The Journal of Toxicological Sciences
Online ISSN : 1880-3989
Print ISSN : 0388-1350
ISSN-L : 0388-1350
Volume 19 , Issue SupplementIII
Showing 1-15 articles out of 15 articles from the selected issue
  • Shuzo OKAZAKI, Koichi SUWA, Yasuhisa HAMASU, Nobuyoshi SUMI
    1994 Volume 19 Issue SupplementIII Pages 295-299
    Published: November 25, 1994
    Released: February 21, 2008
    JOURNALS FREE ACCESS
    The single dose toxicity studies of lactitol, a hepatic encephalopathy drug, were performed in ddY mice and SD rats of both sexes by administering the drug orally, intravenously or subcutaneously. The drug was administered as a single dose followed by a 14-day observation. Oral LD50 values of lactitol were estimated to be between 23 and 30 g/kg in male mice, approximately 30 g/kg in female mice, and more than 30 g/kg in male and female rats. Lethal dose was more than 10 g/kg intravenously and subcutaneously in mice and rats of both sexes. The signs of toxicity in mice and rats observed following the administration of this drug included the following: decreased spontaneous movement [p.o., i.v., s.c.]; diarrhea, oligopnea or prone position, transient decreased body weight [p.o.]. There were no treatment-related changes in gross examination. Based on these results, it was found that lactitol had a very low acute toxicity when administered by a single dose method in mice and rats.
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  • Ryoichi NAGATA, Mizuo ONISHI, Keikou OKASAKI, Yasuhisa HAMASU, Nobuyos ...
    1994 Volume 19 Issue SupplementIII Pages 301-304
    Published: November 25, 1994
    Released: February 21, 2008
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    Male beagle dogs were orally given lactitol, a hepatic encephalopathy drug, in a single dose of 7.5, 15.0 or 30.0 g/kg. Vomiting was seen within 30 minutes after dosing in all treated groups. Diarrhea was observed 3 or 5 hours after dosing in the 15.0 and 30.0 g/kg dose groups. There were no drug related effects on survival, food and water consumption, body weight gain or tissues and organs.
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  • Yasuyuki NISHIGUCHI, Seitaro ISHIBASHI, Mutsumi TARUI, Shoji FUJIMOTO, ...
    1994 Volume 19 Issue SupplementIII Pages 305-326
    Published: November 25, 1994
    Released: February 21, 2008
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    Twenty male and 20 female Slc: SD rats were orally given lactitol, a hepatic encephalopathy drug, for 13 weeks at doses of 0, 0.625, 2.5 or 10 g/kg/day. A 5 week recovery test was conducted after the discontinuation of the drug treatment. Soft stool and decreased food consumption were seen in the 2.5 and 10 g/kg groups. In the 10 g/kg group, there were diarrhea, soiled fur, abdominal distention, salivation, piloerection, decreased body weight gain and increased water consumption. Urinalysis showed decreased urine volume and K+ excretion in the 10 g/kg group. In this dose group, biochemical examination showed decreased ALP, total cholesterol, triglyceride, glucose, Ca, Na+, Cl- and total protein. In the pathological examination, the cecum weight was increased in all dose groups. In the 2.5 and 10 g/kg groups, cecum distention with mucosal hyperplasia was observed. The adrenal weight was increased in the 10 g/kg group and hypertrophy of zona fasciculata of adrenal gland were seen in the 2.5 and 10 g/kg groups. The thymic weight was decreased in the 10 g/kg group. Ophthalmoscopic and hematologic examinations failed to reveal any drug induced changes. The increased cecum weight in the 0.625 g/kg group was regarded as toxicologically insignificant because of the failure of the association with any clinical or morphological findings. The above mentioned changes were satisfactorily reversible except for those in the cecum. Based on the results obtained, the NOAEL of this study was suggested to be 0.625 g/kg/day.
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  • Keikou OKASAKI, Takahiro UEDA, Toshio ONIMARU, Hiroaki IKEDA, Takahisa ...
