similar results ( Ex. 5 115), and these results were confirmed in study of female silk screen operators exposed to 2 EE and 2 EEA by Veulemans et al ( Ex. 5 114). The finding of a longer biological half life for 2 EE and 2 EEA in humans prompted Veulemans et al to note that " it would certainly warrant extra caution in the extrapolation of experimental data from laboratory animals to man, since comparable accumulation effects apparently are not found in all species." Although 2 EE and 2 EEA are the only glycol ethers which have been studied in humans, these findings raise enough questions about the similarities of the metabolism and pharmacokinetics of glycol ethers across species to deter the Agency from reducing the uncertainty factor used based on the similarity of the pharmacokinetics and metabolism of glycol ethers across species CMA's fourth argument is that when dose is expressed in the correct units using the correct cross species scaling factor, then a lower uncertainty factor can be used. OSHA intends to discuss this issue later in this section in its review of the risk assessment performed by Environ et al ( Ex. 4 016f). The Agency does agree with CMA that uncertainty is reduced when dose is expressed in the correct units, but the Agency is not as confident as CMA regarding what are the correct units CMA's final argument for supporting a lower uncertainty factor is that lower uncertainty factors should be used because exposure is occupational. In an appendix to CMA's comments, E. M. Johnson argues that the 10 fold factor for intra species variability can be reduced when the exposed population is less diverse than the total population as in the case of workers who tend to be healthier and more homogeneous than the general population ( Ex. 7 17, Appendix A)

OSHA cannot agree with this position for a number of reasons. First of all, while it is plausible that a woman who is a worker may be healthier than a woman who is not a worker, CMA presents no evidence that the " healthy worker effect" is conferred upon the developing fetus. Furthermore, a fetus has two parents who contribute to its genetic identity, and there is no reason to assume that the father of a fetus of a working mother is also a " healthy worker". Finally, although " healthy workers" may constitute a homogeneous population, it does not follow that their offspring will constitute a homogenous population, healthy or otherwise Although OSHA's approach of using an uncertainty factor of 100 may appear conservative, OSHA believes that the uncertainties associated with deriving an ADI for occupational exposure to glycol ethers require the use of this factor. Some of the uncertainties stem from the qualitative nature of the uncertainty factor approach as outlined earlier in this risk assessment ( e. g. the unlikelihood that an exposure level used in a bioassay will be the " true" threshold, varying susceptibilities across species, etc.). Other uncertainties stem specifically from the data available for assessing the risk from glycol ethers as noted above ( e. g. similar exposure levels used across species, possible differences in metabolism and pharmacokinetics across species, etc.). For these reasons, OSHA has used an uncertainty factor of 100. The Agency seeks comment on its choice of uncertainty factor and its justification for this choice. The Agency seeks detailed reasons for either accepting or rejecting the choice of a 100 fold uncertainty factor and any data available to support the position D . Assessment of the Reproductive Risk from Exposure to Glycol Ethers 1. Introduction The Interagency Regulatory Liaison Group, ( IRLG), describes reproductive toxicity as dealing with " the effects of toxicants on adult reproductive function and development of the offspring which may be produced by alteration of a wide range of processes in either the female or the male." As noted by the IRLG, these processes include " those associated with the primary and accessory sexual organs and with fertilization, as well as those which impact more indirectly on normal reproductive function; e. g., neuroendocrine control, general physiological and psychological health, and nutrition." The IRLG continues, "[ f] ollowing fertilization, processes associated specifically with pregnancy are also vulnerable; e. g., implantation, placental formation and function, conceptal development, and parturation and lactation" ( Ex. 5 018) In its Proposed Guidelines for Assessing Male Reproductive Risk ( Ex. 5 123), the EPA identifies a number of measures which may be evaluated to assess the reproductive effects of exposure of males to a potential reproductive toxicant. In animals, these include body weight; weight and histopathology of the testes, epididymides, seminal vesicles, prostate, and pituitary gland; mating ratio and pregnancy ratio; and pregnancy outcomes such as litter size, pre and post implantation loss, the ratio of live to dead pups, sex ratios, malformations, birth and postnatal weights, and survival. Supplemental end points of male reproductive toxicity may be identified through sperm and endocrine evaluations. EPA points out that while these measures are useful for evaluating reproductive risk in humans as well as animals, many of these measures such as early fetal loss, reproductive capacity of the offspring, and the invasive measures of reproductive function are not easily observed in humans The most feasible measures used in studies of reproductive effects in human males are semen evaluations, indirect measures of fertility/ infertility, and certain pregnancy outcomes such as fetal loss, birth weight, sex ratio, congenital malformations, postnatal function, and neonatal growth and survival The measures recommended by EPA for evaluation to determine reproductive effects in female laboratory animals include capacity to conceive; length of time required for conception; alterations in the onset of puberty; alterations in the reproductive cycle; oocyte toxicity; premature reproductive senescence; weight and histopathology of the ovary, the uterus, and the pituitary gland; and the pregnancy outcomes described for males above. In human females, the feasible measures of reproductive toxicity are the measures of fertility and pregnancy outcomes ( Ex. 5 122)

While studies of human populations provide the strongest evidence of the reproductive toxicity of a substance, such studies are usually limited in their ability to detect risk. Like epidemiological studies of cancer mortality and other discrete outcomes, studies of reproductive toxicity in human populations often suffer from lack of statistical power ( usually due to small sample size), inexact exposure measurements, and an inability to control for all potential confounding factors. Studies of reproductive toxicity in human populations, however, have additional limitations. Assessment of reproductive endpoints is often dependent upon voluntary participation and self reporting of outcomes which, in turn, may be influenced by privacy considerations and religious considerations. In addition, there are fewer endpoints which may be feasibly measured in humans than may be measured in laboratory animals. Thus, because of these limitations, reproductive risks are usually assessed from animal studies 2. 2 ME A number of studies showing reproductive effects in male animals exposed to 2 ME are described in the [ page 15566]

Health Effects section of this preamble. Results from studies of animals exposed to 2 ME through inhalation are supported by the results from studies of animals exposed to 2 ME through ingestion The lowest NOEL observed in laboratory animals was observed in a study of New Zealand white rabbits by Miller et al of the Dow Chemical Company ( Exs. 4 045 and 5 023). Groups of five male rabbits were exposed to 2 ME at concentrations of 30, 100, or 300 ppm through inhalation for 6 hours per day, 5 days per week, for 13 weeks. A group of 5 male rabbits served as controls. Food and water was provided to the animals ad libitum except during periods of exposure when neither was available Following 13 weeks of exposure, all surviving animals were sacrificed. Two rabbits in the 300 ppm group died during the exposure phase of the study. The cause of death for one was bronchopneumonia. The cause of death for the second was unknown. All animals were given a complete gross pathological exam, and a histological exam was performed on selected tissues from each animal Reduced testes weight was observed in rabbits in the 300 ppm and 100 ppm exposure groups, and although this effect was statistically significant for the 300 ppm group only, the study authors attributed the observation in both groups to exposure. Gross pathological exam showed that all of the rabbits in the 300 ppm group had very small and flaccid testes. A slight to moderate decrease in testes size relative to the control animals was observed in 4 out of 5 of the rabbits in the 100 ppm group ( p= 0.024, Fisher's Exact Test), and 2 out of 5 of the rabbits in the 30 ppm, group ( p > 0.05). Histopathologic exam confirmed the gross pathological observations. A dose related increase in both the incidence and severity of testicular degenerative changes was seen in the test animals. In all three of the rabbits on the 300 ppm group, which survived through the end of the study, the degeneration was diffuse and severe with virtually every tubule affected. In the three rabbits with testicular degeneration in the 100 ppm group, more of a spectrum of effects was noted in that within the same testes, some tubules were relatively normal in appearance while others contained no germinal elements at all. In the 30 ppm group, the microscopic degenerative changes were apparent in the testes of only one of the two rabbits observed to have decreased testes size in the gross pathological exam. The microscopic degenerative changes observed in this animal were an excess of tubules in which the germinal epithelium was thinner than normal, with a complete complement of germinal stages but very few spermatozoa Histopathologic exam of the epididymis found that the epididymal sperm content generally reflected the degree of testicular damage with noticeable decreases in those cases which were moderately to severely affected. Degenerating spermatic elements were commonly observed, but secondary changes in accessory sex glands were not seen Despite the small number of animals in each exposure group, a significant dose related effect was observed. Based upon the outcome of decreased testes size, one of the outcomes identified by EPA as an adverse reproductive outcome, the NOEL for reproductive effects of 2 ME in rabbits is 30 ppm Given that the NOEL for reproductive effects from 2 ME has been derived from animal studies, OSHA believes that an uncertainty factor of 100 is appropriate for derivation of the ADI as was the case for the assessment of developmental risks from exposure to 2 ME. Here again, an uncertainty factor of 100 provides a factor of 10 for inter species variability and a factor of 10 for intra species variability. Therefore, based upon this study Miller et al, the ADI for 2 ME would be 30/ 100 or 0.3 ppm on the basis of reproductive risks. The ADI for 2 ME based on developmental risks is 0.1 ppm, somewhat lower than the ADI based on reproductive risks but the two ADIs are very close. Thus an ADI, of 0.1 ppm would cover both reproductive and developmental effects, i. e. at this level humans are unlikey to exhibit adverse effects ( both reproductive and developmental) similar to those observed in animals 3. 2 EE There are fewer studies of the reproductive effects of 2 EE in the literature than there are of 2 ME, but like 2 ME, 2 EE has been found to induce adverse reproductive effects in laboratory animals This was the finding of Terrill et al who conducted a study for the Chemical Manufacturers Association exposing rabbits to 2 EE ( Exs. 4 108 and 5 084). Groups of ten male New Zealand white rabbits were exposed to 2 EE at concentrations of 25, 100, and 400 ppm through inhalation for 6 hours per day, 5 days per week, for 13 weeks. A group of ten male rabbits served as controls. Food and water was provided to the animals ad libitum except during periods of exposure when neither was available All animals survived the exposure phase of the study. At terminal sacrifice, all animals were given a complete gross post mortem exam. Animals in the control and high dose groups were given a complete histopathological exam, but for the low and middle dose groups, only the bone marrow, the testes with epididymis, the kidneys, the liver, the lymph nodes, the spleen, the thymus, and any observed gross lesion or tissue mass were examined In the 400 ppm group, there was a statistically significant decrease in absolute testes weight and in testes weight relative to body weight. Gross postmortem examination revealed that in three of the ten rabbits from this group, there was slight focal tubule degeneration. Based upon decreased testes weight, the NOEL for reproductive effects for 2 EE in rabbits is 100 ppm Although there are fewer animal studies of the reproductive effects of exposure to 2 EE than 2 ME, the results of the animal studies are supported by observation in human populations. In a study of male workers at Precision Castparts Corporation, NIOSH reported significantly reduced sperm count among workers exposed to 2 EE compared to workers with no such exposure ( Ex. 5 003). Welch et al also found reduced sperm in a group of shipyard painters exposed to 2 EE, but theses workers were also exposed to 2 ME, so it is impossible to determine whether the effect was due to 2 EE, 2 ME, or both glycol ethers ( Ex. 5 104). These studies are discussed in greater detail in the Health Effects Section of this preamble Applying an uncertainty factor of 100 to the NOEL of 100 ppm reported by Terrill et al in their study of New Zealand white rabbits, one would arrive at an ADI of 100/ 100 or 1 ppm for 2 EE basee on reproductive risk. Here again, however, the ADI must be based on developmental risks as well as reproductive risks. The ADI for 2 EE based on developmental risks is 0.5 ppm, lower than the ADI based reproductive risks. As is the case for 2 ME, for 2 EE the ADI based on reproductive risks is very close to the ADI based on developmental risks. At an ADI of 0.5ppm 2 EE humans are unlikely to exhibit effects ( both reproductive and developmental) similar to those observed in animals E. Assessment of Risk from Exposure to Glycol Ether Acetates The acetates of 2 ME and 2 EE, 2 MEA and 2 EEA, have not been studied [ page 15567]

as extensively as have the parent compounds. As noted in the Health Effects section of this preamble, however, the acetates have been shown to induce adverse reproductive, developmental, and hematological effects in animals similar to those induced by 2 ME and 2 EE. Furthermore, as discussed in the Health Effects section, it has been shown that 2 MEA and 2 EEA are metabolized to the same acetic acids, methoxyacetic acid ( MAA) and ethoxyacetic acid ( EEA) respectively, by the same mediated pathway, an alcohol dehydrogenase ( ADH) mediated pathway, as their parent compounds Because of the similarity in induced effects between the acetates and their parent compounds and because of the similarity in metabolism between the acetates and their parent compounds, OSHA proposes that the ADIs derived for the acetates be the same as for their parent compounds. That is, the ADI for for 2 MEA is 0.1 ppm and the ADI for 2 EEA. is 0.5 ppm There is some experimental evidence to support OSHA's proposal. As reproductive toxicants, the acetates have been shown not only to induce similar effects as their parent compounds, but also to induce these effects at equivalent doses. Nagano et al found that male mice exposed orally to 2 MEA at 500 mg/ kg of body weight experienced significant decreases in testicular weight. When this dose was converted to mmole/ kg, the authors found that on an equimolar basis, exposure to 2 ME and 2 MEA resulted in similar effects ( Ex. 4 135). Likewise, these authors found that on an equimolar basis, male mice exposed to 2 EE and male mice exposed to 2 EEA experienced similar adverse reproductive outcomes ( Ex. 4 135)

