未测定阴离子隙在重症感染患者代谢性酸中毒发生中的作用

探讨未测定阴离子隙（ＵＡＧ）在重症感染患者代谢性酸中毒发生中的作用。方法;对２５例重症 感染并代谢性酸中毒患者进行血气、电解质分析,通过阴离子除（ＡＧ）＝ Ｎａ~＋＋ Ｋ~＋－ Ｃｌ~－ ＨＣＯ~_３和ＵＡＧ＝ＡＧ－ 乳酸盐－磷酸盐－尿酸盐－血清蛋白的阴离子值,分别计算ＡＧ和ＵＡＧ值,并对乳酸值与ＡＧ值、ＵＡＧ值与ＡＧ 值进行直线回归分析。结果：ＡＧ＝（２２．８±１．６）ｍｍｏｌ／Ｌ,ＵＡＧ＝（３．９±０．８）ｍｍｏｌ／Ｌ,乳酸＝（５．８±０．７）ｍｍｏｌ／Ｌ。 乳酸值与ＡＧ值直线相关（ｒ＝０．７８,Ｐ＜０,０１）,ＵＡＧ值与ＡＧ值直线相关（ｒ＝０．８１,Ｐ＜０．０１）。结论：重症感染患 者合并代谢性酸中毒时,乳酸的增加不是导致代谢性酸中毒的唯一因素,而ＵＡＧ的增加在代谢性酸中毒的发生中 有重要作用。     

Severe Anion Gap Acidosis Associated with Intravenous Sodium Thiosulfate Administration

Introduction

Severe anion gap (AG) acidosis associated with intravenous sodium thiosulfate (STS) administration has not been previously described in nondialysis chronic kidney disease (CKD) patients.

Case Report

We present a CKD patient with a baseline creatinine 1.8 mg/dL (eGFR 28 ml/min/1.73 m²) who developed sustained and life-threatening AG acidosis associated with intravenous STS treatment for calciphylaxis.

Discussion

Although marketed as a safe drug, STS can cause life-threatening acidosis as illustrated in this case. STS-induced AG acidosis should be considered in the differential diagnosis of severe acidosis in patients receiving STS. Dosage adjustment and close follow-up of patients’ acid–base status after STS initiation is necessary.     

Toxicity Review of Ethylene Glycol Monomethyl Ether and its Acetate Ester

Ethylene glycol monomethyl ether (EGME) and its acetate ester (EGMEA) are highly flammable, colorless, moderately volatile liquids with very good solubility properties. They are used in paints, lacquers, stains, inks and surface coatings, silk-screen printing, photographic and photo lithographic processes, for example, in the semiconductor industry, textile and leather finishing, production of food-contact plastics, and as an antiicing additive in hydraulic fluids and jet fuel.

EGME and EGMEA are efficiently absorbed by inhalation as well as via dermal penetration. Dermal absorption may contribute substantially to the total uptake following skin contact with liquids or vapours containing EGME or EGMEA. EGMEA is rapidly converted to EGME in the body and the two substances are equally toxic in animals. Therefore, the two substances should be considered as equally hazardous to man.

Effects on peripheral blood, testes, and sperm have been reported at occupational exposure levels ranging between 0.4 and 10?ppm EGME in air, and with additional, possibly substantial, dermal exposure. Severe malformations and disturbed hematopoiesis have been linked with exposure to EGME and EGMEA at unknown, probably high, levels. Embryonic deaths in monkeys and impaired spermatogenesis in rabbits have been reported after daily oral doses of 12 and 25?mg per kg body weight, respectively. In several studies, increased frequency of spontaneous abortions, disturbed menstrual cycle, and subfertility have been demonstrated in women working in the semiconductor industry. The contribution of EGME in relation to other exposure factors in the semiconductor industry is unclear.     