    1994 Volume 19 Issue SupplementIII Pages 327-375
    Published: November 25, 1994
    Released: February 21, 2008
    JOURNALS FREE ACCESS
    13-week repeated dose toxicity studies were conducted on lactitol, a hepatic encephalopathy drug. In the experiment I, male and female dogs were orally treated with lactitol at doses of 0, 1.0, 2.5 and 6.25 g/kg/day for 13 weeks, followed by 4 weeks recovery period. In the experiment II, male and female dogs were orally treated with lactitol at doses of 0, 0.25, 0.50 and 1.0 g/kg/day for 13 weeks in order to require the no-toxic dose. Results: 1. Soft stool and diarrhea were observed at the 0.50 g/kg group and above, and vomiting was observed at the 1.0 g/kg group and above. Increased water consumption was observed at the 6.25 g/kg group. No deaths occurred at all groups. 2. In urinalysis, increased urine volume was observed at the 6.25 g/kg group. 3. Blood chemistry showed decreased BUN at the 6.25 g/kg group. 4. There were no drug-related changes in body weight, food consumption, ophthalmological examination, electrocardiography, hematology and pathology. 5. At the end of the recovery period, all these changes observed at the end of the administration period were disappeared. Based on these results, it was considered that the no-toxic dose of lactitol is 0.25 g/kg/day.
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  • Shuzo OKAZAKI, Junichi KOBAYASHI, Kazutoshi TAMURA, Mariko NAGATANI, Y ...
    1994 Volume 19 Issue SupplementIII Pages 377-404
    Published: November 25, 1994
    Released: February 21, 2008
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    Twenty five male and 25 female Slc: SD rats were given orally lactitol, a hepatic encephalopathy drug, for 52 weeks at doses of 0, 0.4, 2 or 10 g/kg/day. A 9 week recovery test was conducted after the discontinuation of the drug treatment. Treatment related death, soft stool, diarrhea, decreased body weight gain and food intake and increased water consumption were observed in the 10 g/kg group. Urinalysis showed increased Ca excretion in the 2 and 10 g/kg groups. In the 10 g/kg group, there were increased Ca++ excretion and urine specific gravity and decreased K+ and Na+ excretion and urine volume. Hematologic examination showed decreased platelet count in the 10 g/kg group. Biochemical examination revealed highered A/G ratio in the 2 and 10 g/kg groups. In the 10 g/kg group, there were lowered level of total cholesterol, triglyceride, phospholipid, Na+, Cl- and total protein. Distention of the cecum with increased organ weight was seen pathologically in the 2 and 10 g/kg groups. In the 10 g/kg group, cecal mucosa was hyperplasic. The adrenal gland was hypertrophic in the zona glomerulosa in the 2 and 10 g/kg groups. In the 10 g/kg group, the adrenal weight was increased. Dilatation of renal tubules was also found in the 10 g/kg group. The above mentioned changes were satisfactorily reversible except for the increased cecum weight in the 10 g/kg group. Based on the results obtained, the NOAEL of this study was suggested to be 0.4 g/kg/day.
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  • Mizuo ONISHI, Takahiro UEDA, Katsumi OMACHI, Tamon HONDA, Masaharu NOM ...
    1994 Volume 19 Issue SupplementIII Pages 405-427
    Published: November 25, 1994
    Released: February 21, 2008
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    Five male and 5 female beagle dogs were orally given lactitol, a hepatic encephalopathy drug, for 52 weeks at doses of 0, 0.25, 1.25 or 6.25 g/kg/day. A 9 week recovery test was conducted after the discontinuation of the drug treatment. Soft stool; diarrhea, and vomiting were seen in the 1.25 and 6.25 g/kg groups. In the 6.25 g/kg group, bloody stool and increased water consumption were also observed. Urinalysis showed larger amount of the urine volume in the 6.25 g/kg group. The cecum weight of this group was increased without any morphological changes. There were no drug related effects on survival, body weight gain and food consumption. Electrocardiographic, ophthalmoscopic, hematologic and biochemical examinations failed to show any abnormalities related to the drug treatment. The above mentioned changes were satisfactorily reversible. Based on the results obtained, the NOAEL of this study was suggested to be 0.25 g/kg/day.
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  • Hironori NINOMIYA, Junichi KONDO, Yukiharu IDE, Yasuhiro YAMASHITA, Ke ...
