Aquatic Invertebrates (e.g Daphnia )

Species: Artemia salina (Crustacea) Exposure period: 24 hour Unit: mg/l Analytical monitoring: no data TLm : = 1000 Method: other: a static test at 24.5 degree C. Year: GLP: no data Test substance: other TS Remark: TLm is the concentration causing 50% mortality and was determined graphically from measurements at an unspecified number of concentrations. Reference: Price et al, 1974 (55)

Species: Crangon crangon (Crustacea) Exposure period: 96 hour Unit: mg/l Analytical monitoring: no data

LC50 : = 550 - 950 Method: other: not specified Year: GLP: no data Test substance: other TS Source: Verscheuren, 1983 (69)

Species: Crangon crangon (Crustacea) Exposure period: 48 hour Unit: mg/l Analytical monitoring: no data LC50 : = 600 - 1000 Method: other: not specified. Year:OECD SIDS 2 -BUTOXYETHANOL

UNEP Publications 215 GLP: no data Test substance: other TS Source: Verscheuren, 1983 (69)

Species: Daphnia magna (Crustacea) Exposure period: 24 hour Unit: mg/l Analytical monitoring: yes EC0: = 1283 EC50: = 1698 - 1940 EC100: = 2500 Method: other: 20 degree C, immobilisation in artificial fresh water. Year: GLP: no data Test substance: other TS Remark: Analytical monitoring consisted of checking pH at the end of the study to check that it was within the range tolerated by Daphnia magna and checking oxygen concentration. Source: BP Chemicals Ltd. London (71)

Species: Daphnia magna (Crustacea) Exposure period: 24 hour Unit: mg/l Analytical monitoring: no EC50: = 5000 Method: other: DIN 38412 part 11 Year: 1982 GLP: no data Test substance: other TS Source: BP Chemicals Ltd. London (72)

Species: Daphnia magna (Crustacea) Exposure period: 24 hour Unit: mg/l Analytical monitoring: no data EC0: = 1140 EC50: = 1720 EC100: = 2500 Method: other: not specified. Year: GLP: no data Test substance: other TS: 2-butoxyethanol d iluted with tap water. Remark: 24-hour old Daphnia were exposed to a series of dilutions of 2-BE in tap water and swimming ability wa s measured after 24 hour. The EC50 value was calculated for E0 and E100. Source: BP Chemicals Ltd. London (73)

Species: Daphnia magna (Crustacea)OECD SIDS 2 -BUTOXYETHANOL

UNEP Publications 216

Exposure period: 24 hour Unit: mg/l Analytical monitoring: no data LC50: 835 Method: other: Method for Acute Toxicity Te sts with Fish, Macroinvertebrates and Amphibians, USEPA, Corvallis, Oregon, USA Year: 1975 GLP: no data Test substance: other TS Remark: Raw lake water dechlorinated with activated carbon used in test aquariums. Reference: Bartlett, 1979 (37) Source: Dow Chemical, USA

Species: Daphnia magna (Crustacea) Exposure period: 24 hour Unit: mg/l Analytical monitoring: no data EC50: 1815 Method: other: Year: GLP: no data Test substance: other TS Remark: Source: AQUIRE (183)

Species: Other aquatic mollusc (Crassotera virginicas ) Exposure period: 96 hour Unit: mg/l Analytical monitoring: no data LC50: 89.4 Method: other: Method for Acute Toxicity Te sts with Fish, Macroinvertebrates and Amphibians, USEPA, Corvallis, Oregon, USA Year: 1975 GLP: no data Test substance: other TS Remark: Dilution water used was syntheti c sea water, 25.0 ppt, pH = 8.3 Source: Amoco Corporation, USA (43)

Species: Other aquatic crustacea (Panaeus setiferus) Exposure period: 96 hour Unit: mg/l Analytical monitoring: no data LC50: 130 Method: other: Methods for Acute Toxicity Te sts with Fish, Macroinvertebrates and Amphibians, USEPA, Corvallis, Oregon, USA Year: 1975OECD SIDS 2 -BUTOXYETHANOL

UNEP Publications 217 GLP: no data Test substance: other TS Remark: Dilution water used was syntheti c sea water, 25.0 ppt, pH = 8.3 Source: Amoco Corporation, USA (43)

4.3 Toxicity to Aquatic Plants (e.g. Algae)

Species: Microcystis aeruginosa (Algae, blue, cyanobacteria) Endpoint: growth rate Exposure period: 8 day Unit: mg/l other: = 35 Analytical monitoring: no data Method: other: cell multiplication inhibition test Year: GLP: no data Test substance: other TS Remark: Result is given as the toxicity threshold. Test condition: Test conducted in static c onditions at 27 degree C. Source: BP Chemicals Ltd. London (74)

Species: Scenedesmus quadricauda (Algae) Endpoint: growth rate Exposure period: 7 day Unit: mg/l Analytical monitoring: no LOEC: = 900 Method: other: cell multiplication inhibition test Year: GLP: no data Test substance: other TS: 2-butoxyethanol in double-distilled water. Source: BP Chemicals Ltd. London (75)

Species: Selenastrum capricornutum (Green algae) Endpoint: growth rate Exposure period: 7 day Unit: mg/l EC50: > 1000 Analytical monitoring: no data LOEC: = 125 Method: other: Based on US EPA, The Selena strum capricornutum Printz Algal Assay: Bottle Test EPA-600/9- 78-018. Corvallis, Oregon, USA. Year: 1978 GLP: yes Test substance: as prescribed by 1.1-1.4 Reference: Dill and Minazzo, 1988 (57) Source: Dow Chemical, USAOECD SIDS 2 -BUTOXYETHANOL

UNEP Publications 218

4.4 Toxicity to Micro- organisms (e.g. Bacteria)

Type: aquatic Species: Entosiphon sulcatum (Protozoa) Exposure period: 72 hour Unit: mg/l Analytical monitoring: no LOEL : 91 Method: other: cell multiplication inhibition test Year: GLP: no data Test substance: other TS: 2-butoxyethanol in double-distilled water. Test condition: At 25 degree C. Source: BP Chemicals Ltd. London (75)

Type: aquatic Species: other bacteria: Chilomonas paramecium Exposure period: 48 hour Unit: mg/l Analytical monitoring: no data EC5 : 911 Method: other: cell multiplication inhibtion test. Year: GLP: no data Test substance: other TS: 2-butoxyethanol in double-distilled water. Remark: Result value gave a decrease in cell count of 5% at most. Test condition: Test conducted at 20 degreeC and at pH 6.9. Source: BP Chemicals Ltd. London (76)

Type: other Species: Pseudomonas putida (Bacteria) Exposure period: 16 hour Unit: mg/l other : = 700 Analytical monitoring: no Method: other: cell multiplication inhibition test Year: GLP: no data Test substance: other TS: 2-butoxyethanol in double-distilled water. Remark: Result expressed as the toxicity threshold. Test condition: Butoxyethanol solution was added to culture medium at pH 7 and 25 degree C. Endpoint measured by extinction. Source: BP Chemicals Ltd. London (75)(77)

Type: other Species: Bacteria from domestic sewage Exposure period: 16 hour Unit: mg/lOECD SIDS 2 -BUTOXYETHANOL

UNEP Publications 219 IC50 : > 1000 Analytical monitoring: no Method: other: Growth inhibition test from Al sop et al, J. Water Pollut. Control Fed., vol. 52(10), Oct. 1980 Year: 1980 GLP: no data Test substance: other TS: Remark: Result expressed as the toxicity threshold. Reference: Waggy et al, 1989 (58) Source: Union Carbide Chemicals

4.5 Chronic Toxicity to Aquatic Organisms

4.5.1 Chronic Toxicity to Fish

4.5.2 Chronic Toxicity to Aquatic Invertebrates (e.g. Daphnia)

TERRESTRIAL ORGANISMS

4.6.1 Toxicity to Soil Dwelling Organisms

4.6.2 Toxicity to Terrestrial Plants

4.6.3 Toxicity to Other Non-mamm alian Terrestrial Organisms

Remark: NO RELEVANT DATA. Source: BP Chemicals Ltd. London

4.7 Biological Effects Monitoring

Remark: NO RELEVANT DATA. Source: BP Chemicals Ltd. London

4.8 Biotransformation and Kinetics Excluding Mammals

Remark: NO RELEVANT DATA. Source: BP Chemicals Ltd. London

4.9 Additional Remarks

Remark: NO RELEVANT DATA. Source: BP Chemicals Ltd. London

5. Toxicity CAS-No: 111-76-2

5.1 Acute Toxicity

5.1.1 Acute Oral ToxicityOECD SIDS 2 -BUTOXYETHANOL

UNEP Publications 220

Type: LD50 Species: rat Value: = 1190 - 2800 mg/kg bw Method: other: Butoxyethanol administered by oral gavage to 5 males/group. Year: GLP : no data Test substance: other TS Remark: Tests carried out in 8 different laboratories. Reference: Weil and Wright, 1967 (79)

Type: LD50 Species: rat Value: = 1150 - 1910 mg/kg bw Method: other: administered at concentrations < 10% by gavage to groups of 10 male rats. Year: GLP : no data Test subs.: other TS: commercial grade in water Remark: Effects on kidneys rarely proc eeded as far as bl ood-stained urine and free blood beneath the capsul e at the highest doses. Reference: Smyth et al, 1941 (80)

Type: LD50 Species: rat (male) Value: = 1746 mg/kg bw Method: other: Eastman Kodak Company, H ealth, Safety and Human Factors Lab. Protocol Year: GLP: no Test subs.: other TS Remark: Groups of 5 fed and 5 fasted rats re ceived one of 5 di fferent doses and were observed for 14 days. The LD50 was the same in both fed and fasted rats. Clinical signs included inactivity and weakness. Haemoglobinuria was evident in both fed and fasted animals at the highest dose level and blood was noted in the urine and gastrointestinal tract in animals dying befo re scheduled necropsy. Reference: Eastman Kodak Co, 1981 (81)

Type: LD50 Species: rat Value: = 530 - 3000 mg/kg bw Method: other: no details; observation period of 14 days. Year: GLP : no data Test subs.: other TS: commercial material. Remark: Results are for several studies cond ucted over 16 years. Doses at or above the LD50 value caused sluggishness, ruffled fur, prostration and narcosis. Autopsy of rats showed congested or haemorrhaged lungs, mottled livers, severely congested kidneys and haemoglobinuria. Tolerance to single doses decreased with age; LD50's in weanlings, 6-OECD SIDS 2 -BUTOXYETHANOL

UNEP Publications 221 week-old and yearling rats were 3000, 2400 and 560 mg/kg respectively. Reference: Carpenter et al, 1956 (82)

Type: LD50 Species: rat Value: = 1950 mg/kg bw Method: other: keine Angaben Year: 1966 GLP : no Test subs.: other TS: Hoechst AG Remark: Mixed strains, female. Source: BP Chemicals Ltd. London (83)

Type: LD50 Species: rat (male) Value: = 2410 mg/kg bw Method: other: gavage at 4 doses 1.25 - 10 ml/kg Year: 1980 GLP : no Test subs.: other TS: 2-BE in water Remark: Observed effects included breathi ng difficulty, bloody saliva; liver, kidney and adrenal disclouration; distended stomach, intestinal blood. Reference: Bushy Run, 1980 (59) Source: Union Carbide Chemicals USA

Type: LD50 Species: rat (female) Value: = 1000-2000 mg/kg bw Method: other: gavage at 5 doses 130 - 2000 mg/kg Year: 1981 GLP : no Test subs.: other TS: crude Dowanol EB in water Remark: Observed effects included breathing di fficulty and necrosis of tails. Source: Dow Chemical, USA (62)

Type: LD50 Species: mouse Value: = 1519 - 2005 mg/kg bw Method: other: Eastman Kodak Company, H ealth, Safety and Human Factors Laboratory Protocol. Year: GLP: no Test subs.: other TS: Eastman Kodak Company. Remark: Groups of 5 fed and 5 fasted mice received one of 5 different dose levels and were observed for 14 da ys. The first value in the LD50 range is for fasted mice and the second is for fed mice. Haemoglobinuria was noted at intermediate dose levels in fed mice and blood was found in the stomach and intestines. Reference: Eastman Kodak Co, 1981 (81)OECD SIDS 2 -BUTOXYETHANOL

UNEP Publications 222

Type: LD50 Species: mouse Value: = 1230 mg/kg bw Method: other: gavage, observation period of 14 days. Year: GLP : no data Test subs.: other TS: commercial material. Remark: Reference: Carpenter et al, 1956 (82)

Type: LD50 Species: rabbit (male) Value: = 320 - 370 mg/kg bw Method: other: gavage, observation period 14 days. Year: GLP : no data Test subs.: other TS: commercial material. Remark: Reference: Carpenter et al, 1956 (82)

Type: LD50 Species: guinea pig Value: = 1200 mg/kg bw Method: other: no details. Observation period 14 days. Year: GLP: no data Test subs.: other TS: commercial material. Remark: Reference: Carpenter et al, 1956 (82)

Type: LD50 Species: guinea pig Value: = 960 - 1500 mg/kg bw Method: other: in water at <=10%, by gavage Year: GLP: no Test subs.: other TS Reference: Smyth et al, 1941 (80)

Type: LD50 Species: guinea-pig Value: 1414 mg/kg bw Method: OECD TG 401 Year: GLP: yes Test subs.: purity 99.8% Remark: Test conducted in males and females. At necropsy, necrosis and haemorrhage in the gastric mucosa observed. No signs of haematotoxicity were seen in the study. Reference: Eastman Kodak Co, 1994 (87)OECD SIDS 2 -BUTOXYETHANOL

UNEP Publications 223 Type: other: study to show effect of age on toxicity and metabolism. Species: rat (male) Value: Method: other: Gavage at doses of 32, 63, 125, 250 or 500 mg/kg 2-BE in

water. Year: 1987 GLP: no data Test subs.: other TS: 99% pure. Remark: Older rats significantly more suscep tible. There was a dose-dependent decrease in circulating red blood ce ll count, haemoglobin concentration and haematocrit together with an in crease in free haemoglobin in blood and subsequent haemoglobinuria. Histopathological changes were found in the liver and kidney. There were significant increases in relative spleen weights at 125 and 500 mg/kg. Reference: Ghanayem et al, 1987 (84)

Type: other: haematotoxicity study. Species: rat Value: Method: other: doses (by gavage) of 50-500 mg/kg and blood samples taken after 0.5, 2, 4 hours Year: 1992 GLP : no data Test subs.: other TS Remark: Scanning microscopy of erythrocytes showed a change from discocyte to spherocyte and flow cytometric an alysis showed an increase in mean cell volume and decreased mean cell haemoglobin concentration compared with the controls. Whol e blood viscosity increased at doses of 50 and 100 mg/kg and decreased at higher dosages due to haemolysis. Reference: Kurantsin-Mills and Lessin, 1990 (85)

Type: other: haematotoxicity study. Species: rat Value: Method: other: 250 mg/kg by gavage, blood sampled at 2, 8 or 24 hours Year: 1993 GLP: no data Test subs.: other TS: Aldrich Chemical Co., >99% pure. Remark: Mean cell volume and haem atocrit values were raised immediately after treatment and decreased with time following exposure. Haemolysis and decreased haemogl obin concentrations and red cell numbers occurred. Reference: Ghanayem and Sullivan, 1993 (86)

5.1.2 Acute Inhalation Toxicity

Type: LC50 Species: rat Exposure time: 4 hours Value: = 2.2 - 2.4 mg/l [450 - 486 ppm]OECD SIDS 2 -BUTOXYETHANOL

UNEP Publications 224

Method: other: rats exposed to 202, 523 or 867 ppm; observation period 14 days. Year: 1983 GLP : no data Test subs.: other TS: commercial Butyl Cellosolve Remark: Lowest value in range is for females; highest value for males. Signs of toxicity included rapid, shallow brea thing,loss of coordination and red staining around the urogenitalarea. Autopsy of animals that died revealed enlarged, discoloured kidn eys and red fluid in the bladder. Tail lesions observed in survivors at 523 ppm. Reference: Bushy Run, 1980 (90) Source: Union Carbide Chemicals USA

Type: other: inhalation hazard test. Species: rat Expos. time: 7 hours Value: Method: OECD TG 403 Year: 1981 GLP: no data Test subs.: other TS: 99% Remark: Values are expressed as the zero leth ality time = 3 hour (5 laboratories) and = l hour (l laboratory). Exposure times were 3 min to 7 hour. Reference: Klimisch et al, 1988 (91)

Type: other: single exposure toxicity test. Species: rat Expos. time: 18 hours Value: Method: other: Groups of male and female rats exposed to 500 or 800 ppm for up to 18 hours or to saturated air (4500 mg/m^3) for up to 9 hours. Year: GLP : no data Test subs.: other TS Remark: Death occurred in 0/6, 2/6 and 4/6 males after exposure to 4500 mg/m^3 for 2, 4 and 9 hours respective ly. 1/12 female rats died after 8 hours of exposure to < 800 ppm (3.8 mg/l). Haemoglobinuria was evident. 3/6 females died at 800 ppm for 18 hours and 1/6 females died at 500 ppm (2.4 mg/l) for 4 ho urs. Haemoglobinuria was evident. 11/13 males and 23/23 females died after exposure to 375 ppm (1.8 mg/l) for 7 hours. Haemoglobinuria was evident. Reference: Carpenter et al, 1956 (82)

Type: LC50 Species: mouse Expos. time: 7 hours Value: = 3.4 mg/l [700 ppm] Method: other: concentrations of 1.87, 2.71, 3.22, 3.72, 4.46 and 5.86 mg/l used and animals observed for 3 weeks. Year: 1943 GLP : no dataOECD SIDS 2 -BUTOXYETHANOL

UNEP Publications 225 Test subs.: other TS: described as relatively pure Remark: Dyspnoea and severe haemoglobinuria were seen at near lethal concentrations. Mortality was seen 7-32 hours after start of exposure and toxic effects were evident on the spleen. Reference: Werner, 1943 (92)

Type: other: single exposure toxicity test. Species: guinea pig Expos. time: 4 hours Value: Method: other: exposure to concentrated vapour. Year: GLP : no data Test subs.: other TS Remark: Animals were exposed to concentrat ed vapour; saturated air contains 0.093% butoxyethanol which, at 25 de gree C, is equivalent to 4500 mg/m^3. One animal died. No haemoglobinuria was observed. Reference: Carpenter et al, 1956 (82)

