制药工程论文英文文献翻译.doc

北京化工大学北方学院毕业设计文献翻译醋酐马克路易斯（商业化学药品评估部门 加拿大 351圣约瑟林荫大道）摘要介绍了醋酐的性质，在北美制造的两个程序及对环境、人类健康的影响。关键词醋酐 纤维素 分解1 性质分子的公式：C4H6O3结构的公式：（CH3CO）2O分子的重量：102.09沸腾的点（760 mmHg）：138.6（282）冰点：-73（-100）2 在暴露上的一般资讯2.1 一般的讨论醋酐在北美被制造二个程序。大部份的生产使用ketene醋酸技术，包括对 ketene 的热很快的醋酸和那用形成醋的醋酐另外的醋酸的后来反应。甲基醋酸盐是第二条路径。一些醋的酸在甲基中当做一种共同产品被生产醋酸盐处理1。醋酐在制造业的醋酸盐酯中用当做一个试药，醋酐的反应用氢氧基小组产生对应的醋酸盐酯与醋酸。醋酐是二手的使乙醯化对阿斯匹林方面的得自水杨酸的酸。大部份的醋醋酐生产被消耗在制造业的纤维素醋酸盐酯。纤维素醋酸盐酯包括纤维素和混合的酯。在纤维素醋酸盐的产品中，小组从每个醋的醋酐分子与纤维素起化学反应，而且另一个小组被转换到醋的酸哪一个能向后地被使再循环制造更多的醋醋酐或者被用来生产其他的醋酸引出之物。过滤器是从拖和可塑剂的一种混和制造，纤维素醋酸盐细丝纱被用于衣服和回家家具。纤维素被用于照相的电影而且强迫敏感的音带。2.2 生产释放这些释放全部是对气氛，浇水的任何释放诉诸于注入，适当的到这会只是礼物的水解和可发觉的当做醋的酸，任何的释放以这一样子是期望是最小的。2.3 使用的释放2.3.1 从纤维素醋酸盐生产释放主要的下游使用在纤维素醋酸盐生产，哪里醋的醋酐是一中间物。释放编号给予的在2.2年，是给 Celanese 加拿大爱德蒙顿设备整体而言，和如此包括生产和使用。虽然没有限定的数字是可得的，但是给性质纤维素醋酸盐程序任何的排放物预期很小的（10%的总计排放物）和由于水解，以醋酸的形式。2.3.2 消费者的释放使用醋酐被当作反动的中间物使用。当反应，举例来说制造纤维素醋酸盐，它不在使用被再产生。因为它是反动的而且不迟疑地加水分解，它的出现在结束使用的产品是不可能的。为较进一步的数据见到第4.1.2节。2.3.3 广大的释放一般的广大释放不是醋酐的一个可适用情节。它只被用当做一俘虏，反动的中间物。2.4 关于安全的处理资讯如果意外释放，点火来源应该被除去。泄漏容器应该是用溢出包含放在一个通风的良好区域之内。如果火潜能存在，总括性的溢出与酒精类型水的形成电影的泡沫或使用水喷雾驱散蒸汽。扫除方法可能包括能吸收材料或一个真空卡车的使用。表面流水进入暴风雨下水道和沟渠之内哪一个领引对天然的航路应该因溢出包含而避免。醋醋酐容器的储藏应该与适当的通风和容器当不在使用中的时候，应该被关闭。连络用眼睛、皮肤或衣服，而且呼吸醋的醋酐蒸汽应该被避免。被弄脏的衣服应该以前被彻底地净化关于使用和受污染的皮革衣服应该被破坏。工人应该彻底地洗藉由肥皂和水在处理醋的醋酐容器之后。醋的醋酐应该从热、火花和火焰来源被储存，而且不应该是以不相容的材料储存。不相容的材料包括水；水的碱如此的当做腐蚀剂苏打解决；酒精；乙二醇；氢、酸、氮的酸，铬三氧化物、和其他的氧代理人；胺；硼酸。醋的醋酐与水起化学反应形成醋的酸和热。3 环境3.1 环境的暴露3.1.1 一般的讨论在天然的水域中，醋酐对的第一次序反应根据加水分解醋的酸。根据实验式地决定的比率常数2，一能计算一半生命，t12，4.4 分钟，在 25和8.1 分钟。对醋酸降格也在气氛下发生。根据一实验式地决定了比率常数，为醋酸的完成反应的降格与光化学地形成急进份子在22天的一半生活已经被计算的气氛下3。然而，因为它的高可溶性，醋的酸将会快速地被洗掉那气氛。在生物降解能力的静态测试中，醋酸是被降级的至超过95%在5天4。在再肺活量计测试（在修正的 MITI 测试中的2224小时）醋的酸中是被降级的到99%5。对于醋的醋酐一个水的分割系数，记录 Pow，-0.27 已经被计算，当为醋的酸，记录-0.17 Pow 已经被实验式地决定的时候6-7。两者皆不的价值为生物体内蓄积提供潜能的任何指示。3.1.2 被预测的环境的集中给每年被释放到气氛定态州的醋酐的体积使用易逃逸模型作为北方亚伯达的区域的集中能是估计8。释放至这一378 000公里2个区域在空气中造成2.4 x 10-15 毫克m3，2.33 x 10-9 gg 在土壤，在水中的 1.8 x 1.11 克m3，和在沉淀物的 1.9 x 1.14 克m3 在空气中假定住宅时间2.42为这一个区域的在水中的数天和75.1天。全部的反应持续在0.107点被估计hrs。对于水的集中能被当作计算的 PEC 使用（也就是 PEC 1.7 x 10-11毫克L）。当做先前注意，醋酐的副产物是醋的酸。它很快地是和不。（伐木 Pow -0.17）它在类似的水生种方面是比较不有毒超过醋酐和以它的被使中立的形式（醋酸盐）它在新陈代谢方面扮演重要角色所有的种。3.2 对环境的效果各种不同实验室的结果以水生的生物测试9，在哪一个有毒的门槛对于醋的醋酐集中为醋的酸被发现是有关一半那些，建议一开始的有毒效果，只要不是所有的那都已经加水分解到醋的酸（在第一个期间几分钟）10。3.3 起始评估为环境要决定 PNEC，18 毫克L 的慢性最低效果水平被采取而且分开的2到获得从经济合作暨发展组织 SIDS 手册被基于指导的9的被估计的 NOEC 毫克L（六月1997) 11。应用一个100安全因素（因为慢性的 NOECs 不是另一个可以使用营养的水平）提供0.09的 PNEC 毫克L。 因为慢性的 NOECs 不是可得对水蚤或鱼一个比较一定在起源于的 PNEC 之间被做最低的敏锐的价值12。最低的敏锐效果水平正在给在55毫克L。的水蚤应用一个500安全因素因为慢性的数据可用来13，藻类和物质不是固执给0.11 PNEC些微地比起源于慢性的数据的 PNEC 高的毫克L。4 人类的健康4.1 人类的暴露4.1.1 职业的暴露OSHA PEL，MAK 价值和 ACGIH TLV 为醋酐现在是5个百万分之一。内在的和 Celanese 加拿大工作地点暴露水平（WEL）是1个百万分之一。在一典型的醋酸酐生产那里的设备是少于100工人。基于工业的卫生保健监听数据在 Celanese 加拿大爱德蒙顿获得植物而且在 Hoechst Celanese 美国植物，吸入暴露在下面被公开和内在的工作地点暴露指导方针14。这应用两者都对醋的醋酐生产和主要的使用（纤维素醋酸盐生产）。工业的卫生保健监听的特定的数据记录在 Celanese 加拿大爱德蒙顿厂（醋的醋酐和纤维素醋酸盐生产）是提供了下一个。最时常暴露已经被藉由在空气中测量醋的酸集中检测15。那方法有少于0.1个百万分之一的一个发现的界限。基于110空气样品测量每一在过去六年上的年，在各种不同的工作种类中以对醋的醋酐暴露，工人是暴露90时候至少于0.10.4个百万分之一。