The Journal of Toxicological Sciences
Online ISSN : 1880-3989
Print ISSN : 0388-1350
ISSN-L : 0388-1350
Volume 15 , Issue SupplementII
Showing 1-12 articles out of 12 articles from the selected issue
  • Kiyotaka SATOH, Nobuko YAMAMOTO, Emiko KUWASAKI, Tsutomu ICHIKI, Hisao ...
    1990 Volume 15 Issue SupplementII Pages 1-9
    Published: June 30, 1990
    Released: February 21, 2008
    JOURNALS FREE ACCESS
    Mofezolac (N-22) is a newly developed analgesic and antiinflammatory agent. The acute tokicities of N-22 were investigated in ICR mice and Wistar rats in oral (p.o.), intraperitoneal (i.p.) and subcutaneous (s.c.) routes. LD50 values of N-22 in mice were 1528 mg/kg (p.o.), 275 mg/kg (i.p.) and 612mg/kg (s.c.) for males, and 1740 mg/kg (p.o.), 321 mg/kg (i.p.) and 545 mg/kg (s.c. ) for females. Those in rats were 920 mg/kg (p.o.), 378 mg/kg (i.p.) and 572mg/kg (s.c.) for males, and 887 mg/kg (p.o.), 342 mg/kg (i.p.) and 510 mg/kg (s.c.) for females. The sex difference was not clearly observed in mice and rats, but the species difference was observed in p.o. routes. As an initial toxic sign, the hypoactivity was observed in mice and rats of all routes, subsequently, paleness of skin, anemic conjunctiva, emaciation, stupor and/or coma were observed in mice and rats of p.o. and i.p. routes. In rats of those routes, tonic and/or asphyxial convulsion and dyspnea were also observed. In pathological examination of mice and rats, gastrointestinal disorders were observed in p.o. and i.p. routes, and changes of subcutaneous tissue at the injection site were observed in s.c. route.
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  • Kotaro SHIMPO, Masaya TAKEUCHI, Shuzo OKAZAKI, Masao KIGUCHI, Yukari H ...
    1990 Volume 15 Issue SupplementII Pages 11-41
    Published: June 30, 1990
    Released: February 21, 2008
    JOURNALS FREE ACCESS
    A three-month oral subacute toxicity study of mofezolac (N-22), a non-steroidal anti-inflammatory agent, was performed using dose levels of 6, 20, 60 and 200 mg/kg in rats, and recovery was also assessed one month after withdrawal. 1. Toxic signs caused by N-22 administration, observed only in the 200 mg/kg group, were as follows : soiling around the mouth and/or nose, piloerection, anemia, diarrhea, emaciation and decreased spontaneous locomotor activity. Nine males and thirteen females in the 200 mg/kg group excreted bloody diarrhea and died of general exhaustion between weeks four and thirteen of study. 2. In the 200 mg/kg group, decrease in food consumption and suppression of body weight gain were noted in males from about week four and in females from about week six aftef initiation of administration, and increase in water consumption was noted in males from about week seven. 3. Urinary examination revealed a decline in urinary pH in males of the 20 mg/kg and above groups and elevation of urobilinogen levels in males of the 60 and 200 mg/kg groups. 4. Hematological examination showed decreases in erythrocyte count (RBC), hematocrit value (Ht) and hemoglobin concentration (Hb) and increase in reticulocyte rate in both sexes of the 200 mg/kg group and an increase in neutrophil rate in males of the 200 mg/kg group. 5. Biochemical examination demonstrated a decrease in chloride (Cl-) in males receiving the 20 mg/kg or above doses and a decrpase in calcium (Ca++) in males of the 60 and 200 mg/kg groups. Moreover, there were decreases in cholinesterase (ChE) activity, total protein (TP) and albumin (Alb) values, as well as increases in blood urea nitrogen (BUN), uric acid (UA) and potassium (K+) in both sexes of the 200 mg/kg group, along with elevations in GOT and lactate dehydrogenase (LDH) activities in females of the 200 mg/kg group. 6. The absolute and/or relative organ weights for liver, kidneys, spleen and adrenals were increased in the 200 mg/kg group. 7. On pathological examination, perforating ulceration in the jejunum and ileum, turbid ascites, adhesion and inflammatory changes in capsules of the abdominal organs, splenomegaly, mesenteric lymph node hyperplasia and inflammatory changes in the thoracic cavity were observed in dead animals of the 200 mg/kg group. Similar pathological changes were observed in a few survival cases of the 200 mg/kg group. 8. After a one month recovery period, the above-mentioned changes had mostly recovered, indicating that they were reversible. 9. These results suggested no-effect dose levels of N-22 in rats to be 6 mg/kg for males and 60 mg/kg for females, and the toxic dose level to be 200 mg/kg for both sexes.