Type: other: single exposure toxicity test Species: guinea-pig Expos. time: 1 hour Value: Method: OECD TG 403, except one hour exposure instead of 4 hours Year: GLP : yes Test subs.: 2-BE vapour, purity of 2-BE 99.9% Remark: No mortality or clinical signs of toxicity resulted when male and female animals were exposed (whole body) to 633 or 691 ppm (3.1 or 3.4 mg/L) 2-butoxyethanol. Reference: Bushy Run, 1994 (95) Source: Union Carbide Chemicals USA

5.1.3 Acute Dermal Toxicity

Type: other: single dermal application toxicity. Species: rat Value: Method: other: single doses of 200, 260, 3 20, 375 or 500 mg/kg applied to dorsal shaved skin and cove red with a glass capsule. Year: 1987 GLP: no data Test subs.: purity 99% Remark: Percutaneous absorption, metabolis m and haemolytic activity study. 500 mg/kg caused haemolytic effects and/or haemoglobinuria within 6 hours of application. Some effects we re seen at lower doses but not at 200 mg/kg. Reference: Bartnik et al, 1987 (93)

Type: LD50 Species: rabbitOECD SIDS 2 -BUTOXYETHANOL

UNEP Publications 226

Value: = 610 mg/kg bw Method: other: as described in 21 CFR 191.10 but with abdraded skin. Year: GLP: no data Test subs.: . other TS: Eastman Organic Chemicals Reference: Roudabush et al, 1965 (94)

Type: LD50 Species: rabbit (male) Value: = 400 - 500 mg/kg bw Method: other: applied to male rabb its for 24 hours, covere d intact and observed for 14 days. Year: GLP: no data Test subs.: other TS Remark: Animals that died showed extr eme congestion of the kidneys, haemoglobinuria, pale liver and engorged spleen. Animals tolerated higher doses when a single dose was rubbed onto uncovered skin (2.0 ml killed 2/4 rabbits over a period of 14 days). Reference: Carpenter et al, 1956 (82)

Type: LD50 Species: rabbit Value: = 99 mg/kg bw Method: other: Applied to clipped back s (area 1.54 cm^2) for 8 hours and observed for 15 days. Doses were 0.08, 0.10, 0.12, 0.15, 0.20 or 0.25 ml/kg. Year: GLP: no data Test subs.: other TS: > 99.5% Remark: Signs before death were pr ostration, hypothermia and haemoglobinuria. Early deaths were caused by narcosis, respiratory failure or possibly cardiac failure. Late deaths were due to renal impairment. In animals that died there were changes in the liver, spleen, lung and kidn ey tissues including ha emoglobinuria, nephrosis and interstitial reaction. Skin damage occurred at all dose levels. There were no changes in surv iving animals treated at 0.08 and 0.10 ml/kg. There were persistent kidne y lesions in other groups. Reference: Duprat and Gradiski, 1979 (96)

Type: LD50 Species: rabbit Value : = 435 mg/kg bw Method: other: Eastman Kodak Company, H ealth, Safety and Human Factors Laboratory Protocol (sim ilar to OECD TG 402). Year: GLP : no Test subst.: other TS: Eastman Kodak Company Remark: Clipped and abraded skin was exposed to dosages of 153, 307, 614 or 1239 mg/kg for 14 days under occlusive wrap. Moderate irritation of the skin was noted. Clinical signs included reduced ac tivity, salivation,OECD SIDS 2 -BUTOXYETHANOL

UNEP Publications 227 nasal discharge, cyanosis, iritis and prostration. Fi ndings at necropsy included discoloration of th e kidney and liver, increased vascularization of the small and la rge intestines, and haemoglobinuria. No treatment-related gross effects we re noted at the two lowest dose levels. Reference: Eastman Kodak Co., 1981 (97)

Type: LD50 Species: rabbit Value : 567 mg/kg (male): 636 mg/kg (female) Method: other: 4 animals at 2 dose levels (0.5 and 1.0 ml/kg) were used. Year: GLP no data Test subst.: commercial Butyl Cellosolve Remark: . The effects observed at necropsy were; discoloured liver, kidneys, adrenals and intestines, and bl oated stomach. Haemoglobinuria was observed in animals at both doses. Nystagmus was seen in two high dose females some hours after exposure. Reference: Bushy Run, 1980 (99) Source: Union Carbide Chemicals, USA

Type: LD50 Species: guinea pig Value : = 210 mg/kg (intact skin), 270 mg/kg bw (abraded skin) Method: other: As described in 21 CFR 191.10 but with abdraded skin. Applied neat on a cellulose pad to intact or abraded skin. Year: GLP no data Test subst.: other TS: Eastman Organic Chemicals Remark:

. Reference: Roudabush et al, 1965 (94)

Type: LD50 (limit dose) Species: guinea pig Value : > 2000 mg/kg bw Method: OECD TG 402 (limit test) Year: GLP yes Test subst.: purity 99.8% Remark: . No clinical signs of toxicity observed during study. No effects on organs noted at necropsy. Reference: Eastman Kodak Co. 1994 (102)

5.1.4 Acute Toxicity, Other Routes

Type: LD50 Species: rat (female) Route of admin.: i.p. Value: = 300 - 850 mg/kg bw Method: other: Year:OECD SIDS 2 -BUTOXYETHANOL

UNEP Publications 228

GLP no data Test subst.: other TS: neat Reference: Carpenter, 1956 (82)

Type: LD50 Species: rat Route of admin.: i.v. Value: = 290 - 500 mg/kg bw Method: other Year: GLP: no data Test subst.: other TS: neat or as a 3% solution in 0.75% NaC1 solution. Remark Value presented is for the preparat ion in saline. Neat butoxyethanol gave an LD50 value of 270-340 mg/kg and caused haemolysis Reference: Carpenter et al, 1956 (82)

Type: LD50 Species: mouse Route of admin.: i.v. Value: = 1130 mg/kg bw Method: other Year: GLP no data Test subst.: other TS: neat or as a 3% so lution in 0.75% NaCl solution. Remark: LD50 value is for preparation in saline. Reference: Carpenter et al, 1956 (82)

Type: LD50 Species: rabbit Route of admin.: i.v. Value: = 380 - 650 mg/kg bw Method: other Year: GLP: no data Test subst.: other TS: neat or as a 3% so lution in a 0.75% NaCl solution. Remark: LD50 value given is for a solution in saline. Neat butoxyethanol gave an LD50 of 280 mg/kg. Reference: Carpenter et al, 1956 (82)

Type: other: single injec tion toxicity study. Species: rat Route of admin.: i.v. Value: 25, 37.5, 50, 62.5 or 75 mg/kg Method: other: doses of 25, 37.5, 50, 62.5 or 75 mg/kg in 5 ml/kg solution infused at 1 ml/min. Year : GLP: no data Test subst.: other TS: possibly in phosphate buffered saline. Remark: Haemolysis detected only at the highest dosage. Reference: Bartnik et al, 1987 (93)OECD SIDS 2 -BUTOXYETHANOL

UNEP Publications 229 Type: LD50 Species: rat (female Sprague-Dawley) Route of admin.: i.p. Value: The respective LD50 values for n-Butyl Oxitol and Dowanol EB were 252 mg/kg (confidence limits 203- 312) and 317 mg/kg (confidence limits 241-417). Method: other Year : GLP: no data Test subst.: 2 brands of 2-butoxyethanol - n-Butyl Oxitol and Dowanol EB Remark: Haemoglobinuria and bloody nasal di scharge were observed in all animals. In surviving animals at 398 or 500 mg/kg bw, tremors were noted at 22 hours after injection. Body weight gains seemed normal in surviving animals after the two-w eek post-exposure period. There were no controls in the study. Source: Dow Chemical, 1972 (109)

5.2 Corrosiveness and Irritation

5.2.1 Skin Irritation

Species: rabbit Result: not irritating EC classif.: not irritating Method: other: BASF AG Test Year: GLP: no Test subst.: other TS: BASF AG Source: BASF (100)

Species: rabbit Result: slightly irritating EC classif.: irritating Method: other: undiluted material, 4 hour unoccluded application. Year: GLP: no data Test subst.: other TS Reference: Tyler, 1984 (101)

Species: rabbit Result: Response was described as slight er ythema, with slight oedema after the seventh application. EC classif.: No firm conclusion can be drawn from this study as only a single rabbit was tested. Method: no data Year: GLP: no data Test subst.: 2-Butoxyethanol (undiluted) Remark: 0.5 mL was applied to the clipped int act skin under an occlusive wrap for a series of ten app lications over 14 days Source: Dow Chemical, USA (62)OECD SIDS 2 -BUTOXYETHANOL

UNEP Publications 230

Species: rabbit Result: moderate irritant EC classif.: insufficient data Method: other: Eastman Kodak Company, Healt h, Safety and Human Factors Laboratory Protocol Year: GLP: no data Test subst.: Other TS; 2-Butoxyethanol(undiluted) Remark: 2-BE applied under an occlusive dr essing for 24 hours at a dose just below the mortality level (at 0.3 g/kg bw). Reference: Eastman Kodak Co., 1981 (97)

Species: New Zealand albino rabbit Result: irritating EC classif.: irritant Method: EEC method (similar to OECD Test Guideline 404) Year: GLP: no data Test subst.: Other: Remark: Individual data were not reported fo r the 3 animals used per substance in the study Reference: Zissu 1995 (67)

Species: rabbit (male, New Zealand White) Result: irritating EC classif: irritant Method: EEC method (similar to OECD Test Guideline 404) Year: GLP: no data Test subst.: 2-butoxyethanol Remark: 0.5 mL of 2-butoxyethanol was applied to 6 animals for 4 hours. Skin reactions were scored at 5 hours; 1 day; 3 days and 7 days. The results were variable, with severe and persistent erythema with eschar and severe oedema observed in 3 rabbits and very slight oedema and erythema observed in the others. No oedema was observed in any rabbit after 7 days. Reference: Rohm and Haas, 1983 (70)

Species: guinea pig Result: irritating EC classif.: irritating Method: other: Eastman Kodak Company, Healt h, Safety and Human Factors Laboratory Protocol Year: GLP: no Test subst.: other TS: undiluted 2-BE Remark: Depilated skin was exposed to dos es of 1, 5, 10 or 20 ml/kg for 24 hours under an occlusive wrap. The response was described as 'strong irritant'. Reference: Eastman Kodak Co., 1981 (97)OECD SIDS 2 -BUTOXYETHANOL

UNEP Publications 231 Species: guinea-pig Result: 25% solution irritating, 10% non-irritating EC Classif.: insufficient data Method: other: Year: GLP: no data Test subs. : other TS; 10% and 25% 2- butoxyethanol in 0.9% saline Remarks: Conducted as a preliminary occluded patch irritation te st designed to determine dose levels for the main skin sensitisation study. Reference Unilever Research, 1989 (107)

5.2.2 Eye Irritation

Species: rabbit Result: highly irritating EC classif.: irritating Method: Draize Test Year: 1944 GLP no data Test subst.: other TS: butoxyethanol in polyethylene glycol. Remark: Scores for different concentrations tested at 24 hours post-instillation were 100% - 66; 70% - 49; 30% - 39; 20% -2 and 10% - 1 by the Texaco single-digit toxicity classification system (De Sousa et al. (1984) Toxicol. Appl. Pharmacol. 76, 234). In assessment by measurement of corneal thickness, highe st concentration still classified as severely irritating, 70% concen tration moderately irritating and others mildly irritating. Reference: Kennah et al, 1989 (103)

Species: rabbit Result: irritating EC classif. : irritating Method: other: Directive 79/83/EEC Annex V part B with lesions evaluated by Directive 83/467/EEC Annex VI, part IID. Year: 1979 GLP: no data Test subs. : other TS: 99%, neat. Remark : Mean erythema scores and % corneal thickening indicated that the substance should be clas sified as irritant. Reference: Jacobs and Martens, 1989 (104)

Species : rabbit Result: not irritating EC classif. : not irritating Method: other: BASF test Year: GLP: no data Test subs. : other TS: BASF AG Source: BASF, 1956 (106)OECD SIDS 2 -BUTOXYETHANOL

UNEP Publications 232

Species : rabbit Result: strong irritant EC classif .: irritating Method: other: Instillation of 0.1 mL. Only one animal used. Year: GLP: no data Test subs. : 2-Butoxyethanol (undiluted) Remark: Severe conjunctivitis, iritis and corn eal opacity, with irritation still obvious 21 days after exposure Source: Dow Chemical, USA (62)

Species : rabbit Result: strong irritant EC classif .: irritating Method: Other: Internal protocol used. Year: GLP: no data Test subs. : 2-butoxyethanol (undiluted & aqueous) Remark: 0.005 mL of undiluted 2-BE caused severe corneal injury and iritis, 0.5 mL of a 15% aqueous solution cau sed moderate corneal injury, no effects with 0.5 ml of 5% aq. solution. Reference: Bushy Run, 1980 (59) Source: Union Carbide Chemicals, USA

5.2.3 Respiratory Irritation

Type: RD50 Species: mice (male) Result: weak respiratory irrita nt [RD50 = 2825 ppm] EC Classif.: insufficient data Method: Alarie test Year: GLP: no data Test subs. : 2-BE vapour Remarks: Animals exposed to vapour concentrations up to approx. 1100 ppm, so result obtained by extrapolation. Reference Kane et al, 1980 (78)

5.3 Sensitisation

Type: Magnusson and Kligman guinea-pig maximisation test Species: guinea-pig Result: not sensitising EC Classif.: not sensitising Method: other: minor deviations fr om OECD Test Guideline 406 Year: GLP: yes Test subs. : other TS; aqueous solutions of 2-BE in 0.9% saline Remarks: In induction phase, group of 6 male and 4 female animals treated intradermally with 0.5% 2-BE in 0.9% saline, followed by dermal application of 25% solution (in 0. 9% saline) 7 days later under anOECD SIDS 2 -BUTOXYETHANOL

UNEP Publications 233 occlusive wrap. Animals then challenged twice with 10% 2-BE, firstly at 13 days after induction, and then a week later. Reference Unilever Research, 1989 (107)

Type: Magnusson and Kligman guinea-pig maximisation test Species: guinea-pig Result: not sensitising EC Classif.: not sensitising Method: Magnusson and Kligman protocol Year: 1969 GLP: no data Test subs. : other TS; purity 99% Remark: Sensitising and challenge concentrations 1% 2-BE. Reference: Zissu, 1995 (67)

Type: repeated insult patch test Species: human Result: not sensitising EC Classif.: not sensitising Method: Induction phase: 0.2 ml of 10% a queous solution of 2-BE applied under a patch for 24 hours to the backs of the subjects fo r a total of 9 times over a 3-week period Challenge phase: 10% 2-BE applie d to previously unexposed sites two weeks later Year: GLP: yes Test subs. : other TS; Remark: The skin sensitisation potential of a 10% aqueous solution 2- butoxyethanol (2-BE) was tested by repe ated insult patch test on 200 volunteers. In the induc tion phase, a slight re dness (without swelling) was observed in 4 subjects after the first application. By the eighth application, 40 subjects exhibited slight erythema and in another 14, erythema was more definite. In th e challenge phase, slight erythema was noted in 7 subjects after 48 hour s and in 12 subjects after 72 hours. Reference: TKL Research, 1992 (175) Source: CMA USA

5.4 Repeated Dose Toxicitv

Species: rat Sex: male/female Strain: Fischer 344 Route of admin.: inhalation Exposure period: 9 days Frequency of treatment: 6 hours/day for 5 days, 2 days non-exposure and 6 hours/day for 4 days. Post obs. period 14 days Doses: 0.97, 0.415 and 1.183 mg/l [20, 86, 245 ppm] Control Group: yes, concurrent vehicle NOAEL: = 0.97 mg/l [20 ppm] Method: similar to OECD TG 412.OECD SIDS 2 -BUTOXYETHANOL

UNEP Publications 234

Year: GLP: no data Test subst.: other TS: commercial Butyl Cellosolve, purity > 99% Result: 8 animals/sex/group. No deaths occurred. Treatment-related observations were audible respiratio n and nasal discharge and reduced body weight gain in rats of one or both sexes at the highest or intermediate dose levels. At 245 ppm, red stained urine was seen in both sexes of the highest concentr ations after first and second exposures but not subsequently. Haematological effects including decreased red blood cell counts, haem oglobin concentrations and mean corpuscular haemoglobin concen tration and increased mean corpuscular volume (MCV), nucleated red blood cells and, in males only, reticulocytes. A substantial recovery was observed after 14 days, but the decrease in erythrocyte count and the increases in MCV and haemoglobin were still apparent. At 86 ppm, the haematological effects were less marked. Relative liver weights in both sexes were increased at 245 ppm, and in females only at 86 ppm. These changes were not apparent at 14 days. There were no gross lesions. At 20 ppm, no significant effects were observed. Reference: Bushy Run 1981; Dodd et al 1983 (88)(108) Source: Union Carbide Chemicals USA

Species: rat Sex: male/female Strain: Fischer 344 Route of admin.: inhalation Exposure period: 42 or 90 days Frequency of treatment 6 hours/day, 5 days/week

Post obs period: not specified Doses: 0.024, 0.121 and 0.372 mg/l [5.0, 24.6, 77 ppm] Control Group: yes, concurrent vehicle NOAEL: = 0.121 mg/l [24.6 ppm] Method: Similar to OECD TG 413. Some rats killed after 42 days and the remainder maintained to 90 days. Gross and histopathological examinations conducted in rats from controls and highest dosage

groups. Year: GLP : no data Test subst.: other TS: commercial Butyl Cellosolve, purity > 99% Result: 16 animals/sex/group. There were no deaths or signs of toxicity. Decrease in bodyweight gain during weeks 2-4 in high dose females was transient. Haematological eff ects were observed at 77 ppm only, with the effects greater at 6 weeks than at 13 weeks. These effects included decreases in red bloo d cell count, haemoglobin and haematocrit, and an increase in mean corpuscular haemoglobin. There were no significant treatment-relate d changes in gross or microscopic lesions or in serum chemistry or urinalysis observations. Reference: Bushy Run 1981; Dodd et al 1983 (60)(108) Source: Union Carbide Chemicals USAOECD SIDS 2 -BUTOXYETHANOL

UNEP Publications 235 Species: rat Sex: male/female Strain: Fischer 344 Route of admin.: drinking water Exposure period: 2 weeks Frequency of treatment: continuous

Post obs period: none Doses: males: 0, 73, 108, 174, 242, 346 mg/kg/day females: 0, 77, 102, 152, 203, 265 mg/kg/day Control Group: yes NOAEL: males: 346 mg/kg/day, females: 203 mg/kg/day LOAEL: females: 265 mg/kg/day Method: other: clinical observations, water consumption, complete necropsies, organ weight measurements. Year: GLP: yes Test subst.: other TS: Aldrich Chemical Co. Ltd. Result: 5 animals/sex/group. None of the animals died during treatment and there were no treatment-related ch anges in body weight of males. Female rats had lower weight gain in the highest dosage group. Water consumption was lowered at the highe st dosages in both sexes; this resulted in lower target dosages. A slight decrease in thymus weight was observed in female rats at highe st dose. Microscopic examination of the testis and epididymis wa s only conducted in the lower dose group and controls. Reference: NTP, 1993 (110)

Species: rat Sex: male/female Strain: Sprague-Dawley Route of admin.: drinking water Exposure period: 21 days Frequency of treatment: continuous

Post obs period: none Doses: 180, 506 mg/kg/day in males; 204, 44 4 mg/kg/day in females. Control Group: yes, concurrent vehicle Method: other: toxicity including immunot oxicity study following injection with Keyhole Limpet haemocyanin on day 20. Year: GLP: no data Test subst.: other TS: 97%. Result: Body weights were decreased in ma les at the highest dosage and in females at both dosages. No treatm ent-related effects occurred in absolute or relative organ weights and no pathological changes were seen in thymus, testes, liver or kidneys. Natural killer cell activity was enhanced at the low dose level in both males and females but there was no effect on the production of antibody, interferon, interleukin-2 or splenocytes, or evidence of delayed-type hypersensitivity reaction. Reference: Exon et al, 1991 (111)OECD SIDS 2 -BUTOXYETHANOL

UNEP Publications 236

Species: rat Sex: male/female Strain: Fischer 344 Route of admin.: drinking water Exposure period: 13 weeks Frequency of treatment: continuous

Post obs period: none Doses: males: 0, 69, 129, 281, 367, 452 mg/kg/day females: 0, 82, 151, 304, 363, 470 mg/kg/day Control Group: yes NOAEL: males: 129 mg/kg/day, females: not reached LOAEL: males: 281 mg/kg/day, females: 82 mg/kg/day Method: other: clinical observations, body wei ght changes, water consumption, haematology and clinical chemistry evaluations, urinalysis, complete necropsy examminations and histopat hology of tissues were recorded. Year: GLP: yes Test subst.: other TS: Aldrich Chemical Co. Result: None of the animals died during the exposure period. Bodyweights were decreased in both sexes in th e top two dose leve ls. Dose-related decrease in water consumption in females resulting in reduced target dosages. Diarrhoea was noted. Ma les showed mild decreases in haemoglobin levels at dosages >= 129 mg/kg/day, mild anaemia, moderately increased reticulocyte counts and mild-markedly increased leukocyte counts at 281 mg/kg/day. Thrombocytopaenia and mild increases in bone marrow cellularity were noted at >= 367 mg/kg/day. In females, there was mild-moderate anaemia at all doses and mild increases in bone marrow cellularit y, transient changes in platelet counts and marked leukocytos is at >= 304 mg/kg/day.

