n-Butyl acrylate

40 Pages·2007·0.12 MB·English

1 INTERIM 1: 08/2007
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BUTYL ACRYLATE
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(CAS Reg. No. 141-32-2)
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INTERIM ACUTE EXPOSURE GUIDELINE LEVELS
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(AEGLs)
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For
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NAS/COT Subcommittee for AEGLs
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32 Oak Ridge National Laboratory, managed by UT-Battelle, LLC., for the U.S. Dept. of Energy under contract
33 DE-AC05-00OR22725
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n-BUTYL ACRYLATE Interim 1: 08/2007
1 PREFACE
2
3 Under the authority of the Federal Advisory Committee Act (FACA) P. L. 92-463 of
4 1972, the National Advisory Committee for Acute Exposure Guideline Levels for Hazardous
5 Substances (NAC/AEGL Committee) has been established to identify, review and interpret
6 relevant toxicologic and other scientific data and develop AEGLs for high priority, acutely toxic
7 chemicals.
8
9 AEGLs represent threshold exposure limits for the general public and are applicable to
10 emergency exposure periods ranging from 10 minutes to 8 hours. Three levels — AEGL-1,
11 AEGL-2 and AEGL-3 — are developed for each of five exposure periods (10 and 30 minutes, 1
12 hour, 4 hours, and 8 hours) and are distinguished by varying degrees of severity of toxic effects.
13 The three AEGLs are defined as follows:
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15 AEGL-1 is the airborne concentration (expressed as parts per million or milligrams per
16 cubic meter [ppm or mg/m3]) of a substance above which it is predicted that the general
17 population, including susceptible individuals, could experience notable discomfort, irritation, or
18 certain asymptomatic, non-sensory effects. However, the effects are not disabling and are
19 transient and reversible upon cessation of exposure.
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21 AEGL-2 is the airborne concentration (expressed as ppm or mg/m3) of a substance above
22 which it is predicted that the general population, including susceptible individuals, could
23 experience irreversible or other serious, long-lasting adverse health effects or an impaired ability
24 to escape.
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26 AEGL-3 is the airborne concentration (expressed as ppm or mg/m3) of a substance above
27 which it is predicted that the general population, including susceptible individuals, could
28 experience life-threatening health effects or death.
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30 Airborne concentrations below the AEGL-1 represent exposure levels that could produce
31 mild and progressively increasing but transient and nondisabling odor, taste, and sensory
32 irritation or certain asymptomatic, non-sensory effects. With increasing airborne concentrations
33 above each AEGL, there is a progressive increase in the likelihood of occurrence and the
34 severity of effects described for each corresponding AEGL. Although the AEGL values
35 represent threshold levels for the general public, including susceptible subpopulations, such as
36 infants, children, the elderly, persons with asthma, and those with other illnesses, it is recognized
37 that individuals, subject to unique or idiosyncratic responses, could experience the effects
38 described at concentrations below the corresponding AEGL.
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n-BUTYL ACRYLATE Interim 1: 08/2007
1 TABLE OF CONTENTS
2
3 PREFACE ................................. ..................................1
4
5 LIST OF TABLES .............................................................4
6
7 SUMMARY ...................................................... ............5
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9 1. INTRODUCTION ..........................................................8
10
11 2. HUMAN TOXICITY DATA ..................................... ............8
12 2.1. Acute Lethality .........................................................8
13 2.2. Nonlethal Toxicity ......................................................9
14 2.2.2. Case Reports .....................................................9
15 2.2.3. Epidemiologic Studies/Occupational Exposures ..........................9
16 2.3. Neurotoxicity .........................................................10
17 2.4. Developmental/Reproductive Toxicity .....................................10
18 2.5. Genotoxicity ..........................................................10
19 2.6. Carcinogenicity .......................................................10
20 2.7. Summary.............................................................10
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22 3. ANIMAL TOXICITY DATA ............... .................................10
23 3.1. Acute Lethality ........................................................10
24 3.1.1. Hamsters .......................................................10
25 3.1.2. Rats ...........................................................11
26 3.1.3. Mice ...........................................................11
27 3.2. Nonlethal Toxicity .....................................................11
28 3.2.1. Rats ...........................................................11
29 3.2.2. Mice ...........................................................12
30 3.3. Neurotoxicity .........................................................12
31 3.4. Developmental/Reproductive Toxicity .....................................12
32 3.5. Genotoxicity ..........................................................13
33 3.6. Subchronic and Chronic Toxicity/Carcinogenicity ............................13
