The central nervous system effects of xylene are attributed to the low molecular weight and lipophilic nature of xylene allowing the solvent to readily cross the b1ood: brain barrier (see section 4.2). Distribution studies of xylene following inhalation exposures have confirmed high concentrations of xylene in the brain and central and peripheral nervous system immediately after exposure, with elimination often occurring by 1 hour post exposure. The rapid onset of central nervous system effects combined with the transient nature of the xylene induced nervous system disturbances is likely attributable to direct interaction of the chemical with the central nervous system followed by the rapid elimination of xylene. Based on the above information, the xylene blood concentration will be a key determinant in central nervous system effects. Pharmacokinetic 35 1 2 3 4 5 6 7 8 9 10 11 12 13 XYLENES Proposed 1: 5/ 2002 modeling in both humans and rats indicate that venous blood concentrations rapidly increase during the first 15 minutes of exposure, followed by minimal increases in blood concentrations with continuing exposure (i. e,, increases follow a hyperbolic curve) (Tardif et al., 1993; 1995). Likewise, available human data indicate that once the initial increase in blood xylene concentration is reached, blood concentrations level off with increasing exposure duration (see Table 1 1) (Hake et al., 1981; Savolainen et al., 1980; 1981; 1985b). Conversely, available human and animal data demonstrate that increasing exposure concentrations correlate with increases in venous blood xylene concentrations (Hake et al., 1981; Tardif et al., 11993; Laine et al., 1993). These data indicate that once steady state is reached, concentration, not duration, is the prime determinant in xylene induced central nervous system toxicity. Therefore, the AEGL values based upon central nervous system effects are set equal across time once steady state is approached (starting at approximately 1 hour), while pharmacokinetic modeling was used to extrapolate to exposure durations of 10 and 30 minutes (see Appendix 2). XYLENES Proposed 1: 5/ 2002 TABLE 11. Relationship Between gylene Exposure Concentration (In Air) and Blood Xylene Concentration in Human Volunteers 1 2 3 4 5 6 7 8 9 10 11 12 13 Venous blood subjects concentration exposure xylene Comments Exposure concent ration Reference I I I a 11 I 18.4 f 5.3 (pmol/ L,) I m Xylene, javolainen et al. ~

.980 100" I odor masked with peppermint oil B .67 13.3 f 2.2 121.6 f 6.3 1   I 3 I 13.4 f 2.9 1 9 10.25 I 16.6 f 4.8 (pmolL) I m Xylene, 4aine et al., 1993 ZOO" odor masked with peppermint oil 0.33 17.3 Jr 5.5 10.67 121.3 Jr 5.4 I 2 28.5 f 5.2 I 24.9 f 2.1 (p m o l ) m Xylene,

26.7 f 3.4 odor masked with peppermint oil (< 1.0 3.75 28.6 f 3.5 PPm) 1 0.24 (ppm; wlw) p Xylene, Subjects were sub divided into 3 daily 3 0.41 f 0.09 7.5 0.42 f 0.03 groups for 1, 3, or 7.5 hour long exposures. Males were exposed to 1 1.23 f 0.18 3 1.65 f 0.50 100 ppm for the lst week (5 daydweek), 20 ppm the 2nd week, and 150 7.5 1.29 f 0.21 1 2.04 f 0.76 ppm the 31d week. Values reported are for ~~

the first exposure day of ,3 3.18 f 0.11 6 javolainen et al., 1981 200 1 3ake et al., 1981 20 2 3 100 2 2 4 150 2 2 4 17.5 13.86 f 0.65 I each new week. Exposure protocol was: 3 hour exposure in the morning, 40 Mnute break for lunch, follow .by exposure for 1 or 3 hours in afternoon. Only values for continuous exposure in the morning session are reported.

37 XYLENES Proposed 1: 5/ 2002 1 2 3 4 5 6 7 % 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 5. DATA ANALYSIS AND PROPOSED AEGL 1 5.1. Human Data Relevant to AEGL 1 Exposure to 100, 200 or 400 ppm mixed xylenes for 30 minutes resulted in nonstatistically increased incidences of eye irritation; no nose or throat irritation were noted and no changes in behavioral tests or respiratory measurements were evident (Hastings et al., 1986). That the eye irritation was mild is supported by observation that the number of eye blinks/ minute were not affected by exposure. Exposure to 100 or 150 ppm p xylene for 7.5 hourslday, 5 daydweek resulted only in mild eye irritation, most often in one male wearing contact lenses (irritation was noted on the first exposure day) (Hake et a1., 198l). No effects on performance tests were observed. Exposure to 110 ppm mixed xylenes for 15 minutes resulted in intermittent, mild throat irritation in 1/ 6 individuals, while exposure to 230 ppm mixed xylenes for 15 minutes resulted in eye irritation and mild dizziness in 1/ 7 individuals (Carpenter et al., 1975b).