There were transient changes in to tal protein, albumin and alkaline phosphatase activity in males and/or females at dosages >129 mg/kg/day. Urine volumes and specifi c gravity were raised. Uterine atrophy was secondary to a d ecrease in bodyweight gain.

Histopathological lesions of the liver , spleen and bone marrow in both males and females were record ed. The report concluded that butoxyethanol was relative ly nontoxic at the doses tested and affected only the erythroid series of the haematopoietic system. Reference: NTP, 1993 (110)

Species: rat Sex: male Strain: other: COBS CD(SD)BR Route of admin.: gavage Exposure period: 6 weeks Frequency of treatment: 5 days/week

Post obs period: no dataOECD SIDS 2 -BUTOXYETHANOL

UNEP Publications 237 Doses: 222, 443 and 885 mg/kg bw d Control Group: yes, concurrent vehicle NOAEL: not reached LOAEL: 222 mg/kg/day Method: other: blood and histopathol ogy of tissues examined. Year: GLP: no data Test subst.: other TS: 99.5%, neat. Result: 10 animals/group. 2/10 rats in the high dosage and 1/10 in the intermediate dosage group died. Body weight gains and feed consumption were decreased at th e highest dosage. Haemoglobinuria observed at all doses, particularly at two highest doses and particularly after first two days. At all doses, there was a dose-dependent decrease in red blood cell count and haemogl obin concentration and an increase in mean corpuscular haemoglobin. At the two higher doses, there was a decrease in mean corpuscular haemoglobin concentration, and an increase in mean corpuscular volume. Serum alanin eaminotransferase and alkaline phosphatase levels were slightly increased and serum glucose was reduced. Body weight-relat ive liver weights were raised at all dosages whereas increases in kidney, heart, brain and spleen weights increased only at the two highest dosages. Clinical observations included lethargy, rough coats, weakness and inactivity. Enlarged, dark spleens, hepatocytomegaly, focal haemosiderin deposition, minimal haemosiderin accumulation in kidneys and splenic congestion were seen in some an imals at upper dosage levels. No adverse effects were obseerved on th e testes, thymus, white blood cells or bone marrow. Reference: Krasavage, 1986 (112)

Species: rat Sex: male Strain: Fischer 344 Route of admin.: gavage Exposure period: 12 days Frequency of treatment: daily

Post obs period: 24 hours Doses: 0, 125 mg/kg/day Control Group: yes Method: other: treatment for 1,2,3,6 or 12 days . Blood analyses and spleen and liver weights recorded. Year: GLP: no data Test subst.: other TS: Aldrich Chemical Co. Result: There were signs of significant haemolysis which became more pronounced up to the third day of do sing. Gradual recovery followed up to day 12. Mean cell volume, ATP concentration, reticulocyte numbers and body weight-relative spl een weights increased up to the sixth day of dosing and d eclined thereafter. Body weight-relative liver weights were slightly lowered on da ys 3 and 6 and slightly raised on day 12.OECD SIDS 2 -BUTOXYETHANOL

UNEP Publications 238

Reference: Ghanayem et al, 1992 (113)

Species: rat Sex: male Strain: Fischer 344 Route of admin.: gavage Exposure period: 4 days Frequency of treatment: daily

Post obs period: 1-22 days Doses: 500 or 1000 mg/kg bw d Control Group: yes, concurrent vehicle Method: other: rats killed on days 1, 4, 8 and 22 after last treatment; blood and tissues examined. Year: GLP: no data Test subst.: other TS: 99.9% Result: Body weight gain was reduced at th e highest dosage. Relative spleen, liver and kidney weights were increased dosage-relatedly and thymus weight decreased on day 1; changes in spleen and liver weights returned to normal by day 22. Marrow hyperplasia and splenic extramedullary haemopoiesis on da y 1 were not evident on day 8. Reduced red blood cell count, haematocrit and haemoglobin and raised mean corpuscular volume, mean corpuscular haemoglobin and reticulocyte counts were transient except for m ean corpuscular volume and mean corpuscular haemoglobin whic h were still elevated at day 22. Changes at 500 mg/kg were mild. Reference: Grant et al, 1985 (114)

Species: rat Sex: male Strain: Fischer 344 Route of admin.: gavage Exposure period: 3 days Frequency of treatment: daily

Post obs period: 7 days Doses: 0, 125, 250 mg/kg bw d Control Group: yes Method: other: treatment resumed after reco very period at 125 or 250 mg/kg bw d. Blood after 2, 8 or 24 hour and spleens examined. Year: GLP: no data Test subst.: other TS: Aldrich Chemical Co. Result: Treated/recovered rats were less sensitive to the haemolytic effects of subsequent treatment than untreated rats. Treatment-related mean cell volume and ATP depletion were less evident in pretreated animals as was an increase in spleen weight/b ody weight ratio. It was concluded that tolerance to but oxyethanol-induced haemolysis occurred following repeated exposure. Reference: Ghanayem et al, 1992 (113)OECD SIDS 2 -BUTOXYETHANOL

UNEP Publications 239 Species: rat Sex: female Strain: Sprague-Dawley Route of admin.: oral unspecified Exposure period: 7 days Frequency of treatment: daily

Post obs period: none Doses: 125 and 1500 mg/kg/day Control Group: yes, concurrent vehicle Method: other: sublethal dose given for 6 da ys and then lethal dose given on day 7. Year: GLP: no data Test subst.: other TS: purity not specified. Result: Survival rate in pretreated rats was 60% higher than in challenged controls. Protection from lethality and changes in haematocrit values suggested an autoprotective mechanism. Source: BP Chemicals Ltd. London (116)

Species: mouse Sex: male/female Strain: CD-1 Route of admin.: drinking water Exposure period: 7 days pre-mating and 98 days as breeding pairs. Frequency of treatment: continuous

Post obs period: none Doses: 0, 700, 1300, or 2000 mg/kg bw/day Control Group: yes NOAEL: = 700 mg/kg/day Method: other: NTP continuous breeding prot ocol, NTIS No PB89152425/AS. Heindel, J.J. et al. Year: 1989 GLP: yes Test subst.: other TS: >99%. Result: 8 animals /sex/group. 13/20 fema les in high-dose group and 6/20 females in mid-dose group died duri ng the study. Toxic effects were decreased body weight gain, increa sed kidney and liver weights and dose-related decreases in water c onsumption. No treatment-related histopathological lesions were found in the kidneys of females receiving 1300 mg/kg. Remark: See comments also in secti on 5.8 (Toxicity to reproduction) Reference: Heindel et al, 1990 (117)

Species: mouse Sex: male/female Strain: B6C3F1 Route of admin.: drinking water Exposure period: 2 weeksOECD SIDS 2 -BUTOXYETHANOL

UNEP Publications 240

Frequency of treatment: continuous

Post obs period: none Doses: males: 93, 148, 210, 370 or 627 mg/kg/day females: 150, 237, 406, 673, 1364 mg/kg/day Control Group: yes NOAEL: males: 210 mg/kg/day, females: 406 mg/kg/day LOAEL: males: 370 mg/kg/day, females: 673 mg/kg bw Method: other: clinical observations, wate r consumption, complete necropsies and organ weight measurements. Year: GLP: yes Test subst.: other TS: Aldrich Chemical Co. Ltd Result: 5 animals/sex/group. No deaths were noted and there were no effects on body weights and body weight gains. Water consumption was decreased at all dosages except the highest dosage in females. At two highest doses, thymus weights were decreased in males and dehydration was observed in bot h sexes. Histopathological examinations were not performed. Reference: NTP, 1993 (110)

Species: mouse Sex: male/female Strain: B6C3F1 Route of admin.: drinking water Exposure period: 13 weeks Frequency of treatment: continuous

Post obs period: none Doses: males: 118, 223, 553, 676, 694 mg/kg/day females: 185, 370, 676, 861, 1306 mg/kg/day Control Group: yes NOAEL: males: 223 mg/kg/day, females: 370 mg/kg/day LOAEL: males: 676 mg/kg/day, females: 553 mg/kg/day Method: other: clinical observations, wa ter consumption, complete gross necropsies, organ weight meas urements and histopatholgical examination of tissues were recorded. Year: GLP: yes Test substance: other TS Result: No treatment related deaths, eff ects on water consumption, clinical observations or effects on organ we ights were recorded. Reduced body weight gain at the 3 highest dosages in both males and females. There were no treatment-related gr oss or microscopic lesions. Reference: NTP, 1993 (110)

Species: mouse: Sex male Strain: ICR Route of admin.: oral (gavage) Exposure period: 5 weeksOECD SIDS 2 -BUTOXYETHANOL

UNEP Publications 241 Frequency of treatment: 5 days/week

Post obs period: none specified Doses: 500, 1000 or 2000 mg/kg Control Group: yes Method: other: Year: GLP: no data Test substance: other TS Result: 5 mice/group. All mice at the hi ghest dose level died. Red blood cell counts were decreased at 500 an d 1000 mg/kg whereas white blood cell counts, packed cell volume and haemoglobin concentrations were unaffected. Reference: Nagano et al, 1979 (119)

Species: guinea pig Sex: Strain: Route of admin.: dermal Exposure period: 5-7 days Frequency of treatment: continuous

Post obs period: 28 days Doses: 0.5 or 2.0 ml in covered depots Control Group: no data specified Method: other: single dermal applicat ion left in place for 5-7 days. Year: GLP: no data Test substance: other TS: 99% Result: 20 animals/group. 0/20 died after 0.5 ml; 13/20 died after 2.0 ml (all deaths by day 7). There were no treatment-related effects on body weight gain. Reference: Wahlberg and Boman, 1979 (120)

Species: rabbit Sex: male & female Strain: New Zealand White Route of admin.: dermal Exposure period: 9 days Frequency of treatment: 6 hr a day, 5 day a week

Post obs period: 14 days Doses: 18, 90, 180, 360 mg/kg/day Control Group: control group treated with distilled water. NOAEL: 90 mg/kg/day LOAEL: 180 mg/kg/day Method: 5 rabbits/sex/dose were treated with 1 mL/day of undiluted 2- butoxyethanol or aqueous solutions (5%, 25%, 50%). Year: GLP: no data Test substance: commercial Butyl CellosolveOECD SIDS 2 -BUTOXYETHANOL

UNEP Publications 242

Result: With 25% solution (90 mg/kg/day), erythema only was noted. At 180 mg/kg/day, necrosis was seen in 1/5 males and 4/5 females and haemoglobinuria (in all animals) by day nine. With undiluted 2-BE, severe necrosis was seen in all animals, accompanied by oedema and erythema, plus haemoglobinuria an d haematological changes (reduced red blood cell count and haemoglobin and increased mean corpuscular haemoglobin). Haematological parame ters returned to normal by the end of the 14-day post-exposure obs ervation period. At 100%, a clour change of the kidney was noted in 3/5 females. In a preliminary study at approx. 225 mg/kg/day, histologic examination of the kidneys at necropsy revealed changes consistent with the late stages of haemoglobinuric nephrosis. Reference: Bushy Run 1980 (99) Source: Union Carbide Chemicals USA

Species: rabbit Sex: male & female Strain: New Zealand White Route of admin.: dermal Exposure period: 13 weeks Frequency of treatment: 6 hours/day, 5 days/week

Post obs period: Doses: 2.8%, 14.3% or 42.8% aqueous solutions , equivalent to 10, 50 and 150 mg/kg bw respectively. Control Group: control group treated with distilled water NOAEL: 150 mg/kg/day Method: 10 rabbits/sex/dose were treated with 1 mL/day of aqueous solutions of 2-butoxyethanol Year: GLP: yes Test substance: commercial Butyl Cellosolve Result: Haematological and clinical chemistry parameters were measured at weeks 4 and 12 during the study and a comprehensive histopathological examination was conducted on all animals at necropsy. There were no significant findings. Slight erythema was noted intermittently in all animals, including the controls. Reference: WIL Research Laboratories 1983 (68)

Species: various Sex: male and female Route of admin.: inhalation Exposure period: 4 days Frequency of treatment: 7 hours/day

Post obs period: 2 weeks Doses: 57-58 ppm or 100 ppm Control Group: no controls were used Method: other Year: GLP: no dataOECD SIDS 2 -BUTOXYETHANOL

UNEP Publications 243 Test substance: 2 brands of 2-butoxyethanol - n-Butyl Oxitol and Dowanol EB Result: Dose groups comprised 2 Beagle dogs , 6 guinea-pigs and 8 rats. At 57-58 ppm, one guinea-pig died of re spiratory failure during the study b ut there were no other d eaths and no significant clinical observations. At necropsy (guinea-pigs and rats), no treatment-related gross pathological changes were observe d. At 100 ppm, haemoglobinuria observed in rats (after the first e xposure only), female guinea-pigs died after the second day, and one of th e dogs displayed unusual behaviour after the second exposure. Source: Dow Chemical 1972 (109)

Species: various Sex: male and female Route of admin.: inhalation Exposure period: 30, 60 or 90 days Frequency of treatment: 7 hr per day

Post obs period: no data Doses: up to 494 ppm Control Group: no data Method: other Year: GLP: no data Test substance: commercial Butyl Cellosolve Result: Test animals included rats, mice, guinea-pigs, dogs and monkeys. Haemoglobinuria and/or increased red blood cell fragility were observed in all species except th e guinea-pig, with the animals generally returning to normal overn ight. Older animals were more susceptible to haemolytic effects. Increased relative liver and kidney weights were noted at and above 107 ppm in rats and increased relative kidney weight at and above 203 ppm in guinea-pigs. Reference: Carpenter, 1956 (82)

Species: laboratory animal Sex: no data Strain: no data Route of admin.: inhalation Exposure period: 9 days Frequency of treatment: 6 hour/day Post obs period: Doses: 537 ppm (2,645 mg/l) Control Group: no data specified Method: other: BASF Test Year: GLP: no data Test substance: other TS: BASF AG Remark: Dose groups comprised 2 cats, 2 ra bbits, 10 guinea pigs, 10 rats and 20 mice. Result: Eine Katz starb nach 7 Expositio nen, die beiden Ka ninchen starben nach 2 Expositionen, die meisten Ratten starben nach der 2. - 5.OECD SIDS 2 -BUTOXYETHANOL

UNEP Publications 244 Exposition und etwa die Haelfte de r Maeusen wurde eine starke Haemoglobinurie festgestellt, die zu toedlicher Anaemia fuehrte. Die Katzen und Meerschweinchen zei gten keine Anzeichen einer Haemolyse. Source: BP Chemicals Ltd. London (121)

5.5 Genetic Toxicity in Vitro

Type: Ames test Test system: S.typhimurium strains TA 100, TA1535, TA1537, TA97, TA98. Concentration: 0, 100, 333, 1000, 3333 or 10000 ug/plate Metabolic activation: with and without Result: negative Method: OECD Test Guideline 471 Year: GLP: yes Test substance: other TS: Aldrich Chemical Co, >99% Reference: NTP 1993 (110)

Type: Cytogenetic assay Test system: Chinese hamster ovary (CHO) cells Concentration: 2513, 3750 and 5000 ug/ml Met. activation: with and without Result: negative Method: other: Galloway et al. (1987). Envi ron. Mol. Mutagen. lO (Suppl. 10), 1-175 Year: 1987 GLP: yes Test substance: other TS: Aldrich Chemical Co; 99% Remark: 2-Butoxyethanol induced cell cy cle delay but not chromosomal aberrations. Reference: NTP 1993 (110)

Type: Sister chromatid exchange assay Test system: Chinese hamster ovary (CHO) cells Concentration: 500-5000 ug/ml Met. activation: with and without Result: negative Method: other: Galloway et al. (1987). Envi ron. Mol. Mutagen. lO (Suppl 10) 1- 175. Year: 1987 GLP: yes Test substance: other TS: Aldrich Chemical Co. Remark: The highest test concentrations were toxic in systems without metabolic activation but not in the presence of S9. Reference: NTP 1993 (110)