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  • Kotaro SHIMPO, Masaya TAKEUCHI, Masao KIGUCHI, Mieko IWATA, Yukihiro N ...
    1990 Volume 15 Issue SupplementII Pages 43-76
    Published: June 30, 1990
    Released: February 21, 2008
    JOURNALS FREE ACCESS
    Mofezolac (N-22) is a new developed analgesic and antiinflammatory agent. A subacute oral toxicity test of N-22 was carried out at dose-levels of 0, 2, 6 and 20 mg/kg/day using male and female beagle dogs. Treatment for 3 months was followed by 1 month recovery period except in the case of both sexes receiving 20 mg/kg/day. The results obtained from the present study were as follows. 1. Observation of general conditions revealed vomiting, sporadic bloody feces, anemia, recumbency and hyposthenia in both sexes receiving 20 mg/kg/day. Anemia or erosion of tongue was observed in each female receiving 6 mg/kg/day. 2. Respectively 3 dogs of both sexes receiving 20 mg/kg/day died during dosing period. In these animals, perforating ulcers were observed in the pars pylorica ventriculi or duodenum, and loss of blood, peritonitis and aggravation of general exhaustion were considered as causes of death. 3. Body weight tended to decrease in both sexes receiving 20 mg/kg/day, and food and water consumption levels decreased in males receiving 2 mg/kg/day or above and females receiving 20 mg/kg/day. 4. Urinalysis demonstrated an increasing tendency for specific gravity of urine and a decreasing tendency for urine volume in males receiving 2 mt/kg/day or above. 5. Hematological examination showed decreases in red blood cell count and Hb concentration in males receiving 2 mg/kg/day or above, and in Ht values in males receiving 6 mg/kg/day or above. 6. Serum biochemical examination revealed decreases in total protein and albumin in both sexes receiving 20 mg/kg/day. 7. There were no remarkable changes in hepatic and renal function, ophthalmological findings or electrocardiogram. 8. In the ortan weights, significant decrease in thymus weights was observed in the dead animals receiving 20 mg/kg/day. 9. Pathologically, the dead animals receiving 20 mg/kg/day were found to exhibit peritonitis with perforating ulcers in the pars pylorica ventriculi or duodenum. In the surviving animals of this group, scar ulcers in the pars pylorica ventriculi and small intestine were evident on necropsy, and histopathology revealed neutrophils infiltration and thrombosis in blood vessels in the thickened submucosal stomach tissues. Moreover, localized hepatocyte necrosis and intrasinusoidal cellular infiltration in liver, as well as interstitial cellular infiltration, degeneration and dilatation of the renal tubules in the kidney were observed. In females receiving 6 mg/kg/day, the changes in kidney were similar to those in surviving animals receiving 20 mg/kg/day, and male of the group showed atrophy of thymus. 10. Almost all changes observed in the 6 and 2 mg/kg/day groups during dosing period recovered 1 month after the end of dosing. Thus the changes were reversible. 11. From the above results, the toxic dose level was estimated to be 20 mg/kg/day for both sexes, and the no-effect dose to be less than 2 mg/kg/day for males, and 2 mg/kg/day for females, in beagle dogs treated orally with N-22 for 3 months.
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  • Kiyotaka SATOH, Hiromi FURUKAWA, Yuzoh NASU, Hisao SONE, Tsutomu ICHIK ...