The acetate 2 MEA has not been tested for its potential to adversely affect reproductive outcomes. Only limited data exist on 2 MEA, according to CMA, because of the small production volume of this acetate ( Ex. 7 17). Nonetheless, CMA argues that although detailed evaluation of the developmental toxicity of 2 MEA has not been conducted as it has for 2 ME, " the NOELs determined for 2 ME can be reasonably employed for assessing this compound. The likelihood that any effect it may cause would occur through human metabolism of 2 MEA to 2 ME and then to the active metabolite makes it reasonable to employ the NOELs for 2 ME to protect humans against effects of 2 MEA" ( Ex. 7 17). OSHA concurs with CMA's position Unlike 2 MEA, 2 EEA has been tested to determine its potential as a developmental toxicant. Nelson et al reported a statistically significant excess of developmental effects in rats exposed to 2 EEA at levels as low as 130 ppm ( Ex. 5 091). This level was the lowest exposure level used in this bioassay therefore no NOEL was established for this study. Doe et al exposed pregnant Dutch rabbits to 0, 25, 100, or 400 ppm of 2 EEA, and the fetuses of rabbits exposed to levels as low as 100 ppm showed a dose related increase in skeletal defects ( Ex. 5 071). Tyl et al exposed pregnant Fischer 344 rats and pregnant New Zealand white rabbits to 0, 50, 100, 200, or 300 ppm of 2 EEA ( Ex. 5 124). Here again, 100 ppm was the LOEL for developmental effects in both species. This level, 100 ppm, is OSHA's current PEL for 2 EEA. Fifty ppm was established to be the NOEL for both the rats and the rabbits. Because Doe et al and Tyl et al established the same LOEL in two separate studies and in two different species, it is reasonable to use the NOEL from the Tyl et al study, 50 ppm of 2 EEA, as the NOEL for calculating the ADI. As with the parent compounds, an uncertainty factor of 100 is appropriate, and this would lead to an ADI of 50 ppm/ 100 or 0.5 ppm. That is, at an ADI of 0.5 ppm 2 EEA, humans are likely to exhibit effects similar to those observed in humans OSHA's proposal for deriving ADIs for the acetates at the same level as those for the parent compound also has support from a number of commentors who responded to OSHA's ANPR. For example, NIOSH wrote that a separate PEL for each of the acetates and their parent compounds " should not be necessary because of the similarities in the adverse effects, the similarity in route of exposure, and the fact that in many situations, several of the ethers and their acetates are used simultaneously" ( Ex. 7 22). Similarly, Du Pont noted that " 2 methoxyethanol ( 2 ME) and its acetate ( 2 MEA) and the [ sic] 2 ethoxyethanol ( 2 EE) and its acetate ( 2 EEA) could be regulated together because the toxic effects of these glycol ethers and their respective acetates are the same" ( Ex. 7 28), and Kodak proposed the same PELs for 2 ME and 2 MEA and for 2 EE and for 2 EEA, ( Ex. 7 23), although the levels proposed are different than those proposed by OSHA. OSHA seeks comment on this approach to deriving ADIs for the glycol ether acetates F. Other Approaches to the Assessment of Risk for Glycol Ethers 1. The Crump Risk Assessment Under contract to OSHA, K. S. Crump and Company performed a risk assessment for developmental and reproductive effects from exposure to 2 ME, 2 EE, and their acetates ( Ex. 5 136). The data used for this analysis were from the studies of developmental effects of exposure to 2 ME by Hanley et al ( Exs. 4 042a and 4 106) and to 2 EE by Tinston, Doe et al ( Exs. 4 038 and 4 039; see also Ex. 5 071) and the studies of reproductive effects of exposure to 2 ME by Miller et al ( Ex. 5 057) and to 2 EE by Terrill et al ( Exs. 4 108 and 5 084). At the time Crump performed its analysis, no data were available on the developmental effects of 2 EE as measured in litters. Therefore, Crump limited its analysis of the developmental effects of 2 EE exposure to responses observed in fetuses. No analyses were done on data from studies of the acetates. Crump noted that " 2 MEA and 2 EEA are believed to be quickly hydrolized to their corresponding glycol ether. Furthermore, evidence suggests that from that point on, their metabolism and distribution proceed in the same manner as the ether. If that is the case, a mole of an ether will yield the same amounts of products as a mole of the corresponding acetate. Moreover, a given air concentration in ppm contains the same number of moles ( 1 ppm is about 41 micromoles per cubic meter at standard temperature and pressure), for all chemicals. Consequently, in the absence of data on the acetates needed for risk assessment, it is reasonable to assume that the acetates and their corresponding ethers will produce the same risks at equal air concentrations, in ppm" ( Ex. 5 136)

The goal of the Crump risk assessment was to develop dose response models for developmental and reproductive effects. Only brief descriptions of the models and methods used by Crump are presented here, and the reader is referred to the Crump report ( Ex. 5 136) for additional details. Two approaches were taken to develop these models for the outcomes of interest. The first of these applied methods similar to those applied to cancer data, but the dose response models considered were non linear or incorporated a threshold. Four models employed this approach: the quantal linear regression ( QLR) model, the Weibull model, the continuous linear regression ( QCR) model, and the continuous power ( CP) model. The QLR and Weibull models were used for incidence data measured in fetuses, and [ page 15568]

therefore do not take litter size or intra litter correlation ( i. e. the litter effect) into account. The QCR and CP models were used for incidence data measured in litters, and they account for the litter effect but not for litter size. The QLR and QCR models assume a threshold with a linear response above the threshold. The Weibull and CP models are non threshold models but can be non linear if indicated by the data The second approach taken by Crump was to consider two models recently developed specifically for assessing developmental effects, ( these models use only litter data), and to modify these for the analysis of the glycol ethers data. The first of these was developed by Kodell et al. This model uses the beta binomial distribution to account for the litter effect and takes into account the effect of litter size on the probability of a developmental effect. The second model considered by Crump was originally put forth by Rai and Van Ryzin. This model takes litter size into account but does not account for the litter effect. In its analysis, Crump used two special cases of the Kodell model, the Kodell QLR model which assumes a threshold but is linear above the threshold, and the Kodell Weibull model which assumes no threshold but can be non linear. Only one case of the Rai and Van Ryzin model was considered. This model assumes no threshold and is linear. Crump felt the shortcomings of the Rai and Van Ryzin model made it less appropriate for assessing risk than the other models considered Crump applied the models described here only to data on developmental outcomes. The models developed for use with litter data could not be used with the data Crump had on reproductive outcomes because the data Crump had measured these outcomes in individual animals and not litters. Likewise, the models developed for use with litter data could not be used with the data Crump had on developmental outcomes from 2 EE exposure because, as noted above, litter data for these effects were not available to Crump when it did its analysis. The models developed for use with fetal data could have been used with the data on reproductive outcomes, but Crump did not use these models to analyze the data on reproductive effects because of the small number of animals used in these bioassays Although the goal of the Crump risk assessment was to develop dose response models for the outcomes of interest, two additional approaches for determining a " safe" level of exposure were considered. The first of these was to calculate a NOEL using a nostatistical significance of trend or NOSTASOT approach. In this approach, tests of statistical hypothesis were conducted to determine whether the bioassay data provided sufficient statistical evidence to conclude that a dose related trend existed, ( i. e. whether response increased with dose), and if so, to determine the highest dose used in the bioassay such that there was no statistical evidence of a dose related trend in response at that dose or at lower doses. The highest dose which showed no statistical evidence of a dose related trend is called the NOSTASOT dose and is considered to be a statistically determined NOEL. This approach was used for both developmental and reproductive outcomes for both 2 ME and 2 EE The final approach considered by Crump was calculation of a benchmark dose as an alternative to the NOEL. A benchmark dose is defined as the statistical 95% lower confidence limit on the dose corresponding to a 1% increase in the extra risk. The dose corresponding to a 1% increase in extra risk was estimated using both the QLR model and Weibull model, but only the lower of the two benchmark doses was reported. Crump chose to use only these two models to estimate the benchmark doses because these two models were the only two used to analyze all of the data on adverse reproductive outcomes for both 2 ME and 2 EE The NOSTASOT dose and the benchmark dose calculated by Crump are much like the NOELs calculated by OSHA in that neither of these doses alone represents a " safe" level of exposure. Rather, Crump intended an uncertainty factor to be applied to either of these doses, although Crump did not recommend a particular uncertainty factor in his report. Crump argues that either is preferable to a NOEL established using traditional methods because they make use of all of the dose response data. Crump notes that NOELs " determined by comparing treatment groups individually to the control group . have low power because they involve only the animals in two of the treatment groups, when in fact the data from any intermediate doses are also relevant. Thus a common result is that the trend test is significant, but none of the treated groups differ significantly from the control group."

Results of the Crump analysis are presented in Tables VI K through VI N. Although the sources of the data used by Crump were the same as those used by OSHA, the adverse outcomes considered and the specific estimates of incidence were different. These data are presented in the Crump report Table VI K shows that for 2 ME, NOELs established using the NOSTASOT approach are identical to those established by OSHA using more traditional methods. For 2 EE, Table VI L shows that for all but one outcome in rats, total abnormal ribs, Crump's NOSTAOTs are the same as OSHA's NOELs, but for rabbits, Crump's NOELs are lower. This difference is due to the fact that Crump used fetus data for its analysis of 2 EE whereas OSHA used litter data in its analysis to establish the NOEL Table VI K NOSTASOT and Benchmark Doses Calculated for 2 ME Data Sets ( a)

DEVELOPMENTAL EFFECTS NOSTASOT ( b) Benchmark ( c)

Species Adverse Effect Exposure ( ppm) Dose( ppm)

Rats ( d) Delayed ossification of Centra 10 12 Rib spurs 10 8.5 Major malformations 10 53 Rabbits( d) Resorptions 10 2 Major malformations 10 10 Mice ( e) Resorptions 10 9.3 Extra lumbar ribs 10 2.5 REPRODUCTIVE EFFECTS NOSTASOT Benchmark Species Adverse Effect Exposure ( ppm) Dose ( ppm)

Rats ( f) Testicular degeneration 100 N/ C ( g)

Rabbits( f) Testicular degeneration 30 N/ C [ page 15569] Reduced testes size 30 N/ C a  From the Crump Report, Ex. 5 136 b  NOSTASOT = No statistical significance of trend ( i. e. the NOSTASOT exposure is the highest dose for which dta did not show a statistically significant dose related trend). See text for details c  Benchmark exposure is the 95% lower limit on doses corresponding to an extra risk of 1%. See text for details d  Data from Hanley et al, Ex. 4 042a e  Data from Hanley et al, Ex. 4 106 f  Data from Miller et al, Ex. 4 045 g  N/ C = not calculated Table VI L NOSTASOT and Benchmark Doses Calculated for 2 EE Data Sets ( a)

DEVELOPMENTAL EFFECTS NOSTASOT( b) Benchmark( c)

Species Adverse Effect Exposure ( ppm) Dose ( ppm)

Rats ( d) Minor skeletal defects 50 15 Minor visceral defects 50 46 Total abnormal ribs 10 1.8 Late intra uterine deaths 50 18 Rabbits( e) Minor skeletal defects N/ D ( f) 3.5 Skeletal variants 10 2.2 REPRODUCTIVE EFFECTS NOSTASOT Benchmark Species Adverse Effect Exposure ( ppm) Dose ( ppm)

Rabbits( g) Focal tubule degeneration 100 N/ C ( h)

Weights of testes/ epididymis 100 N/ C a  From the Crump Report, Ex. 5 136 b  NOSTASOT = No statistical significance of trend ( i. e. the NOSTASOT exposure is the highest dose for which dta did not show a statistically significant dose related trend). See text for details c  Benchmark exposure is the 95% lower limit on doses corresponding to an extra risk of 1%. See text for details d  Data from Tinston et al, Ex. 4 038 e  Data from Tinston et al, Ex. 4 039 f  Not defined. A significant effect was seen at the lowest dose g  Data from Terrill et al, Ex. 4 108 h  N/ C = not calculated For almost every adverse outcome considered, Tables VI K and VI L show that the benchmark dose is lower than the NOEL estimated using the NOSTASOT approach. Here again, this could be due to the fact that benchmark doses were estimates from models which use fetal data rather than litter data. Were benchmark doses to be used to calculate the ADIs, the result would be a more conservative estimate of the exposure below which an adverse outcome is unlikely than the estimates derived by OSHA Tables VI M and VI N show that despite the differences among the models used by Crump, for the majority of data sets the models predict surprisingly consistent risks. The largest difference in predicted risks are found at low doses between the threshold and non threshold models. Much less difference can be attributed to whether the models use fetal or litter data. Crump suggests one reason that the shape of the dose response curve is more important in determining a risk estimate than the type of data used may be the low intra litter correlation estimated for the 2 ME data sets. Crump explains that "[ f] or the rat data, intra litter correlations, as estimated by the Kodell QLR or Kodell Weibull models, did not exceed 0.05 . Somewhat larger correlations were observed in some of the rabbit and mouse data sets ( ranging up to about 0.27). Apparently, intra litter correlations of this magnitude are not sufficient to cause maximum likelihood estimates derived ignoring the litter effect to be seriously in error."