Type: other: mutagenic effect on bacteriophage T4D. System of testing: induction of rapid lysis mutants of bacteriophage T4D in bacterial strains of E. coli B, CR63 and K12 lambda-h measured. Concentration: not specifiedOECD SIDS 2 -BUTOXYETHANOL

UNEP Publications 245 Met. activation: no data Result: negative Method: other: as specified above Year: GLP: no data Test substance: other TS Remark: Butoxyethanol had a severe toxic effect upon phage yield. Reference: Kvelland, 1988 (124)

Type: point mutation assay Test system: Chinese hamster ovary (CHO) cells Concentration: 140-9000 μg/mL Met. activation: with and without Result: negative Method: local protocol Year: GLP: no data Test substance: commercial Butyl Cellosolve Remark: Cells were exposed for 5 hours. At the highest dose, 2-butoxyethanol was cytotoxic with S9, but non-toxic without S9. Reference: Bushy Run 1980 (89) Source: Union Carbide Chemicals USA

Type: Sister chromatid exchange (SCE) assay Test system: Chinese hamster ovary (CHO) cells Concentration: 63-2250 μg/mL Met. activation: with and without Result: negative Method: Based on method of Perry and Wolff in Nature 251, p.156 (1974) Year: GLP: no data Test substance: commercial Butyl Cellosolve Remark: Reference: Bushy Run 1980 (89) Source: Union Carbide Chemicals USA

Type: Unscheduled DNA Synt hesis (UDS) assay Test system: rat hepatocytes Concentration: 0.9-900 μg/mL Met. activation: Result: positive Method: Cells treated for 2 hr in the presence of tritiated thymidine. UDS activity determined by measurement of radioactivity in liver cell nuclei Year: GLP: no data Test substance: commercial Butyl Cellosolve Remark: A statistically significant inducti on of UDS was observed at the two lowest doses, with the maximum effect at 9 μg/mL. This assay should be regarded as inconclusive as th ere was no clear dose-related response and various experimental probl ems occurred during the study. Reference: Bushy Run 1980 (89)OECD SIDS 2 -BUTOXYETHANOL

UNEP Publications 246

Source: Union Carbide Chemicals USA

Type: Ames test Test system: S.typhimurium strains TA1538, TA1537, TA1535, TA100 and TA98 Concentration: up to 5000 μg/plate Met. activation: with and without Result: negative Method: conducted in accordance with OECD Test Guideline 471 Year: GLP: no data Test substance: T-3722 (3M product), contai ning 18% 2-butoxyethanol Remark: Other components in the product in cluded isopropyl alcohols (18%) and a fluorochemical salt (27%). Reference: SRI International 1985 (98)

Type: Ames test Test system: S.typhimurium strains TA97a, TA98, TA100 and TA102 Concentration: no data Met. activation: with and without Result: positive response to TA97a (2.2 mg/plate) with and without S9 negative response to TA98, TA100 and TA102 Method: no data Year: GLP: no data Test substance: 2-butoxyethanol Remark: The metabolite 2-butoxyacetic acid a nd the intermediate metabolite 2- butoxyacetaldehyde were ne gative to all strains. Reference: Hoflack et al 1995 (115)

Type: gene mutation assay Test system: CHO-AS52 cells Concentration: up to 0.1% v/v (7.6 mM) 2-butoxyethanol up to 0.2% v/v (15.2 mM) 2-butoxyacetaldehyde (BAL) Met. activation: without Result: negative Method: cells treated with 2-BE or BAL in plain F12 medium for 5 hours Year: GLP: no data Test substance: 2-BE - Aldrich Chemical Co.; BAL purity > 98% Remark: 2-BE is metabolised to BAL 2-BE cytotoxic at 0.5%, BAL cytotoxic at 0.26% Reference: Chiewchanwit and Au 1995 (118)

Type: Ames test System of testing: S. typhimurium strains TA97a & TA100 and the E. coli strain WP2 uvr A Concentration: up to 10 mg/plate Met. activation: with and without Result: negative Method: standard OECD and EC protocol s, except a higher dose used Year:OECD SIDS 2 -BUTOXYETHANOL

UNEP Publications 247 GLP: no data Test substance: purity 99% Remark: Assay includes repeat of assay by Hoflack et al 1995 Reference: Gollapudi et al 1995 (123) Source: CMA, USA

Type: sister chromatid exchange (SCE) assay Test system: human lymphocytes Concentration: 500, 1000, 2000, 3000 ppm Met. activation: without Result: positive Method: no data Year: GLP: no data Test substance: Remark: As the assays were conducted without metabolic activation or positive controls, no firm conclusions can be drawn. Reference: Villalabos-Petrini et al 1989 (125)

Type: chromosomal aberrations Test system: human lymphocytes Concentration: 500, 1000, 2000, 3000 ppm Met. activation: without Result: negative Method: no data Year: GLP: no data Test substance: Remark: As the assays were conducted without metabolic activation or positive controls, no firm conclusions can be drawn. Reference: Villalabos-Petrini et al 1989 (125)

Type: Various Test system: V79 cells Concentration: no data Met. activation: no data Result: positive at high 2-BE concentrations Method: no data Year: GLP: no data Test substance: Remark: 2-BE induced mutations at the HGPRT locus. In other tests, 2-BE was a weak inducer of SCEs and an euploidy at high doses, and at noncytotoxic doses 2-BE elicited a dose-dependent inhibitory effect on intercellular communication. Metabo lites BAA and BAL also tested. Reference: Elias et al 1996 (131)

5.6 Genetic Toxicity in Vivo

Type: Micronucleus assay (bone marrow) Species: miceOECD SIDS 2 -BUTOXYETHANOL

UNEP Publications 248

Strain: CD-1 Route of admin.: intraperitoneal injection Exposure period: 24, 48 and 72 hr Doses: 2-BE: single doses 150-1000 mg/kg; BAL 50-200 mg/kg. Method: Other: Eight (4/sex) test anim als were used per test group. Year: GLP: Result: negative Test substance: Remark: There was no induction of micronucle ated polychromatic erthrocytes in bone marrow for 2-BE or BAA. The P/N ratio 1.7 at 1000 mg/kg (2- BE) and 0.78 at 200 mg/kg (BAA) indi cating that BAA was more toxic to erythropoiesis than 2-BE. Reference: Elias et al, 1996 (131)

Type: DNA adduct formation Species: rat Strain: Route of admin.: Exposure period: single dose Doses: 120 mg/kg Method: Other: Animals killed 24 hours after dosing Year: GLP: Result: DNA adducts were not detected an d methylation status was unaltered in the all organs Test substance: Remark: 3 treated and 3 control anim als were used in study. No DNA binding in liver, brain, kidne y, spleen and testis observed (using 32 P postlabelling) following exposure. Reference: Keith et al, 1996 (132)

Type: DNA adduct formation Species: mouse Strain: Transgenic (carrying the v-Ha- ras oncogene) Route of admin.: subcutaneous Exposure period: 2 weeks Doses: 1500 mg/kg (approximately 120 mg/kg/day) Method: Other: animals (8 to 24 per group) were used and killed at between 5 and 120 days Year: GLP: Results: DNA adducts were not detected an d methylation status was unaltered in all organs following exposure. Test substance: 2-butoxyethanol. Remark: No DNA binding in liver, brain, kidne y, spleen and testis observed (using 32 P postlabelling) following exposure. Animals were also examined for tum our formation at 120 days with no statistical difference from controls. Reference: Keith et al, 1996 (132)OECD SIDS 2 -BUTOXYETHANOL

UNEP Publications 249 5.7 Carcinogenicity

Remark: No chronic studies have been completed. NTP started chronic inhalation studies in rats and mice in 1993. Source: BP Chemicals Ltd. London (122)

5.8 Toxicity to Reproduction

Type: two generation study Species: mouse Sex: male/female Strain: CD-1 Route of admin.: drinking water Exposure Period: Frequency of treatment: c ontinuous

Premating Exposure Period male and female: 7 days

Test duration: For 105 days Doses: continuous breeding phase: 0, 720, 1340, 2050 mg/kg/day; crossover mating phase: 1830 mg/ kg/day; final phase: 950 mg/kg/day Control Group: yes Method: other: Continuous breeding protoc ol in CD-1 mice. NTIS No PB89152425/AS, Heindel et al, F und. Appl. Toxicol. vol. 15, p.683- 696, 1990. Continuous breeding of Fo for 14 weeks then cross-over mating with control and mid-dose groups then assessment of F1 fertility in low dose group Year: 1989 GLP: no data Test substance: other TS: >99% NOAEL Parental: = 720 mg/kg/day Result: Effects in Fo include high mort ality in high-dose (13/20) and medium-dose (6/20) females and body weight loss in both sexes. Water consumption was lowered dose -relatedly in all groups. At 1% and 2%, dose-related decr ease in litter size, pup viability and live pup weight. At 0.5%, slight decrease in live pup weight

At crossover mating, no effect on mating index but fertility index and number of live pups/litter redu ced when treated females mated with control males. Results suggest that fertility effects primarily due to effects on female mice.

In final phase, no significant fe rtility and reproductive effects observed in F1 animals as indicated by proportion of successful copulation and fertile females, litte r size, pup viability and live pup weights. No treatment-related changes in weights of reproductive organs, sperm motility, morphology, and the oestrous cycle and frequency. However, significant in crease in relative kidney weight in females, and significant increase in relative liver weights in males.OECD SIDS 2 -BUTOXYETHANOL

UNEP Publications 250

Remark: Females were more sensitive to the reproductive toxicity of 2- butoxyethanol. The high dose was too toxic to be used to determine reproductive toxicity. Reference: Heindel et al, 1990 (117)

Type: other: effects on reproductive organs Species: mouse Sex: male Strain: JCL-ICR Route of admin.: gavage Exposure Period: Frequency of treatment: 5 days/week Test duration: 5 weeks Doses: 500, 1000 and 2000 mg/kg Control Group: yes Method: other: effects on testes and asso ciated structures determined. Year: GLP: no data Test substance: other TS Result: All mice died at the highest dosage. There were no significant effects on the relative weights of th e testes or seminal vesicles and coagulating gland. Reference: Nagano et al, 1984 (126)

Type: other: effects on reproductive organs. Species: rat Sex: male Strain: Fischer 344 Route of admin.: drinking water Exposure Period: Frequency of treatment: continuous Test duration: 60 days Doses: 0, 1500, 3000 or 6000 ppm [0, 124, 234, 443 mg/kg/day] Control Group: yes NOAEL Parental: = 443 mg/kg bw Method: other: Stop exposure study. Testes and epididymides were removed for weighing and examination. Year: GLP: yes Test substance: other TS: Aldrich Chemical Co. Remark: 30 animals/dose Result: No deaths occurred. Treatment changes included loss of bodyweight and decreased water intake. Testes and epididymides weights normal and no apparent treatm ent-related lesions. Reference: NTP, 1993 (110)

Type: other: effects on reproductive organs. Species: rat Sex: male/female Strain: Fischer 344OECD SIDS 2 -BUTOXYETHANOL

UNEP Publications 251 Route of admin.: drinking water Exposure Period: Frequency of treatment: continuous Test duration: 13 weeks Doses: males: 0, 281, 367, 452 mg/kg/day females: 0, 304, 363, 470 mg/kg/day Control Group: yes NOAEL Parental: males: 452 mg/kg/day; fe males: 304 mg/kg/day Method: other: Morrissey, R.E. et al. (1988) . Fund. appl. Toxicol. 11, 343- 358. Year: 1988 GLP: yes Test substance: other TS: Aldrich Chemical Co.; 99% Result: Water consumption was lowered re sulting in lower than target dosages. Epididymal weights were lowered in mid- and high-dosage males but these were related to re duced body weight changes. Small but significant reduction in sperm concentration at all 3 doses, but not dose-dependent; no other changes in sperm morphology parameters. In females, oestrous cycle length was unchanged but, in mid- and high-dose groups, differences in length of various stages of oestrous cycle noted. Remark: Reproductive tissue evaluations on 10 animals/sex/dose at 3 highest concentrations and controls from main study. Reference: NTP, 1993 (110)

Type: other: effects on reproductive parameters. Species: mouse Sex: male/female Strain: B6C3F1 Route of admin.: drinking water Exposure Period: Frequency of treatment: continuous Test duration: 13 weeks Doses: males: 0, 553, 676, 694 mg/kg/day females 0, 676, 861, 1306 mg/kg/day Control Group: yes NOAEL Parental: males: 694 mg/kg/day; fe males: 1306 mg/kg/day Method: other: Morrissey, R.E. et al. (1988). Fund. appl. Toxicol. 11, 343- 358. Year: 1988 GLP: yes Test substance: other TS: Aldrich Chemical Co. 99% Result: Slight decreases in sperm motility and testis weight but not dosedependent. Remark: Reproductive tissue evaluations on 10 animals/sex/dose at 3 highest concentrations and controls from main study. Reference: NTP, 1993 (110)

5.9 Developmental Toxicity/Teratogenicity

Species: ratOECD SIDS 2 -BUTOXYETHANOL

UNEP Publications 252

Sex: female Strain: Fischer 344 Route of admin.: inhalation Exposure period: days 6-15 of gestation Frequency of treatment: 6 hours/day Test duration: to day 21 of gestation Doses: 25, 50, 100, 200 ppm [0.12, 0.24, 0.48, 0.97 mg/l] Control Group: yes NOAEL Maternal: = 50 ppm NOAEL Developmental: = 50 ppm NOAEL Teratogenicity: = 200 ppm Method: other: Internal protocol. Year: GLP: yes Test substance: other TS: 99.6% Remark: The NOAEL for teratogenicity do es not account for skeletal variations. Result: Maternal toxicity incl uded evidence of h aemoglobinuria at 100 and 200 ppm. Haematological effects included increases in haemoglobin and haematocrit values, mean corpuscular volume and mean corpuscular haemoglobin, and decrea ses in red blood cell count and mean corpuscular haemoglobin co ncentration. Body weights, body weight gains and food consumption values were reduced at higher doses. At necropsy, gravid uterus weights were reduced and relative spleen and kidney weights were in creased at the highest dosage.

Embryotoxic effects significantly incr eased in resorbed litters at 200 ppm. Foetotoxic effects minimal w ith evidence of delayed skeletal ossification at 100, 200 ppm. Reference: Tyl et al, 1984 (127)(135)

Species: rabbit Sex: female Strain: New Zealand white Route of admin.: inhalation Exposure period: day 6-18 of gestation Frequency of treatment: 6 hours/day Test duration: up to day 29 of gestation Doses: 25, 50, 100, 200 ppm [0.12, 0.24, 0.48, 0.97 mg/l] Control Group: yes NOAEL Maternal: = 100 ppm NOAEL Developmental: foetotoxicity: = 200 ppm embryotoxicity: = 100 ppm NOAEL Teratogenicity: = 200 ppm Method: OECD TG 414 Year GLP: yes Test substance: other TS: 99.6% Result: At highest dose, signs of maternal toxicity included mortality, increased number of abortions and reduced body and uterus weight. No significant dose-dependent haematological changes.OECD SIDS 2 -BUTOXYETHANOL

UNEP Publications 253 Embryotoxic effects were a reducti on in the number of total and viable implantations/litte r at the highest dose.

Fusion of the papillary mu scles in the left ventri cle of 5 foetuses in 4/19 litters at 100 ppm only suggests that this was not a foetotoxic effect of 2-butoxyethanol treatment. Reference: Tyl et al, 1984 (127)(135)

Species: mouse Sex: female Strain: CD-1 Route of admin.: gavage Exposure period: 8-14 days of gestation Frequency of treatment: daily Test duration: dams sacrificed on day 18 of gestation Doses: 0, 350, 650, 1000, 1500 or 2000 mg/kg/day Control Group: yes NOAEL Maternal: = 350 mg/kg/day NOEAL Developm.: = 650 mg/kg/day NOAEL Teratogen.: = 650 mg/kg/day Method: other: teratology; implantation site s, resorptions and live and dead foetuses and foetuses weighed and examined at day of gestation. Year: GLP: no data Test substance: other TS: 97% Result: Maternal toxicity incl uded mortality (6/6 and 3/6 at 2000 and 1000 mg/kg bw/day respectively). There was a distinctive green-brown or red-brown staining of cage papers at dosages of 650 mg/kg bw/day and above. Treatment-related clin ical observations were lethargy, failure to right, abnormal breat hing and green or red vaginal discharge, the latter at 1500 mg /kg bw and above. Developmental toxicity was increased embryo reso rption at 1000 mg/kg bw/day and above. Reference: Wier et al, 1987 (128)

Species: mouse Sex: female Strain: CD-1 Route of admin.: gavage Exposure period: 8-14 days of gestation Frequency of treatment: daily Test duration: dams and offspring sacrificed on post-natal day 22 Doses: 0, 650 and 1000 mg/kg/day Control Group: yes NOAEL Maternal: = 650 mg/kg/day NOAEL Teratogenicity: = 1000 mg/kg/day Method: other: Post-natal study - da m and offspring toxicity Year: GLP: no data Test substance: other TS: 97%OECD SIDS 2 -BUTOXYETHANOL

UNEP Publications 254

Result: Reduction in body weight gain of da ms at high dose. No effects on survival and body weight gain of offspring. No adverse reproductive or developmental effects observed. Reference: Wier et al, 1987 (128)

Species: rat Sex: female Strain: Sprague-Dawley Route of admin.: dermal Exposure period: days 6-15 of gestation Frequency of treatment: 0.12 ml 4 times per day Test duration: up to day 20 of gestation Doses: total per day approx. 1760 mg/kg bw/day Control Group: yes NOAEL Teratogenicity: = 1760 mg/kg bw/day Method: other: a two-replicate study of mate rnal toxicity, embryotoxicity and teratogenicity. Year: GLP: no data Test substance: other TS: Fisher Scientific Remark: Preliminary dosage of 0.35 ml 4 tim es daily was reduced in second replicate because of high mortality. Result: At the lower dose, body weight was slightly reduced, and there was no evidence of embryo- or foetot oxicity, gross malformations or variations. Haemoglobinuria was ob served at the preliminary dose, but not at 1760 mg/kg/day. Reference: Hardin et al, 1984 (129)

Species: rat Sex: female Strain: Fischer 344 Route of admin.: oral (gavage) Exposure period: days 9-11 or 11-13 of gestation Frequency of treatment: daily Test duration: 20 days Doses: group 1 (gd 9-11): 0, 30, 100 or 200 mg/kg/day group 2 (gd 11-13): 0, 30, 100 or 300 mg/kg/day Control Group: yes NOAEL Maternal: = 30 mg/kg/day NOAEL Developmental: = 100 mg/kg/day NOAEL Teratogenicity: = 200 mg/kg/day Method: OECD TG 414, except for restricted exposure period Year: GLP: yes Test substance: other: Radian Corp. Results: Groups of 27-33 animals were dosed with 2-BE (in distilled water) during the critical periods of car diovascular development. Doserelated changes in haematological parameters were observed in the dams of both groups at the two hi ghest doses (100 a nd 200 mg/kg or 100 and 300 mg/kg). The effects we re more obvious in the early days after dosing and the effects included decreases in red blood cellOECD SIDS 2 -BUTOXYETHANOL

UNEP Publications 255 count, haemoglobin, haematocrit and MCHC, and increases in MCV, MCH, reticulocytes and white blood cell count. Other signs of toxicity in the dams include d dose-related reductions in body weight gain and food and water co nsumption. The relative spleen weights were increased at 100 and 200/300 mg/kg, relative kidney weights were increased at 200/300 mg /kg and relative liver weights at 200/300 mg/kg. The NOAEL fo r maternal toxicity was 30 mg/kg/day.