Hoechst Celanese 和 Celanese 加拿大发展了和定相现在在较新的方法学中对于特定的醋醋酐监听以0.07个百万分之一的一个发现的界限。在 Hoechst 的结果Celanese 美国设备是类似的至先前为 Celanese 加拿大被讨论的那些16。为例子在去年之上，使用被指出的新的方法 70个空气样品测量醋的醋酐水平在范围中：至 0.35个百万分之一的0.07个百万分之一（发现的界限）。水平在大部分方面样品在发现的界限下面。皮肤、口头的暴露不被预期是暴露的重要路径在标准的职业练习，因为给予保护程序和设备用17。4.1.2 其他的暴露情节作为完全地在被加倍的使用被反应的俘虏中间物的给予醋酐使用藉由它的非常短一半生活，消费者或广大的环境暴露情节是不有可能的。两者皆不的 Celanese 加拿大，唯一的加拿大制造业者，也不 Celanese 化学药品区分，最大的美国生产者之一为消费者申请卖醋的醋酐。醋醋酐的欧洲制造业者被质疑了关于对消费者讲的申请售卖，但是没有为消费者申请指出售卖。注意很重要醋的醋酐售卖紧紧地被控制和被记录的结束使用被制造业者在规则之下避免对违法的药物综合的化学转移。那国际的数据摘要为醋的醋酐在 SRI 化学的经济学手册中没有为醋的醋酐提到任何的消费者申请或市场。基于这最近者输入，没有指示它的使用大体上在消费者中国际性地是练习工业18。4.2 对人类的健康效果在有关的文件准备期间被识别的开始的数据缝隙是：次慢性的毒性，生殖的毒性和在活泼的诱变性中。基于醋醋酐的身体的化学特性，它的新陈代谢产物（醋的酸）加上数据从一次慢性的吸入生殖的毒性研究，测试计画然后讨论在暹逻1995年二月被呈现在威廉斯堡见面，维吉尼亚而且核准。在男性中的一项90天的次慢性的吸入研究而且有着另外的90天的恢复的女性鼠逐步运行估定被提供的可反转性那为计画的基础。也被包括在内的是广泛又显微镜评估那生殖的器官加骨髓的标准分析。结果被描述在相关的区段中的下一个。4.2.1 独身者暴露可接受质量的没有皮肤促进感受性研究是可得的。在一项 1940 的研究中使用注入，要求的一个回应促进感受性反应是指示的是为在橄榄油中受到25%解决的天竺鼠报告。给腐蚀性质醋的醋酐，与动物福利考量一起加倍，促进测试会是困难的证明19。4.2.2 重复的暴露一项使用在动物中的吸入路径的早的研究极少被报告和不确定的有效性20。不够的细节从这一项报告是可得的拉可靠的对醋的醋酐关于重复吸入暴露的效果的结论。因此，新的吸入研究被引导了。4.3 起始评估为人类的健康4.3.1 职业的（工人）最低的 NOEL，1个百万分之一（4.2 毫克m3），经由最有关的以一项最近的次慢性的研究为基础暴露路径吸入。在 LOEL 5个百万分之一（21 毫克m3），最小、可逆的呼吸器官的广阔的地面刺激被观察了，但是没有系统的毒性。在活泼的中和发展上的毒性研究没有揭露在较高的集中（2025个百万分之一）的特性效果。工作地点暴露监听从植物，数据是可得的产生醋的醋酐而且从植物使用它。暴露水平是低的因为程序和设备加上工人训练计划适当地提供保护。因此，醋的醋酐被考虑低潜能为为危险配备人手的。4.3.2 另外地给它的使用式样（俘虏中间物，完全地反应在使用）和迅速的水解。非人类研究的25）对正常的身体新陈代谢产物（醋酸盐），消费者或广大的环境暴露是不人类的暴露的重要的情节到醋的醋酐。5 结论及忠告5.1 环境醋酐为它完全地的化学的综合被独自地当做中间物用反应了。在水圈中，醋的醋酐快速地被加水分解一半到醋的不迟疑可自然腐化的酸。在气氛下，它被转换到醋的酸是依照降格。一半生活 22 天对水生的生物毒性是适度的（18-3400 毫克L），但是由于它的迅速水解它对醋酸盐醋的只坚持短时间酸。它为生物体内蓄积事实上没有潜能。（记录 Kow -0.27)PECPNEC 比是更较少的超过一（1.9 x 10-10）。因此，醋酐为暴露有低的潜能而且是考虑现在对 SIDS 背景的进一步的环境工作低优先。5.2 人类的健康对于醋的醋酐紧要关头的效果连络在现场是刺激21。因为它众所周知的腐蚀的而且对眼睛，皮肤和呼吸器官的广阔地面和低的气味门槛的刺激效果，程序、设备（举例来说，护目镜、手套，口罩），训练和工程控制有已经适当地许多年避免暴露。工业的卫生保健监听数据指出，醋酐的水平在1个百万分之一下面8hr的。时间重量平（4.2 毫克m3）在醋酐被生产的设备和醋酐的主要使用拿的地方中地方。醋酐被独有地当做化学的中间物用，而且没有指示它的使用大体上是在消费者业中的练习。一般建议职业的暴露极限被再访基于在这一 SIAR 中被报告的另外的测试。醋酐被考虑为了SIDS 背景的比较进一步的讲健康的工作现在是低优先。参考文献1 CEH-史丹福的研究設立国际的数据摘要603.5000 A（1996).2 黄金（1948)：Trans 法拉第 Soc .44，506-515.3 Hoechst AG（1975)：（31.07.1975)在 IUCLID 引述（1996).4 Placak，Ruchhoft（1947):公共卫生报告，XVII.有机基体的利用被刺激的泥，第62册，697-716.5 IUCLID（1996):国际的统一化学的数据数据库.6 BUA-Stoffbericht第70号(1991).7 Bringmann 等人（1980):Z . Wasser Abwasser Forsch.13(5),170-173.8 Bringmann（1978)Z . Wasser Abwasser Forsch.11(6)，210-215.9 Bringmann，Kuehn（1981):瓦斯-Wasserfach，Wasser-Abwasser 122(7)，308-313.10 Hoechst AG（1975):（13.08.1975)在 IUCLID 引述（1996).11 Bringmann，Kuehn（1976):瓦斯-Wasserfach，Wasser-Abwasser 117(9)，410-413.12 Bringmann（1975):Gesund.-Ing . 96(9)，238-241.13 Bringmann，Kuehn（1980):浇水关于.14，231-241.14 Gloyna，Thirumurthi（1967):水污水工作 114(3)，83-88.15 Bringmann，Kuehn（1982):Z . Wasser Abwasser Forsch.15(1)，1-6.16 Juhnke，Luedemann（1978):Z . Wasser Abwasser Forsch.11(5)，161-164.17 Takhirov，M . T .