A number of controlled human exposures reported no effects following exposure to xylenes. Exposure to 100 or 200 ppm m or p xylene for 3 or 7 hours did not effect blood pressure, pulse rate, flicker value, or reaction time (Ogata et al., 1970). Olson et al. (1985) found exposure to 70 ppm p xylene for 4 hours did not effect choice reaction time, simple reaction time, short term memory, heart rate, or subjective symptoms in exposed volunteers. No adverse effects on visual evoked potential, tapping speed, body sway, reaction time, or critical flicker fusion were measured in volunteers exposed to 200 ppm m xylene for 4 hours (Savolainen et al., 1981; Seppalainen et al., 1983). Body sway, reaction times, and active or quiet sleep were not effected by exposure to 200 ppm for 5.5 hours (Line et al., 1993).

5.2. Animal Data Relevant to AEGL 1 No effects were observed in dogs exposed to 530 ppm or in rats exposed to 580 ppm mixed xylenes for 4 hours (Carpenter et al., 1975b). Lacrimation in dogs and poor coordination in rats were observed at the next higher exposure concentrations of 1200 ppm and 1300 ppm, respectively (Carpenter et al., 1975b).

5.3. Derivation of AEGL 1 The AEGL 1 is based upon slight eye irritation noted in the Hastings et al. (1986) study during a 30 minute exposure to 400 ppm mixed xylenes. The Hastings et al. (1986) study was chosen because the exposure was to mixed xylenes as opposed to individual isomers, and the exposure concentration represented a concentration at which an effect was observed, i. e., that of mild eye irritation. An interspecies uncertainty factor was not applied because the key study used human data, An intraspecies uncertainty factor of 3 was applied because the toxic effect (slight irritation) was less severe than that defined for the AEGL 1 tier (notable discomfort). Because irritation is considered a threshold effect and should therefore not vary over time, the threshold value is applied to all times. AEGL 1 values are presented in Table 12. BO 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 XYLENES Proposed 1: 5/ 2002 TABLE 12. AEGE 1 Values for Xylenes [ppm (mg/ m3)]

lO nlhute 30 minute 1 hour . 4 hour I I I %hour I I I I 130 (560) I 130 (560) I 130 (560) I 130 (560) I 130 (560)

%& e 130 pprn value is supported by several other studies, including: the 150 gpm p xylene exposure resulting in eye irritation in a contact lens wearer (represents sensitive population; Hake et al., 1981); the 15 minute exposure to 230 ppm mixed xylenes resulting in mild eye irritation and dizziness in one individual; and the 3 hour exposure to 200 ppm m or p xylene (Ogata et al., 1970), the 4 hour exposure to 200 ppm m xylene (Savolainen et al., 1981), and the 5.5 hour exposure to 200 ppm m xylene (Laine et al., 1993), all representing no effect levels.

4. DATA ANALYSIS AND PROPOSED AEGL 2 6.1. Human Data Relevant to AEGL 2 One of six or seven individuals noted dizziness during a fifteen minute exposure to 230 ppm (during the last 2 minutes of exposure) or 460 ppm mixed xylenes (starting at the 6" minute and continuing to the end of exposure; same individual), while a 15 minute exposure to 690 ppm mixed xylenes resulted in dizziness/ lightheadedness in 4/ 6 individuals (Carpenter et al., 1975b). In the same study, a 15 minute exposure resulted in eye irritation in 1/ 7, 4/ 6 and 4/ 6 individuals exposed to 230, 460, or 690 ppm mixed xylene, respectively.

6.2. Animal Data Relevant to AEGL 2 Exposure to 1200 ppm or 1300 ppm mixed xylenes for 4 hours represents a threshold for lacrimation in dogs and poor coordination (reversible) in rats, respectively (Carpenter et al., 1975b). The 4 hour m xylene EC50 for decreased rotarod performance in rats was 1982 ppm (Korsak et al., 1993), and the 4 hour minimum narcotic concentrations for the 3 xylene isomers in rats ranged from 1940 2180 ppm (Molnar et al., 1986). Exposure of rats to 1600 ppm p xylene for 4 hours resulted in hyperactivity, fine tremor, and unsteadiness (Bushnell, 1989), induced flavor aversion (Bushnell and Peele, 1 988), and caused changes in the flash evoked potential suggestive of increased arousal (Dyer et al., 1988).