An increase in non-viable and ad versely-affected implants, postimplantation loss and resorptions per litter resulted in the animals at 200 mg/kg/day (group 1 only). In th e foetus, a decr eased platelet count was noted at 300 mg/kg/da y (group 2 only). No foetal malformations, and in particular no cardiovascular malformations, were observed at any dose. Remark: The study was conducted under the NT P after the results of Tyl’s inhalational rat study indicated th at 2-BE may adversely affect cardiovascular development. Reference: Sleet et al, 1989 (139)

Species: rat Sex: female Strain: Sprague-Dawley Route of admin.: inhalation Exposure period: day 7-15 of gestation Frequency of treatment: 7 hours/day Test duration: 20 days Doses: 150 or 200 ppm Control Group: yes NOAEL Maternal: not reached NOAEL Developm.: = 200 ppm NOAEL Teratogenicity: = 200 ppm Method: other: embryotoxicity, foetot oxicity and teratogenicity Year: GLP: no data Test substance: Other TS: Eastman Kodak - purity 98-99.5% Result: Haemoglobinuria was noted (on first day only) in the dams at both doses, but no evidence of embryotoxicity, foetotoxicity or teratogenicity was observed. Reference: Nelson et al 1984 (137)

Species: mouse Sex: female Strain: CD-1 Route of admin.: gavage Exposure period: 7-14 days of gestation Frequency of treatment: once per day Test duration: 20 days Doses: 0, 1180 mg/kg/day Control Group: yes NOAEL Maternal: not reachedOECD SIDS 2 -BUTOXYETHANOL

UNEP Publications 256

Method: other: Screening study - da m and offspring toxicity Year: GLP: no data Test substance: other TS: 99% Result: Maternal mortality 20%. Viable litters 77%. No significant difference from controls in num ber of live pups/litter, pup weight, pup post-natal survival, and pup weight gain. Reference: Schuler et al, 1984 (162)

Species: rat Sex: female Strain: CD Route of admin.: subcutaneous injection Exposure period: day 6-15 of gestation Frequency of treatment: daily Test duration: 21 days Doses: 0, 45, 90 or 180 mg/kg/day Control Group: yes NOAEL Maternal: = 45 mg/kg/day NOAEL Developm.: = 180 mg/kg/day NOAEL Teratogenicity: = 180 mg/kg/day Method: OECD TG 414. Groups of 20 pr egnant animals were used. Year: GLP: no data Test substance: other TS: Result: No mortality resulted. Haemoglobi nuria and body weight loss were observed in the medium and high dose dams after the first 2 injections only. Pre-implantation loss was evident at maternally toxic doses, but not dos e-dependent and within laboratory’s normal range. In the foetuses, a slight increase in rib effects and a dosedependent increase in incomplete o ssification of cranial bones were observed but such effects were no t considered as malformations. No significant pathological fi ndings were noted at necropsy. Reference Tesh, 1976 (26)

Species: rat Sex: female Strain: other: albino Crl:CD Route of admin.: other: in vitro Exposure period: Frequency of treatment: Test duration: Doses: 0, 3.12, 6.25, 12.5 or 25 mM Control Group: yes NOAEL Embryotoxicity: = 3.12mM Method: other: Explanted embryos were cultured for 48 hours in Trowell medium containing 2-BE at stated concentrations. Embryos were examined histologically and by total protein content. Year: GLP: no data Test substance: other TS: Janssen Chimica; >98%OECD SIDS 2 -BUTOXYETHANOL

UNEP Publications 257 Result: Embryonic development was blocked at 25 mM; at 12.5 mM there were severe dysmorphogenic eff ects and at 6.25 mM there was a reduction in somite numbers and of protein/embryo ratio. Extensive necrosis in the neuroepithelium and its derivatives and in the neuromesenchyma of the branchia l arches was noted in embryos exposed to 12.5 mM. Reference: Giavini et al, 1993 (130)

5.10 Other Relevant Information

A. Specific toxicities

Type: Other: cytotoxicity to haemopoietic cells in vitro Remark: 2-Butoxyacetic acid (BAA) had markedly higher haemolytic activity than 2-BE in vitro. Af ter 1 hour 7.5 mM BAA completely lysed rat erythrocytes compared to 175-200 mM for 2-BE. Human erythrocyes incubated for up to 180 min. showed haemolysis by 2- BE at 225 mM and BAA did not cause haemolysis at max. concentration (15 mM). For 180 mi n. incubation, BAA caused total haemolysis of rat cells at 3.75 mM . The findings show that human erythrocytes are less susceptible than rat cells to haemolysis of red blood cells. Reference: Bartnik et al, 1987 (93)

Type: Other: cytotoxicity to haemopoietic cells in vitro Remark: In a comparative study in rat and human red blood cells, haemolysis was observed in rat cells exposed for 4h to BAA at the lowest dose (0.5mM). No effects were observed in human cells exposed to 2mM BAA for 4h, but slight swelling of the cells was noted at 4mM, and slight but significant haemolysis was observed at 8mM BAA. Reference: Ghanayem et al, 1989 (133)

Type: Other: cytotoxicity to haemopoietic cells in vitro Remark: Blood from different animals was incubated with 0, 1 or 2 mM BAA (the primary metabolite of 2-BE) in vitro. Blood parameters were measured after incubation for 1, 2 and 4 hr. The studies confirmed the haemolytic effect of BAA in vitro in mice and rats (at 1mM BAA), and the yellow baboon (at 2mM), but no significant effect was observed in the red blood cells of guinea-pigs, dogs, cats, domestic pigs and humans afte r exposure to 2mM BAA for 4h. Rabbit and hamster cells swelled at 2mM, but no haemolysisoccurred. These findings demonstrate species differences in BAAdependent haemolysis; human erythroc ytes are less sensitive to this effect. Reference: Ghanayem and Sullivan, 1993 (86)

Type: Other: cytotoxicity to haemopoietic cells in vitro Remark: In a study on blood cells from human, rat, dog and rabbit, 2- butoxyacetic acid (BAA) lysed rat erythrocytes at 0.05%. Erythrocytes from the other specie s were stable up to the maximum concentration of 2% BAA.OECD SIDS 2 -BUTOXYETHANOL

UNEP Publications 258

Reference: Hext 1985 (33) Source: ICI, UK

Type: Other: cytotoxicity to haemopoietic cells in vitro Remark: Red blood cells from humans and Fisc her 344 rats were treated with 2-butoxyacetic acid (BAA). On expos ure to 2 mM for 4 hr, the rat cells exhibited significant haemolys is, preceded by a decrease in red cell deformability (noted at 1 hr); whereas no haemolysis or change in deformability occurred in hu man cells. On exposure to 0.2 mM for 6 hours, the rat cell s exhibited very sli ght haemolysis and a significant decrease in red cell deformability (noted at 4 hr). Reference: Udden and Patton 1994 (167)

Type: Other: cytotoxicity to haemopoietic cells in vitro Remark: Red blood cells from 9 healthy young adults (5m,4f), 9 aged persons (5m,4f), 7 patients with sickle cell disease and 3 persons with hereditary spherocytosis were treated with 2 mM 2- butoxyacetic acid (BAA) for 4 hr. Ha emolysis in treated cells was higher than controls for aged adults, but the difference was not statistically significant. The deform ability of red cells from persons with sickle cell disease or hered itary spherocytosi s was reduced, but BAA had no added effect. No other haemolytic or morphological changes were observed. Reference: Udden 1994 (166)

Type: Cytotoxicity Remark: Measured IC50 concentrations of 2-BE were 53, 44 and 60 mM respectively in the MTT, leucine incorporation and neutral red assays in rabbit corneal epithelial cells in vitro. Measured IC50 concentrations of 2-BE were 40 and 45 mM respectively in the MTT and leucine incorporation as says in Chinese hamster lung fibroblast (V79) cell cultures. Reference: Sina et al, 1992 (134)

Type: other: Cytotoxicity to haem opoietic cell lines in vitro. Remark: The IC50 of 2-BE to growth-factor dependent or leukaemic mouse, rat or human haemopoietic cell line s in vitro was determined. 2-BE inhibited growth of the human promyelocytic lin e NB4 (96 hour IC50 = 0.1 mM) and the growth fact or dependent line DA1 (48 hour IC50 = 0.08 mM). The authors concl uded that the toxicity of 2-BE towards certain haemopoietic cells was in the same concentration range as benzene and phenol. Howeve r, it is noted that that these conclusions are contrary to in vivo data (from 90-day studies) which show that 2-BE is not toxic to bone marrow (Teheux 1994 - ref 150). Due to doubts about the purity of reagents used in the study, the authors have publicly withdraw n the conclusions (Boiron et al 1994 - ref 168). Reference: Ruchaud et al, 1992 (149)

Type: Immunotoxicity Remark: See Section 5.4 of this dossier for results of a toxicity study whichOECD SIDS 2 -BUTOXYETHANOL

UNEP Publications 259 contained an immunotoxicol ogy component. Butoxyethanol enhanced natural killer cell ac tivity evoked by Keyhole Limpet haemocyanin injection in rats but had no effects on antibody, interferon or interleukin-2 produc tion or on splenocyte numbers or delayed-type hypersensitivity. Reference: Exon et al, 1991 (111)

Type: Immunotoxicity Remark: 2-Butoxyethanol did not suppress the primary plaque-forming cell response to trinitrophenol-lipopolys accharide in male F344 rats at gavage doses ranging 50 to 400 mg/kg. Reference: Smialowicz et al, 1992 (140)

Type: Immunotoxicity Remark: Cultured guinea-pig lymphoid cells were exposed (48 hours) to 2- butoxyethanol (2-BE) or 2-butoxyace tic acid (BAA) in the presence of the mitogen phytohaemagglutinin (PHA) at 2.5-10 μg/mL or concanavalin A (Con A) at 5-20 μg/mL) or an antigen (tuberculin at 25-100 μg/mL). Doses of 2-BE and BAA were 0.4, 2.0 and 10mM and 0.2, 1.0 and 5.0mM respectively.

No significant effects on lymphoc yte proliferation were observed for 2-BE, apart from slight reduct ions at the two highest PHA doses. At the cytotoxic dose of 10mM, a significant reduction in proliferative capacity resulted, partic ularly for PHA and tuberculin. No significant effects were obser ved for BAA at any dose tested. Reference: Crevel et al 1990 (139) Source: Unilever UK

Type: Behavioural effects Remark: No effect on growth-rate or beha vioural performance occurred in female rats exposed by inha lation to 50, 100, 200 or 400 ppm 2- butoxyethanol for 4 hours/day, 5 days/week for 10 days.Behavioural effects were measured using a conditioned avoidanceescape test. Transient haemoglobi nuria was observed at 200 and 400 ppm. Reference: Golberg et al 1964 (49)

B. Toxicodynamics, toxicokinetics

Type: Metabolism Remark: Treatment of rats with pyrazole (alcohol dehydrogena se inhibitor) protected rats against 2-BE indu ced haemotoxicity and inhibited 2- BE metabolism to BAA, with i nhibition accompanied by increased metabolism to the 2-BE glucoronide (BEG) and sulfate (BES). There was a 10-fold decrease in th e ratio of BAA to (BEG+BES) in the urine of rats treated with pyrazole+2-BE compared to rats treated with 2-BE alone. Pretreatment of rats with cyanamide (aldehyde dehydrogenase inhibitor) al so significantly protected rats and against 2-BE BE induced ha emotoxicity and modified 2-BEOECD SIDS 2 -BUTOXYETHANOL

UNEP Publications 260 metabolism in a manner similar to pyrazole. Administration of equimolar doses of 2-BE, the in termediate 2-butoxyacetaldehyde (BAL), or the ultimate metabolite BAA caused similarhaematotoxic effects. Cyanamide also protected rats against BALinduced haemotoxicity. Reference: Ghanayem et al, 1987 (141)

Type: Toxicokinetics Remark: Radiolabelled 2-BE (125 or 500 mg /kg/day by gavage) was rapidly absorbed and distributed in all or gans, the highest levels were found in the forestomach, liver, kidneys, spleen and glandular stomach. Radioactivity was also detected in the lung, heart, skin, testes, muscle, blood and fat. The major r oute of elimination was in urine followed by exhaled air. The majo r metabolites in urine were BAA (75% of label) followed by the glucuronide conjugate (BEG). Sulphate conjugate and unchanged 2-BE were found in the urine of low-dose but not high-dose animals. There was evidence of saturation of 2-BE metabolising en zymes. At the high dose, rats eliminated 8% of labelled substance in the bile within 8 hours, this being mainly BEG then BAA. Reference: Ghanayem et al, 1987 (142)

Type: Metabolism Remark: After receiving 28, 47 or 140 mg/kg bw /day of radiolabelled 2-BE in drinking water for 24 hours, male rats eliminated 50-60% of the label in urine as BAA, 10% as et hylene glycol and 8-10% as C02 in exhaled breath. There was no differe nce in excretion pattern for the three doses, with >75% of labe l excreted over 72 hour. Ethylene glycol, a previously unreported metabolite, was thought to arise from the dealkylation of 2-BE. Reference: Medinsky et al, 1990 (143)

Type: Metabolism Remark: In a gavage study, young rats (4-5 weeks old) eliminated a higher proportion of administered dose of radiolabelled 2-BE as exhaled C02 and in urine than older rats (9-13 we eks old). Older rats eliminated a higher ratio of BAA to conjugated 2-BE in urine and retained more radiolabelle d 2-BE in their tissues. Reference: Ghanayem et al, 1987 (144)

Type: Toxicokinetics Remark: Following nose-only inhalation exposure to radiolabelled 2-BE at doses of 0.024, 0.24 or 2.16 mg/l for 6 hours, the body burden in male Fischer 344 rats ranged from 21-26% of the inhaled dose and 17-24% was metabolised. The majority (64-76%) was eliminated in the urine, 1.2-2.3% in the faeces and 5.9-7.6% exhaled as C02. The carcass contained 12.9-19.8% up to 66 hours postexposure at all concentrations. 2-Butoxyacetic acid was eliminated in urine as the major metabolite at all dosages. Uptake and metabolism was proportional to exposure. Ethyle ne glycol, the glucuronide conjugate and two unknown minor me tabolites were also found.OECD SIDS 2 -BUTOXYETHANOL

UNEP Publications 261 Urinary excretion was highest at th e low dosages. Analysis of whole blood showed the majority of the la bel in plasma and 20% in the red blood cell fraction after 2 hours exposure. Reference: Sabourin et al, 1992 (136)

Type: Toxicokinetics Remark: Following occluded dermal applica tion of radiolabelled 2-BE at 14.4, 43.4 and 76.8 mg/rat for 23 hours, Fischer 344 rats absorbed and metabolized about 20-26% of the dose over 72 hours. 82-83% was excreted in the urine, 2.9-5.6% in the faeces, 3.0-5.0% in exhaled air and 8.3-9.7% remained in the carcass. The application site retained about 0.3-2%. 2-Butoxyacetic acid (BAA) was the major metabolite with evidence of glucuronide conjugate and ethylene glycol. No dose-related trend was apparent in type or quantity of metabolites produced. More than 80% of the label was found in blood plasma and < 20% was found in the red blood cell fraction; 53-75% of the plasma label was associated with BAA. Reference: Sabourin et al, 1992 (137)

Type: Toxicokinetics Remark: A physiologically-based pharmacokinetic model of human metabolism, excretion and disposition of inhaled 2-BE was reported. Modelled and observed data were in agreement. Increased physical activity and co-exposure to ethanol were predicted to influence the kinetics of 2-BE. Th e model indicated that 2-BE is unlikely to accumulate in the body. Reference: Johanson, 1986 (146)

Type: Absorption Remark: In an occlusive study in 10 fema le guinea-pigs using undiluted 2- butoxyethanol, the mean absorp tion rate obtained was 1.77 mg/cm 2 /h (range 0.35-3.3), measured by analysing blood samples at intervals up to 2h after application. Reference: Johanson and Fernstrom, 1986 (170)

Type: Absorption Remark: In a later study by the same authors using aqueous solutions of 2- butoxyethanol (5-80%) and undilute d chemical, higher absorption rates were obtained for the a queous solutions (range 0.52-0.73 mg/cm 2 /h) than for undiluted 2-BE (0.27 mg/cm 2 /h). Only 2 guinea-pigs per concentration were used (except for 40% solution - 4 animals). Following this initial exposure, all animals (14) were then exposed to 100% 2-BE for 2h and a mean uptake rate of 0.94 mg/cm 2 /h (range 0.45-2.9) was obtained.

