Cytotoxicity,Acute Oral Toxicity,and Skin Irritation of 2-ethylhexyl-2,4,5-trimethoxycinnamate and di(2-ethylhexyl)-2,4,5-trimethoxybenzalmalonate

Safety of two new ultraviolet (UV) filters, 2-ethylhexyl-2,4,5-trimethoxycinnamate (E8) and 2-ethylhexyl-2,4,5-trimethoxybenzalmalonate (B8), has been evaluated through the human melanoma cytotoxicity test and seven-day acute oral toxicity studies in rats. At 2.5 mg/mL, both compounds gave similar cell viability to the control. LD₅₀ values for E8 and B8 are more than 5000 and 1000 mg/kg body weight, respectively. No significant difference in body weight and hematological parameters among the 0, 5, 50, 500, and 5000 mg/Kg E8-treated animals could be detected. Pathological examination of rat tissues collected at the end of the study period revealed no significant difference between the control and all E8-administered rats. There was no significant difference in all clinical blood chemistry parameters (aspartate aminotransferase, creatinine, blood urea nitrogen, and cholesterol), except alanine aminotransferase (ALT), between the control and the E8-treated animals. All ALT values were, however, in the normal range of SD rats. E8 showed negative results for the skin irritation study on human volunteers, using patch and photopatch tests. Excitation of respiratory signs of dypsnea in 10, 100, and 1000 mg/Kg B8-treated rats could be observed during 1–24 h. All groups were, however, normal during the second to the seventh day. Hematological parameters of the 0, 10, 100, and 1000 mg/Kg B8-treated animals showed no significant difference. Pathological examination revealed no significant difference between the control and all B8-administered rats. However, significant differences in some clinical blood chemistry parameters and body weights between the control and some B8-treated animals could be detected. All values, however, were in the normal ranges of the SD rats.     

2-Ethylhexyl-2,4,5-trimethoxycinnamate and di-(2-ethylhexyl)-2,4,5-trimethoxybenzalmalonate as novel UVA filters

A series of 2-ethylhexylmethoxy substituted cinnamates and benzalmalonates have been synthesized and characterized. 2-Ethylhexyl-2,4,5-trimethoxycinnamate (E8) and di-(2-ethylhexyl)-2,4,5trimethoxybenzalmalonate (B8) show UVA absorption with high molar absorption coefficients (12000-14 000 cm(-1) M(-1) at 350 nm). E8 undergoes trans to cis photoisomerization under UVA exposure causing the decrease in UV absorption efficiency. E8 is more photostable than butyl methoxy-dibenzoylmethane (BMDBM). For example, 41.64 J cm(-2) UVA irradiation produces 20+/-2% and 25+/-2% loss in UV absorption for E8 and BMDBM, respectively. Similar irradiation produces no change in the UV absorption of B8. Both the oily liquid E8 and the yellow solid B8 can be dissolved in various organic solvents, ranging from methanol to hexane, various silicone fluids and 2-ethyl-hexyl-4-trimethoxycinnamate (EHMC, a widely used UVB filter). A liquid broadband filter comprising B8 and EHMC shows excellent photostability in both UVB and UVA regions.     

Acute and subchronic (28-day) oral toxicity study in rats fed with novel surfactants

The toxicity of 2 new synthetic lipids, 1,2-dioleoyl-rac-glycerol-3-dodecaethylene glycol, GDO-12 (lipid 1) and 1,2-distearoyl-rac-glycerol-3-dodecaethylene glycol, GDS-12 (lipid 2) has been evaluated in acute and subchronic toxicity studies. Acute oral toxicity studies in male and female rats documented no deaths or treatment-related signs at high doses. The lipids were individually administered (by gavage) to male and female Sprague-Dawley rats at concentrations of 250, 500, and 1000 mg/Kg bodyweight for 28 days. All animals survived the duration of the study, with no significant changes in clinical signs, hematological parameters, organ weights, ophthalmology evaluations, or histopathological findings. These studies establish that both GDO-12 (lipid 1) and GDS-12 (lipid 2) are nontoxic in rats following oral administration. The no-observed-adverse-effect level ranged between 250 mg/Kg and 1000 mg/Kg following oral administration.     