Ethylene Glycol Monopropyl Ether: A Developmental Toxicity Study in Rabbits

Ethylene Glycol Monopropyl Ether A Developmental Toxicity Studyin Rabbits. KRASAVAGE, W. J., HOSENFELD, R. S., AND KATZ, G.V. (1990). Fundam. Appl. Toxicol. 15, 517–527. To determinethe potential developmental toxicity of ethylene glycol monopropylether (EGPE), groups of pregnant New Zealand white rabbits wereexposed to target concentrations of 0, 125, 250, or 500 ppmEGPE vapors for 6 hr a day on Days 6–18 of gestation.Maternal effects included a slight reduction in feed consumptionduring the first week of treatment at the 250- and 500-ppm exposurelevels and slightly reduced body weight gain at the 500-ppmlevel compared to those of the controls, but the differenceswere not statistically significant. One doe exposed to 500 ppmhad red-colored urine during the 24-hr period following thesecond exposure. Hemato-logic determinations, absolute and relativeorgan weights, and observations at necropsy revealed no treatment-relatedmaternal effects. Reproductive indices, i.e., pregnancy rate,number of corpora lutea, implantation sites, viable fetuses,early and late resorptions, fetal body weights, fetal sex ratio,and the gravid uterine and corrected body weights, were notaffected by exposures to EGPE. The occurrences of external andinternal soft tissue malformations and variations and the incidencesof skeletal malformations in the EGPE-exposed groups were notsignificantly different from those in the control group. Commonskeletal variations, in many instances, were seen less frequentlyin EGPE-exposed fetuses than in control fetuses. In those caseswhere the incidence of fetuses with a skeletal variation wasgreater for EGPE-exposed fetuses than that for control fetuses,the number of litters involved was not significantly differentfrom that of the control group. Thus, EGPE vapor concentrationsas high as 500 ppm did not produce teratoge-nicity or otherdevelopmental toxicity in the rabbit conceptus.     

Subchronic Oral Toxicity of Ethylene Glycol Monobutyl Ether in Male Rats

Subchronic Oral Toxicity of Ethylene Glycol Monobutyl Etherin Male Rats. KRASAVAGE, W. J. (1986). Fundam Appl. Toxicol.6, 349–355. Adult male rats (Crl:COBS CD (SD)BR) weregiven undiluted ethylene glycol monobutyl ether (EGBE) by gavagein doses of 222, 443, or 885 mg/kg/day, 5 days/week over a 6-weekperiod. A dose-dependent decrease, which was statistically significantat the high dose, was seen in body weight gain. Feed consumptionwas also significantly reduced at the 885-mg/kg dose. The mostsignificant toxic effects produced by EGBE were on the red bloodcells including a significant dose-dependent decrease in hemoglobinconcentration. red blood cell counts, and mean corpuscular hemoglobinconcentration. Mean corpuscular hemoglobin and mean corpuscularvolume were increased at all dose levels. Effects secondaryto the red cell effects included increased spleen weights, spleniccongestion, and hemosiderin accumulation in the liver and kidneys.Relative liver weights and serum alkaline phosphatase (443-and 885-mg/kg doses) and serum alanine aminotransferase (885-mg/kgdose) levels were increased. Glucose was significantly reducedin the animals given 885 mg/kg/day. EGBE had no adverse effectson the testes, bone marrow, thymus, or white blood cells.     

The Developmental Toxicity of Ethylene Glycol Diethyl Ether in Mice and Rabbits

Timed-pregnant CD-1 outbred Albino Swiss mice and New ZealandWhite rabbits were dosed by gavage with ethylene glycol diethylether (EGdiEE) in distilled water during major organogenesis.Mice were dosed on Gestational Days (gd) 6 through 15 (0, 50,150, 500, or 1000 mg/kg/day) and rabbits on gd 6 through 19(0, 25, 50, or 100 mg/kg/day). Maternal clinical status wasmonitored daily during treatment. At termination (gd 17, mice;gd 30, rabbits), confirmed-pregnant females (22–24 pergroup, mice; 26–32 per group, rabbits) were evaluatedfor clinical status and gestational outcome; each live fetuswas examined for external, visceral, and skeletal malformations.In mice, no maternal mortality was observed, but maternal bodyweight gain during gestation and treatment, and at terminationwas reduced at 1000 mg/kg/day. The reduction of maternal bodyweight gain during gestation was secondary to embryo/fetal toxicity,i.e., reduced gravid uterine weight as a consequence of decreasedlitter size and fetal weight. The no-observed adverse effectlevel (NOAEL) for developmental toxicity was 50 mg/kg/day. At150 mg/kg/day the number of litters of mice with malformed fetuseswas increased. At 500 mg/kg/day fetal body weight was reduced,and malformation incidence was significantly increased. Exencephalyand fused ribs were observed most often. In rabbits, maternalbody weight was unaffected by treatment even though 6% maternalmortality was observed at 100 mg/kg/day. The developmental NOAELwas 25 mg/kg/day. Malformations were increased at 50 mg/kg/day,short tail, small spleen, fused sternebrae, and fused rib cartilagewere observed most often. In summary, oral administration ofEGdiEE to mice and rabbits during organogenesis produced profoundadverse developmental effects even in the absence of significantmaternal toxicity. Developmental effects in rabbits were morevaried.     