34 3.7. Summary.............................................................13
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36 4. SPECIAL CONSIDERATIONS ..............................................14
37 4.1. Metabolism and Disposition ..............................................14
38 4.2. Mechanism of Toxicity .................................................15
39 4.3. Structure Activity Relationships ..........................................15
40 4.4. Other Relevant Information ..............................................16
41 4.4.1. Species Variability ................................................16
42 4.4.2. Susceptible Populations ............................................16
43 4.4.3. Concentration-Exposure Duration Relationship .........................16
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45 5. DATA ANALYSIS FOR AEGL-1 ............................................16
46 5.1. Summary of Human Data Relevant to AEGL-1 ...............................16
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1 5.2. Summary of Animal Data Relevant to AEGL-1 ..............................16
2 5.3. Derivation of AEGL-1 ..................................................17
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4 6. DATA ANALYSIS FOR AEGL-2 ............................................17
5 6.1. Summary of Human Data Relevant to AEGL-2 ...............................17
6 6.2. Summary of Animal Data Relevant to AEGL-2 ..............................17
7 6.3. Derivation of AEGL-2 ..................................................18
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9 7. DATA ANALYSIS FOR AEGL-3 ............................................18
10 7.1. Summary of Human Data Relevant to AEGL-3 ...............................18
11 7.2. Summary of Animal Data Relevant to AEGL-3 ..............................18
12 7.3. Derivation of AEGL-3 ..................................................19
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14 8. SUMMARY OF AEGLS ....................................................19
15 8.1. AEGL Values and Toxicity Endpoints ......................................19
16 8.2. Comparison with Other Standards and Guidelines ............................20
17 8.3. Data Adequacy and Research Needs .......................................22
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19 9. REFERENCES ...........................................................22
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21 APPENDIX A: Derivation of AEGL Values .......................................26
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23 APPENDIX B: Benchmark Calculations ...........................................30
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25 APPENDIX C: Derivation Summary for Butyl Acrylate AEGLs .......................34
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27 APPENDIX D: Time-scaling Category Plot for Butyl Acrylate ............. ............38
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n-BUTYL ACRYLATE Interim 1: 08/2007
1 LIST OF TABLES
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3 1. Chemical and Physical Properties .. .......................................... ...8
4 2. Summary of toxicity data in laboratory animals exposed to BA ......................14
5 3. AEGL-1 Values for Butyl Acrylate ............................................17
6 4. AEGL-2 Values for Butyl Acrylate ............................................18
7 5. AEGL-3 Values for Butyl Acrylate ............................................19
8 6. Summary of AEGL Values ....... ............................................20
9 7. Extant Standards and Guidelines for Butyl Acrylate ................... ............21
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n-BUTYL ACRYLATE Interim 1: 08/2007
1 SUMMARY
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3 n-Butyl acrylate (BA) is a flammable liquid that is slightly soluble in water and miscible with
4 most organic solvents (ECETOC 1994). BA is an acrylate monomer used to prepare
5 homopolymers and copolymers with other monomers. The chemical reacts readily with
6 numerous organic and inorganic compounds so it is used as a starting product for chemical
7 synthesis (ECETOC 1994). BA is also used in surface coatings, leather finishes, adhesives,
8 paper coatings, fibers, plastics, and resins (Bisesi 2001; ECETOC 1994). BA is the largest-
9 volume production commodity acrylate ester (Lacson et al. 2001).
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11 Few data were available concerning human exposures to BA and none of the data were
12 suitable for derivation of any AEGL values. Worker monitoring studies reported up to 10.5 ppm
13 as a short-term exposure average concentration (Rohm and Haas, Co. 1987), but no health effects
14 were included.
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16 Few animal data were available for derivation of AEGL-1 values. In a developmental
17 toxicity study (Rohm and Haas Co. 1992; Merkle and Klimisch 1983), no clinical signs were
18 reported for rats exposed repeatedly to 25 ppm. Clinical signs reported in other studies were too
19 severe for AEGL-1 (concentrations of 135 ppm and higher resulted in eye and nasal discharge,
20 dyspnea, gasping). The no-effect level for respiratory depression in mice was 30 ppm
21 (Kirkpatrick 2003). A concentration of 25 ppm was chosen as a concentration below AEGL-1
22 effects. Extrapolations were not performed. A total uncertainty factor of 3 was used including a
23 1 for interspecies extrapolation and 3 for intraspecies extrapolation. Use of greater uncertainty
24 factors was not necessary because the mechanism of irritation is not expected to differ between
25 individuals.