Acute and 90-day subchronic toxicity studies of Silk peptide E5K6, in Sprague-Dawley rats

Acute and 90-day subchronic oral toxicity studies of Silk peptide E5K6 were performed in Sprague-Dawley rats. In the acute toxicity study, Silk peptide E5K6 was administered orally to male and female rats at a single dose of 2000 and 5000 mg/kg. Mortality, clinical signs and body weight changes were monitored for 14 days. There were no treatment-related changes in these parameters. Therefore, the Approximate Lethal Dose (ALD) of Silk peptide E5K6 in male and female rats is higher than 5000 mg/kg. In the subchronic toxicity study, Silk peptide E5K6 was administered orally to male and female rats for 90 days at a single dose of 500, 1000, and 2000 mg/kg. There were no toxicologically significant changes in clinical signs, body weight, food and water consumptions, ophthalmoscopic examination, urinalysis, hematological and serum biochemical examinations, necropsy findings, organ weights and histopathological examination of all of the animals treated with Silk peptide E5K6. These results suggest that the oral No Observed Adverse-Effect Level (NOAEL) of Silk peptide E5K6 is greater than 2000 mg/kg/day in both sexes and the target organs were not established.     

The fate of 2,4,5-trichlorophenoxyacetic acid (2,4,5-T) following oral administration to rats and dogs

Clearance of ¹⁴C activity from the plasma and its elimination from the body of rats and dogs were determined after single oral doses of [carboxy-¹⁴C]2,4,5-T. The half-life values for the clearance of ¹⁴C activity from the plasma of rats given doses of 5, 50, 100 or 200 mg/kg were 4.7, 4.2, 19.4 and 25.2 hr, respectively; half-lives for elimination from the body were 13.6, 13.1, 19.3 and 28.9 hr, respectively. The apparent volume of distribution also increased with dose. Urinary excretion of unchanged 2,4,5-T accounted for most of the ¹⁴C activity eliminated from the body of rats. A small amount of unidentified metabolite was detected in the urine when rats were given 100 or 200 mg/kg but not 5 or 50 mg/kg. These results show that the distribution, metabolism and excretion of 2,4,5-T are markedly altered when large doses are administered.In dogs given 5 mg/kg, the half-life values for clearance from plasma and elimination from the body were 77.0 and 86.6 hr, respectively, offering a plausible explanation of why 2,4,5-T is more toxic in dogs than in rats. Appreciable excretion in the feces was noted and three unidentified metabolites were detected in urine of dogs, indicating a considerable difference in metabolism of 2,4,5-T by dogs and rats given the same dose.     

2,4,5-Trichlorophenoxyacetic Acid Influence on 2,6-Dinitrotoluene-Induced Urine Genotoxicity in Fischer 344 Rats: Effect on Gastrointestinal Microflora and Enzyme Activity

2,4,5-Trichlorophenoxyacetic acid (2,4,5-T) and 2,6-dinitrotoluene(2,6-DNT) are hazardous chemicals that have potential harmfuleffects. 2,6-DNT is recognized as a hepatotoxicant while 2,4,5-T,a component of Agent Orange, is also suspect. 2,6-DNT requiresboth oxidative and reductive metabolism to elicit genotoxiceffects. To determine what effect 2,4,5-T had on 2,6-DNT metabolism,intestinal enzymes, microbial populations, and urine mutagenicitywere examined during 2,4,5-T treatment. Weanling Fischer 344male rats were treated daily with 54.4 mg/kg 2,4,5-T by gavagefor 4 weeks. One, two, and four weeks after the initial 2,4,5-Tdose, rats were administered (po) 2,6-DNT (75 mg/kg) and urinewas collected for 24 hr in metabolism cages. Azo reductase,nitroreductase, ß-glucuronidase, dechlorinase, anddehydrochlorinase activities were examined concurrently. Treatmentof rats for 1 week reduced the transformation of 2,6-DNT tomutagenic urinary metabolites. This was accompanied by a decreasein the fecal anaerobic microorganisms. The elimination ofLactobacillusfermentum from the small intestine and cecum of treated animalsaccompanied a significant increase in oxygen-tolerant lactobacilliand other unidentified aerobic microorganisms. However, therewere no significant alterations in the intestinal enzyme activitiesexamined. By 2 weeks of 2,4,5-T treatment, microbiota and urinegenotoxicity returned to the levels observed in control animals.This trend continued for the duration of the experiment After2 weeks, while cecal nitroreductase and azo reductase activitiesincreased, small intestinal ß-glucuronidase activitydecreased. By 4 weeks, treated and untreated animal intestinalenzyme activities were indistinguishable. The transient increasein azo reductase and nitroreductase after treatment with 2,4,5-Tfor 2 weeks may have been counteracted by the reduced ß-glucuronidaseactivity, thus resulting in no change in 2,6-DNT-derived urinemutagenicity. However, other environmental chemicals, unaffectedby ß-glucuronidase, potentially could be activatedby 2,4,5-T exposure.     