Chronic Toxicity and Oncogenicity Studies of Ethylene Glycol in Rats and Mice

Chronic Toxicity and Oncogenicity Studies of Ethylene Glycolin Rats and Mice. DEPASS, L.R., GARMAN, R.H., WOODSIDE, M.D.,GIDDENS, W.E., MARONPOT, R.R., AND WEIL, C.S. (1986). Fundam.Appl. Toxicol. 7, 547-565. These studies were performed to assessthe chronic toxicity and oncogenicity of ethylene glycol (EG)in rats and mice. Groups of 130 Fischer 344 rats and 80 CD-Imice per sex were fed diets yielding approximate dosages of1.0, 0.2, or 0.04 g/kg/day of EG. Two separate control groupsin each study received no EG. Mortality rate was increased inhigh-dose male rats all of which died by 475 days. The followingeffects were also observed in high dose male rats: reduced bodyweight gain, increased water intake, increased blood urea nitrogenand creatinine, reduced erythrocyte count, reduced hematocritand hemoglobin, increased neutrophil count, increased urinevolume, reduced specific gravity and pH. Urinary calcium oxalatecrystals and increased kidney weight were seen in all high-doserats. Uric acid crystals were seen in the urine of high-dosefemale rats at 18 and 24 months. Histopath-ologic changes inhigh-dose male rats included tubular cell hyperplasia, tubulardilation, peritu-bular nephritis, parathyroid hyperplasia, andgeneralized soft tissue mineralization. Fatty change of theliver was seen in high- and intermediate-dose female rats. Noclinical signs, or gross or microscopic evidence of toxicitywas seen in mice at the dosages used. Water intake and clinicalpathologic parameters were not measured in the mouse study.In these studies there was no evidence of an oncogenic effectof EG in rodents.     

Developmental Toxicity Evaluation of Ethylene Glycol by Gavage in New Zealand White Rabbits

Artificially inseminated New Zealand white (NZW) rabbits wereadministered ethylene glycol (EG) by gavage on Gestational Days(GD) 6 through 19 at doses of 0, 100, 500, 1000, or 2000 mg/kg/day,with 23–24 inseminated animals per group. Clinical signswere recorded and water consumption was measured daily; doeswere weighed on GD 0, 6–19, 25, and 30. At necropsy (GD30), maternal liver, kidney, and gravid uterine weights wererecorded. Histopathologic examination was performed on kidneysfrom 10 does/dose and for all unscheduled deaths. Ovarian corporalutea were counted and uterine implantation sites (total sites,resorptions, dead and live fetuses) were recorded. All livefetuses were weighed, sexed, and examined for external, visceral,and skeletal malformations and variations. EG resulted in profoundmaternal toxicity at 2000 mg/kg/day (42% mortality; three earlydeliveries and one spontaneous abortion) associated with renalpathology and unaccompanied by any other indicators of maternaltoxicity. Renal lesions at 2000 mg/kg/day involved the corticalrenal tubules and included intraluminal oxalate crystals, epithelialnecrosis, and tubular dilatation and degeneration. No dose-relatedmaternal toxicity occurred at 100–1000 mg/kg/day. Therewas no indication of developmental toxicity at any dose tested,including no effects on pre- or postimplantation loss, numberof fetuses, fetal body weight, or sex ratio (% male fetuses)per litter, and no evidence of teratogenicity. The "no observableadverse effect level" (NOAEL) for maternal toxicity was therefore1000 mg/kg/day and the NOAEL for developmental toxicity wasat least 2000 mg/kg/day in this study. The sensitivity of NZWrabbits relative to that of Sprague—Dawley rats and Swissmice for maternal and developmental toxicity from gavage administrationof EG during organogenesis can be determined for maternal toxicity:rabbits>mice>rats, and for developmental toxicity, mice>>rats >> rabbits.     