    1990 Volume 15 Issue SupplementII Pages 77-109
    Published: June 30, 1990
    Released: February 21, 2008
    JOURNALS FREE ACCESS
    Fifty two-week oral toxicity study of mofezolac (N-22), a new developed analgesic and anti-inflammatory agent, was carried out in Wistar rats with dose levels of 5, 20, 60 and 120 mg/kg/day, and the 5-week withdrawal was followed fof recovery study. Hematuria, blanching of the skin and suppression of body weight gain were observed in females given 120 mg/kg, and 9 of these prostrated and died from week 20 to week 52, or were euthanized when moribund. These symptoms were not seen in males at any dose levels. In 120 mg/kg group, increased positive cases of fecal occult blood were observed during the administration period, and the pathological examination revealed gastrointestinal lesions such as erosion, ulcer, hemorrhage and mucosal regeneration in the small intestine. Renal disorder was also involved mainly in females given 120 mg/kg, as shown by increase in urine volume with declined osmotic pressure and specific gravity, serum urea nitrogen, creatinine, inorganic phosphorus, and other related parameters. In addition to enlargement, rough surface and scar formation, dilated tubular lumen and papillary ducts of the kidney were observed as a main lesion. Incidental findings with those disorders, observed mainly in females given 120 mg/kg, included increase in leucocytes with high neutrophils ratio, and enlargement of the spleen, adrenals and mesenteric lymph node. There were some of the similar gastrointestinal and renal changes mainly in females given 60 mg/kg. Anemic findings were noted in both sexes of 120 mg/kg and in females of 60 mg/kg group, and mainly females given 120 mg/kg showed increase in platelets, reticulocytes and fibrinogen, shortening of blood coagulation time, as well as extramedullary or accented hematopoiesis of the liver, spleen and bone marrow. Other serum bibchemical changes observed mainly in females given 120 mg/kg were decredse of decreasing trend in total protein, A/G ratio, and transaminase activity. Fine structure of the liver from females given 20 mg/kg or more revealed cisternal dilatation of smooth-surfaced endoplasmic reticulum of hepatocytes, and the increased liver weight was observed in females given 120 mg/kg. Accordingly, non-effective dose level of N-22 in 52-week chronic toxicity study was estimated to be 20 mg/kg for males and 5 mg/kg for females.
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  • Mitsunobu OHKUBO, Toshihiro KATSUTA, Akihiko MASUNAGA, Eiichi ARAKI, T ...
    1990 Volume 15 Issue SupplementII Pages 111-149
    Published: June 30, 1990
    Released: February 21, 2008
    JOURNALS FREE ACCESS
    The chronic toxicity study of mofezolac (N-22), a new developed analgesic and anti-inflammatory agent, was carried out in beagle dogs by oral administration of the test compound at dose levels of 1, 3, 6 and 12 mg/kg once daily for 52 weeks. The recovery study was also carried out by withdrawal for 5 weeks. 1. No death occurred during the administration and recovery periods in all groups, there were no abnormal findings due to N-22 administration on behavior and appearance, body weight and food consumption. 2. There were no abnormal findings due to N-22 administration on fecal test, urinalyses, hematological and biochemical examinations, hepatic and renal function tests, ophthalmological examination, electrocardiography, blood pressure and organ weight. 3. By histopathological examination, loss of villi in small intestine was found in one female of 6 mg/kg group, erosion in small intestine in one male of 12 mg/kg group, and shortening of villi and ulcer in small intestine in each one female of 12 mg/kg group. 4. Accordingly, the non-effective dose levels of N-22 were estimated to be 6 mg/kg for male and 3 mg/kg for femalb in this study.
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  • Osamu YAMAKITA, Masahiro KOIDA, Mitsuhiro SHINOMIYA, Shigenori KATAYAM ...