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27 The best animal data relevant to derivation of AEGL-2 are from a subchronic study in which
28 male and female Sprague-Dawley rats (n = 20) were exposed to 0, 21, 108, 211, or 546 ppm BA
29 for 6 hours/day, 5 days/week, for 13 weeks (Klimisch et al. 1978). At the highest concentration,
30 mortality, reduced body weight gain, and clinical signs of bloody ocular and nasal discharges
31 and rhinitis were observed; marked lesions of the respiratory tract were found at necropsy. At
32 211 ppm all animals survived but had reduced body weight gain and showed bloody ocular and
33 nasal discharges; slight edema and erosion of the nasal mucosa were observed histologically in a
34 few individuals. Slight decreases in weight gain but no histopathological changes were observed
35 in animals exposed to 108 ppm. The NOAEL was 21 ppm. In other studies, no maternal or
36 developmental toxicity was seen in rats repeatedly exposed to 25 or 100 ppm during gestation
37 (Rohm and Haas Co. 1992; Merkle and Klimisch 1983; Saillenfait et al. 1999).
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39 The concentration of 211 ppm for 6 hours/day was used as the basis for AEGL-2 derivation.
40 Values were scaled using the equation Cn × t = k where n ranges from 0.8 to 3.5 (ten Berge et al.
41 1986). In the absence of an empirically derived, chemical-specific exponent, scaling was
42 performed using n = 3 for extrapolating to the 30-minute and 1- and 4-hour time points and n = 1
43 for the 8-hour time point. A total uncertainty factor of 3 was used including 1 for interspecies
44 extrapolation and 3 for intraspecies extrapolation. Use of greater uncertainty factors was not
45 necessary because the mechanism of irritation is not expected to differ between individuals.
46 According to Section 2.7 of the Standing Operating Procedures for Developing Acute Exposure
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n-BUTYL ACRYLATE Interim 1: 08/2007
1 Guideline Levels for Hazardous Chemicals (NRC 2001), 10-minute values are not to be scaled
2 from an experimental exposure time of $4 hours. Therefore, the 30-minute AEGL-2 value was
3 also adopted as the 10-minute value.
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5 The best animal data relevant to derivation of AEGL-3 values is the Oberly and Tansy
6 (1985) 4-hour LC study in rats. This was a well conducted study with a wide range of
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7 analytically determined exposure concentrations. Clinical signs of irritation were observed in
8 animals during exposure and death was attributed to cardiopulmonary collapse. The calculated
9 4-hour LC value was 2730 ppm. From these data a 4-hour BMCL value was calculated by a
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10 log-probit analysis using US EPA Benchmark Dose Software version 1.3.2. The resulting 4-
11 hour BMCL of 1652 ppm was used to derive the 30-minute, and 1-, 4- and 8-hour AEGL-3
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12 values. Values were scaled using the equation Cn × t = k where n ranges from 0.8 to 3.5 (ten
13 Berge et al. 1986). A value of n = 1.3 was calculated by combining 1- and 4- hour LC data sets
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14 from ethyl acrylate (NAC 2004) in a 3-dimensional probit analysis (Zwart et al. 1992). Use of
15 an n value calculated from a structurally related chemical was considered appropriate because
16 the mechanism leading to death is similar for both compounds. A total uncertainty factor of 10
17 was used including 3 for interspecies extrapolation and 3 for intraspecies extrapolation. Use of
18 greater uncertainty factors was not necessary because the mechanism of toxicity (local damage
19 in the lower airways/lungs) is not expected to differ between individuals. According to Section
20 2.7 of the Standing Operating Procedures for Developing Acute Exposure Guideline Levels for
21 Hazardous Chemicals (NRC 2001), 10-minute values are not to be scaled from an experimental
22 exposure time of $4 hours. Therefore, the 30-minute AEGL-3 value was also adopted as the 10-
23 minute value.
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25 The reported odor threshold concentrations are not sufficiently qualified to derive a level of
26 odor awareness (LOA) according to van Doorn et al. (2002).
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28 The calculated values are listed in the tables below.