Table VI M Estimates of Number of Extra Cases of Various Developmental Effects per 1000 Fetus from Exposure to 2 ME a Rats: Delayed Ossification of the Centra b Kodell Kodell Rin and Dose( c) QLR Weibull QCR CP QLR Weibull Van Ryzin 25 33 31 30 27 33 31 25 ( 50) ( 51) ( 47) ( 47) ( 46) ( 270)

5 4 4.1 3.6 3.1 4.1 4.1 3.1 ( 10) ( 10) ( 9.3) ( 9.4) ( 8.2) ( 62)

1 0 0.54 0 0.36 0 0.54 0.57 ( 2) ( 2.1) ( 1.9) ( 1.9) ( 0.48) ( 13)

0.5 0 0.23 0 0.14 0 0.23 0.28 ( 1) ( 1) ( 0.93) ( 0.94) ( 0) ( 6.4)

0.1 0 0.03 0 0.016 0 0.03 0.056 ( 0.2) ( 0.21) ( 0.19) ( 0.19) ( 0) ( 1.3)

0.03 0 0.0066 0 0.0033 0 0.0065 0.017 ( 0.061) ( 0.062) ( 0.056) ( 0.057) ( 0) ( 0.38)

Rats: Rib Spurs b Kodell Kodell Rin and Dose( c) QLR Weibull QCR CP QLR Weibull Van Ryzin 25 89 75 89 86 97 82.4 89 [ page 15570] ( 120) ( 120) ( 150) ( 150) ( 130) ( 132)

5 3.8 5.8 0 7.3 6.7 7.2 16 ( 24) ( 24) ( 30) ( 30) ( 27) ( 28)

1 0 0.43 0 0.62 0 0.61 3 ( 4.8) ( 4.9) ( 6.1) ( 6) ( 5.6) ( 5.6)

0.5 0 0.14 0 0.22 0 0.21 1.5 ( 2.4) ( 2.5) ( 3) ( 3) ( 2.8) ( 2.8)

0.1 0 0.011 0 0.018 0 0.018 0.3 ( 0.48) ( 0.49) ( 0.61) ( 0.6) ( 0.56) ( 0.57)

0.03 0 0.0015 0 0.0029 0 0.0028 0.091 ( 0.15) ( 0.15) ( 0.18) ( 0.18) ( 0.17) ( 0.17)

Rats: Total Major Malformations b Kodell Kodell Rin and Dose( c) QLR Weibull QCR CP QLR Weibull Van Ryzin 25 6.2 6.2 6.5 6.5 5.3 5.4 6.2 ( 15) ( 15) ( 10) ( 12) ( 13) ( N/ P)

5 1.3 1.3 1.3 1.3 0.64 0.97 1.3 ( 3.1) ( 3.1) ( 2) ( 2.4) ( 2.6) ( N/ P)

1 0.25 0.25 0.26 0.26 0 0.18 0.25 ( 0.62) ( 0.62) ( 0.41) ( 0.47) ( 0.53) ( N/ P)

0.5 0.13 0.13 0.13 0.13 0 0.084 0.13 ( 0.31) ( 0.31) ( 0.2) ( 0.24) ( 0.27) ( N/ P)

0.1 0.025 0.025 0.026 0.026 0 0.015 0.025 ( 0.062) ( 0.062) ( 0.041) ( 0.047) ( 0.053) ( N/ P)

0.03 0.0075 0.0075 0.0078 0.0078 0 0.0042 0.0075 ( 0.019) ( 0.019) ( 0.012) ( 0.014) ( 0.016) ( N/ P)

Rabbits: Resorptions b Kodell Kodell Rin and Dose( c) QLR Weibull QCR CP QLR Weibull Van Ryzin 25 140 140 150 150 150 150 180 ( 190) ( 190) ( 210) ( 210) ( 240) ( 240)

5 31 31 29 29 33 33 49 ( 41) ( 41) ( 43) ( 43) ( 53) ( 53)

1 6.2 6.2 5.8 5.8 6.7 6.7 10 ( 8.3) ( 8.3) ( 8.6) ( 8.6) ( 11) ( 11)

0.5 3.1 3.1 2.9 2.9 3.3 3.3 5.2 ( 4.2) ( 4.2) ( 4.3) ( 4.3) ( 5.5) ( 5.5)

0.1 0.62 0.62 0.58 0.58 0.67 0.67 1.1 ( 0.84) ( 0.84) ( 0.86) ( 0.86) ( 1.1) ( 1.1)

0.03 0.19 0.19 0.18 0.18 0.2 0.2 0.32 ( 0.25) ( 0.25) ( 0.26) ( 0.26) ( 0.33) ( 0.33)

25 430 2.2 360 1.4 420 36 230 ( 490) ( 290) ( 430) ( 220) ( 520) ( 280)

5 0 0 0 0 0 0.0001 19 ( 0) ( 5.4) ( 0) ( 3.5) ( 0) ( 6.3)

1 0 0 0 0 0 0 3.3 ( 0) ( 0.088) ( 0) ( 0.056) ( 0) ( 0.12)

0.5 0 0 0 0 0 0 1.6 ( 0) ( 0.015) ( 0) ( 0.0094) ( 0) ( 0.022)

0.1 0 0 0 0 0 0 0.31 ( 0) ( 0.00024) ( 0) ( 0.00015) ( 0) ( 0.00042)

0.03 0 0 0 0 0 0 0.094 ( 0) ( 0.00001) ( 0) ( 0) ( 0) ( 0.00002)

Mice: Resorptions d Kodell Kodell Rin and Dose( c) QLR Weibull QCR CP QLR Weibull Van Ryzin 25 35 35 45 45 44 44 51 ( 65) ( 65) ( 80) ( 80) ( 78) ( 78)

5 7.1 7.1 8.9 8.9 8.9 8.9 19 ( 13) ( 13) ( 16) ( 16) ( 16) ( 16)

1 1.4 1.4 1.8 1.8 1.8 1.8 4.2 ( 2.7) ( 2.7) ( 3.2) ( 3.2) ( 3.3) ( 3.3)

0.5 0.72 0.72 0.89 0.89 0.89 0.89 2.1 ( 1.3) ( 1.3) ( 1.6) ( 1.6) ( 1.6) ( 1.6)

0.1 0.14 0.14 0.18 0.18 0.18 0.18 0.43 ( 0.27) ( 0.27) ( 0.32) ( 0.32) ( 0.033) ( 0.033)

0.03 0.043 0.043 0.054 0.054 0.053 0.053 0.13 ( 0.08) ( 0.08) ( 0.096) ( 0.096) ( 0.098) ( 0.098)

Mice: Extra Lumbar Ribs d Kodell Kodell Rin and Dose( c) QLR Weibull QCR CP QLR Weibull Van Ryzin 25 140 140 160 160 140 140 140 ( 190) ( 190) ( 240) ( 240) ( 240) ( 240)

5 29 29 31 31 30 30 34 ( 41) ( 41) ( 48) ( 48) ( 52) ( 52)

[ page 15571] 1 4.2 5.7 6.2 6.2 6.2 6.2 7.2 ( 8.4) ( 8.4) ( 9.6) ( 9.5) ( 11) ( 11)

0.5 1.1 2.8 3.1 3.1 3.1 3.1 3.6 ( 4.2) ( 4.2) ( 4.8) ( 4.8) ( 5.4) ( 5.4)

0.1 0 0.54 0.62 0.62 0.62 0.62 0.73 ( 0.84) ( 0.84) ( 0.96) ( 0.95) ( 1.1) ( 1.1)

0.03 0 0.16 0.19 0.19 0.19 0.19 0.22 ( 0.25) ( 0.25) ( 0.29) ( 0.29) ( 0.32) ( 0.32)

a  From the Crump Report, Ex. 5 136. The models considered are the quantal linear regression ( QLR) model, the Weibull model, the continuous linear regression ( QCR) model, the continuous power ( CP) model, two cases of the Kodell model  the Kodel QLR model and the Kodel Weibull model, and the Rai and Van Ryzin model. The number in parentheses are the 95% upper confidence limit on risk. No 95% upper confidence limit was calculated for the Rai and Van Ryzin model. See text for details b  Dose is adjusted by a factor of 8/ 6. See the Crump report for details c  Data from Hanley et al, Ex. 4 042a d  Data from Hanley et al, Ex. 4 106 Table VI N Estimates of Number of Extra Cases of Various Developmental Effects per 1000 Fetus from Exposure to 2 EE a Rats: Minor Skeletal Defects b Dose c QLR Weibull 5 0 1.8 ( 0) ( 15)

1 0 0.065 ( 0) ( 1.4)

0.5 0 0.015 ( 0) ( 0.51)

0.25 0 0.0037 ( 0) ( 0.19)

0.1 0 0.00056 ( 0) ( 0.049)

Rats: Minor Visceral Defects b Dose c QLR Weibull 5 1.4 1.4 ( 2.8) ( 2.8)

1 0.29 0.29 ( 0.56) ( 0.56)

0.5 0.14 0.14 ( 0.28) ( 0.28)

0.25 0.072 0.072 ( 0.14) ( 0.14)

0.1 0.029 0.029 ( 0.056) ( 0.056)

Rats: Total Abnormal Ribs b Dose c QLR Weibull 5 37 23 ( 45) ( 44)

1 7.5 3.7 ( 9.1) ( 8.9)

0.5 3.8 1.7 ( 4.6) ( 4.5)

0.25 1.9 0.76 ( 2.3) ( 2.2)

0.1 0.75 0.27 ( 0.91) ( 0.9)

Rabbits: Minor Skeletal Defects d Dose c QLR Weibull 5 19 0 ( 27) ( 21)

1 3.9 0 ( 5.5) ( 4.3)

0.5 1.9 0 ( 2.7) ( 2.2)

0.25 0.97 0 ( 1.4) ( 1.1)

0.1 0.39 0 ( 0.55) ( 0.43) Rabbits: Skeletal Variants d Dose c QLR Weibull 5 29 29 ( 41) ( 41)

1 6 6 ( 8.4) ( 8.4)

0.5 3 3 ( 4.2) ( 4.2)

0.25 1.5 1.5 ( 2.1) ( 2.1)

0.1 0.6 0.6 ( 0.84) ( 0.84)

Rabbits: Late Intra uterine Death d Dose c QLR Weibull 5 0 0.0035 ( 15) ( 15)

1 0 0.000022 ( 3) ( 3)

0.5 0 0.000002 ( 1.5) ( 1.5)

0.25 0 0 ( 0.74) ( 0.74)

0.1 0 0 ( 0.3) ( 0.3)

a  From the Crump Report, Ex. 5 136. The models considered are the quantal linear regression ( QLR) model, the Weibull model, the continuous linear regression ( QCR) model, the continuous power ( CP) model, two cases of the Kodell model  the Kodel QLR model and the Kodel Weibull model, and the Rai and Van Ryzin model. The number in parentheses are the 95% upper confidence limit on risk. No 95% upper confidence limit was calculated for the Rai and Van Ryzin model. See text for details b  Dose is adjusted by a factor of 8/ 6. See the Crump report for details c  Data from Tinston et al, Ex. 4 038 d  Data from Tinston et al, Ex. 4 039 Crump notes that although the maximum likelihood estimates ( MLEs) of risk are similar regardless of whether one accounts for the litter effect, the 95% upper confidence level ( UCL) can be noticeably affected. Crump states that for " several data sets for which the maximum likelihood estimates are similar when estimated by the QLR ( or Weibull) model and the Kodell QLR ( or Kodell Weibull) model ( e. g. extra lumbar ribs in mice, for which the intra litter correlation estimates are highest), the upper limits are smaller when the litter effect is ignored."

For 2 ME, the models and data sets predict a range of risks of developmental effects from 2.2 to 430 per 1000 fetuses at the current OSHA PEL of 25 ppm. The lowest risk comes from the Weibull model applied to data on total major malformations in rabbits. The highest risk comes from the QLR model applied to these same data. Crump attributes this large spread within the same data set to the non linearity of the dose response relationship and " the lack of experimental evidence regarding the dose response curve between 10 and 50 ppm." Crump concludes that if " there had been an additional experimental exposure between 10 ppm and 50 ppm, the difference among the models would likely have been sharply reduced."

For 2 EE, Crump did not estimate risks at the current OSHA PEL of 200 ppm. The highest dose level which Crump considered for its analysis of 2 EE was 5 ppm. At this exposure level, the models and data sets predict a range of risk of developmental effects from 0 to 37 per 1000 fetuses. The lowest risk comes from the QLR model applied to data on minor skeletal defects in rats. The highest risk comes from the same [ page 15572]

model applied to data on total abnormal ribs in rats.

At 0.1 ppm, Table VI M shows that the predicted risks of developmental effects range from 0 to .67 per 1000 fetuses when derived from models which incorporate thresholds and from approximately zero to 1.1 per 1000 fetuses when derived from models which do not incorporate thresholds. At 0.5 ppm, Table VI N shows that the predicted risks of developmental effects range from 0 to 3 per 1000 fetuses when derived from the model which incorporates a threshold and from approximately zero to 3 per 1000 fetuses when derived from the model which does not incorporate a threshold Although Crump's approach provides methods for quantifying reproductive and developmental risks, none of the methods proposed in the report has been generally accepted within the risk assessment community. The NOEL/ uncertainty factor approach, on the other hand, has broad acceptance for the assessment of reproductive and developmental risks. Furthermore, Crump's risk assessment provides no criteria for selecting one model or method over another. Since none of the models has a biological basis, it is impossible to determine which is the most appropriate model to use. Given the broad range of risks predicted from each of the models, some criteria must be developed for choosing one or another before Crump's approach can be used for quantitative risk assessment. For these reasons, OSHA has not relied upon the Crump report as the basis of its quantitative risk assessment for glycol ethers Crump  s risk assessment raises a number of issues including whether developmental and reproductive risks can be quantified and these issues deserve serious discussion. In addition to proposing dose response models for quantifying the risk of developmental effects, Crump has proposed two alternatives, the NOSTASOT dose and the benchmark dose, to the traditional NOEL used by OSHA in its risk assessment. OSHA seeks comment on the issues raised in this report as well as on the specific methodology employed by Crump to quantify the risk of adverse reproductive and developmental effects 2. The Hattis Risk Assessment In an attempt to quantify the reproductive and developmental risks associated with glycol ethers exposure, Dale Hattis et al developed three quantitative approaches: one for estimating the risks of adverse effects on male fertility ( Ex. 5 109); one for estimating the risks of adverse developmental outcomes ( Ex. 5 121); and one for estimating the risks of infant mortality ( Ex. 5 121). To estimate risks on male fertility, sperm counts and pharmacokinetically derived exposures from workers exposed to 2 ME and 2 EE were used as a basis for estimating percentage reductions in fertility. Animal studies in which 2 ME and 2 EE induced fetal death and fetal malformations were used as a basis for estimating the risk of adverse developmental outcomes in human fetuses. Animal studies in which 2 ME and 2 EE induced fetal weight reduction were used as a basis for estimating the risk of infant mortality in humans. The following discussion briefly summarizes these approaches. For a more complete description of these analyses and the underlying assumptions, the original studies should be consulted a. Risk Analysis on Male Fertility Effects ( Ex. 5 109)