    1994 Volume 19 Issue SupplementIII Pages 429-439
    Published: November 25, 1994
    Released: February 21, 2008
    JOURNALS FREE ACCESS
    A study of fertility and fetal development was conducted in Sprague-Dawley rats. Male rats were given lactitol, a hepatic encephalopathy drug, orally from 63 days before mating to the end of mating period. Female rats were given from 14 days before mating to day 7 of pregnancy. The dose levels for both males and females were 0 (control), 0.7, 2.65 and 10 g/kg. The females were sacrificed on day 20 of pregnancy for examination of their fetuses. The decrease in food consumption in either male or female was observed in the intermediate and high dose groups. The high dose caused soft stool, diarrhea and increase in water consumption in either male or female. Moreover, the high dose caused salivation and suppresion of body weight gain in male. In the pathological examination, the enlargement of cecum were observed in male of the intermediate and high dose groups. The increase in cecum weight were observed in male in all lactitol groups, and in female of the high dose group. Lactitol did not affect on copulation and fertility indexes in either male or female rats. Lactitol failed to affect on estrous cycle in female rats, and number of corpora lutea, implantations and preimplantation egg losses. In the fetal examination, lactitol did not affect on the development of live fetuses. The results show that no-effect dose levels of lactitol are less than 0.7 g/kg in male rats and 0.7 g/kg in female rats for general toxicity, and 10 g/kg for reproductive function in parent animals and fetuses.
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  • Hironori NINOMIYA, Kenji NISHIKAWA, Yukiharu IDE, Junichi KONDO, Kouic ...
    1994 Volume 19 Issue SupplementIII Pages 441-461
    Published: November 25, 1994
    Released: February 21, 2008
    JOURNALS FREE ACCESS
    A teratogenicity study of lactitol, a hepatic encephalopathy drug, was conducted in Sprague-Dawley rats. Female rats were given lactitol orally at dose levels of 0 (control), 0.7, 2.65 and 10 g/kg from day 7 to day 17 of pregnancy. Twenty-two female rats per dose level were sacrificed on day 20 of pregnancy for examination of their fetuses, and thirteen pregnant rats per dose level were allowed to deliver naturally for postnatal examination of their offspring. The high dose of lactitol caused diarrhea or soft stool in pregnant rats. The food consumption of female fats decreased in the intermediate and high dose groups. The water consumption of female rats increased in the high dose group. The drug failed to alter the body weight of female rats. The weights of cecum of dams increased in the intermediate and high dose group. The high dose caused enlargement of cecum in dams. The drug failed to alter the numbers of corpora lutea and implantations, fetal mortality, the number of live fetuses, body weight of live fetuse, sex ratio, and external, visceral and skeletal development of fetuses. Lactitol did not affect the delivery of dams, the number of live newborns, birth index, external development, body weight, viability index, weaning index, and sex ratio of weanlings. Nor did lactitol have any adverse effect on the postnatal development of the first (F1) generation offspring, such as differentiation, emotionality, motor ability, learning ability or reproductive performance. Nor did lactitol have any adverse effect on the second (F2)generation offspring. The results show that the no-effect dose levels of lactitol are 0.7 g/kg for general toxicity in mother animals, 10 g/kg for reproductive function in mother animals and their offspring.
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  • John M. TESH, Frank W. ROSS, Timothy J. WIGHTMAN, Owen K. WILBY, Andre ...
    1994 Volume 19 Issue SupplementIII Pages 463-470
    Published: November 25, 1994
    Released: February 21, 2008
    JOURNALS FREE ACCESS
    Lactitol, a hepatic encephalopathy drug, was administered by oral gavage to pregnant New Zealand White rabbits during organogenesis from day 6 to day 18 of gestation inclusive, at dosages of 0, 0.25, 0.75 or 4.5 g/kg/day. On day 29 of gestation, females were killed to allow examination of their uterine contents. There was a slight reduction in food intake and faecal output among females receiving 4.5 g/kg. One female receiving 4.5 g/kg aborted following a prolonged period of weight loss. No adverse effects on litter parameters were recorded that could be attributed to treatment. Foetal morphogenesis was unaffected by treatment with lactitol. The results show that no-effect dose levels of lactitol are 0.75 g/kg in mother rabbits for general toxicity and for reproductive functions, and 4.5 g/kg for their fetuses.
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  • Hironori NINOMIYA, Kenji NISHIKAWA, Yukiharu IDE, Junichi KONDO, Kouic ...