Following 30 minute static exposures in mice, Moser et al., (1985) determined the EC,, for decreased performance on the inverted screen test to be 3790 ppm for m xylene, 3640 ppm for o xylene, and 2676 ppm for p xylene, while the EC,, for disruption of operant performance was 6 176 ppm for m xylene, 5 179 ppm for o xylene, and 56 1 1 ppm for p xylene.

6.3. Derivation of AEGL 2 The AEGL 2 is based upon poor coordination resulting when rats were exposed to 1300 ppm mixed xylenes for 4 hours (Carpenter et al., 1975b). This concentration represents the threshold for reversible equilibrium disturbances. This concentration and endpoint are consistent with the preponderance of available data for 4 hour exposures in rats: the EC50 for decreased rotarod performance was 1982 ppm (Korsak et al., 1993); the minimum narcotic concentrations for m, o , and p xylene ranged from 1940 2180 ppm (Molnar et al., 1986); and exposure to 1600 ppm p

39 5 4 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 XYLENES Proposed 1: 5/ 2002 v 4 " 8

xylene resulted in hyperactivity, fine tremor, and unsteadiniss (Bushnell, 1989), induced flavor aversion (Bushnell and Peele, 1988), and caused changes in the flash evoked potential suggestive of increased arousal (Dyer et al., 1988). In dogs, exposure to 1200 ppm for 4 hours represented a threshold for eye irritation (Carpenter et ai., 197%).

An interspecies uncertainty factor of 1 was applied because rats receive a greater systemic dose ofinhaled xylene as compared to humans. An intraspecies uncertainty factor of 3 was applied because the MAC (minimum alveolar concentration) for volatile anesthetics should not vary by more than a factor of 2 3 fold among humans. A 3 fold factor is also adequate to account for moderate physical activity during exposure, which would result in greater uptake of the chemical.

Data indicate that once steady state is reached, concentration, not duration, is the prime determinant in xylene induced central nervous system toxicity (see Section 4.4.3). Therefore, the AEGL 2 values are set equal across time once steady state is approached (starting at approximately 1 hour), while pharmacokinetic modeling was used to extrapolate to exposure durations of 10 and 30 minutes (see Appendix B).

AEGL 2 values are presented in Table 13 TABLE 13. AEGL 2 Values for Xylenes [ppm (mg/ m3)]

PO minute 30 minute 1 hour 4 hour 8 hour I I I I I 990 (4300) I 480 (2 100) I 430 (1900) I 430 (1900) I 430 (1900)

The human data reported by Carpenter et al. (1975b) were not used for the AEGL 2 derivation because the exposure duration was for only a short time (1 5 minutes) and because it not consistent with the preponderance of human data from other controlled human exposures. If one were to use the highest exposure concentration (690 ppm which resulted in eye irritation and dizziness in 4/ 6 individuals; threshold for equilibrium effects) and apply the intraspecies uncertainty factor of 3, one obtains a value of 230 ppm. This concentration is supposed to represent a concentration at which exposed individuals could experience irreversible or other serious, long lasting adverse health effects, or have an impaired ability to escape. However, a number of studies demonstrate that this concentration has no adverse effects upon exposed individuals: no adverse effects were observed following exposure to 100 or 200 ppm m or p xylene for 3 or 7 hours (Ogata et al., 1970); 200 ppm m xylene for 4 hours (Savolainen et al., 1981; Seppalainen et al., 1985), or 200 ppm for 5.5 hours (Laine et al., 1993).

Additionally, numerous human studies investigated the effects of exposure to: 200 ppm m xylene with 20 minute peaks of 400 ppm (Seppalainen et al., 1989; 1991; Laine et al,, 1993; Savolainen and Linnavuo, 1979); 135 ppm m xylene with 20 minute peaks of 400 ppm (Savolainen et al., 1984; 1985a; 1985b); or 140 ppm m xylene with 10 minute peaks of 400 ppm (Riihimaki and Savolainen, 1980; Savolainen and Riihimaki, 1981). The studies also combined peak exposures with exercise, thereby increasing the uptake of the chemical. These studies found either no effect, or reported only minimal central nervous system effects. 1 2 3 4 5 6 3 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 XYLENES 7. DATA ANALYSIS AND PROPOSED AEGL 3 7.8. Human Data Relevant to AEGL 3 Proposed 1: 5/ 2002 Morley et al. (1970) reported the cases of3 individuals exposed to approximately 10,000 ppm xylene for approximately 18 hours. One individual died, while the other two individuals were found unconscious but experienced a full recovery.