莲子心总生物碱的毒性试验研究

摘要 目的： 探讨莲子心总生物碱的毒副作用,以对莲子心总生物碱作出安全性评价。方法 ：小鼠急性毒性试验中一次性给予最大灌胃量5000mg/kg莲子心总生物碱,观察小鼠中毒症状。长期口服毒性实验,Sprague-Dawley(SD)大鼠随机分为四组,分别按照400mg/kg?d、200 mg/kg?d、100 mg/kg?d的剂量给予SD大鼠灌胃实验室自制莲子心总生物碱,对照组给予等量体积0.3%羧甲基纤维素钠,连续服用30天。结果 ：在急性毒性试验中给予5000mg/kg莲子心总生物碱对小鼠不产生毒性作用。在长期毒性试验中,除不同剂量给药组SD大鼠血清尿素氮与对照组具有显著性差异(P<0.05),高、中剂量组SD大鼠血糖含量与对照组有明显差异(P<0.05)外余下指标与对照组相比均无明显差异。高、中、低剂量组大鼠肝组织病理切片与对照组相比均明显异常,表现为肝小叶结构正常。结论 ： 莲子心总生物碱对小鼠最大耐受剂量为5000mg/kg,同时灌胃给药400mg/kg/天莲子心总生物碱对大鼠无毒副作用。     

Sequential histopathologic, hematologic, and blood chemistry changes induced in mice by a technical and a purified preparation of 2,4,5-trichlorophenoxyacetic acid.

Maternal mice were given 2,4,5-trichlorophenoxyacetic acid (2,4,5-T) on days 6 through 14 of pregnancy in a tetratologic study at the National Center for Toxicological Research. Sick or moribund mice sacrificed after 4-8 doses of 120 mg/kg 2,4,5-T often showed severe myocardial lesions, hypocellularity of the bone marrow, and depletion of lymphocytes in the thymus, spleen, or lymph nodes. Healthy mice sacrificed on day 17, 11 days after treatment began, showed few or no severe lesions. To determine if lesions earlier in gestation contributed significantly to an increase in fetal abnormalities in the healthy 17-day survivors, dihybrid croos F2 pregnant and nonpregnant mice received by gavage 0, 60, or 120 mg/kg 2,4,5-T on days 6 through 14 of pregnancy. One group received a technical preparation containing 97.9 +/- 0.4% 2,4,5-T; another received a purified preparation containing 99 +/- 0.3% 2,4,5-T. Mice were sacrificed when they became moribund and at 6, 24, and 30 hr, as well as at 4, 6, 8, and 11 days after beginning treatment. Almost all mice given 60 mg/kg and many given 120 mg/kg 2,4,5-T appeared normal at sacrifice either early or late in pregnancy and showed little or no pathologic changes. Mice that became ill or moribund often showed severe lesions; few survived 11 days. Severe myocardial lesions were seen in 26 of 70 moribund mice fiven the technical 2,4,5-T and 24 of 33 given the purified preparation of 2,4,5-T. The moribund mice, particularly those given the purified compound, also showed a high incidence of lesions in other organs and marked hematological and blood chemistry changes. These findings indicate that the lesions are primarily due to 2,4,5-T rather than to impurities in the technical preparation; also impaired maternal health is not the primary cause of the increase in fetal abnormalities.     

Altered ontogeny of glutathione S-transferases by 2,4,5-2',4',5'-hexachlorobiphenyl.

