The Journal of Toxicological Sciences
Online ISSN : 1880-3989
Print ISSN : 0388-1350
ISSN-L : 0388-1350
Volume 17 , Issue SupplementIII
Showing 1-12 articles out of 12 articles from the selected issue
  • Shuzo OKAZAKI, Eiichi YAMAZAKI, Kazutoshi TAMURA, Toru HOSHIYA, Kazuhi ...
    1992 Volume 17 Issue SupplementIII Pages 1-48
    Published: November 30, 1992
    Released: February 21, 2008
    JOURNALS FREE ACCESS
    The toxicity of Prednisolone farnesylate (PNF), a synthetic glucocorticoid, was investigated in the Sprague-Dawley rat. PNF was injected subcutaneousy at doses of 0.03, 0.3, 3 and 30 mg/kg/day for 13 weeks. In addition, 18.7 mg/kg/day prednisolone (PN), which is approximate to 30 mg/kg/day PNF in prednisolone molarity, was also administered to the rat for comparison. The results are summarized as follows: 1. All animals from the PN 18.7 mg/kg/day group, and four(4) out of ten(10) males and three(3) out of ten(10) females from the PNF 30 mg/kg/day group died having shown weakened condition such as unkempt fur and emaciation. Histopathologically, systemic suppurative inflammation, as shown by pyeronephritis and abscess formation in many organs and tissues, was observed and it was considered that the administration of steroid induced weakened condition and systemic suppuration which resulted in death. In addition, atrophy was noted in the adrenal glands, lymphatic organs and skin, and histopathological lesions were also observed in the lungs, liver, pancreatic islets, bone, bone marrow and mammary glands. 2. Surviving animals in the PNF 30 mg/kg/day group showed almost the same changes as those observed in the dead animals that died. Hematological examination revealed an anemic change and a decrease in lymphocytes with an increase in segmented neutrophils and eosinophils. In the urinalysis and blood chemistry, the changes suggesting damages to the liver and kidneys were mainly observed. 3. In the PNF 3 and 0.3 mg/kg/day groups, several changes such as atrophy of the adrenal glands, lymphatic organs and skin were noted in a dose dependent manner. 4. In the PNF 0.03 mg/kg/day group, there were no toxic signs. 5. Based on these results, it was concluded that the overt toxic dose of PNF was 0.3 mg/kg/day and the non-toxic dose was 0.03 mg/kg/day in the present study.
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  • Shuzo OKAZAKI, Eiichi YAMAZAKI, Kazutoshi TAMURA, Toru HOSHIYA, Kazuhi ...
    1992 Volume 17 Issue SupplementIII Pages 49-89
    Published: November 30, 1992
    Released: February 21, 2008
    JOURNALS FREE ACCESS
    The toxicity of Prednisolone farnesylate (PNF) gel, a synthetic glucocorticoid, was investigated in the Sprague-Dawley rat. PNF gel was administered dermally to the rats at doses of 0.25, 1, 4 and 16 mg/kg/day for 13 weeks, then the drug was withdrawn for 5 weeks to evaluate the reversibility. In addition, 10 mg/kg/day prednisolone gel (PN gel), which is approximate to 16 mg/kg/day PNF gel in prednisolone molarity, was also administered to the rats for comparison. The results are summarized as follows: 1. In the PNF gel 16 mg/kg/day group, temporary erythema at the application site, retarded body weight gains, a decrease in the white blood cell count and lymphocyte ratio with an increase in the segmented neutrophil ratio, an elevation of serum AIP activity were observed. The pathological examinations revealed atrophy of the adrenal glands, lymphatic organs and skin. In addition, histopathological lesions were also found in the liver, pancreatic islets, bone, bone marrow and mammary glands. 2. In the PNF gel 4 mg/kg/day group, retarded body weight gains were observed, and histopathological lesions were noted in the adrenal glands, lymphatic organs, skin at the application site, liver and bone marrows. 3. In the groups that received less than 1 mg/kg/day of PNF gel, there were no toxic signs induced by the drug. 4. In the PN gel 10 mg/kg/day group, drug-related changes were almost similar to those of the PNF gel group, but the severity of the lesions was stronger than in the PNF gel group. 5. After the 5-week recovery period, the above changes almost completely disappeared and so it was demonstrated that the changes were reversible. 6. Based on these results, it was concluded that the overt toxic dose of PNF gel was 4 mg/kg/day and the non-toxic dose was l mg/kg/day in the present study.