7.2. Animal Data Relevant to AEGL 3 Two cats exposed to 9500 ppm mixed xylenes exhibited central nervous system effects followed by death 2 hours into the exposure (Carpenter et al., 1975b). In rats, 4 hour LC5, s values for mixed xylenes have been reported as 6350 ppm (fine and Zuidema, 1970), 601 1 ppm (Carpenter et al., 1975b), and 11,000 ppm (Lundberg et al., 1986), and for p xylene as 4645 ppm (Harper et al., 1975). Six hour LC,, values for the m, 0, and p isomers were 5984,4330, and 4591 ppm in rats, respectively, and 5267,4595, and 3907 ppm in mice, respectively (Bonnet et al., 1979; 1982).

A no effect level for death in rats following exposure to mixed xylenes for 4 hours was 2800 ppm (Carpenter et al., 1975b). Clinical signs observed during exposure to 2800 ppm included prostration between 2 3.5 hours into the exposure. Recovery occurred within 1 hour post exposure, but coordination remained poor until the following day. At the next lower concentration of 1300 ppm, poor coordination was noted 2 hours into the exposure, with coordination returning to normal after the exposure. Molnar et al. (1986) reported 4 hour minimum narcotic concentrations of 2100, 2180, and 1940 ppm for the m, 0, and p xylene isomers, respectively.

R D 5 0 values in mice were 1467 ppm for o xylene (De Ceaurriz et al., 1981), 1361 ppm for m xylene (Korsak et al., 1993), and 2440 ppm for mixed xylenes (Korsak et al., 1988). It should be noted, however, that Korsak et al. (1993; 1988) did not use the recommended strain of mice.

7.3. Derivation of AEGL3 The AEGL 3 derivation is based upon prostration occurring in all 10 rats exposed for 4 hours to 2800 ppm mixed xylenes, with recovery occurring within 1 hour of exposure (Carpenter et al., 1975b) Although coordination initially remained poor, it returned to normal the following day. This concentration also represents a no effect level for lethality.

An interspecies uncertainty factor of 1 was applied because rats receive a greater systemic dose of inhaled xylene as compared to humans. An intraspecies uncertainty factor of 3 was applied because the MAC (minimum alveolar concentration) for volatile anesthetics should not vary by more than a factor of 2 3 fold among humans. A 3 fold factor is also adequate to account for moderate physical activity during exposure, which would result in greater uptake of the chemical.

Data indicate that once steady state is reached, concentration, not duration, is the prime determinant in xylene induced central nervous system toxicity (see Section 4.4.3). Therefore, the 41 XYLENES Proposed I: §/ 2002 Classification 10 Minute AEGL 1 (Nondisabling) 130 (560) 1 2 3 30 Minute 1 Hour 4 Hour 8 Hour 130 (560) 130 (560) 130 (560) 130 (560) 4 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 AEGL 3 values are set equal across time once steady state is approached (starting at approximately I hour), while pharmacokinetic modeling was used to extrapolate to exposure durations of 10 and 30 minutes (see Appendix B).

AEGE 3 values are presented in Table 14.

TABLE 14. AEGL 3 Values for Xylenes [ppm (mg/ m3)) l 10 minute I 30 minute I 1 hour I &hour I $ hour I I I 2100 (9100) 1000 (4300) I 930 (4000) I 930 (4000) I 930 (4000) I I Available data indicated that these values should be protective of human health. A 15 minute exposure to 690 ppm for 15 minutes resulted in eye irritation and dizziness and/ or lightheadedness (Carpenter et al., 1975b), and a 30 minute exposure to concentrations as high as 700 ppm xylene resulted in headache, nausea, vomiting, dizziness or vertigo, eye irritation, or nose or throat irritation (Klaucke et al., 1982).

8. SUMMARY OF PROPOSED AEGLs 8.1. AEGL Values and Toxicity Endpoints The proposed AEGL values for xylenes are summarized in Table 15.