    1994 Volume 19 Issue SupplementIII Pages 471-485
    Published: November 25, 1994
    Released: February 21, 2008
    JOURNALS FREE ACCESS
    A perinatal and postnatal study of lactitol, a hepatic encephalopathy drug was conducted in Sprague-Dawley rats. Female rats were given lactitol orally at dose levels of 0 (control), 0.7, 2.65 and 10 g/kg from day 17 of pregnancy to day 21 after delivery. All pregnant rats per level were allowed to deliver naturally for postnatal examination of their offspring. The high dose caused diarrhea or soft stool in dams. The high dose suppressed the body weight of dams during the perinatal period. The food consumption of dams decreased in the intermediate and high dose groups. The water consumption of dams increased in the high dose group. The high dose caused enlargement of cecum and increase of weights of cecum in dams. The drug failed to affect the delivery of dams and gestation index. However, high dose caused prolongation of gestation period. Two dams in the high dose group failed to nurse their all newborns during early lactation. The drug did not affect the number of live newborns, birth index, external appearance, body weight, viablity index, weaning index, and sex ratio of weanlings. Nor did lactitol have any adverse effect on the postnatal development of the first (F1) generation offspring, such as differentiation, emotionality, motor ability, learning ability or reproductive performance. Nor did lactitol have any adverse effect on the second (F2) generation offspring. The results show that the no-effect dose levels of lactitol are 0.7 g/kg for general toxicity in mother animals, 2.65 g/kg for reproductive function in mother animals, and 10 g/kg for their offspring.
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  • Keiko IWAKURA, Hironobu TAMURA, Masataka WATANABE, Nobuyoshi SUMI
    1994 Volume 19 Issue SupplementIII Pages 487-497
    Published: November 25, 1994
    Released: February 21, 2008
    JOURNALS FREE ACCESS
    Lactitol (NS-4), a hepatic encephalopathy drug, was examined for mutagenicity in the reverse mutation test in bacteria, the chromosome aberration test with cultured mammalian cells, and the micronucleus test in mice. 1. In the reverse mutation test using Salmonella typhimurium (TA1535, TA100, TA1537, and TA98) and Escherichia coli (WP2uvrA), the drug did not significantly increase revertant colonies in any of the test strains with or without metabolic activation system (S-9mix). 2. In the chromosome aberration test with cultured Chinese hamster lung cells (CHL/IU), the drug did not significantly increase aberrant cells in the direct method or in the metabolic activation method. 3. In the micronucleus test with Slc: ddY male mice, the drug did not significantly increase micronucleated polychromatic erythrocytes in the bone marrows. These results suggest that lactitol has no mutagenicity in vitro or in vivo.
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  • Keikou OKASAKI, Hidenobu SAMEJIMA, Ryoichi NAGATA, Hiroshi FUJISAWA, K ...
    1994 Volume 19 Issue SupplementIII Pages 499-505
    Published: November 25, 1994
    Released: February 21, 2008
    JOURNALS FREE ACCESS
    Lactitol hydrate (lactitol) was tested for its antigenicity in guinea pigs and mice. The following results were obtained. 1. No active systemic anaphylaxis reactions were found in guinea pigs sensitized subcutaneously with lactitol alone or in combination with Freund's complete adjuvant (FCA). 2. No 24 hr heterologous passive cutaneous anaphylaxis reactions were elicited in rats by sera from mice sensitized intraperitoneally with lactitol alone or in combination with 3% aluminum hydroxide gel. 3. No passive hemagglutination reactions were elicited by sera from mice sensitized subcutaneously with lactitol in combination with FCA. From these results, it is concluded that lactitol has no antigenicity under the present experimental conditions.