The goal of this analysis was to quantify the effects on male fertility that could be expected from reductions of sperm counts induced by 2 EE and 2 ME. Thus sperm count was the basic measure used to calculate a risk of infertility. The authors acknowledged that sperm counts are not ideal for this purpose because sperm counts are only one of several parameters ( e. g. % normal sperm, % motile sperm, and age of patient) that are known to have an effect on male reproductive potential. In addition the authors stated that a direct relationship between sperm count and male fertility performance may be an over simplification. However the authors chose sperm counts because no other type of sperm quality parameters were available in the underlying data used for this quantitative analysis The sources of experimental data used in this analysis included ( 1) a pharmacokinetic model developed by Hattis et al for 2 EE ( Ex. 5 095), ( 2) worker exposure studies on shipyard painters ( Exs. 5 101, 5 102 and 5 103) and foundry workers ( Ex. 5 003) and ( 3) a quantitative model developed by Meistrich ( Ex. 4 161) for estimating sperm reduction factors and increases in excess infertility In their pharmacokinetic analysis ( Ex. 5 095), Hattis et al developed four different pharmacokinetic models using clinical data from studies in which human volunteers were exposed to 2 EE. These models described the uptake and metabolism of 2 EE to its primary metabolite ethoxyacetic acid ( EAA). The models also described the urinary excretion of EAA. Mathematical formulas derived from these models were presented as a means for calculating 2 EE equivalent air exposure levels from urinary EAA excretion data As a first step in the risk analysis, urinary EAA excretion data from the foundry workers and the shipyard painters were converted to 2 EE equivalent air exposures ( ppm) using the formulas derived from the Hattis et al pharmacokinetic model. The authors noted that the shipyard painters also had " appreciable" exposures to 2 ME. Thus 2 EE equivalents for these workers were adjusted to account for 2 ME. This was accomplished by assuming that 2 ME was 4.3 times more potent than 2 EE ( based on animal studies ) and that workers were exposed to 0.8 ppm 2 ME for every 2.6 ppm 2 EE In the second step of this analysis, sperm counts were analyzed and found to decline among both sets of workers although neither of the observations from these groups was statistically significant. The percent reduction in sperm count for these groups of workers was then compared to the calculated 2 EE equivalents air levels:

2 EE equivalent Overall %

( ppm 8 Hr/ day) Sperm Count Reduction Shipyard Painters Arithmetic Mean 6.1 27.5 Geometric Mean 4.9 Foundry workers Arithmetic Mean 13.9 14 Geometric Mean 12.8 The authors noted that results from both of these studies reinforced one another showing suggestive declines in sperm counts with 2 EE exposure. However these results indicate that there is a stronger sperm reduction effect with lower dose among the shipyard painters. Possible explanations offered by the authors included ( 1) chance statistical fluctuations in the data and ( 2) potential peak exposures prior to sampling the population. Nevertheless, the shipyard painter data was selected for the authors " best estimate" risk projections as this study had more complete exposure data and a larger number of workers, making this study " more likely representative of reality" In the final step in this analysis, work by Meistrich ( Ex. 4 161) was applied to sperm count reductions calculated in [ page 15573]

the previous steps to estimate an " excess infertility risk". Meistrich developed a method, using testicular toxicity data in rats and analyses of sperm count distributions in " fertile" and " infertile" couples, to calculate the " risk of infertility" as a function of sperm count. In his model Meistrich defined infertility as the degree of subfertility required to bring about a need to consult a physician. Meistrich assumed that a 1% increase in infertility ( i. e. 1 in 100 couples) was an " acceptable risk". He also assumed that the background risk of infertility in the general population was 15%. Using these assumptions and definitions, Meistrich estimated that a 1% increase in excess infertility corresponds to a sperm reduction factor of 1.24. Using this basic relationship, Hattis et al. calculated sperm reduction factors and corresponding increases in excess infertility for the sperm count reductions observed among the shipyard painters at various 2 EE equivalent air exposures:

Geometric Mean % sperm count reduction excess dose ( ppm) reduction factor infer

8 Hr TWA tility 0.89 5.70 1.06 0.25%

1.72 10.80 1.12 0.50%

3.28 19.40 1.24 1.00%

4.9 27.5 1.38 1.58%

5.97 32.40 1.48 2.00%

Based on the results of this analysis Hattis concluded that in order to achieve a goal of having no more than 1 in 100 couples ( i. e. 1%) suffering " infertility", exposures to 2 EE must be kept below a geometric mean of 3.3 ppm. Achieving a goal of no more than 1 in 400 couples suffering infertility would require exposures 1/ 4 of that level ( i. e. 0.82 ppm). Furthermore assuming that 2 ME is 4.3 times more potent than 2 EE, Hattis estimates that a corresponding dose for 2 ME of 0.46 ppm would be required to assure that no more than 1 in 100 couples will suffer from infertility These quantitative estimates must be viewed in light of the uncertainties and assumptions used to calculate them. First, both the shipyard painter and foundry worker studies had a small number of exposed workers with sperm count reductions bordering on statistical significance. Furthermore, as noted by Hattis et al, as well as the original authors of the shipyard painter studies, the EAA excretion levels calculated from these may be a poor proxy for exposures associated with sperm count reduction. The EAA excretion levels represented exposure to 2 EE in the last few days whereas the sperm counts which were measured at approximately the same time. would have been effected by exposures weeks earlier. Because the shipyard painters changed tasks at the shipyard frequently, EAA excretion levels representing these workers' exposure within the last few days may not adequately represent exposure levels weeks earlier which would have been responsible for the sperm counts collected Second, the Meistrich approach for calculating sperm reduction factors assumes a " onehit killing function for sperm which may or may not be biologically correct. Furthermore Meistrich uses a very subjective definition of infertility ( i. e. degree of subfertility required to bring about the need to consult a physician)

These sources of uncertainty are compounded by the uncertainty of the 2 EE air equivalents which were calculated using the Hattis pharmacokinetic model. This pharmacokinetic model carries with it its own set of assumptions and uncertainties. Thus considerable uncertainty is associated with the quantitative estimates derived from this risk analysis on male fertility b. Risk Analysis on Developmental Effects ( Ex. 5 121)

The goal of this analysis was to quantify the risk of adverse developmental effects associated with in utero exposure to glycol ethers. Two separate approaches were employed. In the first approach, quantal effects data from animal studies ( e. g. fetal death and malformations) were used to estimate the risk of similar adverse effects in humans. In the second approach, continuous effects data from animal studies ( e. g. changes in fetal weight) were used to project changes in birth weight and potential changes in infant mortality in humans. Quantal Effects Analysis Hattis et al selected six different animal studies examining the developmental toxicity of various glycol ethers. [ Andrew and Hardin ( Ex. 5 069), Doe ( Ex. 5 0710, Hardin and Eisenmann ( Ex. 5 097), Weir ( Ex. 5 120), Greene ( Ex. 5 096), and Hanley et al ( Ex. 4 120)]. These studies reported statistically significant increases in the incidence of adverse developmental effects including fetal death, skeletal defects, external malformations and digit or limb malformations. Dose response data from the animal studies were used to calculate an ED50 for those effects which were statistically significantly different from the controls. An ED50 is the dose at which 50% of an otherwise unaffected proportion of the population suffers an effect. The ED50 was derived using a log probit analysis. This probit analysis assumes that effects occur in individual animals when specific thresholds of dose are exceeded and that there is a lognormal distribution of thresholds in the exposed group of animals or humans. ED50s from the animal studies were then converted to 8 hour human ED50s ( ppm). This ED50 represents a dose at which 50% of an population will be affected by the chemical after an 8 hour exposure. Overall ED50 estimates were derived by taking geometric means of ED50s calculated for 2 ME and 2 EE for individual effects. Six " best estimates" were derived in this manner. These " best estimates" were then used to calculate the doses of 2 ME or 2 EE corresponding to risks of one in a hundred ( 10 2), one in ten thousand ( 10 4) and one in a million ( 10 6) for a particular developmental effect ( Table VI O)

TABLE VI O Doses ( ppm) at " Best Estimate" Risks of One in a Hundred,

One in Ten Thousand, and One in a Million ED50 Dose Dose Dose Response humans ( ppm) ( ppm) ( ppm)

8 hr( ppm) at 10 2 at 10 4 at 10 6 risk risk risk post implantation loss 2 EE 127 8.7 1.8 0.53 2 ME 16 1.1 0.22 0.067 minor skeletal defects 2 EE 5.3 0.36 0.073 0.022 malformations 2 EE " external" 255 17 3.5 1.1 2 ME " total" 9.9 0.68 0.14 0.042 [ page 15574] " forepaw" 35 2.4 0.48 0.147 Extracted from Table 3 7, Hattis et al, ( Ex. 5 121)

Assuming that a ppm exposure in humans would present the same risk as those observed in animals, Hattis et al concluded that these projections suggest that doses as low as 0.36 ppm 2 EE would produce a risk of one in a hundred for skeletal defects and doses as low as 0.68 ppm 2 ME would produce a risk of one in a hundred for total malformations. It is interesting to note that from these two estimates 2 ME appears to be less potent than 2 EE which is contrary to most of the experimental data Continuous Effects Analysis In this analysis animal data showing fetal weight reduction after exposure to 2 ME and 2 EE were used to calculate percentage reductions in fetal weight as a function of dose of 2 ME or 2 EE. For purposes of this analysis it was assumed that animals and humans would exhibit equal growth retardation for a given rate of glycol ether exposures expressed in ppm hours per day. It was further assumed that percentage changes in fetal weight prior to birth would reflect similar percentage changes in birth weight. Percentage reductions in birth weight could then be used to project likely effects on infant mortality As a first step, Hattis et al analyzed birth weight distributions and infant mortality rates from both black and white infants in the United States . These distributions were used to derive a relationship between infant mortality and birth weight changes As a second step, the relationship between fetal weight reduction ( i. e. birth weight reduction) and the dose of 2 ME or 2 EE from the animal studies were combined with the relationship between birth weight changes and infant mortality from human infants. These two sets of relationships were used together to estimate expected changes in infant mortality for a given 8 hour exposure to 2 EE or 2 ME. Table VI P presents the projected changes in infant mortality due to possible changes in infant birth weight associated with 2 EE and 2 ME exposures TABLE VI P Projected Changes in Infant Mortality Due to possible Changes in Infant Birth Weights Associated with 2 ME and 2 EE Exposures PPM Exposure Projected % Total Excess Level Birthwt Reduction Infant Mortality 2 EE:

0.01 .0003 1.45 x 10 7 0.1 .003 1.45 x 10 6 1 .03 1.45 x 10 5 5 .15 7.3 x 10 5 25 .75 3.7 x 10 4 2 ME:

0.01 .00243 1.18 x 10 6 0.1 .0243 1.18 x 10 5 1 .243 1.18 x 10 4 5 1.215 6.1 x 10 4 25 6.075 3.6 x 10 3 Extracted from Table 4 6, Hattis et al ( Ex. 5 121) As was the case for the male fertility analysis, the quantitative estimates derived from both the quantal and continuous effects data incorporate a number of large assumptions. The largest of these may be the assumption that a particular defect observed in an animal will translate into a similar defect in humans. As discussed earlier in the Health Effects section of this preamble, although adverse developmental effects in animals provide clear evidence of a chemical's potential ability to perturb development in humans, the effects observed in animals may not necessarily be identical to those which could potentially occur in humans. Even the authors themselves acknowledge that the risk calculations are based on a series of assumptions which carry considerable uncertainty. OSHA acknowledges that assumptions are often necessary for quantitative risk analyses. However given the lack of knowledge about the biological processes involved in reproductive and developmental toxicity, OSHA believes that the assumptions of these quantitative analyses may carry much more uncertainty than for other types of health outcomes such as cancer where the biological mechanisms are better understood In summary, the quantitative approaches of Hattis et al are very innovative. These approaches however, require that a number of large assumptions be made. These assumptions create considerable uncertainty in the quantitative risk estimates which are derived. In addition, the underlying data upon which these approaches are constructed have weaknesses of their own which further compound the uncertainties in the risk estimates. Nevertheless, these approaches do provide a starting point for a discussion of the quantitative risk assessment for reproductive and developmental toxins. Therefore OSHA welcomes all comments and analyses on these approaches for deriving quantitative risk estimates for adverse reproductive and developmental effects 3. The Environ Risk Assessment Under contract to the Chemical Manufacturer's Association ( CMA), Environ Corporation prepared a report entitled " Scientific Basis for Safety Factors Needed to Protect Workers from Reproductive Toxicities of Glycol Ethers" ( Ex. 4 016f). This report contains a brief review of the data available for a qualitative analysis of the health effects associated with glycol ethers and their acetates, but the primary focus of the report is the choice of uncertainty factor for determining an acceptable daily intake ( ADI) for each of the substances Environ's approach for choosing an uncertainty factor, ( which Environ refers to as a safety factor), was to compare the lowest effective dose ( i. e. the LOEL) in humans measured in milligrams per kilogram per day for ten substances known to cause developmental effects with the lowest effective dose measured in milligrams per kilogram per day in the most sensitive species of animal in which the substance has been tested and in which the observed effects were similar to those in humans. These data come from two sources: a 1981 report from the Council on Environmental Quality ( CEQ) entitled " Chemical Hazards to Human Reproduction" and a 1984 report from the National Center for Toxicological Research ( NCTR) entitled " Reliability of Experimental Studies for Prediction of Hazards to Human Development." By examining these data on other developmental toxicants, [ page 15575]

Environ sought to obtain information which could be " useful for judging the magnitude of the uncertainty factor needed to protect humans from the developmental effects of [ glycol ethers]."

Environ drew two conclusions from its analysis:

1. Application of a safety factor of 10 to NOELs from the most sensitive animal species would have been adequate to protect humans from the effects of most developmental toxicants for which quantitative doseresponse data are available; and 2. A safety factor of 50, similarly applied, would have been adequate to protect humans from the effects of all developmental toxicants for which quantitative human dose response data are available, although this factor may not have been adequate for one substance, thalidomide, assuming the rabbit ( rather than the most sensitive species) had been chosen as the basis for establishing acceptable human exposures. If the most sensitive species had been chosen for thalidomide, a safety factor of 10 20 would have been adequate Environ supplemented this approach with an examination of historical precedents for the selection of uncertainty factors used to protect worker populations from the types of toxicity associated with glycol ethers or from other serious forms of toxicity. Environ stated that such information, " while not strictly scientific in nature, can further assist decision making because it reveals the range of safety margins which other responsible decision makers have accepted, and presumably reveals the safety margins that have proved adequate to protect worker populations. Information on the expected relative susceptibilities of the worker and the general populations and on how this has influenced the selection of safety factors will also be useful."

Environ looked at the guidelines or standards for protecting workers from reproductive hazards developed by OSHA, NIOSH, ACGIH, and the American Industrial Hygiene Association ( AIHA) " in order to provide an estimation of the margin of safety associated with [ their] standards and guidelines." Environ noted that "[ u] nlike the case of standards developed for general population exposure to chemicals, [ for worker populations] there has been no generic approach we can identify for the application of safety factors to the NOEL identified in experimental animals. This is true for both reproductive and other non carcinogenic effects."