（1969):轻便马车.34:(6):122-125.18 醋酐：在鼠的13星期的吸入毒性研究.Huntingdon 报告 HST411|961219(1996年).19 McMahon 等人（1979):巨蟹座关于.39(3)，682-693.20卡梅伦：短期的测试计画根据巨蟹座原因论的区分赞助，国民巨蟹座学会，Y85CCRIS，1991.21 Mortelmans 等人（1986):诱导有机体突变的物质.8（Suppl.7），1-119.Acetic AnhydrideMark Lewis(Commercial Chemicals Evaluation Branch , Canada , 351 St. Joseph Boulevard)Abstract Introduced the property of acetic anhydride , two procedures for making in North Amer-ica and to the environment , influence with healthy mankind.Keywords acetic anhydride；the cellulose；resolve1 IDENTITYMolecular Formula: C4H6O3Structural Formula: (CH3CO)2OMolecular Weight: 102.09Boiling point (760 mmHg): 138.6C (282F)Freezing point: -73C (-100F)2 GENERAL INFORMATION ON EXPOSURE2.1 General DiscussionAcetic anhydride is manufactured in North America by two processes . Most of the production uses the ketene - acetic acid technology , Some acetic acid is produced as a co-product in the methyl acetate carbonylation process(1) . Acetic anhydride used as a reagent in manufacturing acetate esters , acetylation of pharmaceuticals, end-capping polyacetal homopolymers , and other reactions is consumed in the reaction step .Reactions of acetic anhydride with hydroxyl groups yield the corresponding acetate ester with coproduction of acetic acid. Acetylation of amines produce acetamides such as TAED (tetraacetylethylenediamine) , which is used as a perborate bleach activator . Acetic anhydride is used to acetylate salicylic acid to aspirin and p-aminophenol to acetaminophen . In the manufacture of cellulose acetate , one acetyl group from each acetic anhydride molecule reacts with the cellulose and the other acetyl group is converted to acetic acid which can be recycled back to make more acetic anhydride or be used to produce other acetic acid derivatives . Shredded pure alpha cellulose is typically soaked in aqueous acetic acid before the treated pulp is acetylated with a 60-40 mixture of acetic acid and acetic anhydride using a dilute sulfuric acid catalyst . Cellulose acetate fibers are recovered as tow or as filament yarn . Filters are made from a blend of tow and plasticizer. Cellulose acetate filament yarns are used in apparel and home furnishings . Cellulose triacetate is used in photographic film and pressure sensitive tapes .2.2 Production releasesThese releases are all to the atmosphere . Any release to water goes to deepwell injection. Due to hydrolysis this would only be present and detectable as acetic acid . Any releases in this manner are expected to be minimal .2.3 Release from use2.3.1 Release from cellulose acetate productionThe major downstream use is in Cellulose Acetate Production , where Acetic Anhydride is an intermediate . The release numbers given in 2.2. are for the Celanese Canada Edmonton facility as a whole , and so include both production and use . Although no definitive numbers are available , given the nature of the Cellulose Acetate Process any emissions are expected to be small (10% of total emissions) and due to hydrolysis , in the