Assessment of the Developmental Toxicity of Ethylene Glycol Applied Cutaneously to CD-1 Mice

Ethylene glycol (EG; CAS No. 107-21-1) is teratogenic to miceby whole-body exposure to an aerosol at high concentrations,but results were confounded by possible exposure from ingestionafter grooming and/or from percutaneous absorption. Therefore,CD-1 mice were exposed to EG on Gestational Days (GD) 6 through15, 6 hr/day by occluded cutaneous application at 0, 12.5, 50,or 100% (undiluted) EG (0.1 ml/animal, equivalent to {smalltilde}0, 404,1677, or 3549 mg/kg/day, respectively) or by gavageon GD 6 through 15 at 3000 mg/kg/day [10 ml/kg, positive controlgavage group (PCGG)], 30 females/group. Dams were weighed andevaluated daily (including application site) for clinical signsand water consumption throughout gestation. On GD 18, maternaluterus, liver, and paired kidneys were weighed; kidneys of 0and 100% and the PCGG were examined microscopically. Corporalutea and implantation sites were recorded. Live fetuses wereweighed, sexed, and examined for structural alterations. Forcutaneously exposed dams, there was no treatment-related maternaltoxicity, no differences in pre- or postimplantation loss orin fetal body weights/ litter, and no increased incidences ofany fetal malformations. Two skeletal variations, increasedat 100%, may represent effects of restraint stress and/or findingsdue to chance. In the PCGG, 8 females (26.7%) died, water consumptionwas increased, fetal body weights/litter were reduced, and fetalmalformations and variations were increased. PCGG kidneys exhibitedtubular nephrosis and tubular cell degeneration, with no oxalatecrystals, documenting renal toxicity at this oral dose in mice.Minimal-grade renal tubular lesions observed in 3 mice (of 30)at 100% EG may represent treatment-related or incidental findings.Therefore, exposure of pregnant CD-1 mice to 0, 12.5, 50, or100% EG during organo-genesis by occluded cutaneous applicationresulted in minimal or no observable maternal or developmentaltoxicity at 100% ({small tilde}3549 mg/kg/day), the NOEL.     

Evaluation of the Developmental Toxicity of Ethylene Glycol Aerosol in CD-1 Mice by Nose-Only Exposure

Ethylene glycol (EG; CAS No. 107-21-1) is teratogenic to miceby whole-body (WB) exposure to aerosol (1000–2500 mg/m³The WB results were confounded by possible exposure from ingestionafter grooming andior from percutaneous absorption. Therefore,CD-1 mice were exposed to EG aerosol (MIMAD 2.6 ± 1.7µm) on Gestational Days (GD) 6 through 15, 6 hr/day, bynose-only (NO) (0, 500, 1000, or 2500 mg/rn or WB exposures(0 or 2100 mg/m³ as positive control), 30/group. Five additional"satellite" females each at 2500 mg/m³ NO and 2100mg/m³ WB wereexposed on GD 6 for measurement of EG on fur. Control environmentswere water aerosol (4200 mg/rn for NO; 2700 mg/rn for WB). Femaleswere weighed and evaluated for clinical signs and water consumptionthroughout gestation. On GD 18, maternal uterus, liver, andkidneys (2) were weighed, with kidneys examined microscopically.Corpora lutea and implantation sites were recorded. Live fetuseswere weighed, sexed, and examined for structural alterations.For NO dams, kidney weights were increased at 1000 and 2500mg/m³ no renal lesions and no other treatment-related maternaltoxicity were observed. There were no effects on pre- or postimplantationloss; fetal body weights/litter were reduced at 2500 mg/m³ At2500 mg/m³ incidences of fused ribs and skeletal variationswere increased. The 2500 mg/rn NO satellite animals had {smalltilde}330 mg/kg extractable EG. The WB group exhibited maternaland developmental toxicity including increased fetal skeletalmalformations and variations, confirming previous results, with1390 mg/kg extractable EG on fur. Therefore, exposure of CD-1mice to a respirable EG aerosol during organogenesis by NO inhalationresulted in minimal maternal toxicity at 1000 and 2500 mg/m³and developmental toxicity at 2500 mg/m³ The NOAEL was 500 mg/m³NO for maternal and 1000 mg/m³ NO for develop mental toxicity.This study supports the interpretation of the initial EG WBresults as due to systemic exposure from noninhala tion routessince limiting noninhalation routes prevented almost all ofthe effects (including teratogenicity) observed in mice afterWB exposure.     