I ~G L ~ (Disabling) I 990( 4300) I 480( 2100) I 430 (1900) I 430( 1900) I 430 (1900) 11 IGL~ Gethall I 2100( 9100) I lOOO( 4300) I 930( 4000) I 930( 4000) I 930( 4000) I 8.2. Comparisons with Other Standards Standards and guidance levels for workplace and community exposures are listed in Table 16. TABLE 16. Extant Standards and Guidelines for Xylenes II 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 losure Dura ion 4 hour 8 hour Guideline AEGL 1 130 ppm AEGL 2 990 ppm AEGE 3 2 100 ppm 10 min 15 min 30 min 130 ppm 1 hour 130 ppm 430 ppm 930 ppm 480 ppm 1000 ppm NIOSHmLHa I I 900 ppm OSHATWA' 1 1 100 ppm + 100 ppm OSHA PEL ACGIH TLV TWA~

ACGIH STELK 150 ppm SMAC (1996) 200 ppm 100 ppm 440 mg/ m3 100 ppm * 2 10 mg/ m3 I MAKg MAC (Dutch) "

NIOSH 1994, 1997 NIOSH, 1997 ' OSHA, 1996 ACGM, 2000 e NRC, 1984 NRC, 1996 g German Research Association, 1999 Ministry of Social Affairs and Employment, 2000 I 50ppm 25 8.3. Data Quality and Research Needs Human data appropriate for use in AEGL derivations were limited. Although numerous studies investigating controlled human exposures were available, the effects noted, if any, were generally less serious than those defined by the AEGL definitions. Human lethality data were limited to a case report where one of three individuals exposed to approximately 10,000 ppm for almost 19 hours died (Morley et al., 1970). Nonlethal animal data were available in dogs, cats, rats, and mice, although the majority of the data investigating central nervous system effects following acute exposures was in rats. Lethality data were available in rats and mice, and indicated little difference in sensitivity between these species. 26 27 28 29 30 31 32 33 A number of developmental toxicity studies were available, but results were equivocal. One study did not identify a maternal or developmental toxicity LOAEL at the concentrations tested. Another series of studies identified an effect on postnatal development only in female offspring as 34 35 36 43 r3 XYLENES Proposed 1: 5/ 2002 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 assessed by the Morris water maze test; no other effects were observed. Although retarded development of fetuses from exposed dams was evident in several studies as indicated by incomplete or non ossification of skeletal structures and/ or decreased fetal body weights, these studies were generally limited because the data were reported as fetal incidences instead of litter incidences, and generally lacked the reporting of other key data. Therefore, an adequate assessment of the data was not possible.

Because of inadequate evidence, xylene is currently not classifiable as to its carcinogenicity by IARC or the U. S. EPA. However, commercial xylene and all three individual isomers have generally tested negative for genotoxicity.

The proposed AEGL values should be protective of human health. The key study used for the AEGL 1 derivation (Hastings et al., 1986) was an acceptable study, but could have been improved had the number of volunteers been reported. However, the data are consistent with other human studies, and represent a value consistent with exposure concentrations that might result in mild eye irritation. The key study for the AEGL 2 and 3 derivation (Carpenter et al., 1975) was a well conducted study in rats. The AEGL 2 levels are protective, especially when considering numerous human studies investigated the effects of exposure to 200 ppm xylene with 20 minute peak exposures to 400 ppm, in some cases additionally combining peak exposures with physical exercise resulting in greater uptake of the chemical, and found only minimal central nervous system effects. The difficultly in defining an AEGL 2 level for xylene comes from its "all~ r nothing~~ continuum of toxicity: toxicity ranges from mild irritation to narcosis, with little happening in between. The AEGL 3 levels are supported by human data demonstrating that exposure to 690 ppm for 15 minutes resulted in lightheadedneddizziness and a 30 minute exposure to 700 ppm resulted in nausea, vomiting, dizziness or vertigo. XYLENES Proposed 1: 5/ 2002 1 9. REFERENCES 2 3 Abu Al Ragheb, S., Salhab, A. S., and Amr, S. S. 1986. Suicide by xylene ingestion: A case report and review of literature. Am. J. Forensic Med. Path. 7: 327 329.

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APPENDIX A: Rerivation of AEGL Values 58 6J XYLENES Proposed I: 5/ 2QQi!

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 Key study:

Toxicity endpoint:

Scaling:

Uncertainty factors: Derivation sf AEGL 1 Hastings et al., 1986 Eye irritation in human volunteers exposed to 400 ppm mixed xylenes for 30 minutes Data indicate that once steady state is reached, concentration, not duration, is the prime determinant in xylene induced central nervous system toxicity. Therefore, the MGL 2 values are set equal across time once steady state is approached (starting at approximately 1 hour), while pharmacokinetic modeling was used to extrapolate to exposure durations of 10 and 30 minutes.