Environ found that as of 1985, the date of the Environ report, OSHA had regulated five substance principally on the basis of reproductive toxicity. These substances and their respective margins of safety were carbaryl, 5 times lower than the NOEL identified in animals; carbon disulfide, 1.3 times higher than the LOEL identified in animals; DBCP, 38 times lower than the NOEL identified in animals; chloroprene, 5 to 25 times higher than the LOEL identified in humans; and PCBs, 6 times lower than the LOEL identified in humans. ( OSHA notes that the Environ report was written prior to promulgation of OSHA's Final Rule for Air Contaminants, 29 CFR Part 1910, published January 19, 1989. In that rulemaking, OSHA reduced the permissible exposure limits for both carbon disulfide and chloroprene.) In comparison, Environ found that NIOSH used uncertainty factors in its recommended standards for the same five substances ranging from 1 for a 15 minute exposure ceiling for chloroprene to 6000 for PCBs. The ACGIH had issued TLVs for all these substances except DBCP, and these TLVs ranged from 2 to 10 times higher than the LOEL identified in humans for chloroprene to 6 times lower than the LOEL identified in animals for PCBs. According to Environ, the AIHA had established a workplace environmental exposure level only for the reproductive toxicant piperidine, and in making its recommendation, the AIHA provided no margin of safety below the NOEL for embryotoxicity in the rat On the basis of its analysis of the CEQ data, the NCTR data, and historical precedent, Environ concludes that " the 100 fold [ safety] factor has not been used for worker protection" and " there is support for a safety factor of 10 as adequate to protect workers against the developmental toxicities of the [ glycol ethers and their acetates]." Environ goes on to note that a safety factor of 10 " appears to be adequate to cover most cases and it also accords with most past occupational risk management practices. If one seeks a margin that has limited historical precedent but which appears more certain to cover all likely cases, then a factor of 50 is recommended."

Noting that the factors 10 and 50 are not alternatives and that " it may be reasonable to settle on a factor between these two values", Environ applied these two uncertainty factors to the NOELs identified for the glycol ethers and their acetates. In its review of the literature, Environ, like OSHA, found the NOELs to be 10 ppm for 2 ME, 10 ppm for 2 MEA, 50 ppm for 2 EE, and 50 ppm for 2 EEA. ( Environ found no data on the reproductive effects of 2 MEA, and like OSHA, used the NOEL identified for 2 ME to estimate the ADI for 2 MEA.) In its estimation of the ADI's, however, Environ took a different approach. First, that species most sensitive to the effects of the glycol ethers or their acetates was identified. In each case, this was found to be the rabbit. Next, the NOEL was converted from units of ppm to units of milligrams per kilogram per day. Then, the safety factors of 10 or 50 were applied to the converted NOEL to arrive at two estimates of the ADI. These estimates, in turn, were converted back to units of ppm assuming human parameters. Results of these calculations are presented in Table VI Q Table VI Q Estimates of Acceptable Human Daily Intakes ( ADIs)

Of Four Glycol Ethers Based on Animal Data and Safety Factors of 10 and 50 a Glycol NOEL b ADI/ 10 c ADI/ 50 d ADI/ 10 e ADI/ 50 f Ether mg/ kg/ d Species mg/ kg/ d mg/ kg/ d ppm ppm 2 ME 4.3 Rabbit 0.43 0.086 0.9 0.18 2 EE 25.5 Rabbit 2.6 0.52 4.6 0.92 2 MEA 6.7 g 0.67 0.13 0.9 0.18 2 EEA 18.8 Rabbit 2.6 0.52 4.6 0.92 a  From the Environ Report ( Ex. 4 016f) b  The NOEL identified in the most sensitive species converted from units of ppm to units of milligram per kilogram per day c  ADI based on a safety factor of 10 and measured in units of milligrams per kilograms per day d  ADI based on a safety factor of 50 and measured in units of milligrams per kilograms per day e  ADI based on a safety factor of 10 and measured in units of ppm as an 8 hour time weighted average f  ADI based on a safety factor of 50 and measured in units of ppm as an 8 hour time weighted average g  No data available. Assumes 2 MEA is equipotent with 2 ME on a mole basis.

[ page 15576]

The interesting result in Table VI Q is that the ADIs estimated by Environ using a uncertainty factor of 50 are not very different than the ADIs estimated by OSHA using an uncertainty factor of 100 without conversion of the NOEL to milligrams per kilogram per day. For 2 ME and 2 MEA, Environ found the ADI to be 0.18 ppm whereas OSHA found the ADI to be 0.1 ppm. For 2 EE and 2 EEA, Environ found the ADI to be 0.92 ppm whereas OSHA found the ADI to be 0.5 ppm. Obviously, the results are not so similar when an uncertainty factor of 10 is used Despite the similarity in results, OSHA has a number of concerns about the approach used by Environ to estimate the ADI for the glycol ethers and their acetates. First of all, OSHA questions the appropriateness of using the CEQ data and the NCTR data to establish the magnitude of safety factors needed to protect humans from the developmental effects of glycol ethers. Environ acknowledges a number of the data's limitations including the varying quality and extensiveness of the data bases from which these data were drawn, the subjective determination regarding the meaning of the term " lowest effective dose", the relatively small number of compounds examined, and the difficulty of obtaining accurate estimates of the human doses responsible for producing developmental toxicity OSHA believes that these limitations alone make these data unsuitable for the use to which Environ has put them. OSHA, however, sees additional limitations. Environ is comparing experimental LOELs in the most sensitive species to LOELs observed in humans to determine adequate safety factors. Implicit in this approach is the assumption that experimental LOELs are the " true" LOELs and that any exposure below that LOEL for either humans or animals will not result in adverse effects. As noted in a previous section of this risk assessment, there is in fact little reason to believe that the LOEL ( or NOEL) identified in any study is indeed the " true" LOEL. Environ's approach makes no allowance for such a possibility Another limitation which Environ acknowledges is that it is not known whether the empirical relationships observed in the data reflect only interspecies differences or whether they reflect both interspecies differences and intraspecies differences. Environ concludes that it " seems likely although it is not certain, that the empirical relations discussed above would be protective of the most sensitive members of the human population", but OSHA notes that the opposite conclusion could just as easily be drawn. If the human data represent responses for the mid range of the distribution of human responses, then, as Environ states, " the empirical relations reflect only interspecies differences, and an additional safety factor would seem necessary to compensate for intraspecies variability."

OSHA is also concerned about Environ's use of historical precedent to determine the margin of safety acceptable for protecting worker populations. Of the five substances reported by Environ to have been regulated by OSHA on the basis of reproductive toxicity, all but one, DBCP, were adopted as consensus standards by the Agency in 1971 under Section 6( a) of the Occupational Safety and Health Act of 1970. Under that Section of the Act, Congress directed the Agency to " promulgate as an occupational safety and health standard any national consensus standard, and any established Federal standard, unless [ the Secretary of Labor] determines that the promulgation of such a standard would not result in improved safety or health for specifically designated employees" ( 29 U. S. C. 651 et seq). In the case of DBCP, the only one of the five substances to be considered individually in a 6( b) rulemaking, the standard set by OSHA, as Environ acknowledges, was constrained by technological feasibility and not by acceptable margin of safety. In as much as standards for four of these substances were adopted without consideration of the individual substance and the standard for the fifth was constrained by technological feasibility, it is disingenuous of Environ to conclude that OSHA finds any particular margin of safety as acceptable for working populations Finally, OSHA questions the appropriateness of Environ's conversion of NOELs from units of ppm to units of milligrams per kilograms per day to estimate an ADI. On the one hand, Environ states that with regard to interspecies differences, " the available data on the ethers show a remarkably consistent pattern among the species tested. This suggests that the 10 fold factor conventionally used for interspecies extrapolation is not indicated." On the other hand, when the NOEL is converted into units of milligrams per kilogram per day, this " remarkable" consistency vanishes. For example, for 2 ME, Environ found that a NOEL of 10 ppm in rabbits corresponds to 4.3 mg/ kg/ day. For mice, however, the NOEL of 10 ppm found by Hanley et al ( Ex. 4 106) corresponds to approximately 9.2 mg/ kg/ day, ( using the mean weight for the 10 ppm exposure group on day 12, half way through exposure, and assuming, like Environ, 100% absorption), more than two times greater than the NOEL for rabbits measured in the same units. For rats, the NOEL of 10 ppm found by Hanley et al ( Ex. 4 042a) corresponds to approximately 5.93 mg/ kg/ day ( also using the mean weight for the 10 ppm group on day 12, half way through exposure, and assuming 100% absorption.) Thus, if Environ is going to convert the NOEL into units of milligrams per kilogram per day, an adjustment for interspecies variation must be considered OSHA seeks comment on whether the NOEL should be expressed in units of ppm or units of milligrams per kilogram per day. A number of commentors support the latter measure including CMA ( Ex. 7 17) and NIOSH ( Ex. 7 22), but the Agency notes that those commentors who calculated their own ADIs did no such conversion of units ( see, for example, Ex. 7 23). Furthermore, the Agency is uncertain as to how one would convert a NOEL from units of ppm to units of milligram per kilogram per day from a study of developmental effects. Animals exposed during gestation are gaining weight rapidly. Thus, as a study progresses, the dose an animal receives decreases in terms of milligrams per kilogram per day. Clearly weight gain will be a function not only of the genetics of an individual animal but also of the number of fetuses a pregnant female is carrying. OSHA seeks comment on whether these factors should be accounted for in measuring dose, and if so, how this should be done VII. Significance Of Risk OSHA believes that the type of significant risk analysis the Agency has undertaken in this rulemaking is consistent with the studies generally available and, for the reasons set forth below and in the section on risk assessment, is a valid, accepted and customary scientific approach Section 6( b)( 5) of the OSH Act vests authority in the Secretary of Labor to issue health standards. This section provides, in part, that :

The Secretary, in promulgating standards dealing with toxic materials or harmful physical agents under this subsection, shall set the standard which most adequately assures, to the extent feasible, on the basis of the best available evidence, that no employee will suffer material impairment of health or functional capacity even if such employee has regular exposure to the hazard dealt [ page 15577]

with by such standard for the period of his working life.

OSHA is required to make two threshold findings before it can issue a health standard under section 6 ( b)( 5) of the Act. In accordance with the Supreme Court's decision in the benzene case, Industrial Union Department, AFL\ CIO v. American Petroleum Institute, 448 U. S. 601, 642 ( 1980), OSHA may promulgate a standard only if it finds that it is at least more likely than not that the risk OSHA seeks to regulate is " significant" and that the change in practices contemplated in the issuance of a standard would reduce or eliminate that risk OSHA's analytical approach to making a determination that a significant risk of material impairment exists from exposure to hazardous materials or harmful physical agents in the workplace takes into consideration a number of factors that are consistent with recent court interpretations of the Act and with rational, objective policy formulation. As prescribed by section 6( b)( 5) of the Act, OSHA examines the body of the " best available evidence" on the adverse effects of the toxic materials or harmful physical agents to determine the nature and extent of possible health consequences resulting from exposure to the hazard in question. Where possible, quantitative assessments are conducted and the results are considered along with other relevant information, such as the nature and severity of the health consequences, as well as other qualitative evidence and expert opinion, to determine whether a hazard poses a significant risk to workers The Court gave some general guidance to the Agency for determining significant risk:

Some risks are plainly acceptable and others are plainly unacceptable. If, for example, the odds are one in a billion that a person will die from cancer by taking a drink of chlorinated water, the risk clearly could not be considered significant. On the other hand, if the odds are one in a thousand that regular inhalation of gasoline vapors that are 2 percent benzene will be fatal, a reasonable person might well consider the risk significant and take the appropriate steps to decrease or eliminate it. ( I. U. D. v. A. P. I., 448 U. S., 607, 655)

The Court indicated, that where possible, the determination of significant risk should be based upon quantitative risk assessment. However, recognizing the uncertainties involved, the Court qualified its predilection for quantitative assessment, saying:

[ T] he requirement that a " significant" risk be identified is " not a mathematical straitjacket. It is OSHA's responsibility to determine, in the first instance, what it considers to be a " significant" risk. Id. The Court also pointed out that: OSHA is not required to support its findings that a significant risk exists with anything approaching scientific certainty. . . .[ Section] 6 ( b)( 5) [ of the Act] specifically allows the Secretary to regulate on the basis of the " best available evidence." . . . Thus, so long as they are supported by a body of reputable scientific thought, the Agency is free to use conservative assumptions . . . risking error on the side of overprotection rather than under protection. Id., at 656.

The Court noted that the ultimate determination that a particular level of risk is significant " will be based largely on policy considerations." Id., at 655 56, n. 62 Quantification of risk, the Court understood, cannot be achieved for every hazard. The four judge plurality, speaking for the Court in the benzene decision, did not intend to require OSHA to do what cannot be done. The concurring opinion of Mr. Justice Powell and the dissenting opinion of Mr. Justice Marshall, speaking for four other members of the Court, confirm this. Mr. Justice Powell stated:

The statutory preferences for the " best available evidence" . . . implies that OSHA must use the best known techniques for the accurate estimation of risks and benefits when such techniques are available. But neither the statute nor the legislative history suggests that OSHA's hands are tied when reasonable quantification cannot be accomplished by any known methods. . . . In this litigation, OSHA found that " it is impossible to precisely quantify the anticipated benefits. . . " If this finding is supported by substantial evidence, the statute does not prevent the Secretary from finding a significant health hazard on the basis of the weight of expert testimony and opinion. I do not understand the plurality to hold otherwise. Id., at 666 7.