Date-bred rats were treated orally from the 8th through the 18th day of gestation with pure congeners of polychlorinated biphenyls (PCBs). At designated stages of postnatal development offspring of treated dams were sacrificed and glutathione S-transferase (G S-t) activity levels were determined using the substrates 1-chloro-2, 4-dinitrobenzene (CDNB) and 1,2-dichloro-4-nitrobenzene (DCNB). Male and female rats exposed perinatally to 2,4,5-2′,4′,5′-hexachlorobiphenyl (6-CB) had higher levels of G S-t than the controls at all ages examined (Days 6, 21, 55 postpartum). Treatment of adult male rats with increasing doses of 6-CB revealed that glutathione conjugation toward CDNB could be more easily enhanced than toward DCNB. Pure 6-CB added to control cytosol did not change G S-t activities. Mixtures of cytosol from 21-day-old control and 6-CB animals had activities similar to the calculated mean average of the two.     

Induction of Leydig cell adenomas by ammonium perfluorooctanoate: a possible endocrine-related mechanism.

Ammonium perfluorooctanoate (C8) produced an increased incidence of Leydig cell adenomas in Crl:CD BR (CD) rats fed 300 ppm for 2 years. A hormonal (nongenotoxic) mechanism was examined since C8 was negative in short-term tests for genotoxicity. Adult male CD rats were gavaged with either 0, 1, 10, 25, or 50 mg/kg C8 for 14 days. In addition, a control group was pair-fed to the 50 mg/kg C8 group. A dose-dependent decrease in body and relative accessory sex organ (ASO) weights was seen, with the relative ASO weights of the 50 mg/kg group significantly less than those of the pair-fed control. Serum estradiol levels were elevated in the 10, 25, and 50 mg/kg C8-treated animals. Estradiol levels in the 50 mg/kg C8 group were 2.7-fold greater than those in the pair-fed control. The increase in serum estradiol levels occurred at the same dose levels as the increase in hepatic beta-oxidation activity. A statistically significant downward trend with dose was seen in serum testosterone levels when compared with the ad libitum control. However, when the 50 mg/kg C8-treated rats were compared with their pair-fed control, no significant differences were seen. Challenge experiments, which can identify the presence and location of a lesion in an endocrine axis, were undertaken to clarify the significance of this downward trend in serum testosterone following C8 exposure. In the challenge experiments, adult CD rats were gavaged with either 0 or 50 mg/kg C8 for 14 days. One hour before termination, rats received either a human chorionic gonadotropin (hCG), gonadotropin-releasing hormone (GnRH), or naloxone challenge. Following hCG challenge, serum testosterone levels in the 50 mg/kg C8 were significantly decreased (50%) from those in the ad libitum controls. Similar decreases, although not significant, were seen in serum testosterone following GnRH and naloxone challenge. The challenge experiments suggest that the decrease in serum testosterone following C8 exposure is due to a lesion at the level of the testis. In addition, progesterone, 17 alpha-hydroxyprogesterone, and androstenedione were examined in the 50 mg/kg C8-treated males following hCG challenge. A 60% decrease was observed in androstenedione levels in the C8-treated animals from those in the ad libitum controls; no other differences were seen. These data suggest that the decrease in serum testosterone following hCG challenge may be due to a decrease in the conversion of 17 alpha-hydroxyprogesterone to androstenedione. The observed effects described above can be attributed to the elevated serum estradiol levels.(ABSTRACT TRUNCATED AT 400 WORDS)     

Diazinon-induced hepatotoxicity and protective effect of vitamin E on some biochemical indices and ultrastructural changes