1 for interspecies variability 3 for intraspecies variability Modif) ing factor: Not applicable 10 minute, 3 0 minute,

1 hour. 4 hour, 8 hour AEGL 1: Concentration producing effect applied to all times: 400 ppd3 = 130 ppm 59 XYLENES 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 Key study:

Toxicity endpoint:

Scaling:

Uncertainty factors: Derivation of' AEGL 2 Carpenter et aP., 197%

Rats exposed to 1300 ppm for 4 hours exhibited poor coordination Data indicate that once steady state is reached, concentration, not duration, is the prime determinant in xylene induced central nervous system toxicity. Therefore, the AEGL 2 values are set equal across time once steady state is approached (starting at approximately 1 hour), while pharmacokinetic modeling was used to extrapolate to exposure durations of 10 and 30 minutes (see Appendix B).

1 for interspecies variability 3 for intraspecies variability Modifling factor: Not applicable 1 0 minute, 30 minute AEGL 2: Concentration producing effect extrapolated back to ]I 0 and 30 minutes (see Appendix B): 990 and 480 ppm, respectively 1 hour, 4 hour, %hour AEGL 2: Concentration producing effect applied to all times: 1300 ppd3 = 430 ppm eo 70 XYLENES Proposed 1: 5/ 2002 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 Key study:

Toxicity endpoint:

Scaling:

Uncertainty factors: Derivation of AEGL 3 Carpenter et al., 1975b Rats exposed to 2800 ppm for 4 hours exhibited prostration followed by full recovery Data indicate that once steady state is reached, concentration, not duration, is the prime determinant in xylene induced central nervous system toxicity. Therefore, the AEGL 3 values are set equal across time once steady state is approached (starting at approximately 1 hour), while pharmacokinetic modeling was used to extrapolate to exposure durations of 10 and 30 minutes (see Appendix B).

1 for interspecies variability 3 for intraspecies variability Modifying factor: Not applicable 10 minute, 30 minute AEGL 3 : Concentration producing effect extrapolated back to 10 and 30 minutes (see Appendix B): 2100 and 1000 ppm, respectively 1 hour, 4 hour. 8 hour AEGL 3: Concentration producing effect applied to all times: 2800 ppd3 = 930 ppm 61 71 XYLENES 1 Proposed 1: 5/ 2002 APPENDIX B: Time Scaling Calculations XYLENES Proposed 1: 5/ 2002 conc (mmoVL)

10 min B 65 (mean) 55 ( 2 SD) 50 ( 3 SD)

1165 ppm 985 ppm 896 ppm 2 3 4 5 6 a 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 Derivation of AEGL 2 (10 minutes and 30 minutes)

Because the key study for the AEGL 2 derivation is a study with a 4 hour exposure duration, extrapolation to shorter time periods was necessary. It was decided to use a toxicokinetic approach to calculate AEGL 2 values for 10 minutes and for 30 minutes.

The following assumptions were made:

(i) the toxicological endpoint and the intensity of toxicological effect should be the same as (ii) it is the concentration and not the amount of the substance (AUC) which is responsible for (iii) the data from kinetic studies in human volunteers (see Table 11, page 37) are appropriate (iv) the data of m xylene were used to represent the mixture of all xylenes (v) the kinetics of m xylene are linear in the concentratioddose range which is under observed after administration of 430 ppm for 4 hours the effect, qualitatively and quantitatively for hrther kinetic calculations consideration.

Calculations: The data of three studies were used. The external concentration in the air multiplied by inhalation volume and frequency was used as input rate. A one compartment body model described the data appropriately. The calculations were done using NONMEM program. After the concentration at 4 hours was calculated, the input rate to reach this concentration with 10 minutes and 30 minutes, respectively, was estimated. As we assumed inhalation volume and frequency being constant, the external air concentration was obtained by eliminating the constant. \

The outcome of the calculations was as follows: k which is the first order elimination constant was 2.74/ hour; the corresponding half life is 0.25 hours. The concentration at 4 hours was 6.5 f 10 mmol/ L (mean f 2 SD) for 430 ppm. The external air concentration to reach this concentration within 10 minutes is 1165 f180 ppm (mean f 2 SD) and within 30 minutes is 570f87.5 (meanf2 SD).

Calculating the lower boundary value for 2 SD results in 10 min: 985 ppm 30 min: 482.5 ppm Calculating the lower boundary value for 3 SD results in 10 min: 896 ppm 30 min: 438.4 pprn 30 min 1 570 ppm I 483 ppm 1 438 ppm I(

Please see Figure. XYLENES Proposed 8 : 5/ 208) 2 ~ B 2 3 4 5 6 a 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 Derivation of AEGL 3 (10 minutes and 30 minutes)

Because the key study was a study with a 4 hour exposure duration, extrapolation to shorter time periods was necessary. It was decided to use a toxicokinetic approach to calculate AEGL 3 values for 10 and for 30 minutes.