Non‐stationary regression with logistic transition

Summary This paper studies the non‐stationary regression model with logistic transition in level or in slope. In the model, the level or slope is specified as a functional coefficient specified parametrically as the logistic function of an integrated state variable driven by a general linear process. For such a model, we derive the limit distributions of the non‐linear least squares (NLS) estimators and their t ‐statistics. As for many other types of non‐stationary non‐linear regressions, the NLS estimators and the usual t ‐tests are generally inefficient and invalid in our model. We propose a new procedure, which yields efficient estimators and valid tests. Our simulation shows that they perform noticeably better than the standard NLS estimators and tests. Finally, our model and methodology are used to investigate the long‐run relationship between per capita real income and consumption using US data.     

Non‐phenolic radical‐trapping antioxidants

Objectives The aim of this review article is to introduce the reader to the mechanisms, rates and thermodynamic aspects of the processes involving the most biologically relevant non‐phenolic radical‐trapping antioxidants. Key findings Antioxidant defences in living organisms rely on a complex interplay between small molecules and enzymes, which cooperate in regulating the concentrations of potentially harmful oxidizing species within physiological limits. The noxious effects of an uncontrolled production of oxygen‐ and nitrogen‐centered radicals are amplified by chain reactions (autoxidations), sustained mainly by peroxyl radicals (ROO^?), that oxidize and alter essential biomolecules such as lipids, lipoproteins, proteins and nucleic acids. Summary Non‐phenolic antioxidants represent an important and abundant class of radical scavengers in living organisms. These compounds react with peroxyl radicals through various mechanisms: (i) formal H‐atom donation from weak X‐H bonds (X = O, N, S), as in the case of ascorbic acid (vitamin C), uric acid, bilirubin and thiols; (ii) addition reactions to polyunsaturated systems with formation of C‐radicals poorly reactive towards O₂, for example β‐carotene and all carotenoids in general; (iii) co‐oxidation processes characterized by fast cross‐termination reactions, for example γ‐terpinene; and (iv) catalytic quenching of superoxide (O₂^??) with a superoxide dismutase‐like mechanism, for example di‐alkyl nitroxides and FeCl₃. Kinetic data necessary to evaluate and rationalize the effects of these processes are reported. The mechanisms underlying the pro‐oxidant effects of ascorbate and other reducing agents are also discussed.     

Non‐stationary non‐parametric volatility model

Summary We investigate a new non‐stationary non‐parametric volatility model, in which the conditional variance of time series is modelled as a non‐parametric function of an integrated or near‐integrated covariate. Importantly, the model can generate the long memory property in volatility and allow the unconditional variance of time series to be time‐varying. These properties cannot be derived from most existing non‐parametric or semi‐parametric volatility models. We show that the kernel estimate of the model is consistent and its asymptotic distribution is mixed normal. For an empirical application of the model, we study the daily S&P 500 index return volatility using the VIX index as the covariate. It is shown that our model performs reasonably well both in within‐sample and out‐of‐sample forecasts.     

新生儿窒息后肾损害的阴离子间隙分析

目的分析窒息后肾功能损害新生儿的阴离子间隙(AG)变化及其与肾损害的关系。方法首先测定151例窒息新生儿的血尿素氮(BUN)、肌酐(Cr)、电解质、动脉血气分析;然后,从中选取肾损害新生儿60例,并同时测定30例正常足月儿的上述指标,计算AG值并分析。结果窒息后肾损害的60例新生儿,代谢性酸中毒发生率为76.7%,且以高AG代酸为主,随窒息程度的加重,BUN、Cr无明显变化。结论窒息后肾功能损害新生儿血AG值可明显异常,需及时处理,BUN、Cr不能早期反映新生儿肾损害。     

Non‐parametric regression with a latent time series

Summary In this paper we investigate a class of semi‐parametric models for panel data sets where the cross‐section and time dimensions are large. Our model contains a latent time series that is to be estimated and perhaps forecasted along with a non‐parametric covariate effect. Our model is motivated by the need to be flexible with regard to the functional form of covariate effects but also the need to be practical with regard to forecasting of time series effects. We propose estimation procedures based on local linear kernel smoothing; our estimators are all explicitly given. We establish the pointwise consistency and asymptotic normality of our estimators. We also show that the effects of estimating the latent time series can be ignored in certain cases.     