form of acetic acid .2.3.2 Release from consumer useAcetic anhydride is used as a reactive intermediate . When reacted, for example to make cellulose acetate , it is not regenerated in use . Because it is reactive and readily hydrolyzed , its presence in end use products is not possible . See Section 4.1.2 for further information .2.3.3 Widespread releaseGeneral widespread release is not an applicable scenario for acetic anhydride . It is used only as a captive , reactive intermediate .2.4 Information on Safe HandlingIn case of accidental release , ignition sources should be eliminated . Leaking containers should be placed in a well-ventilated area with spill containment . If fire potential exists , blanket spill with alcohol-type aqueous film-forming foam or use water spray to disperse vapors . Clean-up methods may include use of absorbent materials or a vacuum truck . Runoff into storm sewers and ditches which lead to natural waterways should be avoided by spill containment . Storage of acetic anhydride containers should be with adequate ventilation and the containers should be closed when not in use . Contact with eyes, skin or clothing , and breathing acetic anhydride vapor should be avoided. Soiled clothing should be decontaminated thoroughly before re-use and contaminated leather clothing should be destroyed . Workers should wash thoroughly with soap and water after handling acetic anhydride containers .Acetic anhydride should be stored away from heat , sparks , and flame sources , and should not be stored with incompatible materials . Incompatible materials include wate ; aqueous alkalis such as caustic soda solution ; alcohols ; glycols ; hydrogen peroxide , perchloric acid , nitric acid , chromium trioxide , and other oxidizing agents ; amines ; boric acid . Acetic anhydride reacts with water to form acetic acid and heat .3 ENVIRONMENT3.1 Environmental Exposure3.1.1 General DiscussionIn natural bodies of water, acetic anhydride hydrolyses according to a first-order reaction to acetic acid . On the basis of experimentally determined rate constants (2) , one can calculate half-lives , t1/2 , of 4.4 min. (at 25C) and 8.1 min . (at 15C) . This hydrolytic degradation to acetic acid also occurs in the atmosphere . On the basis of an experimentally determined rate constant , for the degradation of acetic acid through reaction with photochemically formed OH-radicals in the atmosphere a half-life of 22 days has been calculated (3). However , on account of its high solubility , acetic acid will be rapidly washed out of the atmosphere . In the static Zahn-Wellens test of biodegradability , acetic acid is degraded to more than 95% within 5 days (4) . In the respirometer test (22 - 24 hours in modified MITI test) acetic acid is degraded to 99% (5) .For acetic anhydride an n-octanol/water partition coefficient , log Pow , of -0.27 has been calculated , while for acetic acid a log