The following assumptions were made:

(i) the toxicological endpoint and the intensity of toxicological effect should be the same as (ii) it is the concentration and not the amount of the substance (AUC) which is responsible for (iii) the data from kinetic studies in human volunteers (see Table 11, page 37) are appropriate (iv) the data of m xylene were used to represent the mixture of all xylenes (v) the kinetics of m xylene are linear in the concentratioddose range which is under observed after administration of 930 ppm for 4 hours the effect, qualitatively and quantitatively for fbrther kinetic calculations consideration.

Calculations: The data of three studies were used. The external concentration in the air multiplied by inhalation volume and frequency was used as input rate. A one compartment body model described the data appropriately. The calculations were done using NONMEM program. After the concentration at 4 hours was calculated, the input rate to reach this concentration within 10 minutes and 30 minutes, respectively, was estimated. As we assumed inhalation volume and frequency being constant, the external air concentration was obtained by eliminating the constant.

The outcome of the calculations was as follows: k which is the first order elimination constant was 2.74/ hour; corresponding half life is 0.25hours. The concentration at 4 hours. was 141 f 25 mmol/ L (mean i 2 SD) for 930 ppm. The external air concentrations to reach this concentration within 10 minutes is 2526 f 455 gpm (mean f 2SD) and within 30 minutes is 1237 f 221 ppm (mean f 2 SD).

Calculating the lower boundary value for 2 SD results in 10 min: 2071 ppm 30 min. 1016 ppm Calculating the lower boundary value for 3 SD results in 10 min: 1790 ppm 30 min: 963 ppm !I 11 conc (mmol/ L) 141 (mean) I 116 ( 2 SD) 103.5 ( 3 SD)

30 min 1237 ppm I1016ppm I 963 ppm 1 Please see Figure. XYLENES *' . i *

I "i

Concentration time prediction upper: 930ppm lower: 43Oppm Proposed 1: 512002 0 50 100 150 2M) 250 300 time [min] XYLENES 1 Proposed I: 5/ 2002 APPENDIX C: Derivation Summary for Xylene AEGLs XYLENES Proposed 1: 512002 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 ACUTE EXPOSURE GUIDELINES FOR XYLENES CAS Reg. No. 1330 20 7 DERIVATION SUMMARY AEGL 1 VALUES 10 minutes I 30minutes I 1 hour I] ibhouss 1 $hours I I 130 ppm 130 ppm 130 ppm 130 ppm 130 ppm Key Reference: Hastings, L., Cooper, G. P., and Burg, W. 1986. Human sensory response to selected petroleum hydrocarbons. In: MacFarland, H. N. ed. Advances in Modern Environmental Toxicology. Vol. VI. Applied Toxicology of Petroleum Hydrocarbons. Princeton, NJ: Princeton Scientific Publishers, pp. 255 270.

Test Swcies/ Strain/ Number: Volunteer human &le Exposure Route/ ConcentrationsDurations: Subjects were exposed by inhalation via an olfactometer delivery hood to 0, 100,200, or 400 ppm mixed xylene for 30 minutes Effects: Mild eye irritation reported by 56, 60,70, and 90% of subjects exposed to 0, 100,200, or 400 ppm EndpoinlfConcentratiodRationale: Mild eye irritation was noted by 90% of the subjects exposed to 400 ppm Uncertainty Factors/ Rationale: Total uncertainty factor: 3 mixed xylene, respectively; no effects observed on behavioral test results Interspecies: 1  human data used Intraspecies: 3  the toxic effect (slight irritation) was less severe than that defined for the AEGL 1 tier (notable discomfort).

Modifylng Factor: NA (1)

Animal to Human Dosimetric Adjustment: NA  human data used Time Scaling: Irritation is considered a threshold effect and therefore should not vary over time. The AEGL 1 value based on irritation is therefore not scaled across time, but rather the threshold value is applied to all times.

been reported. However, the data are consistent with other human studies, and represent a value consistent with exposure concentrations that might result in mild eye irritation. Data Adequacy: This was an acceptable study, but could have been improved had the number of volunteers 67 77 XYLENES Proposed 1: 5/ 2002 I 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 AEGL 2 VALUES 18 minutes 30 minutes 1 hour 4 hours 8 hours 990 ppm 480 ppm 430 ppm 438 ppm 430 ppm Key Reference: Carpenter, C. P., Kinkead, E. R., Geary, D. L. Jr., Sullivan, L. J., and King, J. M. 1975. Petroleum hydrocarbon toxicity studies. V. Animal and human response to vapors of mixed xylene. Toxicol. Appl. Pharmacol. 33: 543 58.