Evaluation of the Developmental Toxicity of Ethylene Glycol Aerosol in the CD Rat and CD-1 Mouse by Whole-Body Exposure

Ethylene glycol (EG) is a major industrial chemical, shown tobe teratogenic at high doses by gavage in rodents. Since oneroute of industrial exposure is to the aerosol at high concentrations,timed-pregnant CD rats and CD-1 mice were exposed, whole-body,to a respirable aerosol of EG (mass median aerodynamic diameter,2.3 µm) on Gestational Days (GD) 6 through 15 for 6 hrper day at target exposure concentrations of 0, 150, 1000, or2500 mg/m³ (analytical concentrations of 0, 119 ± 13,888 ± 149, and 2090 ± 244 mg/m³, respectively),with 25 plug-positive animals per species per group. Clinicalobservations and maternal body weights were documented throughoutgestation for both species. Maternal food and water consumptionwas measured in rats only throughout gestation. At schedulednecropsy (GD 21 for rats, GD 18 for mice), maternal animalswere evaluated for body weight, liver weight, kidney weight,gravid uterine weight, number of ovarian corpora lutea, andstatus of implantation sites, i.e., resorptions, dead fetuses,live fetuses. Fetuses were dissected from the uterus, counted,weighed, sexed, and examined for external, visceral, and skeletalmalformations and variations. All rat dams survived to scheduledtermination. Minimal maternal toxicity was indicated by a significantincrease in absolute and relative liver weight at 2500 mg/m³.Food and water consumption, maternal body weights and weightgain, and maternal organ weights (other than liver) were unaffectedby exposure. Gestational parameters were unaffected by exposure,including pre- and post-implantation loss, live fetuses/litter,sex ratio, and fetal body weight/litter. There was no treatment-relatedincrease in the incidence of any individual malformation, inthe incidence of pooled external, visceral, or skeletal malformations,or in the incidence of total malformations by fetus or by litter.There were no increases in the incidence of external or visceralvariations. Evidence of fetotoxicity, expressed as reduced ossificationin the humerus, the zygomatic arch, and the metatarsals andproximal phalanges of the hind-limb, was observed at 1000 and2500 mg/m³. All mouse dams survived to scheduled termination.One dam at 2500 mg/m³ was carrying a totally resorbed litterat termination. Maternal toxicity was observed at 1000 and 2500mg/m³, expressed as reduced body weight and weight gain duringand after the exposure period, and reduced gravid uterine weight.(Maternal effects may have been due, in part or in whole, toeffects on the conceptuses; see below.) Embryo/fetal toxicitywas also observed at 1000 and 2500 mg/m³, expressed as an increasein nonviable implantations/litter, a reduction in viable implantations/litter,and reduced fetal body weights (male, female, and total)/litter.The incidences of individual and pooled external, visceral,and skeletal malformations were increased at 1000 and 2500 mg/m³,as was the incidence of total malformations. Malformations werefound in the head (exencephaly), face (cleft palate, foreshortenedand abnormal face, and abnormal facial bones), and skeleton(vertebral fusions, and fused, forked, and missing ribs). Theincidences of many fetal variations were also increased at 1000and 2500 mg/m³ (and only a few at 150 mg/m³). The no observableadverse effect level (NOAEL) for maternal toxicity in rats was1000 mg/m³ (analytical concentration 888 mg/m³) and in micewas 150 mg/m³ (analytical concentration 119 mg/m³). The NOAELfor development toxicity in rats was 150 mg/m³ and in mice wasat or below 150 mg/m³, under the conditions of this study. Analysisof EG on the fur of rats and mice during and after the exposureperiod at 2500 mg/m³ indicated that much of the EG "dose" (65–95%)was potentially derived from ingestion after grooming and/orpercutaneous absorption. This contribution of the ingested and/orabsorbed chemical could have been sufficient, per se, to producethe teratogenic effects observed in mice. The definitive evaluationof the possible role of inhaled EG aerosol alone in teratogenesisrequires an exposure regimen which limits or precludes exposureby any other route.     