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30 Summary of AEGL Values for Butyl Acrylate
31 Classification 10-minute 30-minute 1-hour 4-hour 8-hour Endpoint (Reference)
32 AEGL–1 8.3 ppm 8.3 ppm 8.3 ppm 8.3 ppm 8.3 ppm No clinical signs with
33 (Nondisabling) (44 mg/m3) (44 mg/m3) (44 mg/m3) (44 mg/m3) (44 mg/m3) repeated exposures (Rohm
and Haas Co. 1992; Merkle
and Klimisch 1983)
34 AEGL–2 160 ppm 160 ppm 130 ppm 81 ppm 53 ppm Clinical signs and
35 (Disabling) (850 mg/m3) (850 mg/m3) (690 mg/m3) (430 mg/m3) (280 mg/m3) histopathology with
repeated exposure
(Klimisch et al. 1978)
36 AEGL–3 820 ppm 820 ppm 480 ppm 170 ppm 97 ppm Calculated BMCL from
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37 (Lethal) (4400 (4400 mg/m3) (2600 mg/m3) (906 mg/m3) (520 mg/m3) LC data (Oberly and
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mg/m3) Tansy 1985)
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39 References
40 Bisesi, M.S. 2001. Esters of mono- and alkenyl carboxylic acids. In: Patty’s Toxicology, Fifth ed., vol. 6. E. Bingham,
41 B. Cohrssen, and C.H. Powell, eds. New York: John Wiley & Sons, Inc. pp. 609-611.
42
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n-BUTYL ACRYLATE Interim 1: 08/2007
1 ECETOC (European Centre for Ecotoxicology and Toxicology of Chemicals). 1994. Joint assessment of commodity
2 chemicals no. 27. n-Butyl acrylate. ECETOC, Brussels. August, 1994. 47pp.
3
4 Kirkpatrick, D.T. 2003. Airway irritation/respiratory depression(RD ) study of butyl acrylate in albino mice. WIL
50
5 Research Laboratories, Inc., Ashland, OH. Study No. WIL-496001. 74pp.
6
7 Klimisch, H.-J., K. Deckardt, and D. Mirea. 1978. Bericht über die prüfung der subakuten toxizität von n-butylacrylat.
8 BASF, Ludwigshafen.
9
10 Lacson, J., A. Leder, and G. Toki. 2001. CEH (Chemical Economics Handbook) Report: Acrylic Acid and Esters.
11 Menlo Park, CA: SRI Consulting. abstract retrieved online 10/16/2003
12 <http://ceh.sric.sri.com/Public/Reports/606.4000/>
13
14 Merkle, J. and H.-J. Klimisch. 1983. N-Butyl acrylate: prenatal inhalation toxicity in the rat. Fundam. Appl. Toxicol.
15 3:443-447.
16
17 NAC (National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances). 2004. Technical
18 support document: Acute exposure guideline levels for ethyl acrylate. Proposed, 04/2004.
19
20 NRC (National Research Council). 2001. Standing Operating Procedures for Developing Acute Exposure Guideline
21 Levels for Hazardous Chemicals. Washington, DC: National Academy Press.
22
23 Oberly, R. and M.F. Tansy. 1985. LC50 values for rats acutely exposed to vapors of acrylic and methacrylic acid esters.
24 J. Toxicol. Environ. Health 16:811-822.
25
26 Rohm and Haas , Co. 1987. Employees exposure monitoring results for Rohm and Haas operations 1978-1986 for ethyl
27 acrylate, butyl acrylate and methyl acrylate with cover letter dated 110687. Doc. ID 40-8710044.
28
29 Rohm and Haas, Co. 1992. Initial submission: 2-Propenoic acid, butyl ester: translation of German article on industrial
30 hygiene and toxicology describing studies in rats with cover letter dated 081292. Doc ID 88-920005597.
31
32 Saillenfait, A.M., P. Bonnet, F. Gallissot, J.C. Protois, A. Peltier, and J.F. Fabriès. 1999. Relative developmental
33 toxicities of acrylates in rats following inhalation exposure. Toxicol. Sci. 48:240-254.
34
35 ten Berge, W.F., A. Zwart, and L.M. Appelman. 1986. Concentration-time mortality response relationship of irritant and
36 systemically acting vapours and gases. J. Hazard. Mat. 13:301-309.
37
38 van Doorn, R., M.W. Ruijten, and T. van Harreveld. 2002. Guidance for the application of odor in chemical emergency
39 response. Version 2.1, August 29, 2002. Presented at the NAC/AEGL meeting September, 2002, Washington, DC.
40
41 Zwart, A., J.H.E. Arts, W.F. ten Berge, and L.M. Appleman. 1992. Alternative acute inhalation toxicity testing by
42 determination of the concentration-time-mortality relationship: experimental comparison with standard LC testing.
50
43 Regul. Toxicol. Pharmacol. 15:278-290.
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n-BUTYL ACRYLATE Interim 1: 08/2007
1 1. INTRODUCTION
2
3 n-Butyl acrylate (BA) is a flammable liquid that is slightly soluble in water and miscible with
4 most organic solvents (ECETOC 1994). BA is an acrylate monomer used to prepare
5 homopolymers and copolymers with other monomers. The chemical reacts readily with
6 numerous organic and inorganic compounds so it is used as a starting product for chemical
7 synthesis (ECETOC 1994). BA is also used in surface coatings, leather finishes, adhesives,
8 paper coatings, fibers, plastics, and resins (Bisesi 2001; ECETOC 1994).