Similarly, Mr. Justice Marshall, in dissent, stated "[ i] t is fortunate indeed that at least a majority of the Justices reject the view that the Secretary is prevented from taking regulatory action when the magnitude of a health risk cannot be quantified on the basis of current techniques" and concluded that " the Court appears willing not to require quantification when it is not fairly possible." Id., 690, 716 17 As a part of the overall significant risk determination, OSHA considers a number of factors. These include the type of risk presented, the quality of the underlying data, the reasonableness of the risk assessments, the statistical significance of the findings and the significance of risk ( 48 FR 1864; January 14, 1983)

The types of risk posed by exposure to glycol ethers are of the most serious kind. Developing fetuses exposed to glycol ethers may suffer the effects of such exposure for a lifetime, leading to a life of dependency instead of a life as a productive member of society. As noted by the Office of Technology Assessment in its report on Reproductive Hazards in the Workplace, " risk to a fetus may also be a risk to the woman herself. It may be direct, as in the risk of her own reproductive health; less direct, as in the risk to her health posed by spontaneous abortion; or indirect, in that she may suffer psychological damage and diminished life prospects with the occurrence of a miscarriage or on the birth of a dead or damaged baby." ( Ex. 5 135, p. 330). It is also important to note that the father may also share the harm caused by the birth of a dead or damaged child The reproductive effects from exposure to glycol ethers are not solely loss of fertility, a serious effect in and of itself, but also include major dysfunction of the reproductive organs. Obviously material impairment of health includes not only death, but also impairments in basic biological processes, such as normal reproductive function, which can be of extraordinary personal importance. In its report on Reproductive Hazards in the Workplace, OTA states, and OSHA agrees, that "[ c] oncern about reproductive processes is not limited to the brief periods in an individual's life during which reproduction may actually occur. Reproductive function is an integral part of everyday human health and well being. Before, during, and after the child bearing years, reproductive hormones may act, for example, on such variables as resistance to heart disease and cancer, immune function, complexion, bone mineral content, and feeling and mood. Threats to reproductive function can take place at nearly any point during an individual's life span." ( Ex. 5 135, p. 43)

The hematological effects associated with exposure to glycol ethers may be reversible but are nonetheless debilitating and may reduce a worker's normal functional capacity. In addition, reduction in the white blood cell count may compromise an individual's capacity to fend off diseases, and for these reasons the hematological effects from exposure to glycol ethers must be considered to represent additional material impairment of health The data which support the finding of adverse health effects from exposure to glycol ethers are of the highest quality. As described in the Health Effects Section of this preamble, studies in [ page 15578]

several animal species, by various routes of exposure, have consistently shown that exposure to 2 ME, 2 EE and their acetates cause adverse reproductive, developmental and hematological effects. For example, male test animals exposed to 2 ME, 2 EE and their acetates have exhibited interferences in spermatogenesis resulting in reduced sperm count and decreased fertility. Exposed males have also exhibited degeneration of the seminiferous tubules resulting in testicular atrophy. Pregnant females exposed to these glycol ethers exhibited signs of maternal toxicity such as decreases in maternal weight, decreased organ weights and increases in the lengths of gestation. Developmental effects among litters from exposed females include increased rates of resorptions ( early embryonic death), decreased litter sizes, decreased fetal weights, visceral malformations, skeletal malformations, heart defects, neurochemical alterations and behavioral abnormalities. Experimental studies have also demonstrated exposure related decreases in several blood parameters including white blood cell counts, red blood cell counts and hemoglobin concentrations. Studies of humans exposed to these agents have reported findings of testicular atrophy, reduced sperm count and blood abnormalities In this preamble, OSHA has assessed the risk of adverse health effects from exposure to 2 ME, 2 EE, and their acetates and has determined that exposure to these glycol ethers poses developmental, reproductive, and hematological risks. While the Agency has assessed these risks, the present risk assessment differs from most previous OSHA risk assessments in that the Agency has not quantified the risks in the manner as it usually does. Instead, OSHA has performed a risk assessment using an uncertainty factor approach to determine its proposed permissible exposure limits ( PELs)

The uncertainty factor approach entails identifying the most appropriate studies for each glycol ether ( i. e., high quality studies using the most sensitive species) and determining the no observed effect level ( NOEL) for each study. The NOELs are then divided by an uncertainty factor to arrive at estimates of the acceptable daily intakes ( ADIs). These ADIs have been put forth as OSHA's proposed PELs For 2 ME, the same NOEL was identified for reproductive effects in three species: rats, rabbits, and mice. The replication of the NOEL in each of these bioassays lends confidence that the finding of any individual bioassay is not a statistical artifact. Likewise the replication of the NOELs for reproductive effects in two species exposed to 2 EE, rats and rabbits, also lends confidence in these studies' results. A NOEL for reproductive effects was identified in only one species for 2 EEA and in no species for 2 MEA, ( this last substance has not been tested), but knowledge of the metabolism and pharmacokinetics of 2 ME and 2 EE supports using the results of studies of these substances to assess the risk from exposure to their acetates OSHA's approach to the assessment of reproductive and developmental risks is consistent with the approach to non carcinogenic risk assessment adopted by a number of governmental agencies and international organizations including the U. S. Environmental Protection Agency ( EPA), the U. S. Food and Drug Administration ( FDA), the Joint Food and Agricultural Organization of the World Health Organization ( FAO/ WHO), and the National Academy of Sciences ( NAS). This approach is favored because it requires no assumptions akin to those underlying carcinogenic risk assessment ( i. e., that cancer is a multi stage process). Little is known about the processes that lead to developmental and reproductive effects from exposure to toxic substances, and there are no generally accepted, biologically based models for assessing these risks In addition, uncertainty factors and qualitative risk assessment have been utilized in other health standards when there have not been quantitative models available like those used to assess carcinogenic risk. ( e. g., Hazard Communication, 48 FR 53280; Ethylene Oxide, 49 FR 25734; Field Sanitation, 52 FR 16050; Formaldehyde, 52 FR 46196) 1. In an analogous context, the Court of Appeals for the District of Columbia Circuit has upheld EPA's use of " margins of safety" in setting ambient air standards to address uncertainties associated with inconclusive scientific and technical information. American Petroleum Institute v. Costle, 665 F. 2d 1176, 1186 87 ( 1981), cert. denied, 449 U. S. 1042 ( 1980)

1 In the update of the air contaminants standard, 54 FR 2332, uncertainty factors were also used in the significant risk analysis for non carcinogens. On July 7, 1992, the Court of Appeals for the Eleventh Circuit determined that OSHA's use of uncertainty factors was unsupported. OSHA has addressed the concerns raised by the Eleventh Circuit in this preamble. In this and the preceding section, OSHA has provided a detailed analysis of the data and evidence that supports use of the NOEL Uncertainty Factor approach as well as the appropriateness of an uncertainty factor of 100. In addition, OSHA has requested public comment on the appropriateness of the NOEL Uncertainty Factor approach for making risk assessment regarding reproductive/ developmental health effects and the use of an uncertainty factor of 100. Moreover, OSHA has requested interested parties to discuss alternative safety factors and methodologies for assessing risk of reproductive/ developmental health effects OSHA's choice of an uncertainty factor for estimating a human ADI from animal studies is also consistent with the recommendations of many of these organizations. For example, the FDA recommends using an uncertainty factor of 100 when NOELs are identified in chronic studies ( such as those used by OSHA) in animals. Likewise, the NAS recommends an uncertainty factor of 100 when calculating an ADI from a NOEL found in animals. Although the choice of uncertainty factor may appear to be arbitrary, Dourson and Stara have provided a review of experimental evidence supporting this choice ( Ex. 4 113)

The 100 fold uncertainty factor used by OSHA in this risk assessment is comprised of two factors: a ten fold factor to account for inter species variability ( i. e., varying sensitivity across species) and a ten fold factor to account for intra species variability ( i. e., varying sensitivity among members of a population). By making these adjustments, we increase the certainty that the ADI represents an exposure level below which adverse effects are unlikely By choosing a 100 fold uncertainty factor, however, OSHA is not regulating below the level of significant risk. A ten fold factor for inter species variability and a ten fold factor for intra species variability are necessary to assure that exposure at or below the OSHA proposed PELs will be unlikely to cause adverse health effects The ten fold factor for inter species variability is necessary to account for the potential differences between species' sensitivity to toxic agents. Differences in sensitivity may result from differences in metabolism or differences in reproductive function. For example, as noted by EPA in their guidelines for assessing male reproductive toxicity ( Ex. 5 123), males of most test species produce sperm in numbers that greatly exceed the minimum requirements for fertility. However, human males, in general, produce fewer sperm relative to the number required for fertility. Thus, human males may be more sensitive to a reduction in sperm, as they may function nearer to the threshold for the number of sperm needed to ensure reproductive competence. Also differences in sensitivity may result from differences in metabolism. In the case of glycol ethers, both animals and humans appear to utilize the same metabolic pathway to produce the same [ page 15579]

primary metabolite. This primary metabolite is generally considered to be the active agent in the induction of adverse reproductive and developmental effects. However, the evidence also indicates that the biological half life of the metabolites in humans is greater than in animals. Thus the accumulation rates between animals and humans are not directly comparable. The above reasons reinforce the general support for the use of a ten fold uncertainty factor for inter species variability Furthermore, while it may appear that there is no inter species variation in the NOELs for 2 ME and 2 EE, as discussed in the Risk Assessment Section of this preamble, this is a function of the study designs used by Hanley et al and Tinston et al and does not prove there is no inter species variation in developmental risk from these glycol ethers. Lastly, although the bounds of normal reproductive function can be very broad, the complexity in the reproductive processes and the difficulty in conducting studies on the broad range of possible outcomes have resulted in experimental studies concentrating for the most part on only a few distinct periods in normal reproductive functioning. OSHA has relied upon these studies to determine the reproductive and developmental risks associated with glycol ethers, but the limitations of these studies provide additional support for a ten fold factor for inter species variability The ten fold factor for intra species variability is also necessary, and use of this factor does not result in reducing insignificant risk. Worker populations exposed to glycol ethers are not as homogeneous as the animal populations used in experimental studies. Furthermore, even if workers are healthier than the general population, it does not necessarily follow that this " healthy worker effect" will be conferred upon a developing fetus. In addition, both parents of the fetus need not necessarily be " healthy workers", and the fetus may inherit the genetic traits of either parent In utilizing the uncertainty factors in setting the proper PELs for the glycol ethers under consideration in this rulemaking, it has not been the Agency's objective to apply an uncertainty factor to eliminate all risk. If that had been the Agency's objective or mandate under the Act, a much higher uncertainty factor would have to have been applied to ensure elimination of all risks. Rather, the Agency has used uncertainty factors to take into account only the highest uncertainties, such as inter species and intra species variability. The Agency believes that it has used the uncertainty factors in a reasonable manner and in utilizing the uncertainty factors the Agency has had as its goal reducing risks that are significant After considering the severity of the types of risk as shown by the qualitative analysis of the data, OSHA preliminarily concludes that exposure to 2 ME, 2 EE and their acetates presents a significant risk to employees exposed to these substances at the current PELs. The current PELs for 2 ME and 2 MEA are 25 ppm, two and one half times larger than the NOEL for 2 ME in three species ( i. e., 10 ppm). The current PELs for 2 EE and 2 EEA are 200 ppm and 100 ppm respectively. For 2 EE, this PEL is four times greater than the NOEL identified in two species ( i. e., 50 ppm), and for 2 EEA, this PEL is two times greater than the NOEL identified in one species ( i. e., 50 ppm). If the NOEL is an estimate of the threshold of exposure resulting in adverse effects in animals, and if humans have the same degree of sensitivity as animals, exposure at the current PELs poses risk of material impairment of health. If humans are more sensitive than animals and respond to exposure in a less homogeneous manner, then the risk is greater still that workers exposed at the current PELs will suffer adverse effects from such exposure OSHA also preliminarily concludes that the new glycol ethers standard will result in a reduction of significant risk. However as discussed earlier in the section on Risk Assessment there are uncertainties to the NOEL/ Uncertainty Factor approach. It is assumed that at exposure levels derived by dividing an experimental NOEL by an uncertainty factor of 100, humans are unlikely to exhibit effects observed in experimental animals. However the ADI does not represent a level of exposure above which there is significant risk and below which there is no significant risk. For some individuals there may be some remaining risk below the ADI. For these reasons OSHA believes that the ancillary provisions of the standard such as exposure monitoring and medical surveillance will provide greater assurance that workers will not be at significant risk. Thus OSHA believes that these provisions are reasonably necessary VIII. Summary Of The Regulatory Impact And Regulatory Flexibility Analysis Introduction Executive Order 12291 ( 46 FR 13197, Feb. 19, 1981) requires that a regulatory analysis be conducted for any rule having major economic consequences on the national economy, individual industries, geographical regions, or levels of government. The Regulatory Flexibility Act ( 5 U. S. C. 601 et. seq.) similarly requires the Occupational Safety and Health Administration ( OSHA) to consider the impact of the proposed regulation on small entities Consistent with these requirements, OSHA has prepared a Preliminary Regulatory Impact and Regulatory Flexibility Analysis ( PRIA) for the proposed glycol ethers standard with 8 hour time weighted average ( TWA) permissible exposure limits ( PELs) of 0.1 parts per million ( ppm) for 2 methoxyethanol ( 2 ME) and 2 methoxyethanol acetate ( 2 MEA), and 0.5 ppm for 2 ethoxyethanol ( 2 EE) and 2 ethoxyethanol acetate ( 2 EEA) ( Ex. 5 165). This analysis describes the industries affected by the standard, the regulatory alternatives considered, some of the potential benefits that will accrue to employees exposed to glycol ethers at their places of work, the costs of the proposed standard, and the technological and economic feasibility of the proposed provisions. The following is a summary of this analysis Background The chemicals 2 ME, 2 EE, 2 MEA, and 2 EEA are members of the family of ethylene glycol ethers. Referred to collectively in this analysis as " glycol ethers", these four chemicals have versatile solvent properties that make them useful in a wide variety of industries. The principal uses of glycol ethers are in chemical intermediates, paints and coatings, inks, and electronics The current OSHA PELs for 8 hour TWAs are 25 ppm for 2 ME and 2 MEA, 200 ppm for 2 EE, and 100 ppm for 2 EEA. They were established in 1971 based on the 1968 Threshold Limit Values ( TLVs) recommended by the American Conference of Governmental Industrial Hygienists ( ACGIH). These TLVs were based on hematotoxic and neurotoxic effects and on exposure concentrations reported in the early case reports on human health effects. More recent information from animal studies, however, indicates that adverse reproductive effects may occur at much lower concentrations. The ACGIH now recommends for all four glycol ethers an 8 hour TLV of 5 ppm, plus a " skin" notation to draw attention to the need to prevent cutaneous absorption In 1984, the U. S. Environmental Protection Agency ( EPA) published an Advance Notice of Proposed Rulemaking ( ANPR) regarding 2 ME, 2

[ page 15580]

EE, 2 MEA, and 2 EEA. In 1986, the EPA referred the issue of rulemaking for these chemicals to OSHA. Subsequently, OSHA made a preliminary determination that the occupational risks identified by EPA could be eliminated or reduced by a revised OSHA standard. In 1987, OSHA published an ANPR announcing its intention to initiate rulemaking action for four glycol ethers ( OSHA Docket, Ex. 6.)