Although the mean absorption rates varied between studies and the individual rates varied within a study, it was clearly demonstrated that 2-butoxyethanol is significan tly absorbed through the skin of the guinea-pig, that uptake is rapid, and that absorption is high from aqueous solution. Reference: Johanson and Fernstrom, 1988 (147)OECD SIDS 2 -BUTOXYETHANOL

UNEP Publications 262

Type: Absorption Remark: In a study in male and fema le Wistar rats, 200 mg/kg of radiolabelled 2-BE (undiluted) was applied to the skin under a perforated glass capsule for 48h. Of the applied dose, 29% was absorbed in males within 48h and 25% in females. The maximum radioactivity in blood and plasma occurred after 2h. As the study was conducted under nonocclusive conditions, some 2-BE may have evaporated. Reference: Bartnik et al, 1987 (93)

Type: Absorption (dermal - in vitro) Remark: A series of in vitro tests wa s conducted (using both undiluted 2- butoxyethanol and aqueous solutions)in different species. The results indicated that absorption th rough rat skin is high and rapid. Absorption through pig and human skin was lower but significant. The percentage dose absorbed from aqueous solutions was higher than for undiluted 2-butoxyethanol, but the applied dose was much lower. The effects on the rate of skin absorption of 2-butoxyethanol by two ingredients typical of those normally used in cleaning product formulations were also eval uated (separately) in rat and pig skin. The addition of 5% isopropanol and 5% linear sodium dodecylbenzene sulfate to 3.5% and 10% aqueous 2-butoxyethanol solutions did not significantly a ffect the absorption rate of 2- butoxyethanol. Reference: Bartnik et al 1987 (93)

Type: Skin absorption in vitro Remark: Absorption rate of 2-butoxyethanol across isolated human epidermis in vitro was 0.20 mg/cm^2/hour. Undiluted 2-BE was allowed to permeate for 8 hours across a hydrated section of tissue held in a glass diffusion cell. Reference: Dugard et al, 1984 (148)

Type: other: in vitro percutaneous absorption Remark: Three sections of stratum corn eum from human abdominal skin were exposed to 2-butoxyethanol via Franz-type diffusion cells. Dulbecco's phosphate buffered saline was used as receptor and control solutions. The rate of increase in concentration of 2- butoxyethanol in receptor solu tion was used to calculate a permeability constant and an absorption rate. The experiment was conducted twice under GLP conditi ons. Mean dermal absorption rate in the first experimental run was 0.857 +/- 0.282 mg/cm^2/hour and in the second run was 1.52 +/- 0.37 mg/cm^2/hour. The overall mean dermal absorption rate was 1.19 +/- 0.472 mg/cm^2/hour, with the range 0.57-1.91. The variability between experiment runs was due to varying degrees of skin damage caused by the test material. The overall mean absorp tion rate excludes data from diffusion cells in which the mean damage ratio was greater than 5. Reference: Barber et al, 1991 (151) Source: Eastman Kodak USAOECD SIDS 2 -BUTOXYETHANOL

UNEP Publications 263 Type: Distribution and Excretion Remark: Following subcutaneous injection with 118 mg/kg radiolabeled 2- BE, male rats excreted label in the urine (79%), exhaled air (10%) and faeces (0.5%) after 72 hours. Th e carcass retained about 5% and high levels were found in the spleen and thymus and, to a lesser extent, in the liver and fat. Reference: Bartnik et al 1987 (93)

Type: Toxicokinetics (inhalation) Remark: The mean uptake rate in ma le Sprague-Dawley exposed continuously to 20 or 100 ppm 2-BE (for periods up to 12 days) was 1.53 mg/h (3.5 mg/kg/h) and 7.73 mg/h (17.8 mg/kg/h) respectively. The rate was independent of duration of exposure.

Mean concentrations (in μ mol/kg) of 2-BE and 2-butoxyacetic acid (BAA) (the principal metabolite) in tissues were (for 20 and 100 ppm): 2-BE - blood (15.1, 72.3), mu scle (9.1, 30.4), testes (3.9, 2.6), liver (10.8, 83.8); BAA - bl ood (41.0, 179.0), muscle (9.3, 36.2), testes (14.1: 26.7), liver (16.4, 85.2).

The total blood clearance of 2-BE was approx. 2.6 L/h/kg throughout the exposure period an d was independent of vapour concentration. The mean renal clearance values for BAA were 0.49 L/h/kg (mean excretion rate 0.98 mg /h) at 20 ppm, and 0.58 L/h/kg (5.3 mg/h) at 100 ppm. Reference: Johanson 1994 (171)

Type: Elimination (in vitro) Remark: In a study of the elimination kineti cs of 2-butoxyetha nol in perfused rat liver, the hepatic blood cl earance of 2-butoxyethanol was reported as approximately 2.0 L/h/kg. The elimination rate was clearly dependent on concentration. The addition of 0.1% ethanol drastically reduced the elimina tion rate, supporti ng the hypothesis that 2-butoxyethanol is normally oxidised by alcohol dehydrogenase in the liver. Reference: Johanson 1988 (172)

Type: Elimination/excretion Remark: In a human study, five male volunt eers were exposed to 2-BE by immersing four fingers of one hand in the chemical (undiluted) for 2 hours. The elimination half-life of 2-BE from blood was approx. 80 min. The BAA concentration in urine reached a maximum at about 3 hours after exposure, with a mean half-life of 3.1 hours. A wide variation in results existed between subjects in the study. Reference: Johanson et al 1988 (156)

Type: Elimination/excretion Remark: In a 2-hour inhalational study in human volunteers, the mean elimination half-life of 2-BE in the blood was 40 min., with a total blood clearance of 1.2 L/min. and a steady-state volume ofOECD SIDS 2 -BUTOXYETHANOL

UNEP Publications 264 distribution of 54 L. The concentrat ion and excretion rate of BAA in urine was variable between subject s, with the respective maxima attained after 5-12 hours and 2- 10 hours. The mean elimination half-life for BAA in urin e after exposure was 5.8 hours. Reference: Johanson et al 1986 (155)

Type: Elimination/excretion Remark: In human inhalation studies, 13-27% of the absorbed dose was excreted as BAA in urine and less than 1% eliminated as 2-BE. Reference: Van Vlem 1987 (173)

Type: Absorption (dermal) Remark: In a human study, five male volunt eers were exposed to 2-BE by immersing four fingers of one hand in the chemical (undiluted) for 2 hours. The mean dermal absorption rate from 12 measurements was 0.142 mg/cm 2 /h, with individual results quite variable (range 0.05- 0.68 mg/cm 2 /h). There was little or no delay in detecting 2-BE in the bloodstream, with the concen tration in blood continuing to increase after exposure in most cases. Reference: Johanson et al 1988 (156)

Type Absorption (dermal) Remark Six male volunteers exposed one arm to 50 ppm of 2-BE for 2 hours. The dermal absorption of vapours was not more than 21% of the total uptake. Blood was sampled from the exposed arm using the finger-prick method and from the unexposed arm using a catheter. The results indicated that sampling via the finger-prick method (as used by Johanson & Boman, 1991) was not representative of systemic blood concentrations of 2-BE. Reference Corley et al 1995 (194)

Type: Toxicokinetics (inhalation) Remark: In a study carried out in an in halational chamber, seven male volunteers were exposed to 20 ppm of 2-BE for 2 hours during light exercise at 50 watts (mean breathi ng rate 22.6 L/min.). The mean respiratory absorption rate was estimated as 71.6 mg/h (range 54.7- 97.1), equivalent to 57.3% of the in spired amount. The uptake was rapid and remained relatively cons tant during exposure. In the study, 41% of the absorbed dose was excreted as BAA in the urine in 24 hours and only 0.03% as 2-BE. Reference: Johanson et al 1986 (155)

Type: Absorption Remark: Four male volunteers were expos ed to 50 ppm 2-BE for 2 hours, first by inhalation (mouth only), and then skin only (the volunteers wore shorts and an air respirat or). At ambient temperature (23 o C), the inhalational abso rption rate was 70.2 mg /h (range 58.9-78.1) whereas the dermal absorption ra te was 227 mg/h (range 61.8-348). The results suggest that dermal uptake accounts for approximately 75% of the total uptake during whole-body exposure to 2-BE vapours. Average absorption rates at raised temperature andOECD SIDS 2 -BUTOXYETHANOL

UNEP Publications 265 humidity were higher (not statis tically significant) and breathing rates were slightly higher with heart rates about the same. Reference: Johanson and Boman 1991 (154)

Type: Absorption (inhalation) Remark: In an inhalational study in male vol unteers, 67-78% of the inspired amount was absorbed after exposure to 12.6 or 25.2 ppm 2-BE, either at rest or duri ng light exercise at 30 watts. The volunteers wore face masks during the 4 hour e xposure. The mean respiratory absorption rate at 25.2 ppm (at re st) was 31 mg/h. At 12.6 ppm the mean uptake (at rest)was 15.5 mg/h, and under a 30 watts workload, it was 33 mg/h. Reference: Van Vlem, 1987 (173)

Type: Metabolism Remark: In a gavage study in the F344 rat, 2-butoxyacetic acid (BAA) was the major metabolite in urine (approx. 65% of 14 C-2-butoxyethanol at dose of 126 mg/kg) with con centrations of approx. 15% and 4% of the glucoronide conjugate and ethylene glycol respectively. Reference: Corley et al 1994 (174)

5.11 Experience with Human Exposure

Type: Case report Remark: A 50-yr-old woman ingested 250 -500 ml of a window cleaning product containing 12% 2-BE (30-60 g 2-BE ingested). Main effects were coma, absence of response to pain stimulus, breathing difficulties, metabolic acidosis, hypokalemia, rise in serum creatinine and increased urinary ex cretion of oxalate. Treatment was effective against hydroelect rolytic disturbances but haemoglobinuria, inducing progressi ve erythropenia, ensued on days 3-6. Her condition improved gr adually and she was discharged on day 10. Reference: Rambourg-Schepens, 1988 (157)

Type: Case report Remark: A 23-yr-old woman ingested 500 ml of a window cleaning product containing 12.7% 2-BE (dose a pprox. 60 g) and 3.2% ethanol. Main effects were coma, dilated pupils, obstructive respiration, hypotension, metabolic acidosis, hyperventilation, depression of blood haemoglobin concentration fro m 11.9 g/dl to 8.9 g/dl over 2 days and haemoglobinuria. The main metabolite of 2-BE, 2- butoxyacetic acid, was detected in urine but no oxaluria was observed. She was discharged from hospital on day 8. Reference: Gijsenbergh et al, 1989 (158)

Type: Case report Remark: A 53-yr-old male ingested 500 ml of a cleaning fluid containing 9.1% 2-BE (dose 45.5 g) and 2.5% ethanol. He was admitted to hospital about 10 hours later in a state of coma with metabolic acidosis, shock and noncardiogenic pulmonary oedema. His heartOECD SIDS 2 -BUTOXYETHANOL

UNEP Publications 266 rate was increased, blood pressure was decreased and there were transient polyuria and hypoxaemia . Non-haemolytic hypochromic anaemia was evident with haemoglobin concentration of 9.1 g/dl, haematocrit 25% and thrombopeni a (platelet c ount 85000). The patient was discharged after 15 days. Reference: Bauer et al, 1992 (159)

Type: Case report Remark: 24 Children (7 months to 9 years) ingested at least 5 ml of glass/window cleaners containing 2- BE at concentrations ranging 0.5 to 9.9%. Most of the quantitie s swallowed were small, but one child ingestd 30 ml of cleaner co ntaining < 10% 2-BE and another 300 ml of an 8% solution. Children undwerwent gastric emptying. No signs of haemolysis, meabolic acidosis or CNS depression were observed Reference: Dean and Krenzelok, 1992 (161)

Type: Case report Remark: Ingestion of a cleaning product co ntaining 22% 2-BE resulted in symptoms consistent with me tabolic acidosis. No signs of haemolysis were apparent. The estimated dose was 80-106 g 2-BE, equivalent to 1.1-1.5 g/kg bw. In a repeat of the incident two weeks later, similar symptoms were observed. Reference: Gualtieri 1995 (160)

Type: Case report Remark: A carpet cleaner using a so lution containing an unknown concentration of 2-BE experienced dizziness, blurred vision, and red urine towards the end of his 8-hour shift a number of times. Reference: Pesticide and Toxic Chemical News, USA, 1993 (176) Source: US EPA

Type: Controlled study Remark: Three experiments were condu cted by Carpenter on human volunteers, with the results as follows: . When 2 men were exposed to 113 ppm for 4 hours, no effect on RBC fragility was observed. The men suffered nasal and eye irritation, nasal discharge a nd a nasty taste in the mouth. At 4-6 hours after exposure, one man was still unwell.

. When 2 men and one woman were exposed to 195 ppm for two 4-hour periods, the RBC fragility was unaffected. 2- Butoxyacetic acid (BAA) was excr eted in the urine of the woman and one male, but only a trace was detected in the second male. Symptoms include d irritation of the eyes, nose and throat, unpleasant taste, and headache.

. When 2 men and 2 women were exposed to 100 ppm for 8 hours, BAA was excreted in all volunteers and no RBC fragility was observed. Symptoms noted were headache and

nausea.OECD SIDS 2 -BUTOXYETHANOL

UNEP Publications 267 Reference: Carpenter et al, 1956 (82)

Type: Exposure monitoring Remark: An analytical method to determin e the absorption of 2-BE following use of formulated products by car window cleaners and office cleaners was reported. The window cleaning agents contained 1- 21% 2-BE and the time weighted average (TWA) exposure concentrations ranged from < 0.1 ppm to 7.3 ppm 2-BE. 2- Butoxyacetic acid (BAA) in urin e ranged from < 2-371 mg/g creatinine. Office cleaners used pr oducts containing between 1-10% 2-BE, with mean exposure appr ox. 0.3 ppm. BAA in urine ranged from < 2-3.3 mg/g creatinine. Urinary BAA results did not correlate well with atmospheric 2-BE concentrations. The results indicated that inhalation exposure was a mi nor component of the systemic dose and that dermal absorption of liquid formulations was a major contributor. Reference: Vincent et al, 1993 (163)

Type: Exposure monitoring Remark: Exposure measurements were made in 55 French firms covering 18 sectors of activity, in cluding the principal end-use categories of products containing glyc ol ethers: paints, inks, diluents and varnishes, cleaning products, co smetics and solvents. Exposure levels were measured in each of the facilities using personal atmospheric monitoring for 2-BE and urinary samples (at the beginning and end of each shift) for the major metabolite, 2- butoxyacetic acid (BAA). The highe st exposures were obtained where paints, inks, varnishes and cl eaning products were used. In some cases, skin absorption was chiefly responsible for the

exposures. Reference: Vincent et al, 1996 (193)

Type: Exposure monitoring Remark: Post-shift urine samples from 6 healthy lacquerers exposed to 2- butoxyethanol-containin g detergent contained 2-butoxyacetic acid (0.13-5.91 mmol/l) and its glutamine conjugate (0.12-2.45 mmol/l). Pre-shift urine samples contained on ly traces of these metabolites. Reference: Rettenmeier et al, 1993 (152)

Type: Exposure monitoring Remark: Post-shift urine samples from a sub-group of 9 workers (in the printing and electrical industries) exposed to 2-butoxyethanol at a time weighted average range of 0.4-0.8 ppm (mean 0.64 ppm) showed 2-butoxyacetic acid con centrations in the range 1.3-9.9 mg/g creatinine (mean 3.9 mg/g). Reference: Sakai et al, 1993 (153)

Type: Exposure Monitoring Remark: Occupational exposure monitoring of school cleaners (in Australia) to products (liquid and sprays) containing 0.25% 2-BE revealed worker airborne exposures below the detection limit (0.7 ppm forOECD SIDS 2 -BUTOXYETHANOL

UNEP Publications 268 personal monitoring & 0.2 ppm for area monitoring conducted in the classroom 1-1.5 hours after appli cation of the cleaning solution). Reference: NICNAS 1996 (11)

Type: Exposure Monitoring Remark: In a silkscreening operation in Vi rginia, USA, workers exposed to undiluted 2-BE reported irritation an d discomfort. In the subsequent inspection of the workplace, atmosphe ric concentrations of 2-BE in the range 13-169 ppm were obtai ned. The mean exposure from personal monitoring was 25 ppm whereas the mean from area monitoring was 69 ppm. Workers us ed 2-BE in open spray troughs without adequate ventilati on or protective equipment. Source: NIOSH 1987 (177)

Type: Exposure Monitoring Remark: Occupational exposure monitoring of print machine operators using a cleaning solvent containing 10-50% 2-BE revealed mean (personal monitoring) levels of 5.2 ppm 2-BE in air (range 1.7-9.7 ppm). Source: NIOSH 1987 (178)

Type: Exposure Monitoring Remark: Occupational exposure monitoring of a cleaner (in USA) carrying out mechanical floor scrubbing w ith a product containing 0.3% 2- BE, revealed 1.6 ppm 2-BE in ai r (personal monitoring - 95 min sampling time). Source: NIOSH 1979 (179)

Type: Exposure Monitoring Remark: Occupational exposure monitoring of hospital window cleaners (in USA) using a spray product cont aining 2-BE revealed < 0.2 ppm 2- BE in air (personal monitoring - sampling over whole shift). Source: NIOSH 1979 (180)

Type: Exposure Monitoring Remark: Occupational exposure monitoring of printing press operators (in USA) cleaning the rollers with a product containing 2-BE revealed < 0.15-0.53 ppm 2-BE in air (perso nal monitoring - sampling time 4-6 hours). Source: NIOSH 1990 (184)

Type: Exposure Monitoring Remark: In a survey of workers at a number of screen printing shops, personal monitoring of silkscreener s using products c ontaining up to 45% 2-BE resulted in a mean of 6.8 ppm 2-BE in air (16 samples). Personal monitoring of spray painte rs in the shops using products containing up to 55% 2-BE resulted in a mean of 2.6 ppm 2-BE in air (5 samples). Air sampling during specific tasks resulted in in the following mean 2-BE in air: sc reening 9.1 ppm, spray painting 3.1 ppm, hand cleaning 1.8 ppm, me tal coating 0.1 ppm, and blast cleaning 115 ppm.OECD SIDS 2 -BUTOXYETHANOL

UNEP Publications 269 Source: NIOSH 1985 (186)

Type: Exposure Monitoring Remark: A silk-screen printer in a fishing rod factory (in USA) experienced headache, throat and nose irritati on, including bleeding of the nose. The worker used a cleaning solvent containing 2-BE, cyclohexanol and petroleum distillates. Occupational exposure (personal) monitoring) revealed 3-5 ppm (mean 4 ppm) 2-BE in air (sampling time 3-7 hours). The solvent was us ed in spray form and ventilation

was poor. Source: NIOSH 1986 (185)

Type: Exposure Monitoring Remark: In occupational exposure monitori ng of varnish production workers, a mean of 1.1 ppm 2-BE in air (p ersonal monitoring) was obtained, with a mean BAA level of 10.5 mg/L urine. For individual results, no correlation between 2-BE in air and BAA in urine was seen. The 2-BE content in the product(s) was not stated. Repeat monitoring of the same group of workers gave a mean of 0.6 ppm 2-BE in air (personal monitoring), with a mean BAA level of 8.2 mg/L urine). Reference: Angerer et al 1990, Sohnlein et al 1993 (181)(182)

Type: Exposure Monitoring Remark: In a survey of 9 parquet floor makers exposed to a variety of organic solvents, including 2-BE, the mean TWA 2-BE in air was 5.0 ppm, with results up to 71 ppm. Reference: Denkhaus et al, 1986 (187)