    1990 Volume 15 Issue SupplementII Pages 151-163
    Published: June 30, 1990
    Released: February 21, 2008
    JOURNALS FREE ACCESS
    Mofezolac (N-22), a newly developed analgesic and anti-inflammatory agent, at dose levels of 0, 10, 30 and 90 mg/kg/day were administered orally to males from pre-mating to mating period and to females from pre-mating to early gestation period. Effects on reproductive performance of both sexes, especially reproductive capability, and development of offspring were examined. 1. In male parents, no changes in body weight and food consumption were found in all male groups, but the increase in gastric mucosal lesions such as ulcers were observed in 30 and 90 mg/kg/day groups. 2. In female parents, the decrease in body weight and food consumption of 90 mg/kg/day group during early gestation period were found, but at necropsy no changes were shown in all female groups. 3. Reproductive capability, mating and pregnancy performance were not affected. 4. No effects of N-22 on fetuses were observed. 5. The suggestions were as follows : No effect dose levels (NOELs) for male and female general-toxicolgically were 10 and 30 mg/kg/day, respectively. NOELs for reproductive capability and for fetal development were 90 mg/kg/day.
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  • Isao TOTENO, Sigeki HAGURO, Shigenori FURUKAWA, Tagahiko MORINAGA, Kyu ...
    1990 Volume 15 Issue SupplementII Pages 165-208
    Published: June 30, 1990
    Released: February 21, 2008
    JOURNALS FREE ACCESS
    The teratogenicity of mofezolac (N-22), a new developed analgesic and anti-inflammatory agent, was investigated in rats. N-22 was given orally to pregnant rats of the Jcl : Wistar strain (30 rats per group) at dose levels of 10, 50, 100 and 150 mg/kg/day from days 7 to 17 of gestation. Caesarean sections were performed on 20 dams per group on day 20 of gestation and their fetuses were examined for external, visceral and skeletal abnormalities. The remaining 10 dams per group were allowed to deliver and their offspring were examined for growth and reproductive performance. Results were as follows. 1. Effects on F0 generation At 150 mg/kg, eleven out of the 30 dams exhibited decreased motor activity, pale eyes, unkempt fur, urine-smeared lower abdomen, weakness and emaciation. At autopsy, twelve dams revealed gastrointestinal ulcers, peritonitic lesions, hypertrophy of the spleen, adrenal and mesenteric lymph node, atrophy of the submaxillary gland, thymus and liver and discoloration of the liver and kidney. Death, sacrificing in extremis, premature or delayed delivery and poor nursing occurred in one to two dams each. Food consumption was significantly decreased and body weight gain was significantly retarded in this dose level group. At 100 mg/kg, urine-smeared lower abdomen, hypertrophy of the spleen and poor nursing were observed in one dam each. 2. Effects on F1 generation At 150 mg/kg, significantly decreased fetal weight, increased number of immature fetuses and significantly retarded ossification of the 5th and 6th sternebrae and coccygeal vertebrae as well as significantly depressed body weight gain of female offspring were observed. No abnormalities were observed in each treated group in terms of development, behavior, learning ability and reproductive performance of offspring. 3. Effects on F2 generation No abnormalities were observed in fetuses and newborn young in each treated group. Based on these results, the maximum non-effective doses of N-22 in this study were considered to be 50 mg/kg/day for dams and offspring and 100 mg/kg/day for fetuses.
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  • Katsuya FUCHIGAMI, Tatsuo OTSUKA, Koichi SAMESHIMA, Kinya MATSUNAGA, R ...
    1990 Volume 15 Issue SupplementII Pages 209-218
    Published: June 30, 1990
    Released: February 21, 2008
    JOURNALS FREE ACCESS
    Mofezolac (N-22) is a new developed analgesic and anti-inflammatory agent. A teratogenicity study of N-22 was carried out in New Zealand White rabbits to examine the effect on the dams and the teratogenic potentiality. N-22 was administered orally at the dose levels of 12.5, 50 and 200mg/kg during the organogenesis from day 6 to day 18 of gestation. All pregnant females were sacrificed on day 28 of gestation and their fetuses were examined. There were no growth retardation and teratogenic effects on fetuses from the dams administered N-22, although the administration of 200 mg/kg produced a decrease in food consumption of the dams concomitant with the embryocidal effects as shown by an increase in the early resorption rate. Thus, non-toxic dose level of N-22 on the dams and fetuses was considered to be 50 mg/kg.