Diazinon, an organophosphate insecticide has been used in agriculture and domestic for several years. The aim of present study was to analyze the hepatotoxic effect of diazinon which caused biochemical and ultrastructural changes in adult male Wistar rats and to evaluate the possible protective effect of vitamin E. Vitamin E (200 mg/kg, twice a week), diazinon (10 mg/kg per day, once a day in corn oil) and vitamin E (200 mg/kg, twice a week)+diazinon (10 mg/kg per day, once a day in corn oil) combination were given to rats (n=8) orally via gavage for 7 weeks. Biochemical indices in serum [total protein, albumin, alkaline phosphatase (ALP), alanine aminotransferase (ALT), aspartate aminotransferase (AST), total cholesterol, triglyceride and low density lipoprotein cholesterol (VLDL-cholesterol)] and ultrastructural changes were investigated at the end of the 1st, 4th and 7th weeks comparatively with control group (n=8). It was observed that; at the end of 1st week, there was a statistically significance in all parameters except total protein and albumin, and at the end of 4th and 7th weeks, there was a statistically significance in all parameters when diazinon-treated group compared to control group (P<0.01). At the end of 1st week, ALP, ALT, total cholesterol and triglyceride, at the end of 4th week, all parameters except VLDL-cholesterol, at the end of 7th week, all parameters were statistically significant when vitamin E+diazinon-treated group compared with diazinon-treated group (P<0.01). In our electron microscopic investigations, while swelling of mitochondria and breaking up of the mitochondrial cristae of hepatocytes in diazinon-treated groups were observing, no pathological findings were observed in vitamin E+diazinon-treated groups. We conclude that vitamin E decreases diazinon hepatotoxicity, but vitamin E does not protect completely.     

Evaluation of Subchronic (13 Week), Reproductive, and in Vitro Genetic Toxicity Potential of 2-Ethylhexyl-2-cyano-3,3-diphenyl Acrylate (Octocrylene)

Use of 2-ethylhexyl-2-cyano-3,3-diphenyl acrylate (Octocrylene)in commercial sunscreen products has increased considerablyin recent years. To support larger scale human exposure to thiscompound, additional toxicological information was needed inseveral key areas. The present studies evaluated subchronictoxicity, developmental toxicity, and in vitro genotoxic potentialof Octocrylene. In the subchronic study, male and female NewZealand white (NZW) rabbits treated topically with concentrationsof octocrylene up to 534 mg/kg/day for 13 weeks showed slightto moderate dose-dependent skin irritation that correlated positivelywith a mild depression in body weight gain. Lack of associatedhistopathologic or clinical hematology abnormalities suggestedthat the body weight effect probably reflected a nonspecificresponse to topical irritation. In percutaneous developmentaltoxicity studies, NZW does were treated topically with Octocryleneat levels up to 267 mg/kg/day on Days 6 through 18 of gestation.Body weight gain, food consumption, and all maternal, reproductive,and offspring parameters evaluated were comparable between Octocrylene-treatedand control animals. In the oral developmental toxicity assay,female CD-1 mice received oral doses of Octocrylene up to 1000mg/kg/day on Days 8–12 of gestation. No evidence of maternalor developmental toxicity was seen at any dose tested. Genotoxicitywas evaluated in vitro using the Chinese hamster ovary cellassay to assess clastogenicity and the mouse lymphoma cell assayto assess forward gene mutations. Octocrylene did not induceany significant increase in genotoxicity. This evaluation oftoxicological potential supports the use of Octocrylene as ahuman photoprotectant.     

The metabolism and distribution of 2,4,5-trichlorophenoxyacetic acid in female rats

[1-¹⁴C]-2,4,5-Trichlorophenoxyacetic acid (2,4,5-T) was fed to pregnant and non-pregnant female rats at various dosages, and expired air, urine, feces, internal organs and tissues were analyzed for radioactivity. During the first 24 hr, 75 ± 7% of the radioactivity was excreted in the urine and 8.2 ± 4.6% in the feces. No ¹⁴C was found in the expired air. There was no significant difference in the rate of elimination between the pregnant and nonpregnant rats, or among the dosages used. Radioactivity was detected in all tissues, with the highest concentration being found in the kidney. The maximum concentration of radioactivity in all tissues was generally reached between 6 to 12 hr after po dosing and then started to decline rapidly. Radioactivity was also detected in the fetuses and in the milk. The average biological half-life of 2,4,5-T in the organs was 3.4 hr for the adult rats and 97 hr for the newborn.     