Type: Exposure Monitoring Remark: In a survey industries and workshops in Belgium, 2-BE was detected in 25/94 air samples in the printing industry, 10/81 in the paint industry, 1/20 car repair shop s, and 17/67 other operations. Mean 2-BE in air results were as follows: 0.8 ppm (range 0.3-5.5) in printing, 3.8 ppm (range 0.7-19) in painting, 1.2 ppm in car repair, and 1.7 ppm in other industries. Reference: Veulemans et al, 1987 (188)

Type: Exposure Monitoring Remark: In a 2-BE manufacturing process, the highest results were obtained during drum filling, 1.7 ppm (area monitoring). Reference: Clapp et al 1984 (164)

Type: Exposure Monitoring Remark: In a survey of house painters in Denmark, the 2-BE in air concentration was in the range 0-12 ppm. Reference: Hansen et al 1987 (189)

Type: Exposure Monitoring Remark: In a survey of house painters in Sweden, the 2-BE in air concentration was in the range 0- 0.015 ppm, with a mean of 0.01

ppm.OECD SIDS 2 -BUTOXYETHANOL

UNEP Publications 270

Reference: Norback et al 1996 (190)

Type: Exposure Monitoring Remark: In a survey of automotive spray painters (in Australia) exposed to a mixture of solvents, the mean TWA 2-BE concentration was 0.4

ppm. Reference: Winder and Turner, 1992 (165)

Type: Exposure Monitoring Remark: At a 2-butoxyethanol (2-BE) ma nufacturing plant in Australia, personal monitoring results (for 2- BE) were generally < 0.1 ppm for both STEL and TWA measurements. The highest monitoring results were obtained during maintenance activities, where a TWA level of 1.8 ppm has been recorded in area monitoring. Source: NICNAS 1996 (11)

Type: Exposure Monitoring Remark: In a survey of workers exposed to glycol ethers in a wide variety of industries in Ontario, Canada over the period 1983-1993, 2-BE was detected in 1404 area monitoring samples and 1683 personal monitoring samples. All 2-BE re sults were less than 25 ppm TWA. Reference: Guirguis et al, 1994 (191)

Type: Exposure Monitoring Remark: Personal monitoring results of workers in a wide variety of industries in Germany over the period 1991-1995. Results (expressed as % of measurements below certain threshold (TWA) concentrations) were presented fo r 3 types of work (formulation; surface coating & cleaning) involvi ng exposure to 2-BE. Of 204 measurements (in 71 companies) during formulation, 5% were > 12 mg/m 3 (2.4 ppm); of 115 measuremen ts (in 47 companies) during screen printing (without mechanical ventilation), 10% were > 8 mg/m 3 (1.6 ppm); of 200 measurements (in 116 companies) during spray-painting (manual), 5% were > 15 mg/m 3 (3.1 ppm); of 59 measurements (in 38 companies) during surface coating (manual), 5% were > 41 mg/m 3 (8.4 ppm); of 54 measurements (in 17 companies) during floor cl eaning, 5% were > 47 mg/m 3 (9.6 ppm) and of 53 measurements (in 31 companies) during surface cleaning (without ventilation), 5% were > 24 mg/m 3 (4.9 ppm).

With each set of measurements at least 50% were below the analytical detection limit (range 0.2-5.0 mg/m 3 ).

Comment: TWA measurements were based on a 1 hour sampling period.

Reference: Berufsgenossenschaftlicher Arbe itskreis Altstoffe (BGAA),1996 (195)

Type: Health surveyOECD SIDS 2 -BUTOXYETHANOL

UNEP Publications 271 Remark: In a qualitative survey of school cleaners in New South Wales, Australia, several reports of eye and throat irritation, headache and nausea were received from cleaner s using products containing 2- butoxyethanol (amongst other cleani ng products). In most cases, the products were being used in spray form. Source: NICNAS 1996 (11)

Type: Case report Remark: Adverse effects observed in cleaner s using floor strippers containing high levels of 2-butoxyethanol included eye irritation and drowsiness when the ventilation wa s poor. Some reddening of the skin and contact dermatitis occurred when the proper safety gloves

were not worn. Source: NICNAS 1996 (11)

Type: Review Remark: ECETOC has critically reviewed the health and toxicological properties of 2-BE to assist the European Commission in the setting of an exposure standard (Indicative Limit Value).

Haemolysis during the first few da ys of exposure is the primary indicator of toxicity in rodents. A NOAEL of 25 ppm (equivalent to 121 mg/m^3) has been reported for rats exposed over 90 days (Dodd et al. 1983) whereas other mammals, including man, are less susceptible. The metabolite 2-buto xyacetic acid is responsible for 2-BE-induced haemolysis. This prod uces lysis of rat red blood cells in vitro at 2 mM whereas only very slight effects (no haemolysis) are seen at 8 mM in red cells from humans susceptible to haemolytic disorders. It was conc luded that human erythrocytes are more resistant than blood cells from the rat.

The rat NOAEL of 25 ppm was cons idered by ECETOC as directly relevant to the setting of a wor kplace exposure standard for 2-BE. This NOAEL also takes account of concurrent dermal absorption occurring during whole body inhalation exposure. In applying this animal data, no uncertainty factor is needed for extrapolation from subchronic to chronic exposure sin ce haemolyis is transient, seen only during the first few days of exposure. A physiologically-based pharmacokinetic model (PBPK model) predicts that the concentration of butoxyacetic acid in blood of humans exposed to 20-25 ppm 2-butoxyethanol will be approximately 0.03 uM. This is 270-fold less than the concentration needed to cause minimal changes in human red blood cells in vitro.

No haemolysis was reported in human volunteers exposed to 50 ppm for 2 hours or 100 or 195 pp m for 8 hours (although irritation of the eyes and respiratory tract we re seen at concentrations of 100 ppm and above).

On the basis of the above data, ECETOC concluded that a long term occupational exposure standard (8 hour TWA) of 20 ppm would beOECD SIDS 2 -BUTOXYETHANOL

UNEP Publications 272 protective of human health.

Source: BP Chemicals Ltd. London (122)

Type: Review Remark: In a safety assessment of 2-butoxyeth anol for its use in cosmetics, the review panel concluded that, on the basis of animal and clinical data, 2-BE is safe in hair and na il products at concentrations up to 10%. Source: The Cosmetic, Toiletry, and Fragrance A ssociation USA (192)OECD SIDS 2 -BUTOXYETHANOL

UNEP Publications 273 6. References

(1) Dutch MAC list 1994

(2) TRGS 900 1993

(3) DFG (1993): MAK-Liste, 26 (01.09.1993)

(4) Hoechst AG (1994): Produktinformation Buty lglykol der Abt. Marketing Chemikalien

(5) National Institute for Occupational Safety and Health, Criteria for a Recommended Standard - Occupational Exposure to Ethylene Glycol Mon obutyl Ether and Ethylene Glycol Monobutyl Ether Acetate , DHHS (NIOSH) Publication no.90-118, U.S. Depa rtment of Health and Human Services, Cincinnati, Ohio, USA, September 1990.

(6) MAK-Liste 1993

(7) ACGIH list 1995-1996

(8) National Occupational Health and Safety Commission, Exposure Standards for Atmospheric Contaminants in the Occupational Environment , Australian Government Publishing Service, Canberra, October 1995

(9) 29 CFR 1910.1000, 1 July 1993.

(10) Bundesminister des Innern (1990): Gemein sames Ministerialblatt Nr. 8 (23.03.90), Kenn-Nr. 47

(11) NICNAS (National Industrial Chemicals No tification & Assessment Scheme), Full Public Report, Priority Existing Chemical No.6 - 2-Butoxyethanol in Cleaning Products , AGPS, Canberra, Australia, 1996.

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UNEP Publications 283OECD SIDS 2 -BUTOXYETHANOL

UNEP Publications 284 

# EXTRACT FROM IRPTC LEGAL FILESOECD SIDS 2 -BUTOXYETHANOL

UNEP Publications 285 file: 17.01 LEGAL rn : 100247 systematic name:Ethanol, 2-butoxy- common name :Ethylene glycol monobutyl ether reported name :2-Butoxyethanol cas no :111-76-2 rtecs no :KJ8575000 area : ARG type : REG

-------------------------------- |subject|specification|descriptor| |-------+-------------+----------| | AIR | OCC | MPC |

-------------------------------- 8H-TWA: 120MG/M3 (25PPM). SKIN ABSORPTION. entry date: OCT 1991 effective date: 29MAY1991

title: LIMIT VALUES FOR CHEMICAL SUBSTANCES IN THE WORKING ENVIRONMENT-RESOLUTION NO. 444/1991 OF THE MINISTRY OF WORK AND SOCIAL SECURITY (AMENDING REGULATION DECREE NO. 351/1979 UNDER LAW NO. 19587/1972: HYGIENE AND SAFETY AT WORK) original : ARGOB*, BOLETIN OFICIAL DE LA REPUBLICA ARGENTINA(ARGENTIAN OFFICIAL BULLETIN), 24170 , I , 1 , 1979 amendment: ARGOB*, BOLETIN OFICIAL DE LA REPUBLICA ARGENTINA(ARGENTIAN OFFICIAL BULLETIN), 27145 , I , 4 , 1991

*******

file: 17.01 LEGAL rn : 300534 systematic name:Ethanol, 2-butoxy- common name :Ethylene glycol monobutyl ether reported name :2-Butoxyethanol cas no :111-76-2 rtecs no :KJ8575000 area : CAN type : REG

-------------------------------- |subject|specification|descriptor| |-------+-------------+----------| | AIR | OCC | TLV |

-------------------------------- TWA: 25 ppm, 120 mg/m3; skin absorption. Prescribed by the Canada Occupational Safety and Health Regulations, under the Canada Labour Code (administered by the Department of Employment and Immigration). The regulations state that no employee shall be exposed to a concentration of an airborne chemical agent in excess of the value for that chemical agent adopted by ACGIH (American Conference of Governmental Industrial Hygienists) in its publication entitled: "Threshold Limit Value and Biological Exposure Indices for 1985-86". The regulations also state that the employer shall, where a person is about to enter a confined space, appoint a qualified person to verify by means of tests that the concentration of any chemical agent or combination of chemical agents will not result in the exposure of the person to a concentration in excess of the value indicated above. These regulations prescribe standards whose enforcement will provide a safe and healthy workplace. entry date: OCT 1994 effective date: 24MCH1994

amendment: CAGAAK, CANADA GAZETTE PART II, 128 , 7 , 1513 , 1994

*******

file: 17.01 LEGAL rn : 301897 systematic name:Ethanol, 2-butoxy-OECD SIDS 2 -BUTOXYETHANOL

UNEP Publications 286 common name :Ethylene glycol monobutyl ether reported name :Ethylene glycol monobutyl ether cas no :111-76-2 rtecs no :KJ8575000 area : CAN type : REG

-------------------------------- |subject|specification|descriptor| |-------+-------------+----------| | TRNSP | | CLASS | | | | RQR | | LABEL | | | | PACK | | |

-------------------------------- Schedule II, List II - Dangerous Goods other than Explosives: PIN (Product Identification No.): UN2369. Class (6.1): Poisonous. Packing group III, (I=Great danger, III=Minor danger). Passenger Vehicles: 60 L. Prescribed by the Transportation of Dangerous Goods Regulations, under the Transportation of Dangerous Goods Act (administered by the Department of Transport). The act and regulations are intended to promote safety in the transportation of dangerous goods in Canada, as well as provide comprehensive regulations applicable to all modes of transport accross Canada. These are based on United Nations recommendations. The act and regulations should be consulted for details. Information is entered under the proper shipping name found in the regulations; this may include general groups of chemical substances. entry date: OCT 1994 effective date: 02DEC1993

amendment: CAGAAK, CANADA GAZETTE PART II, 127 , 25 , 4056 , 1993

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file: 17.01 LEGAL rn : 302515 systematic name:Ethanol, 2-butoxy- common name :Ethylene glycol monobutyl ether reported name :Ethylene glycol monobutyl ether cas no :111-76-2 rtecs no :KJ8575000 area : CAN type : REG

-------------------------------- |subject|specification|descriptor| |-------+-------------+----------| | USE | OCC | RQR | | STORE | | | | LABEL | | |

-------------------------------- Ingredient Disclosure List - Concentration: 1% weight/weight. The Workplace Hazardous Materials Information System (WHMIS) is a national system providing information on hazardous materials used in the workplace. WHMIS is implemented by the Hazardous Products Act and the Controlled Products Regulations (administered by the Department of Consumer and Corporate Affairs). The regulations impose standards on employers for the use, storage and handling of controlled products. The regulations also address labelling and identification, employee instruction and training, as well as the upkeep of a Materials Safety Data Sheet (MSDS). The presence in a controlled product of an ingredient in a concentration equal to or greater than specified in the Ingredient Disclosure List must be disclosed in the Safety Data Sheet. entry date: APR 1991 effective date: 31DEC1987

amendment: CAGAAK, CANADA GAZETTE PART II, 122 , 2 , 551 , 1988OECD SIDS 2 -BUTOXYETHANOL

UNEP Publications 287 *******

file: 17.01 LEGAL rn : 522981 !!! WARNING - not original IRPTC record - WARNING !!! systematic name:Ethanol, 2-butoxy- common name :Ethylene glycol monobutyl ether reported name :Ethylene glycol mono-n-butyl ether cas no :111-76-2 rtecs no :KJ8575000 area : DEU type : REG

-------------------------------- |subject|specification|descriptor| |-------+-------------+----------| | AQ | | CLASS | | USE | INDST | RQR |

-------------------------------- This substance is classified as moderately hazardous to water (Water Hazard Class: WHC 1). (There are 3 water hazard classes: WHC 3 = severely hazardous; WHC 2 = hazardous; WHC 1 = moderately hazardous; and the classification as "not hazardous to water"). The purpose of the classification is to identify the technical requirements of industrial plants which handle substances hazardous to water. entry date: SEP 2001 effective date: 01JUN1999

title: Administrative Order relating to Substances Hazardous to Water (Verwaltungsvorschrift wassergefaehrdende Stoffe) original : BUANZ*, Bundesanzeiger, 51 , 98a , 1 , 1999

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file: 17.01 LEGAL rn : 532419 !!! WARNING - not original IRPTC record - WARNING !!! systematic name:Ethanol, 2-butoxy- common name :Ethylene glycol monobutyl ether reported name :2-Butoxyethanol cas no :111-76-2 rtecs no :KJ8575000 area : DEU type : REG

-------------------------------- |subject|specification|descriptor| |-------+-------------+----------| | AIR | EMI | MPC |

-------------------------------- THIS SUBSTANCE BELONGS TO CLASS II. THE AIR EMISSIONS OF ORGANIC COMPOUNDS MUST NOT EXCEED (AS THE SUM OF ALL COMPOUNDS IN ONE CLASS) THE FOLLOWING MASS CONCENTRATIONS: CLASS I - 20 MG/M3 AT A MASS FLOW OF >= 0.1 KG/H; CLASS II - 100 MG/M3 AT A MASS FLOW OF >= 2 KG/H; CLASS III - 150 MG/M3 AT A MASS FLOW OF >= 3 KG/H. IF COMPOUNDS FROM DIFFERENT CLASSES ARE PRESENT, THE MASS CONCENTRATION MUST NOT EXCEED 150 MG/M3 AT A TOTAL MASS FLOW OF >= 3 KG/H. entry date: JAN 1995 effective date: 01MCH1986

title: Technical Instructions on Air Quality Control (Technische Anleitung zur Reinhaltung der Luft) original : GMSMA6, Gemeinsames Ministerialblatt, , 7 , 93 , 1986

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file: 17.01 LEGAL rn : 540383OECD SIDS 2 -BUTOXYETHANOL

UNEP Publications 288 !!! WARNING - not original IRPTC record - WARNING !!! systematic name:Ethanol, 2-butoxy- common name :Ethylene glycol monobutyl ether reported name :Ethylene glycol monobutyl ether cas no :111-76-2 rtecs no :KJ8575000 area : DEU type : REC

-------------------------------- |subject|specification|descriptor| |-------+-------------+----------| | AIR | OCC | MAK |

-------------------------------- MAK value (8-hour time-weighted average): 20 ml/m3 (ppm) or 98 mg/m3 (20 C, 1013 hPa). Peak limitation category II,1: Substance with systemic effects; onset of effect within 2 h; half-life < 2 h; excursion factor = 2 (peak level is 2 x MAK); maximum duration of peaks is 30 min, average value; maximum frequency 4x/shift. - Danger of cutaneous absorption. - Pregnancy risk group C: There is no reason to fear a risk of damage to the embryo or foetus when MAK and BAT values are observed. entry date: MAY 2001

title: List of MAK and BAT Values 2000. Maximum Concentrations and Biological Tolerance Values at the Workplace. (MAK- und BAT-Werte-Liste 2000. Maximale Arbeitsplatzkonzentrationen und Biologische Arbeitsstofftoleranzwerte.) original : MPGFDF, Mitteilung der Senatskommission zur Pruefung gesundheitsschaedlicher Arbeitsstoffe, 36 , , , 2000

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file: 17.01 LEGAL rn : 542509 !!! WARNING - not original IRPTC record - WARNING !!! systematic name:Ethanol, 2-butoxy- common name :Ethylene glycol monobutyl ether reported name :2-Butoxyethanol cas no :111-76-2 rtecs no :KJ8575000 area : DEU type : REG

-------------------------------- |subject|specification|descriptor| |-------+-------------+----------| | AIR | OCC | BAT |

-------------------------------- Parameter: Butoxyacetic acid. BAT value: 100 mg/l. Assay material: Urine. Sampling time: For long-term exposures: after several shifts. - The BAT value (biological tolerance value for occupational exposures) is defined as the concentration of a substance or its metabolites or the deviation from the norm of biological parameters induced by the substance which generally does not affect the health of the employees adversely. entry date: JUN 2001 effective date: 01APR2001

title: Technical Regulations for Hazardous Substances (TRGS 903): Biological Tolerance Values for Occupational Exposures. (Technische Regeln fuer Gefahrstoffe (TRGS 903): Biologische Arbeitsplatztoleranzwerte - BAT-Werte -.) original : BNDSD6, Bundesarbeitsblatt, , 4 , 52 , 2001

*******OECD SIDS 2 -BUTOXYETHANOL

UNEP Publications 289 file: 17.01 LEGAL rn : 606999 systematic name:Ethanol, 2-butoxy- common name :Ethylene glycol monobutyl ether reported name :ethylene glycol butyl ether cas no :111-76-2 rtecs no :KJ8575000 area : GBR type : REG

-------------------------------- |subject|specification|descriptor| |-------+-------------+----------| | TRNSP | MARIN | RQR | | AQ | MARIN | RQR | | AQ | EMI | RQR |