The objective of this analysis is to measure the regulatory impact of the proposed TWAs and associated requirements, including Excursion Limits ( ELs) equivalent to five times each TWA and action levels ( ALs) equivalent to one half of each TWA The principal source of information for this analysis is a study conducted for OSHA by PEI Associates, Inc., Technological Feasibility and Economic Impact Assessment of a Proposed Revision to the Glycol Ethers Standards, 1990, OSHA Docket, Ex. 5 164. A major source for PEI's report was an earlier study conducted for OSHA by Meridian Research, Inc., Industry Profile and Analysis of Processes, Occupational Exposures, and Substitutes for Glycol Ethers, 1987, OSHA Docket, Ex. 5 108 PEI conducted three major data collection activities:

1) All available monitoring data from work establishments were collected, categorized, and tabulated. These historical data were obtained primarily from OSHA, the National Institute for Occupational Safety and Health ( NIOSH), and a study that PEI had conducted previously for EPA. Only post 1984 data were used because of a change in the limit of detection in the glycol ether sampling and analytical method in 1984 2) A joint PEI/ NIOSH team visited nine facilities selected to be representative of the industries currently manufacturing, processing, and/ or using at least one of the glycol ethers under consideration. Information was obtained at each site regarding processes, use of engineering and work practice controls and personal protective equipment ( PPE), characteristics of the exposed work force, medical and industrial hygiene programs, and experience with substitute chemicals. To characterize full shift and peak exposures in each job category with potential for exposure to glycol ethers, NIOSH also sampled at least one shift at each site 3 ) PEI mailed a survey questionnaire to approximately 2500 randomly selected potential users of glycol ethers in order to characterize the following:

 Extent of usage of glycol ethers in different industry segments  Process operations  Demographics of potentially exposed workers  Engineering and work practice controls currently in place and those necessary to achieve specified exposure levels  PPE currently in place and PPE necessary to achieve specified exposure levels  Financial characteristics of the industries  Experience with potential substitutes for glycol ethers Usable responses were obtained from 1,424 facilities through the mail questionnaire and subsequent telephone followup. Of the establishments submitting usable responses, 70 percent had never handled any of the four glycol ethers which are the subjects of this rulemaking, 13 percent had discontinued handling them, and 17 percent currently handled at least one of them Based primarily on data from the survey questionnaire and site visits, PEI developed model plants to represent average establishments in each industry category. The model plants were used to develop an exposure profile and estimate compliance costs. The number of model plants developed for each industry category depended on market structure and work force characteristics, including exposures. PEI also developed model plants for small businesses Industry Profile The estimated 1987 domestic net sales ( i. e., production less inventory changes) of the four glycol ethers amounted to 286 million pounds. The most widely distributed chemical was 2 EE ( 149 million pounds in 1987), followed by 2 EEA ( 85 million pounds), 2 ME ( 51 million pounds), and 2 MEA ( 1 million pounds). The largest consumption category for these chemicals was export ( 45 percent of sales), followed by use as chemical intermediates ( 24 percent of sales). The remaining 31 percent of sales of the glycol ethers was primarily for solvent use Table VIII 1 presents estimates of the number of glycol ether using establishments covered by the proposed regulation, percent of small establishments, total employment, and number of exposed workers. Although jet fuel additives consume much 2 ME, they are excluded from this analysis because they are used almost exclusively in military applications. All other miscellaneous uses not addressed in this analysis are estimated to account for less than 1 percent of total usage of the glycol ethers Sales of the four glycol ethers have declined steadily over the past decade, probably as a result of increased concern over environmental and health issues Manufacture of Glycol Ethers Four establishments operated by three companies ( Union Carbide, Eastman Chemical, and Oxy Petrochemical) currently produce at least one of the four glycol ethers. ( In 1990, Union Carbide, the sole producer of 2 MEA, discontinued its manufacture and sale. A submission by the Chemical Manufacturers Association ( CMA) to OSHA reported that " only a very few users" were working off inventories of 2 MEA, OSHA Docket, Ex. 3 002.) Because of similarities in the production processes, plant capacity can be shifted from one of the four TABLE VIII 1 GLYCOL ETHERS INDUSTRY PROFILE Estima

ted number Estimated Exopsed Workers of Percent Estimated __________________________

Estab small total lish estab employ Females ments lish ment Total Males under using ments age Industry glyco (*) 45 Category ethers Manufacture of Glycol 4 0 5,120 344 320 24 Ethers Manufacture Of 5 0 44,500 80 60 20 Chemical inter

Mediates Formulation Of 183 57 13,176 2,745 2,562 183 paints and Coatings Aircraft 54 NA 244,782 1,998 1,998 0 manufacturing/

Repainting Motor vehicle Body 16 57 69,920 736 736 0 manufacturing Other metal 366 55 37,698 1,464 1,464 0 applications Automobile 8,777 75 43,885 26,331 26,331 0 refinishing Wood Furniture 370 67 27,750 8,140 3,330 2,590 manufacturing Formulation of inks 86 67 5,848 946 860 86 Inks Application of inks 86 89 11,180 946 516 430 Inks Semiconductor 142 54 47,428 1,704 710 852 manufacturing [ page 15581] Printed Circuit 44 61 7,392 352 220 132 Board manufacturing Total 10,133 . 558,679 45,786 39,107 4,317 (*) Establishments with fewer than 20 employees NA = Not Available Source: PEI chemicals to another, as well as to other ethylene oxide derivatives Manufacture of Chemical Intermediates In addition to the plants that produce 2 EEA and 2 MEA, four major producers of chemicals use 2 EE or 2 MEA as an intermediate in five other plants: Eastman Chemical, Reichold Chemical, CPS Chemical, and Sartomer Company. The major use of 2 EE ( 86 percent of domestic consumption) is as a chemical intermediate. Its principal product is 2 EEA; 2 EE is also used as a chemical intermediate in the manufacture of ethoxyethyl methacrylate, ethoxyethyl ricinoleate, ethoxyethyl acrylate, and di( ethoxyethyl) phthalate The use of 2 ME as an intermediate to produce other chemicals, including 2 MEA, accounts for 24 percent of its domestic consumption. These chemicals also include di( 2 methoxyethyl) phthalate ( DEMP), which is used as a plasticizer in the manufacture of 35 mm film, vinyl tris B methoxyethoxysilane, methoxyethylacrylate, 2 methoxyethyl silicate, methoxyethyl oleate, methoxyethyl acetyl ricinoleate, methoxyethyl ricinoleate, and methoxyethyl stearate Formulation of Paints and Coatings Glycol ethers are used in polymerization, as a medium for pigment dispersion, and as a " let down" solvent to achieve desired coating application properties. They are used primarily in the formulation of Original Equipment Manufacture ( OEM) paints for automobiles, metal furniture, and appliances and also as special purpose coatings. The formulation of paints and coatings involves mixing glycol ethers and other solvents with resins, pigments, or base materials Aircraft Manufacturing/ Repainting Glycol ethers are contained in aircraft top coat paint and sometimes in paint additives. Aircraft are generally repainted every 4 to 5 years. Painting takes place in open bays in aircraft hangars, where the paints are applied by brush, roller, airless spray, or electrostatic spray. Smaller parts and support equipment are usually spray painted in a separate paint shop Motor Vehicle Body Manufacturing Glycol ethers can be contained in electrocoat primers that are initially applied for corrosion protection, as well as in other primer and exterior color coatings. Electrocoats are applied to vehicle bodies by using conveyors to dip them into tanks containing the primer. Other primers and paints are generally applied by electrostatic guns in spray booths equipped with downdraft flow through ventilation. Automatic spray guns are used to apply the primer coats on passenger car bodies Other Metal Applications This industry category includes miscellaneous other establishments at which paints and coatings are spray painted onto metal:

SIC 2514 ( Metal Household Furniture) SIC 2522 ( Metal Office Furniture)

SIC 3411 ( Metal Cans) SIC 3412 ( Metal Shipping Barrels, Drums, Kegs, and Pails) SIC 34421 ( Metal Doors, Sash and Frames Except Storm Doors) SIC 34699 ( Other Stamped and Pressed Metal Products) SIC 3523 ( Farm Machinery and Equipment) SIC 3563 ( Air and Gas Compressors) SIC 3631 ( Household Cooking Equipment) SIC 3632 ( Household Refrigerators and Home and Farm Freezers) SIC 3714 ( Motor Vehicle Parts and Accessories)

Automobile Refinishing Some paints and coatings used in automobile refinishing contain small quantities of glycol ethers. Some spray painting operations take place in a spray booth, while other painting operations occur in the general shop environment. Wood Furniture Manufacturing Glycol ethers are used in some wood stains or lacquers because of their solvent properties. In general, the stains or lacquers are applied by spraying in booths, followed by additional hand padding operations. The stains or lacquers may also be blended prior to the finishing operations. Formulation of Inks Glycol ethers are used as a solvent in inks, primarily in gravure, flexographic, and screen inks. They serve as co solvents for ink resins and dyes in water based inks. They are also used as solvents for textile printing and as active solvents to dissolve organic dyes. Glycol ethers are used in inks that are typically manufactured in small batches, to achieve the desired viscosity Application of Inks Glycol ethers are used as ink solvents and thinners in silk screen, flexographic, and gravure printing. In silk screening, solvent based inks are spread over and squeezed through the pores of a screen to print an image. After printing, the screen is washed by hand with a lacquer thinner. In flexographic printing, the plate with the image area is fastened to a cylinder, which is then immersed into the ink filled reservoir of a letterpress. The image is transferred from the raised surface of the plate to a [ page 15582]

flexible substrate. In gravure printing, an image is etched into the surface of a cylinder, which is then immersed in the reservoir of a web rotogravure or sheet fed press. In a high speed process, ink is transferred from the cylinder to the substrate by a capil lary action. Printing operators may be exposed to glycol ethers during blending of inks and cleaning of printing press rollers Semiconductor Manufacturing Glycol ethers are used primarily as photoresists in the photolithographic portion of the wafer manufacturing process. The photoresist may be applied to the silicon wafer either manually by syringe or in an automated system that pumps the solution directly from storage to a spin coater. Glycol ethers may also be used as components of the inks used for marking the completed devices with a part number. The cleaning compounds used to dissolve the epoxy resin that mounts wafers to polishing fixtures also may contain glycol ethers Printed Circuit Board Manufacturing Glycol ethers are used as a solvent in epoxy resin that is laminated onto fiberglass reinforcement. It is normally applied in enclosed spray chambers. Glycol ethers also may be present in formulations used for marking, bonding, and labeling the printed circuit boards Worker Exposures Workers may be exposed to glycol ethers in many of the activities in the 12 industry categories evaluated in this study. Table VIII 2 lists the principal job categories in each industry category and the current weighted plant geometric mean ( GM) exposures and weighted plant arithmetic mean ( AM) exposures for each glycol ether Geometric means are usually the preferred measure of expressing central tendency for observations which are log normally distributed. By design, the formula for geometric means suppresses the value of outlying data observations. When used in combination with prescriptions for engineering controls to reduce employee exposure levels, for example, it makes the case for technological feasibility clearer by using geometric means ( compared with a single arithmetic mean calculation, in which the values of outlyers are not suppressed)

TABLE VIII 2 EXPOSURE CHARACTERIZATION BY INDUSTRY AND JOB CATEGORY | | |

Industry | Esti | Weighted plant | Weighted plant catagory | mated | geometric mean | arithmetic mean and | number | baseline | baseline job | of | exposure, PPM | exposure, PPM category | expos | |

| ed | _________________________ | __________________________

| work | | | | | | | |

| ers | 2 ME* | 2 MEA* | 2 EE* | 2 EEA | 2 ME* | 2 MEA* | 2 EE* | 2 EEA _________ | ______ | _____ | ______ | _____ | ______ | _____ | _______ | ______ | _____

|

Manufacture of Glycol Ethers: |

All |

workers 344 |

Loading |

Tech 96 0.046 N/ A 0.022 0.027 | 0.151 ( a) 0.047 0.043 Process |

Tech 72 0.032 N/ A 0.092 0.049 | 0.044 ( a) 0.177 0.077 Lab Tech 68 0.023 N/ A 0.015 0.023 | 0.027 ( a) 0.017 0.031 Maint. |

Tech 92 ( b) N/ A 0.057 0.058 | ( b) ( c) 0.079 0.116 Super |

visor 16 0.017 N/ A 0.026 0.017 | 0.017 ( a) 0.047 0.017 |

Manufacture of Chemical Intermediates**: |

All |

workers 80 |

Tech 50 0.046 N/ A 0.022 N/ A | 0.151 N/ A 0.047 N/ A Process |

Tech 10 0.032 N/ A 0.092 N/ A | 0.044 N/ A 0.177 N/ A Lab Tech 10 0.023 N/ A 0.015 N/ A | 0.027 N/ A 0.017 N/ A Maint. |

Tech 10 ( b) N/ A 0.057 N/ A | ( b) N/ A 0.079 N/ A |

Formulation of Paints and Coatings: |

All |

workers 2,745 |

Packer 732 ( b) ( c) 1.249 1.370 | ( b) ( c) 1.980 3.643 Batch |

maker 1,464 0.354 ( a) 0.673 0.870 | 0.906 ( a) 0.714 1.072 Lab Tech 549 0.215 ( a) ( d) 0.107 | 0.215 ( a) ( d) 0.118 |