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  • Osamu YAMAKITA, Masahiro KOIDA, Mitsuhiro SHINOMIYA, Shigenori KATAYAM ...
    1990 Volume 15 Issue SupplementII Pages 219-237
    Published: June 30, 1990
    Released: February 21, 2008
    JOURNALS FREE ACCESS
    peri- and postnatal study of mofezolac (N-22), a new developed analgesic and anti-inflammatory agent, was carfied out with Wistar rats. N-22 at dose levels of 0, 25, 50 and 100 mg/kg/day were administered orally to pregnant and subsequent delivered dams from day 17 of gestation through day 21 of lactation. Body weight gains of dams treated with 50 and 100 mg/kg/day were depressed during perinatal period. Prolongation of pregnancy period, low performance of pup care with decrease in body weights and food consumptions were observed in 100 mg/kg/day group. Decrease in number and birth index, increase in number of stillborns and tendency to decrease in viability index on day 4 were found in 100 mg/kg/day group. Other parameters of development, behavior or reproductive capability of F1 animals showed no changes related to administration of N-22. It was suggested that no effect dose levels of N-22 were 25 mg/kg/day for dams viewpoint of general toxicity and that was 50 mg/kg/day for dams on reproductive performance and for offspring on development.
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  • Akinobu OHUCHIDA, Akemi FURUKAWA
    1990 Volume 15 Issue SupplementII Pages 239-251
    Published: June 30, 1990
    Released: February 21, 2008
    JOURNALS FREE ACCESS
    1. The reverse mutation test was carried out on mofezolac (N-22) at dose range of 50-5000 μg/plate using Salmonella typhimurium strains, TA100, TA98, TA1535 and TA1537, and Escherichia coli strain WP2uvrA. In all tester strains no significant increases were observed in the number of revertant colonies as compared with solvent control in the absence or presence of mammalian metabolic activation system. 2. The chromosomal aberration test on N-22 was carried out using cultured Chinese hamster lung cells (CHL). The cells were treated with N-22 at the doses of 37.5, 75.0, 150 and 300 pg/ml without S9 Mix and at the doses of 150, 300, 450 and 600 μg/ml with S9 Mix. No significant differences were found in the incidence of structural-and numeral-aberrations of chromosomes as compared with the solvent control in the system without S9 Mix. However, in the system with S9 Mix, structural aberration (11.5%) and numeral aberration (14.2%) of chromosomes were observed in the groups of dosing 600 μg/ml with dose dependency. 3. These results indicate that N-22 has clastogenic activity by the metabolic activation.
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  • Akinobu OHUCHIDA, Akemi FURUKAWA
    1990 Volume 15 Issue SupplementII Pages 253-260
    Published: June 30, 1990
    Released: February 21, 2008
    JOURNALS FREE ACCESS
    A micronucleus test using BDF1 male mice was conducted in order to evaluate the in vivo mutagenicity of mofezoldc (N-22). N-22 was orally administered at doses of 75, 150, 300 and 600 mg/kg, with a sampling time of 24hr. The frequency of polychromatic erythrocytes with micronuclei was 0.07-0.08% in the groups treated with N-22 and did not differ markedly from that of the vehicle control (0.13%). The present study indicates that N-22 has no in vivo mutagenic properties.
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  • Minoru TAKEMOTO, Kohya MATSUO, Shinji KATOH, Ryouichi YOSHIDA
    1990 Volume 15 Issue SupplementII Pages 261-268
    Published: June 30, 1990
    Released: February 21, 2008
    JOURNALS FREE ACCESS
    Antigenicity studies of mofezolac (N-22) were examined in mice and guinea pigs and the following results were obtained. The findings of active systemic anaphylaxis, passive hemagglutination test, 4 hour passive cutaneous anaphylaxis (4-hr PCA) and 8-day PCA in guinea pigs revealed that N-22 possessed neither immunogenic nor eliciting potentiality. However, N-22 was shown to be eliciting antigenicity in mice when given N-22-ovalbumin conjugate plus Freund's complete adjuvant (FCA) as immunogen.
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