Test SpeciesIStrainlNumber: 10 male albino rats (Harlan Wistar strain) approximately 5 weeks old/ group Exposure Route/ Concentrations/ Durations: Rats were exposed by inhalation to 580, 1300,2800,4000, or 9000 ppm mixed xylene for 4 hours Effects: Conc.( mm) Mortalitv Other effects 580 0110 none observed 1300 0110 poor coordination after 2 hours, returned to normal 2800 6000 9900 10110 none stated 0/ 10 4110 irritation; all rats prostrate between 2 3.5 hours recovered within 1 hr, coordination returned to normal next day rats prostrate within 30 minutes; all survivors prostrate but recovered promptly EndpointEoncentrationIRationale: Exposure to 1300 ppm for 4 hours resulted in poor coordination Uncertainty Factorsktionale: Total uncertainty factor: 3 Interspecies: 1  An interspecies uncertainty factor of 1 was applied because rats receive a greater systemic Intraspecies: 3  The MAC (minimum alveolar concentration) for volatile anesthetics should not vary by dose of inhaled xylene as compared to humans.

more than a factor of 2 3 fold among humans. A 3 fold factor is also adequate to account for moderate physical activity during exposure, which would result in greater uptake of the chemical.

Modifying Factor: NA (1)

Animal to Human Dosimetric Adjustment: NA Time Scaling: Data indicate that once steady state is reached, concentration, not duration, is the prime determinant in xylene induced central nervous system toxicity. Therefore, the AEGL 2 values are set equal across time once steady state is approached (starting at approximately 1 hour), while pharmacokinetic modeling was used to extrapolate to exposure durations of 10 and 30 minutes.

Data Adequacy: This was a well designed and conducted study. The data are supported by numerous other studies in rats, as well as a study in dogs. The AEGL 2 levels are protective of human health, especially when considering numerous human studies investigated the effects of exposure to 200 ppm xylene with 20 minute peak exposures to 400 ppm, in some cases additionally combining peak exposures with physical exercise resulting in greater uptake of the chemical, and found only minimal central nervous system effects. XYLENES Proposed 1: 5/ 2002 ,1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 AEGL 3 VALUES Key Reference: Carpenter, C. P., Kinkead, E. R., Geary, D. L. Jr., Sullivan, L. J., and King, J. M. 1975. Petroleum hydrocarbon toxicity studies. V. Animal and human response to vapors of mixed xylene. Toxicol. Appl. Pharmacol. 33: 543 58.

Test Species/ Strain/ Number: 10 male albino rats (Harlan Wistar strain) approximately 5 weeks oldgroup Exposure Route/ Concentrations/ Durations: Rats were exposed by inhalation to 580, 1300, 2800,4000, or 9000 gpm mixed xylene for 4 hours Effects: Conc.( mm) Mortality Other effects 580 0/ 10 none observed 1300 0/ 10 poor coordination after 2 hours, returned to normal 2800 6000 9900 10/ 10 none stated 040 4/ 10 irritation; all rats prostrate between 2 3.5 hours recovered within 1 hr, coordination returned to normal next day rats prostrate within 30 minutes; all survivors prostrate but recovered promptly EndpointKoncentratiodRationale: Exposure to 2800 ppm for 4 hours resulted in prostration followed by full recoverv ~

Uncertainty Factors/ Rationale: ~o t a l incertainty factor: 3 Interspecies: 1  An interspecies uncertainty factor of 1 was applied because rats receive a greater systemic dose of inhaled xylene as compared to humans. Intraspecies: 3  The MAC (minimum alveolar concentration) for volatile anesthetics should not vary by more than a factor of 2 3 fold among humans. A 3 fold factor is also adequate to account for moderate physical activity during exposure, which would result in greater uptake of the chemical.

Modifying Factor: NA (1)

Animal to Human Dosimetric Adjustment: NA Time Scaling: Data indicate that once steady state is reached, concentration, not duration, is the prime determinant in xylene induced central nervous system toxicity. Therefore, the AECGL 3 values are set equal across time once steady state is approached (starting at approximately 1 hour), while pharmacokinetic modeling was used to extrapolate to exposure durations of 10 and 30 minutes.

Data Adequacy: This was a well conducted study. The AEGL 3 levels are supported by human data demonstrating that exposure to 690 ppm for 15 minutes resulted in lightheadednesddizziness and a 30 minute exposure to 700 ppm resulted in nausea, vomiting, dizziness or vertigo.

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