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10 BA is the largest-volume production commodity acrylate ester (Lacson et al. 2001). In 1993,
11 the United States produced 340 million kg BA (HSDB 2004) which increased to >454 million kg
12 in 2002 (U.S. EPA 2004). The most common manufacturing process is by catalyzed
13 esterification of acrylic acid with n-butanol (ECETOC 1994).
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15 Selected chemical and physical properties of BA are listed in Table 1.
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17 TABLE 1. Chemical and Physical Properties
18 Parameter Value Reference
19 Synonyms 2-propenoic acid butyl ester O’Neil et al. 2001
20 Chemical formula C H O O’Neil et al. 2001
7 12 2
21 Molecular weight 128.17 O’Neil et al. 2001
22 CAS Reg. No. 141-32-5
23 Physical state liquid O’Neil et al. 2001
24 Solubility in water 0.14 g/100 mL at 20°C O’Neil et al. 2001
25 Vapor pressure 4.3 mmHg at 20°C ECETOC 1994
26 Vapor density (air =1) 4.4 ECETOC 1994
27 Liquid density (water =1) 0.8986 O’Neil et al. 2001
28 Melting point -64°C, approximately ECETOC 1994
29 Boiling point 145°C O’Neil et al. 2001
30 Auto-ignition 267°C ECETOC 1994
31 Conversion factors 1 ppm = 5.33 mg/m3 ECETOC 1994
1 mg/m3 = 0.188 ppm
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34 2. HUMAN TOXICITY DATA
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36 2.1. Acute Lethality
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38 No reports of human fatalities from exposure to BA were found.
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1 2.2. Nonlethal Toxicity
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3 2.2.1. Odor Threshold/Odor Awareness
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5 AIHA (1995a) listed the range of reported odor thresholds as 0.00096-0.10 ppm; however,
6 all values were from either unpublished data or anonymous references.
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8 2.2.2. Case Reports
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10 Contact dermatitis to BA has been demonstrated with patch testing (Hambly and Wilkinson
11 1978), but no reports of respiratory sensitization were found.
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13 2.2.3. Epidemiologic Studies/Occupational Exposures
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15 No epidemiologic studies were found concerning human exposures to BA.
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17 Tu…ek et al. (2002) conducted a prospective cohort study during 1992-1999 of workers
18 involved in the production of acrylic acid and its esters. Groups of 60 controls and 60 exposed
19 individuals were followed with the average exposure period for the exposed group 13±5 years.
20 Exposures to up to eight chemicals, including BA, were determined by personal passive
21 dosimetry. Concentrations of all chemicals remained low, however, the maximum allowable
22 concentration for BA (not specified) was exceeded for 2% of the measurements. Throughout the
23 study chemical workers did not show any health-related changes as measured by interview,
24 general medical examination, hematology, clinical chemistry, serum immunity parameters,
25 selected tumor markers, and spirometry. Subjective complaints at the workplace of burning eyes
26 and throat, occasional irritating cough, headaches, and less frequently nausea or dizziness, and
27 fleeting dermatological complaints were reported by approximately 40% of the exposed workers;
28 the study authors did not correlate symptoms with exposure concentrations. In contrast only
29 20% of the controls reported subjective complaints with symptoms associated with ergonomics.
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31 Rohm and Haas, Co. (1987) submitted employee exposure monitoring results for a number of
32 operations during 1978-1987. Average concentrations of BA for full shift ranged from 0.1-1.0
33 ppm and short-term exposure average concentrations ranged from 0.4-10.5 ppm. No other
34 information was included in the report.
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36 Time-weighted average concentrations of BA at four job sites in a polystyrene production
37 plant were 12-93 ppb (range: not detected-270 ppb) in the breathing zone of workers and 1-93
38 ppb (range: not detected-525 ppb) in the atmosphere of the workplaces (Samimi and Falbo
39 1982). Samples were collected in charcoal tubes from 50 minutes to 7.5 hours and quantitated
40 with a gas chromatograph. No information on worker health status was given.
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42 2.2.4. Clinical Studies
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44 Olfactory function was investigated in chemical workers exposed to acrylates and
45 methacrylates (Schwartz et al. 1989; Rohm and Haas 1988). Specific chemicals were not
46 identified. Workers were administered a standardized smell identification test consisting of an
9