Pow of -0.17 has been experimentally determined (6,7) . Neither value gives any indication of a potential for bioaccumulation .3.1.2 Predicted Environmental ConcentrationGiven the volume of acetic anhydride released to the atmosphere annually the steady state concentrations using Mackay fugacity model ChemCan IV for the region of northern Alberta can be estimated . Releases to this 378 000 km2 area result in 2.4 x 10-15 mg/m3 in air, 2.33 x 10-9 g/g in soil , 1.8 x 10-11 g/m3 in water , and 1.9 x 10-14 g/m3 in sediment assuming a residence time in air of 2.42 days and 75.1 days in water for this region . Overall reaction persistence is estimated at 0.10 hrs(8) . The concentration for water can be used as a PEC in the calculation (i.e. PEC = 1.7 x 10-11 mg/L) . As previously noted, the by-product of acetic anhydride is acetic acid . It is quickly biodegraded and does not bioaccumulate (log Pow = -0.17). It is less toxic in comparable aquatic species than acetic anhydride and in its neutralized form (acetate) it plays an important role in the metabolism of all species(9) .3.2 Effects on the EnvironmentThe results of various laboratory tests with aquatic organisms , in which the toxic threshold concentrations for acetic anhydride were found to be about half those for acetic acid, suggest an initial toxic effect , so long as not all of the substance has hydrolyzed to acetic acid (during the first few minutes) .3.3 Initial Assessment for the EnvironmentTo determine the PNEC , the chronic lowest effect level of 18 mg/L is taken and divided by 2 to obtain an estimated NOEC of 9 mg/L based on guidance from the OECD SIDS Manual (June 1997) . Applying a safety factor of 100 (because chronic NOECs are not available for the other trophic levels) provides a PNEC of 0.09 mg/L . Because chronic NOECs are not available for Daphnia or fish a comparison must be made between the PNEC derived from the lowest acute value . The lowest acute effect level is for Daphnia at 55 mg/L(10) . Applying a safety factor of 500 because chronic data is available for algae and the substance is not persistent gives a PNEC of 0.11 mg/L which is slightly higher than the PNEC derived from chronic data(11) . 4 HUMAN HEALTH4.1 Human Exposure4.1.1 Occupational ExposureThe OSHA PEL , MAK value and ACGIH TLV for acetic anhydride is currently 5 ppm (8-hr. TWA) . The internal Hoechst Celanese and Celanese Canada Workplace Exposure Level (WEL) is 1 ppm (8-hr. TWA) . In a typical acetic anhydride production facility there are fewer than 100 workers . Based on industrial hygiene monitoring data obtained at the Celanese Canada Edmonton plant and at the Hoechst Celanese U.S . plants , inhalation exposure is below published and internal workplace exposure guidelines(12) . This applies both to acetic anhydride production and the major use (cellulose acetate production) . Specific information from industrial hygiene monitoring