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  • Hiroshi OHNO, Hiroko TOJO, Tetuyo KAJIMURA, Mamoru NOMURA
    1994 Volume 19 Issue SupplementIII Pages 507-518
    Published: November 25, 1994
    Released: February 21, 2008
    JOURNALS FREE ACCESS
    DT-5061, a steroid oral contraceptive which contains norethisterone (NET) and ethinyl estradiol (EE) in a ratio of 100:7, was administered orally to rats for 14 days in order to investigate a possible origin of the increased serum alkaline phosphatase (ALP). Increased serum total ALP was noted in rats receiving DT-5061 at 5.35 mg/kg/day or EE at 0.35 mg/kg/day. Electrophoresis of serum ALP revealed that both liver and bone-type ALP isozymes were increased in the DT-5061 5.35 mg/kg and EE 0.35mg/kg group, and the ratio of increase in the liver-type was greater than that in the bone-type although the increase in concentration of the bone-type was greater as compared to the liver-type. ALP level in the liver was elevated together with an increase in liver weight, consistently with the increased serum liver-type isozyme. However, neither histological changes indicative of cholestasis nor increase in serum leucine aminopeptidase, bilirubin, GOT or GPT were seen. No changes were observed in bone ALP activity; hence inconsistent with the increased serum bone-type isozyme. From these results, it is considered that the increased serum ALP induced by this drug was due to the increased liver-type isozyme induced in the liver and to the increased bone-type isozyme, and among the ingredients of this oral contraceptive, EE was mainly involved in the increased serum ALP induced by this drug.
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  • Hiroko TOJO, Hiroshi OHNO, Mamoru NOMURA
    1994 Volume 19 Issue SupplementIII Pages 519-530
    Published: November 25, 1994
    Released: February 21, 2008
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    DT-5061, a steroid oral contraceptive which contains norethisterone (NET) and ethinyl estradiol (EE) was administered orally to adrenalectomized rats for 3 days to investigate involvement of the adrenals in the increased serum alkaline phosphatase (ALP). In addition, corticosterone or aldosterone were administered to the adrenalectomized rats to examine their effects on serum ALP. Increases in serum total ALP, liver-type and bone-type ALP isozymes were observed in rats with intact adrenals following administration of DT-5061, but these responses were not noted in adrenalectomized rats. Increases in liver weight and ALP activity in the liver after administration of the drug were reduced but not abolished in the adrenalectomized rats. The adrenalectomized rats receiving corticosterone showed increases in serum total ALP, liver-type ALP isozyme and liver weight but did not exhibit any increase in bone-type ALP isozyme. On the other hand, aldosterone did not increase and even reduced serum ALP although ALP activity in the liver was increased in the adrenalectomized rats. From these results, it is considered that the increased serum ALP induced by DT-5061 in rats is mainly due to an action through the adrenals. It is also suggested that a direct action of this drug on the liver is partly involved in the increased liver ALP activity and liver weight induced by this drug, and that corticosterone possibly plays a role in the action of DT-5061 through the adrenals.
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  • Shinji SUGIMOTO, Miho IMAWAKA, Harushige OZAKI, Takayasu ITO, Takao AN ...
    1994 Volume 19 Issue SupplementIII Pages 531-542
    Published: November 25, 1994
    Released: February 21, 2008
    JOURNALS FREE ACCESS
    A procedure for recording the electroretinogram (ERG) in rats with a contact lens-type electrode was developed in order to examine visual toxicity over-time. Rats received a single intravenous injection of sodium iodate (SI), a retinotoxic compound, via the tail vein at a dose of 12.5, 20, 25 or 50 mg/kg, and the ERG was recorded for 10 days after dosing. Histopathologic examination of the retinas was then conducted. 1. The rats were anesthetized with ketamine hydrochloride (50 mg/kg, i.m.) after 90 to 120 min of dark-adaptation. Thirty-two responses to repetitive 1.2 joule light stimuli at 0.5 Hz interstimulus intervals were averaged by a microcomputer. Under these conditions, stable ERG a-wave, b-wave and oscillatory potentials could be recorded for 10 days. 2. At 12.5 mg/kg of SI, no treatment-related abnormalities were observed on the ERG. Doses of 20 mg/kg or more of SI caused depression of the amplitudes of the ERG a-wave and oscillatory potentials 2 hrs or 1 day after dosing. Following these changes, the amplitude of the ERG b-wave decreased 1 or 2 days after dosing. 3. Upon histopathologic examination of the retina, folding of the outer nuclear layer, disarrangement of the rods and cones and swelling and decrease of the pigment epithelial cells were observed at 20 mg/kg or more. The severity of the retinal lesions correlated well with the changes in the ERG. 4. Using this recording technique, it was confirmed that a stable ERG could be recorded repeatedly in rats, and the effects of SI on the ERG could be detected. Furthermore, histopathologic examination revealed that the severity of the retinal lesions correlated well with the changes in the ERG. These results indicate that the ERG recording technique employed in this study is useful for evaluating retinal toxicity in rats.
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