-------------------------------- CLASSIFIED AS A NON-POLLUTING LIQUID SUBSTANCE. DOCUMENTARY EVIDENCE OF ASSESSMENT AND APPROVAL REQUIRED BY A CARRIER. DISCHARGE INTO THE SEA IS NOT PROHIBITED. entry date: 1992 effective date: 06APR1987

title: THE MERCHANT SHIPPING (CONTROL OF POLLUTION BY NOXIOUS LIQUID SUBSTANCES IN BULK) REGULATIONS 1987, SCHEDULE 2 original : GBRSI*, STATUTORY INSTRUMENTS, 551 , , 15 , 1987 amendment: GBRSI*, STATUTORY INSTRUMENTS, 2604 , , 2 , 1990

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file: 17.01 LEGAL rn : 700489 systematic name:Ethanol, 2-butoxy- common name :Ethylene glycol monobutyl ether reported name :Butoxyethanol cas no :111-76-2 rtecs no :KJ8575000 area : IND type : REG

-------------------------------- |subject|specification|descriptor| |-------+-------------+----------| | MANUF | | RQR | | SAFTY | | RQR | | STORE | | RQR | | IMPRT | | RQR |

-------------------------------- These rules define the responsabilities of occupiers of any industrial activity in which this toxic and hazardous substance may be involved. These responsabilities encompass: (a) assessment of major hazards (causes, occurrence, frequency); (b) measures to prevent accidents and limit eventual impairment to human health and pollution of the environment; (c) provision of relevant factual knowledge and skills to workers in order to ensure health and environmental safety when handling equipments and the foregoing chemical; (d) notification of the competent authorities in case of major accidents; (e) notification of sites to the competent authorities 3 months before commencing; (f)preparation of an on-site emergency plan as to how major accidents should be coped with; (g) provision of competent authorities with information and means to respond quickly and efficiently to any off-site emergency; (h) provision of information to persons outside the site, liable to be affected by a major accident; (i) labelling of containers as to clearly identify contents, manufacturers, physical, chemical and toxicological data; (j) preparation of a safety data sheet including any significant information regarding hazard of this substance and submission of safety reports to the competent authorities; (k) for the import of a hazardous chemical to India, importers must supply the competent authorities with specified information regarding the shipment.OECD SIDS 2 -BUTOXYETHANOL

UNEP Publications 290 entry date: SEP 1992 effective date: 27NOV1989

title: THE MANUFACTURE, STORAGE AND IMPORT OF HAZARDOUS CHEMICALS RULES. 1989 original : GAZIN*, THE GAZETTE OF INDIA, 787 , , , 1989

*******

file: 17.01 LEGAL rn : 1010486 systematic name:Ethanol, 2-butoxy- common name :Ethylene glycol monobutyl ether reported name :2-Butoxyethanol cas no :111-76-2 rtecs no :KJ8575000 area : MEX type : REG

-------------------------------- |subject|specification|descriptor| |-------+-------------+----------| | AIR | OCC | MXL |

-------------------------------- AT ANY WORKPLACE WHERE THIS SUBSTANCE IS PRODUCED, STORED OR HANDLED A MAXIMUM PERMISSIBLE LEVEL OF 120MG/M3 (26PPM) MUST BE OBSERVED FOR A PERIOD OF 8 HOURS OR 360MG/M3 (75PPM) FOR 15 MINUTES FOUR TIMES A DAY WITH INTERVALS OF AT LEAST 1 HOUR. entry date: DEC 1991 effective date: 28MAY1984

title: INSTRUCTION NO.10 RELATED TO SECURITY AND HYGIENIC CONDITIONS AT WORKPLACES. (INSTRUCTIVO NO. 10, RELATIVO A LAS CONDICIONES DE SEGURIDAD E HIGIENE DE LOS CENTROS DE TRABAJO). original : DOMEX*, DIARIO OFICIAL, , , , 1984

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file: 17.01 LEGAL rn : 1105361 systematic name:Ethanol, 2-butoxy- common name :Ethylene glycol monobutyl ether reported name :2-Butoxyethanol cas no :111-76-2 rtecs no :KJ8575000 area : RUS type : REG

-------------------------------- |subject|specification|descriptor| |-------+-------------+----------| | AIR | OCC | MAC |

-------------------------------- CLV: 5.0MG/M3 (VAPOUR) HAZARD CLASS: III entry date: MAY 1990 effective date: 01JAN1988

amendment: GOSTS*, GOSUDARSTVENNYI STANDART SSSR(STATE STANDARD OF USSR), 12.1.005 , , , 1988

*******

file: 17.01 LEGAL rn : 1143058 systematic name:Ethanol, 2-butoxy- common name :Ethylene glycol monobutyl ether reported name :ethylene glycol butyl ether cas no :111-76-2 rtecs no :KJ8575000OECD SIDS 2 -BUTOXYETHANOL

UNEP Publications 291 area : RUS type : REG

-------------------------------- |subject|specification|descriptor| |-------+-------------+----------| | AIR | OCC | PSL |

-------------------------------- CLV: 5.0MG/M3 (VAPOUR) entry date: MAY 1990 effective date: APR1988

amendment: OBUVR*, ORIENTIROVOCHNYE BEZOPASNYE UROVNI VOZDEISTVIYA (OBUV) VREDNYKHVESHCHESTV V VOZDUKHE RABOCHEI ZONY (TENTATIVE SAFE EXPOSURE LEVELS OF HARMFUL SUBSTANCES IN OCCUPATIONAL AIR), 4613-88 , , , 1988

*******

file: 17.01 LEGAL rn : 1200089 systematic name:Ethanol, 2-butoxy- common name :Ethylene glycol monobutyl ether reported name :2-Butoxyethanol cas no :111-76-2 rtecs no :KJ8575000 area : SWE type : REG

-------------------------------- |subject|specification|descriptor| |-------+-------------+----------| | AIR | OCC | HLV |

-------------------------------- 1D-TWA: 100MG/M3 (20PPM), 15MIN-STEL: 250MG/M3 (50PPM), SKIN ABSORPTION. entry date: 1992 effective date: 01JUL1991

title: HYGIENIC LIMIT VALUES. original : AFS***, ARBETARSKYDDSSTYRELSENS FOERFATTNINGSSAMLING, 1990:13 , , 5-64 , 1990

*******

file: 17.01 LEGAL rn : 1301142 systematic name:Ethanol, 2-butoxy- common name :Ethylene glycol monobutyl ether reported name :2-n-Butoxyethanol cas no :111-76-2 rtecs no :KJ8575000 area : USA type : REG

-------------------------------- |subject|specification|descriptor| |-------+-------------+----------| | MANUF | REQ | PRMT | | USE | OCC | PRMT | | SAFTY | OCC | MXL |

-------------------------------- ; Summary - THE FOLLOWING CHEMICAL IS INCLUDED ON A LIST OF CHEMICALS AND MIXTURES FOR WHICH REPORTING IS CURRENTLY REQUIRED UNDER THE TOXIC SUBSTANCES CONTROL ACT SECTION 2607A. THIS TOXIC SUBSTANCE IS SUBJECT TO PRELIMINARY ASSESSMENT INFORMATION RULES ON PRODUCT ION QUANTITIES, USES, EXPOSURES, AND ADVERSE EFFECTS. MANUFACTURERS INCLUDING IMPORTERS MUST SUBMIT A REPORT FOR THIS LISTED CHEMICAL MANUFACTURED AT EACH SITE. entry date: OCT 1991 effective date: 1982

title: PRELIMINARY ASSESSMENT INFORMATION RULESOECD SIDS 2 -BUTOXYETHANOL

UNEP Publications 292 original : FEREAC, FEDERAL REGISTER, 47 , , 26998 , 1982 amendment: CFRUS*, CODE OF FEDERAL REGULATIONS, 40 , 712 , 30 , 1990

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file: 17.01 LEGAL rn : 1322104 systematic name:Ethanol, 2-butoxy- common name :Ethylene glycol monobutyl ether reported name :2-Butoxyethanol cas no :111-76-2 rtecs no :KJ8575000 area : USA type : REG

-------------------------------- |subject|specification|descriptor| |-------+-------------+----------| | CLASS | PESTI | RQR | | MANUF | PESTI | PRMT | | FOOD | ADDIT | RQR |

-------------------------------- CASE NAME CELLOSOLVE ESTERS; Summary - THIS SUBSTANCE IS INCLUDED ON A LIST OF ACTIVE INGREDIENTS CONTAINED IN A PRODUCT FIRST REGISTERED BEFORE NOVEMBER 1, 1984, FOR WHICH A REGISTRATION STANDARD HAS NOT BEEN

ISSUED. PUBLICATION OF THIS LIST INITIATES AN ACCELERATED REREGISTRATION AND DATA C ALL-IN FOR PRODUCTS CONTAINING THE LISTED ACTIVE INGREDIENTS. IN PARTICULAR THE LIST INCLUDES A NUMBER OF ACTIVE INGREDIENT CASES HAVING INDIRECT FOOD OR FEED USES. entry date: JAN 1992 effective date: 1988

title: FEDERAL INSECTICIDE, FUNGICIDE, AND RODENTICIDE ACT PESTICIDES REQUIRED TO BE REREGISTERED; LIST C. original : FEREAC, FEDERAL REGISTER, 54 , 140 , 30846 , 1989 amendment: FEREAC, FEDERAL REGISTER, 54 , 140 , 30846 , 1989

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file: 17.01 LEGAL rn : 1325174 systematic name:Ethanol, 2-butoxy- common name :Ethylene glycol monobutyl ether reported name :Ethylene glycol mono-n-butyl ether cas no :111-76-2 rtecs no :KJ8575000 area : USA type : REC

-------------------------------- |subject|specification|descriptor| |-------+-------------+----------| | SAFTY | OCC | MXL | | USE | OCC | MXL |

-------------------------------- 700 PPM entry date: OCT 1991 effective date: JUN1990

title: POCKET GUIDE TO CHEMICAL HAZARDS original : XPHPAW, US PUBLIC HEALTH SERVICE PUBLICATION, 90 , 117 , 50 , 1990 amendment: XPHPAW, US PUBLIC HEALTH SERVICE PUBLICATION, 90 , 117 , 50 , 1990

*******OECD SIDS 2 -BUTOXYETHANOL

UNEP Publications 293 file: 17.01 LEGAL rn : 1340162 systematic name:Ethanol, 2-butoxy- common name :Ethylene glycol monobutyl ether reported name :Ethylene glycol mono-n-butyl ether cas no :111-76-2 rtecs no :KJ8575000 area : USA type : REC

-------------------------------- |subject|specification|descriptor| |-------+-------------+----------| | AIR | OCC | TLV |

-------------------------------- Time Weighted Avg (TWA) 25 ppm, 121 MG/M3, skin; Summary - THIS

THRESHOLD LIMIT VALUE IS INTENDED FOR USE IN THE PRACTICE OF INDUSTRIAL HYGIENE AS A GUIDELINE OR RECOMMENDATION IN THE CONTROL OF POTENTIAL HEALTH HAZARDS. entry date: DEC 1991 effective date: 1989

title: THRESHOLD LIMIT VALUES original : ACGIH*, AMERICAN CONFERENCE OF GOVERNMENT INDUSTRIAL HYGIENISTS, , , 11 , 1989 amendment: ACGIH*, AMERICAN CONFERENCE OF GOVERNMENT INDUSTRIAL HYGIENISTS, , , 11 , 1991

*******

file: 17.01 LEGAL rn : 1345130 systematic name:Ethanol, 2-butoxy- common name :Ethylene glycol monobutyl ether reported name :2-n-Butoxyethanol cas no :111-76-2 rtecs no :KJ8575000 area : USA type : REG

-------------------------------- |subject|specification|descriptor| |-------+-------------+----------| | MONIT | | RQR |

-------------------------------- ; Summary - THIS IS A CHEMICAL OR MIXTURE FOR WHICH REPORTING IS CURRENTLY REQUIRED UNDER THE TOXIC SUBSTANCE CONTROL ACT HEALTH AND SAFETY STUDIES SECTION 2607D. PERSONS WHO CURRENTLY MANUFACTURE OR PROCESS CHEMICAL SUBSTANCES OR MIXTURES FOR COMMERCIAL PURPOSES, THOSE WHO PROPOSE TO DO SO, AND THOSE WHO ARE NOT CURRENTLY INVOLVED WITH A LISTED CHEMICAL BUT WHO MANUFACTURED OR PROCESSED IT OR PROPOSED TO DO SO ANY TIME DURING THE TEN YEAR PERIOD PRIOR TO THE TIME IT BECAME LISTED MUST SUBMIT TO THE ADMINISTRATOR OF THE U.S. EPA STUDIES OR LISTS OF HEALTH AND SAFETY STUDIES CONDUCTED ON THIS SUBSTANCE FOR EVALUATION. entry date: OCT 1991 effective date: 1986 title: HEALTH AND SAFETY DATA REPORTING RULES SECTION 8(D) original : FEREAC, FEDERAL REGISTER, 51 , , 32726 , 1986 amendment: CFRUS*, CODE OF FEDERAL REGULATIONS, 40 , 716 , 120 , 1990

*******

file: 17.01 LEGAL rn : 1407014 systematic name:Ethanol, 2-butoxy- common name :Ethylene glycol monobutyl ether reported name :Ethylene glycol monobutyl etherOECD SIDS 2 -BUTOXYETHANOL

UNEP Publications 294 cas no :111-76-2 rtecs no :KJ8575000 area : EEC type : REG

-------------------------------- |subject|specification|descriptor| |-------+-------------+----------| | FOOD | | RQR | | FOOD | | MXL | | FOOD | | RSTR |

-------------------------------- THE SUBSTANCE MAY BE USED FOR THE MANUFACTURE OF REGENERATED CELLULOSE FILM WHICH IS INTENDED TO OR DOES COME INTO CONTACT WITH FOODSTUFFS UNDER THE CONDITIONS LAID DOWN. THE SUBSTANCE MAY BE USED AS COATING SOLVENT IN COATED REGENERATED CELLULOSE FILM. NOT MORE THAN 50 MG OF COATING/DM2 OF FILM ON THE SIDE IN CONTACT WITH FOODSTUFFS IS ALLOWED. THE TOTAL QUANTITY OF SOLVENTS MAY NOT EXCEED 0.6 MG/DM2 IN THE UNCOATED REGENERATED CELLULOSE FILM, INCLUSIVE OF THE COATING ON THE SIDE IN CONTACT WITH FOODSTUFFS.

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file: 17.01 LEGAL rn : 1407014 systematic name:Ethanol, 2-butoxy- common name :Ethylene glycol monobutyl ether reported name :Ethylene glycol monobutyl ether cas no :111-76-2 rtecs no :KJ8575000 entry date: AUG 1995 effective date: 01JAN1994

title: COMMISSION DIRECTIVE OF 15 MARCH 1993 RELATING TO MATERIALS AND

ARTICLES MADE OF REGENERATED CELLULOSE FILM INTENDED TO COME INTO CONTACT WITH FOODSTUFFS (93/10/EEC). original : OJEC**, OFFICIAL JOURNAL OF THE EUROPEAN COMMUNITIES, L93 , , 27 , 1993 amendment: OJEC**, OFFICIAL JOURNAL OF THE EUROPEAN COMMUNITIES, L310 , , 41 , 1993

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file: 17.01 LEGAL rn : 1470439 !!! WARNING - not original IRPTC record - WARNING !!! systematic name:Ethanol, 2-butoxy- common name :Ethylene glycol monobutyl ether reported name :2-Butoxyethanol cas no :111-76-2 rtecs no :KJ8575000 area : EEC type : REG

-------------------------------- |subject|specification|descriptor| |-------+-------------+----------| | MANUF | INDST | CLASS | | IMPRT | INDST | CLASS |

-------------------------------- The substance is included in a list of existing substances produced or imported within the Community in quantities exceeding 1000 tonnes per year. - A system of data reporting by any manufacturer who has produced or any importer who has imported the substance, as such or in a preparation, in quanities exceeding 10 tonnes per year is established. entry date: AUG 1999 effective date: 04JUN1993

title: Council Regulation (EEC) No 793/93 of 23 March 1993 on theOECD SIDS 2 -BUTOXYETHANOL

UNEP Publications 295 evaluation and control of the risks of existing substances original : OJECFC, Official Journal of the European Communities, L84 , , 1 , 1993

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file: 17.01 LEGAL rn : 1477556 !!! WARNING - not original IRPTC record - WARNING !!! systematic name:Ethanol, 2-butoxy- common name :Ethylene glycol monobutyl ether reported name :2-Butoxyethanol cas no :111-76-2 rtecs no :KJ8575000 area : EEC type : REG

-------------------------------- |subject|specification|descriptor| |-------+-------------+----------| | CLASS | | CLASS | | LABEL | | RQR | | PACK | | RQR |

-------------------------------- Classification: Xn; R20/21/22. Xi: Irritant; R36/38. - Labelling: Xn: Harmful. Risk phrases (R): 20/21/22-36/38. Harmful by inhalation, in contact with skin and if swallowed (R20/21/22). - Irritating to eyes and skin (R36/38). Safety advice phrases (S): (2-)36/37-46. (Keep out of the reach of children (S2).) - Wear suitable protective clothing and gloves (S36/37). - If swallowed, seek medical advice immediately and show this container or label (S46). entry date: OCT 2001 effective date: 24AUG2001

title: Council Directive of 27 June 1967 on the approximation of the laws, regulations and administrative provisions relating to the classification, packaging and labelling of dangerous substances (67/548/EEC) original : OJECFC, Official Journal of the European Communities, 196 , , 1 , 1967 amendment: OJECFC, Official Journal of the European Communities, L225 , , 1 , 2001

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file: 17.01 LEGAL rn : 1861014 !!! WARNING - not original IRPTC record - WARNING !!! systematic name:Ethanol, 2-butoxy- common name :Ethylene glycol monobutyl ether reported name :2-Butoxyethanol cas no :111-76-2 rtecs no :KJ8575000 area : WHO type : REC

-------------------------------- |subject|specification|descriptor| |-------+-------------+----------| | AIR | AMBI | MTC |

-------------------------------- Average ambient air concentration: 0.1 - 15 ug/m3. Health endpoint: haematoxicity in rats; no observed adverse effect level (NOAEL): 242 mg/m3; uncertainty factor: 10; tolerable concentration: 13100 ug/m3; averaging time: 1 week. entry date: JAN 2001OECD SIDS 2 -BUTOXYETHANOL

UNEP Publications 296 title: Guidelines for Air Quality original : WHOAI*, Guidelines for Air Quality, WHO, Geneva, , , , 2000OECD SIDS 2 -BUTOXYETHANOL

UNEP Publications 297