注射用丹参多酚酸盐延缓衰老作用的实验研究

目的 观察丹参多酚酸盐延缓大鼠衰老的作用.方法 取健康6个月龄雄性Wistar大鼠100只,完全随机分为空白对照组、衰老模型组、阳性对照药（维生素E 200 mg/kg）组、丹参多酚酸盐30.0 mg/kg和15.0 mg/kg两个剂量组,每组20只.采用皮下注射5.0%D-半乳糖的方法制作大鼠衰老模型,观察给药后大鼠大脑组织中的超氧化物歧化酶（SOD）活性及丙二醛含量以及大脑蒲肯野细胞的凋亡指数.结果 与空白对照组比较,衰老模型组大鼠大脑组织SOD活性降低、丙二醛含量增加、蒲肯野细胞的凋亡指数增加[SOD：（140.60±2.67）U/mgprot比（189.00±3.95）U/mgprot;丙二醛：（0.83±0.04）nmol/mgprot比（0.38±0.04）nmoL/mgprot凋亡指数：（18.53±1.64）%比（6.00±0.38）%;P＜0.01];维生素E 100 mg/kg组、丹参多酚酸盐30.0 mg/kg和15.0 mg/kg两个剂量组与衰老模型组相比,大脑组织SOD活性均明显增加[（157.21±3.12）、（159.33±3.99）、（149.36±2.72）U/mgprot,均P＜0.01]、丙二醛含量显著降低（0.5999±0.030）、（0.606±0.042）、（0.657±0.046）,均P＜0.01,蒲肯野细胞凋亡指数显著降低[（36.24±1.76）%,（38.97±1.81）%,（45.70±1.96）%,均P＜0.01].丹参多酚酸盐30.0 mg/kg组与维生素E200 mg/kg组的作用差异无统计学意义（P＞0.05）,而丹参多酚酸盐15.0 mg/kg组与前两者的作用有统计学意义（P＜0.05）.结论 丹参多酚酸盐具有延缓大鼠大脑衰老的作用.     

Acute and subchronic oral toxicity studies in rats of a hydrolyzed chicken sternal cartilage preparation.

Two acute and subchronic oral toxicity studies were conducted in rats to evaluate safety of a patented preparation of hydrolyzed chicken sternal cartilage (BioCell Collagen II) containing collagen type II, chondroitin sulfate, and hyaluronic acid. In the acute oral toxicity study, five males and five females of Sprague-Dawley rats were administered a single dose of 5000 mg of the test product per kg body weight and observed for 14 days. All animals survived and exhibited normal body weight gain throughout the study. Macroscopic necropsy examination conducted on day 15 revealed no gross pathological lesions in any of the animals. In the subchronic study, Sprague-Dawley rats (40 males, 40 females) were divided into four same-sex groups (10 animals/group). Animals in each group were administered daily either 0, 30, 300 or 1000 mg of the test product per kg of body weight for over 90 days. All animals survived and showed no significant changes in their body weights and histopathology. Although some differences were observed between the treated and control animals in several parameters, they were generally not dose-related or considered to be of toxicological significance. In conclusion, the results from the two oral toxicity studies with male and female young adult rats indicated that the test preparation from hydrolyzed chicken sternal cartilage collagen (BioCell Collagen II) was well tolerated at all four doses tested.     

Pharmacokinetics of 2,4,5-T in mice as a function of dose and gestational status

A pharmacokinetic study was conducted in CD-1 mice with the herbicide 2,4,5-trichlorophenoxyacetic acid (2,4,5-T) as a function of dose (15, 30, 60, and 90 mg/kg, iv) and gestational status (nonpregnant, day 6, 10, 13, and 17 of gestation, and postpartum). Analysis for 2,4,5-T and its metabolites was based on an electron-capture gas-liquid chromatographic method. Pharmacokinetic stimulation of the blood, urine, and feces data from each mouse was performed on an analog-digital hybrid computer system based on a two-compartment model with parallel, first-order elimination kinetics. Data analysis demonstrated dose-independent kinetics for most pharmacokinetic parameters but a gestational status-dependence. There was a tendency, as indicated by an increase in the biologic half-life and AUC and decrease in clearance and total percent recovery, for pregnant animals to eliminate 2,4,5-T more slowly as gestation progressed, resulting in potentially increasing fetal exposure during the later stages of pregnancy.     