Aircraft Manufacturing/ Repainting: |

Spray |

paint 1,998 N/ A N/ A ( d) 3.781 | N/ A N/ A ( d) 7.916 |

Motor Vehicle Body Manufacturing: |

All |

workers 736 |

Spray |

painter 576 N/ A N/ A ( d) 0.005 | N/ A N/ A ( d) 0.035 Dip |

painter 64 N/ A N/ A ( d) 0.012 | N/ A N/ A ( d) 0.013 Paint | mixer 96 N/ A N/ A ( d) 0.010 | N/ A N/ A ( d) 0.227 |

Other Metal Applications: |

Painter 1,464 0.218 0.104 0.052 0.072 | 0.275 0.364 0.111 0.397 |

Automobile Refinishing***: |

Spray |

paint |

er 26,331 0.218 0.104 0.052 0.071 | 0.275 0.364 0.111 0.395 |

Wood Furniture Manufacturing: |

Finisher 8,140 ( e) N/ A ( d) 0.656 | ( e) N/ A ( d) 0.830 |

Formulation of Inks****: |

All |

workers 946 |

Packer 86 ( b) ( c) 1.249 1.370 | ( b) ( c) 1.980 3.643 Batchmaker 602 0.354 ( a) 0.673 0.870 | 0.906 ( a) 0.714 1.072 Lab Tech 258 0.215 ( a) ( d) 0.107 | 0.215 ( a) ( d) 0.118 |

Application of Inks: |

Printing 946 0.035 ( a) 0.056 0.038 | 0.043 ( a) 2.441 2.071 operator |

Semiconductor Manufacturing: |

Techni |

cian ,704 0.020 ( a) ( d) 0.011 | 0.022 ( a) ( d) 0.048 |

Printed Circuit Board Manufacturing: |

All |

workers 352 |

Coater 176 0.078 ( a) 0.017 0.012 | 0.378 ( a) 0.031 0.030 Lab Tech 132 ( e) ( c) ( d) 0.134 | ( e) ( c) ( d) 0.217 Mfg Spec. 44 N/ A N/ A N/ A N/ A | N/ A N/ A N/ A N/ A [ page 15583]

Total 45,786 |

|

__________________________________________ | __________________________ * If no monitoring data were available for a substance, PEI assumed that exposures were equal to those for similar glycol ether in the same industry and job category:

( a) indicates 2 MEA exposures were assumed to equal 2 ME exposures ( b) indicates 2 ME exposures were assumed to equal 2 EE exposures ( c) indicates 2 MEA exposures were assumed to equal 2 EEA exposures ( d) indicates 2 EE exposures were assumed to equal 2 EEA exposures ( e) indicates 2 ME exposures were assumed to equal 2 EEA exposures ** Baseline exposures were assumed to equal those for Manufacture of Glycol Ethers *** Baseline exposures were assumed to equal those for Other Metal Applications **** Baseline exposures were assumed to equal those for Formulation of Paints and Coatings N/ A = Not Applicable Source: PEI But there is a problem for health analysis when the traditional geometric mean representation is used to categorize employee exposures to hazardous substances. Epidemiological and animal studies often document or suggest the greater vulnerability of the human organism to short term high dose exposures to hazardous substances, as opposed to continual, routine exposure at lower doses. In statistical terms, the intermittent, infrequent, high dose exposures represent outlyers in the data. The values which are potentially most threatening or harmful to humans are deliberately suppressed when a geometric mean is used to categorize the data In policy terms, because the underlying distribution is normally distributed ( lognormal) and susceptible to a geometric mean representation, does not require that this measure of central tendency be used for health benefits calculations. In fact, to the extent that it camouflages or distracts attention from potentially dangerous short term exposure conditions, it probably should not be used for such calculations or used only in combination with information on the distribution of the outlying data. In this analysis, geometric mean analysis is supplemented with arithmetic mean data which better reflect the influence of the outlying observations. In most industry/ job categories, average exposures are already below the proposed TWAs ( although it is possible that individual exposures may exceed the proposed levels). The lowest average exposures occur during the manufacture of glycol ethers and in the manufacture of semiconductors and printed circuit boards There are a total of 45,786 exposed workers in 10,133 establishments in the 12 industry categories. The largest number of exposed workers occurs in the automobile refinishing category, which also has the lowest number of exposed workers per establishment Benefits Analysis The benefits of reducing employee exposure to glycol ethers are estimated using incidence data from animal studies and worker exposure data. The levels above which adverse health effects are likely to occur in humans are developed from the animal studies using an uncertainty factor of 100; that is, each " no observed effect level" ( NOEL) observed in the animal studies is reduced by a factor of 100 to yield the corresponding human exposure level OSHA's analysis of the benefits that are likely to occur as a result of limiting exposures to glycol ethers does not consider decreases in adverse hematological effects and in behavioral abnormalities in the offspring of exposed adults. Also, OSHA's analysis relies on animal studies that use inhalation as the route of exposure; the dosages of glycol ethers administered in inhalation studies are more readily quantifiable than those in absorption or ingestion studies and the majority of job categories considered at risk involve the inhalation of glycol ether vapors. However, dermal workplace exposures do occur, but these were not quantified. Thus, the benefits in this analysis are underestimated. The health effects estimated in this analysis and shown in Table VIII 3 are the estimated incidence of developmental effects of glycol ether exposure on the pregnancies of females under age 45 and the estimated incidence of adverse reproductive effects in male employees. The benefits were calculated assuming a 45 year working lifetime for both sexes. No effort is directed at delineating the types of fetal defects avoided. Since both 2 ME and 2 MEA are metabolized in humans to methoxyacetic acid, the benefits of limiting exposure to these compounds are displayed together. Similarly, the benefits associated with reductions in 2 EE and 2 EEA exposures are displayed together TABLE VIII 3 PROJECTED BENEFITS OF PROPOSED STANDARD Number of Annual Workers Number of Exposed Adverse above Effects Proposed or Cases Effects PEL Avoided Developmental Effects/

Female Workers Aged 18 to 45 From Exposure to 2 ME/ 2 MEA 157 0.4 to 4.5 From Exposure to 2 EE/ 2 EEA 573 1.7 to 8.0 Total Developmental Effects 730 2.0 to 12.4 Reproductive Cases/ Male Workers From Exposure to 2 ME/ 2 MEA 2,604 200 to 490 [ page 15584] From Exposure to 2 EE/ 2 EEA 4,294 63 to 611 Total Reproductive Cases 6,898 262 to 1,101 Note: Other benefits have not been quantified: reductions in hematological effects, behavioral abnormalities in offspring, and effects of dermal exposure Sources: PEI, Office of Regulatory Analysis An estimated total of 2.0 to 12.4 adverse effects on fetal development per year would be avoided under the proposed standard ( TWAs of 0.1 ppm for 2 ME and 2 MEA; 0.5 ppm for 2 EE and 2 EEA). These adverse developmental effects would be avoided principally in ink application, electronics, formulation of paints and coatings, and wood furniture manufacturing For male workers, an estimated 262 to 1,101 adverse reproductive conditions ( reduced testes size, reduced sperm count and/ or other impairment of reproductive functioning) would be avoided per year under the proposed standard. The impairments will persist in exposed workers for as long as they are exposed. New cases will develop among new workers as, over time, work forces turn over and new individuals become exposed. These benefits would occur principally in automobile refinishing, aircraft manufacturing and repainting, and formulation of paints and coatings Technological Feasibility OSHA has preliminarily determined that the proposed standard is technologically feasible. OSHA determines that the proposed TWAs are capable of being achieved in most of the operations most of the time by means of engineering and work practice controls. In certain situations for a very limited number of employees ( i. e., under 2% of all full time equivalent ( FTE) workers exposed to glycol ethers in the industries involved) supplementary respiratory protection may be necessary. In most instances, when the 8 hour TWA has been met through engineering controls, no use of respirators would be necessary to meet the 15 minute EL For example, in auto refinishing, which employs an estimated 26,331 exposed workers, who constitute 58% of all workers exposed to glycol ethers, OSHA estimates that the exposure levels for 98% of these workers can be reduced to or below the proposed TWAs and ELs by means of substitution, engineering, and work practice controls. OSHA estimates that, on an FTE basis, fewer than 1% of all currently exposed auto refinishing workers would require respiratory protection. In addition, OSHA preliminarily determines that exposure levels, as measured by geometric means, can be controlled to or below the proposed 8 hour TWAs solely by means of engineering and work practice controls in a vast majority of operations across the affected industries. Specifically, geometric mean exposure levels can be controlled to or below the TWAs in 16 of 22 2 ME operations, in 8 of 12 2 MEA operations, in 25 of 26 2 EE operations, and in 17 of 18 2 EEA operations The best evidence of technological feasibility is that the proposed levels are already being achieved in the affected industries with current controls. Across industries using glycol ethers, geometric mean exposures are already at or below the proposed TWAs in a majority of operations. These exposure data suggest that relatively few additional controls would be necessary to consistently reduce 8 hour exposures and peak exposures to or below the proposed standard In order to assess technological feasibility, PEI considered substitution of other solvents for glycol ethers, other engineering controls, personal protective equipment ( PPE), and administrative measures, such as inspections to detect leaks in areas where glycol ethers are handled. PEI applied specific engineering or other controls until the predicted exposure level for each industry/ job category was reduced to no more than one half of each of the proposed alternative TWAs for each glycol ether. The exposure level for determining when additional controls would be necessary was based on weighted plant geometric mean exposures or weighted plant arithmetic mean exposures. The purpose of conducting the technological feasibility analysis using each of the two types of means was to determine if the costs and exposure levels differ significantly with the varying degrees of engineering controls and respirators necessitated by the two different approaches. In most cases, there is little difference The technological feasibility of meeting ELs that were equivalent to five times each TWA was assessed separately. During its site visits, PEI was able to collect both short term and full shift monitoring data on some individuals whose jobs involved the potential for peak exposures. PEI assumed that job categories with TWA levels that are currently below one half the proposed TWA would not experience excursions above the EL during normal operations. In establishments that required only engineering controls to meet a proposed TWA, the use of ASRs would be required for about one quarter of the workers in job categories that had a potential for peak exposures. With both respirators and engineering controls, no additional requirements were assumed to be necessary to meet the EL Engineering Controls The systems which PEI specified were based on American Conference of Governmental Industrial Hygienists ( ACGIH) recommendations for good engineering practice. They are conventional, readily available, and in use today. The primary engineering control recommended for most categories was local exhaust ventilation ( LEV). Process enclosures, which provide greater exposure control than hoods, were recommended for some operations The following incremental engineering controls are considered technically feasible for the industry categories in this study:

Manufacture of Glycol Ethers:  Closed loop transfer for loading operations  Enclosed sampling systems with sample coolers  Laboratory hood in quality control ( QC) laboratory Manufacture of Chemical Intermediates:  Automated drum filling station with LEV  Enclosed sampling systems with sample coolers  Laboratory hood in QC laboratory Formulation of Paints and Coatings:

[ page 15585]  Closed loop transfer system  LEV on packaging line  LEV on mixing tank  Drum hoist/ scale ( small formulator plants)  Laboratory hood in QC and R& D laboratories Aircraft Manufacturing/ Repainting:  Paint spray booth for small parts  Airless spray guns with " cup collars"

Motor Vehicle Body Manufacturing:  LEV on paint mixing tank  Paint spray booth Other Metal Applications:  Paint spray booth Automobile Refinishing:  Paint spray booth Wood Furniture Manufacturing:  Paint spray booth Formulation of Inks:  Closed loop transfer system  LEV on packaging line  LEV on mixing tank  Drum hoist/ scale ( small formulator plants)  Laboratory hood in QC and R& D laboratories Application of Inks:  LEV at press rollers and inkwell  Process enclosure of press Semiconductor Manufacturing:  LEV at the application of photoresist  Process enclosure at the application of photoresist Printed Circuit Board Manufacturing:  LEV on blending/ mixing operations  LEV on masking operation  LEV on coating operation  Process enclosure of coating operation Personal Protective Equipment When the implementation of engineering controls did not reduce the predicted exposures for a job category to below the target level, ASRs were prescribed. Cartridge respirators are considered inadequate because the odor thresholds of the four glycol ethers do not allow workers to adequately detect breakthrough at concentrations as low as the proposed regulatory alternatives Dermal exposure can be reduced through gloves, protective clothing, and eye protection. Evidence indicates that butyl rubber gloves may be appropriate for operations that involve heavy handling and high potential for direct contact. Neoprene gloves may be appropriate for some production related activities, such as loading rail cars and taking quality control samples. Latex gloves may be appropriate for operations that involve light handling and only occasional contact Substitution Substitution of other chemicals is an option for eliminating exposure to 2 ME, 2 MEA, 2 EE, and 2 EEA, although no single " drop in" substitute exists for all applications. The most common substitutes, according to PEI's survey, are propylene glycol monomethyl ether ( PGME), ethylene glycol monobutyl ether ( 2 BE), ethylene glycol monopropyl ether ( 2 PE), and their acetates. Together, these six chemicals account for almost 90 percent of reported substitutions. Evidence suggests that they would pose a lower hazard in the workplace than the four glycol ethers being considered in this standard A substitution rate was assumed for each industry category based on the availability, suitability, and cost of substitutes; the capital and operating and maintenance ( O& M) costs of compliance techniques; and the industry category's position in the chain of distribution ( i. e., its flexibility in forcing or responding to substitution). The rate of substitution is assumed to be the same for the geometric mean and arithmetic mean exposure approaches. The following substitution rates were developed: Manufacture of Glycol Ethers and Intermediates: No substitution; export and chemical intermediate uses represent large proportions of total production of all four glycol ethers Formulation of Paints and Coatings: 90%; most formulators already have or are developing substitutes Aircraft Manufacturing/ Repainting: 70%

Motor Vehicle Body Manufacturing: 70%

Other Metal Applications: 70%

Automobile Refinishing: 90%

Wood Furniture Manufacturing: 90%; use of glycol ethers is already dropping rapidly Formulation and Application of Inks: 90%; much substitution has already taken place Semiconductors: 10%; acceptable substitutes are not generally available Printed Circuit Boards: 50%; acceptable substitutes are generally available Exposure Reduction Tables VIII 4 through VIII 7 show exposure reductions for each glycol ether after applying engineering controls. In many industry/ job categories, no engineering controls would be needed to meet the proposed TWAs, although respirators might be needed to meet the proposed ELs.