Assessment of Ethylene Glycol Monobutyl and Monophenyl Ether Reproductive Toxicity Using a Continuous Breeding Protocol in Swiss CD-1 Mice

Assessment of Ethylene Glycol Monobutyl and Monophenyl EtherReproductive Toxicity Using a Continuous Breeding Protocol inSwiss CD-1 Mice. HEINDEL, J. J., GULATI, D. K., RUSSELL, V.S., REEL, J. R., LAWTON, A. D., AND LAMB, J. C., IV. (1990).Fundam. Appl Toxicol. 15,683–696. A continuous breedingreproduction study design was utilized to examine the reproductivetoxicity of ethylene glycol monobutyl ether (EGBE) and ethyleneglycol monophenyl ether (EGPE). Swiss CD-1 mice were administeredEGBE in drinking water (0, 0.5, 1.0, and 2.0%, i.e., 0.7, 1.3,and 2.1 g/kg body wt/day) and EGPE was administered via thefeed (0, 0.25, 1.25, and 2.5%, i.e., 0,0.4,2.0, and 4 g/kg bodywt/day). Both male and female mice were dosed for 7 days priorto and during a 98-day cohabitation period. EGBE was toxic atthe high (2%) and mid dose (1%) to adult F₀ female mice: 13out of 22 females at the high dose and 6 out of 20 at the middose died during the cohabitation period. Both the high- andmid-dose animals produced fewer litters/pair, fewer pups/litter,with decreased pup weight. These effects occurred in the presenceof decreased body weight, decreased water consumption, and increasedkidney weight. A crossover mating trial indicated that the reproductiveeffects could be attributed primarily to an effect on the female.This was substantiated at necropsy where testes and epididymisweights were normal as were sperm number and motility. Fertilityof the offspring of the 0.5% group was normal in the presenceof increased liver weights. With respect to EGPE, there wasno change in the ability to produce five litters during thecontinuous breeding period. There was, however, a significantbut small (10–15%) decrease in the number of pups/litterand in pup weight in the high-dose group. A crossover matingtrial suggested a female component of the reproductive toxicityof EGPE. While fertility was only minimally compromised, severeneonatal toxicity was observed. By Day 21 there were only 8out of 40 litters in the mid- and high-dose groups which hadat least one male and female/litter. Second generation reproductiveperformance of the mid-dose group (1.25%) was unaffected exceptfor a small decrease in live pup weight. In summary the reproductivetoxicity of EGBE and EGPE was only evident in the female andoccurred at doses which elicited general toxicity. EGBE wasparticularly toxic to adult female mice while EGPE was particularlytoxic to immature mice of both sexes.     

Evaluation of the Developmental Toxicity of Ethylene Glycol Monohexyl Ether Vapor in Fischer 344 Rats and New Zealand White Rabbits

Evaluation of the Developmental Toxicity of Ethylene GlycolMonohexyl Ethyl Vapor in Fischer 344 Rats and New Zealand WhiteRabbits. TYL, R. W., BALLANTYNE, B., FRANCE, K. A., FISHER,L. C., KLONNE, D. R., AND PRITTS, I. M. (1989). Fundam Appl.Toxicol. 12, 269-280. Timed pregnant Fischer 344 rats and NewZealand White rabbits were exposed to vapor from ethylene glycolmonohexyl ether (EGHE, CAS No. 112-25-4) for 6 hr/day on gestationaldays (gd) 6 through gd 15 (rats) or gd 6 through gd 18 (rabbits)at analytically measured concentrations (as means ± SD)of 20.8 ± 0.90,41.1 ± 1.77, or 79.2 ± 10.8ppm; control animals were exposed to air alone. Monitors formaternal toxicity were body weight, food and water consumption,clinical signs, and hematology. At sacrifice (gd 2 1 rats, gd29 rabbits) maternal weight, liver weight, and gravid uterineweight were measured. Gestational parameters monitored werenumbers of corpora lutea, preimplantation losses, viable implants,early and late resorptions, and dead fetuses. Live fetuses weresexed, weighed, and examined for external, visceral, and skeletalmalformations and variations. Rabbit maternal toxicity occurredat 79.2 ppm as transient weight gain reduction during the exposureperiod. For maternal rats at 79.2 ppm, there were transientdecrease in body weight and body weight gain during exposure,reduced food consumption, increased water consumption, and excesslacrimation. At 41.1 ppm, maternal body weight gain was reducedduring the exposure period only. There were no treatment- relatedeffects with respect to hematology, necropsy, or gestationalparameters and no significant change in the incidence of malformationsor variations (expressed as total, individual. external, visceral.or skeletal). Thus, exposure of rats and rabbits to EGHE vaporduring the period of organogenesis produced maternal toxicityat near-saturation vapor concentrations (79.2 ppm), but no evidencefor developmental toxicity or teratogenicity. The no-effectvapor concentrations for maternal toxicity were 41.1 ppm forrabbits and 20.8 ppm for rats.