Chronic Toxicity and Oncogenicity Study with Vinyl Acetate in the Rat: In Utero Exposure in Drinking Water

The purpose of this study was to evaluate vinyl acetate forpotential chronic toxicity and oncogenicity when given to ratsin drinking water from the time of gestation. Target concentrationswere 0, 200, 1000, and 5000 ppm (v/v). Drinking water solutionswere prepared daily and analyzed at approximately 4-week intervals.F₀ rats were given solutions of vinyl acetate for 10 weeks andthen mated. Offspring (F₁ rats) were culled to equal group sizesof 60 main study rats and 30 rats for satellite groups. F₁ ratswere treated for up to 104 weeks with interim kills of satellitegroups at 52 and 78 weeks. Body weights and clinical signs oftoxicity were monitored in F₀ and F₁ rats. Food and water consumptionwere measured in F₁ rats. At Weeks 52 and 78 of the test, clinicalpathology and urine analysis examinations were conducted on10 rats per group from satellite animals. A complete gross andhistopathological examination of F₁ rats was conducted at theinterim kills and on main study rats at Week 104. Average vinylacetate consumption over the course of the study in male ratsof the 200, 1000, and 5000 ppm groups was 10, 47, and 202 mg/kg/day,respectively. Female rats consumed an average of 16, 76, and302 mg/kg/day, respectively. Compound-related effects observedduring the study included a concentration-related decrease inwater consumption among rats of the 1000 and 5000 ppm groupsand a decrease in food consumption among rats of the 5000 ppmgroups. Concurrent body weight decrement was observed only inthe 5000 ppm groups. There were no compound-related effectson clinical chemical, hematological, or urinalysis parameters.The pathological evaluations revealed no compound-related effectson organ weight, nonneoplastic lesions, or neoplastic lesions.The no-observable-effect level was 200 ppm while the no-observable-adverse-effectlevel was 1000 ppm. Under the conditions of this study, vinylacetate showed no evidence of systemic target organ toxicityand was not oncogenic when administered to rats in the drinkingwater.     

Toxicological studies on 5-methoxymethyl-2′-deoxyuridine,a new antiviral agent

Toxic effects of 5-methoxymethyl-2′-deoxyuridine (MMUdR) were studied in White Swiss mice. Pathological, hematological, and clinical chemistry parameters were examined. No morbidity or mortality was observed after administration of MMUdR in a single dosage of 4000 mg/kg and in repeated dosages of 1000 mg/kg daily for 15 days. No gross or histopathological lesions related to MMUdR treatment were observed in the tissues examined from mice of the acute toxicity studies. Histopathological lesions were found in liver and intestine of mice treated with 1000 mg/kg/day for 15 days. These lesions consisted of cytoplasmic vacuolation of hepatocytes and atrophy of intestinal villi. The latter was associated with dilation of the intestine. Control livers contained significantly more mitotic figures than did those of treated animals. The mean corpuscular volume (MCV) of treated mice (4000 mg/kg) was significantly lower than that of controls. After repeated low doses, treated animals exhibited a hemoconcentration effect as evidenced by a lower packed cell volume and MCV and a higher mean corpuscular hemoglobin concentration and total solids in serum. Microscopic examination of marrow smears from control and treated animals from both acute and subacute toxicological studies demonstrated normal hematopoiesis. Differences in serum alkaline phosphatase and serum glutamic oxaloacetic transaminase activities between treated and control mice were observed in the subacute toxicity study. No toxic effect upon fetuses and no teratogenic effects were observed in 152 offspring from mice receiving 500 mg/kg/day of MMUdR for 19 or 21 days.     

In vitro uptake of organic ions by renal cortical tissue of rats treated acutely with 2,4,5-trichlorophenoxyacetic acid.

The effect of 2,4,5-trichlorophenoxyacetic acid (2,4,5-T) on renal cortical function has been studied in male adult rats. Significant decreases in organic acid and organic base transport were measured when rats were pretreated with 2,4,5-T 24 hr before in vitro analysis of renal function. Experiments in which injections of p-aminohippurate were given showed no effect on organic acid or organic base transport by renal cortical slices. The data are interpreted to mean that pretreatment with 2,4,5-T has a depressive influence on the transport of some organic ions. Adult animals which were treated daily with 2,4,5-T accumulated a large body store of this herbicide during the first 6 days of administration. However, by 9 days the animals excreted essentially the dose of 2,4,5-T administered, and by 16 days the herbicide accumulated during the first 6 days had been almost totally eliminated. This chronic excretion pattern may explain why only moderate toxicity has been reported for this herbicide.