records at the Celanese Canada Edmonton Plant (acetic anhydride and cellulose acetate production) is provided next .Most often exposure has been monitored by measuring acetic acid concentration in the air . The method has a limit of detection of less than 0.1 ppm . Based on 110 air sample measurements per year over the last six years(13) , in various job categories with exposure to acetic anhydride , workers were exposed 90 m% of the time to less than 0.1 to 0.4 ppm . Hoechst Celanese and Celanese Canada developed and are currently phasing in newer methodology for specific acetic anhydride monitoring with a limit of detection of 0.07 ppm . Results at Hoechst Celanese U.S. facilities are comparable to those previously discussed for Celanese Canada(14) . For example over the last year , using the new method 70 air sample measurements indicated acetic anhydride levels were in the range: 0.07 ppm (limit of detection) to 0.35 ppm . Levels in most of the samples (15) were below the limit of detection. Dermal and oral exposure would not be anticipated to be significant routes of exposure under standard occupational practice , because of protective procedures and equipment used(16) .4.1.2 Other Exposure ScenariosGiven acetic anhydrides use as a captive intermediate which is completely reacted in use coupled with its very short half-life , consumer or widespread environmental exposure scenarios are not likely(17) . Neither Celanese Canada , the sole Canadian manufacturer , nor the Celanese Chemicals Division , one of the largest U.S. producers, sell acetic anhydride for consumer applications . European manufacturers of acetic anhydride (BP , Hoechst and Wacker-Chemie) were queried regarding sales to consumer-related applications , but indicated no sales for consumer applications . It is important to note that acetic anhydride sales are tightly controlled and end uses recorded by manufacturers under regulations to prevent chemical diversion to illegal drug synthesis . The International Data Summary for Acetic Anhydride in the SRI Chemical Economics Handbook did not mention any consumer applications or markets for acetic anhydride(18) . Based on this recent input, there is no indication that its use is in general practice internationally in the consumer industry .4.2 Effects on Human HealthThe initial data gaps identified during dossier preparation were: subchronic toxicity , reproductive toxicity and in vivo mutagenicity . Based on the physical/chemical properties of acetic anhydride , its metabolite (acetic acid) plus data from a subchronic inhalation/reproductive toxicity rangefinding study , the testing program discussed next was presented at the February , 1995 SIAM Meeting in Williamsburg , Virginia and approved . A 90-day subchronic inhalation study in male and female rats with an additional 90-day recovery phase to assess reversibility provided the foundation for the program . Als