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  • Shuzo OKAZAKI, Eiichi YAMAZAKI, Kazutoshi TAMURA, Toru HOSHIYA, Kazuhi ...
    1992 Volume 17 Issue SupplementIII Pages 91-122
    Published: November 30, 1992
    Released: February 21, 2008
    JOURNALS FREE ACCESS
    The toxicity of Prednisolone farnesylate (PNF) gel, a synthetic glucocorticoid, was investigated in the Sprague-Dawley rat. PNF gel was administered dermally to the rats at doses of 0.125, 0.5 and 2.0 mg/kg/day for 52 weeks, then the drug was withdrawn for 8 weeks to evaluate the reversibility. The results are summarized as follows: 1. In the PNF gel 2.0 mg/kg/day group, thinning of the skin at the application site, slightly retarded body weight gains, a tendency toward a decrease in the white blood cell count, an elevation of serum GOT and GPT activity, free fatty acid level, and a decrease in αl-globulin fraction were observed. In the pathological examinations, decreased organ weights of the thymus, spleen and adrenal glands, and thinning of the skin were observed. Histopathological examination revealed atrophy of the thymus and zona fasciculata of the adrenal glands, thinning of the skin with atrophied skin appendages, and hepatocellular hypertrophy with hypertrophied uncleus in the perilobular zone. 2. In the PNF gel 0.5 mg/kg/day group, thinning of the skin at the application site and a decrease in αl-globulin fraction were observed. Histopathologically, thinning of the skin with atrophied skin appendages was observed. 3. In the PNF gel 0.125 mg/kg/day group, there were no toxic signs induced by the drug. 4. After the 8-week recovery period, the changes in the skin were observed in the 2.0 mg/kg/day group, but the severity was lowered. The other changes disappeared and so it was demonstrated that the changes were reversible. 5. Based on these results, it was concluded that the overt toxic does of PNF gel was 0.5 mg/kg/day and the non-toxic does was 0.125 mg/kg/day in the present study.
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  • Yoshikazu Nagashima, Fumisato Hisaoka, Makoto Ide, Kazutoshi Tamura, K ...
    1992 Volume 17 Issue SupplementIII Pages 123-160
    Published: November 30, 1992
    Released: February 21, 2008
    JOURNALS FREE ACCESS
    The toxicity of Prednisolone farnesylate (PNF) gel, a synthetic glucocorticoid, was investigated in the Beagle dog. PNF gel was administered percutaneously at doses of 0.2, 0.8 and 3.2 mg/kg/day for 13 weeks, then the drug was withdrawn for 5 weeks to evaluate the reversibility. In addition, 2 mg/kg/day prednisolone gel (PN gel), which is approximate to 3.2 mg/kg/day PNF gel in prednisolone molarity, was also administered for comparison. The results are summarized as follows: 1. No deaths were observed in any of the PNF gel test groups or the PN gel group, nor were there any abnormal findings in the clinical signs of the animals. 2. In the hematology, a tendency toward a decrease in the lymphocyte ratio was observed in males from the PNF gel 0.8 mg/kg/day and above groups. In the PN gel group, a significant decrease or a tendency toward a decrease in the lymphocyte ratio was observed, as well as an increase in the white blood cell count in some animals. 3. In the blood biochemistry, a significant decrease or a tendency toward a decrease in total cholesterol and phospholipid was observed in males from the PNF gel 3.2 mg/kg/day group and a tendency toward an increase in triglyceride in females from the PNF gel 3.2 mg/kg/day group was observed. In the PN gel group, a tendency toward an increase in AlP activity, a tendency toward an increase in triglyceride were observed. 4. In the histological examinations, a decrease in the weight of the thymus and adrenal glands, vacuolation of hepatocytes in the middle zone of the liver, atrophy of zona fasciculata of the adrenal glands, hypertrophy of zona glomeruli, swelling of cortical cells of zona faciculate and atrophy of the thymus were observed in the PNF gel 0.8 mg/kg/day and above groups. In the PN gel group, atrophy of submandibular lymph nodes and mesenteric lymph nodes was observed in addition to the same changes as observed in the PNF gel groups. Furthermore, thinning, atrophy or a decrease in the weight of the adrenal glands was also observed both in the PNF gel 3.2 mg/kg/day group and the PN gel group at the end of the 5-week recovery period. 5. As described above, a decrease in the lymphocyte ratio, in the weight of the thymus and adrenal glands and vacuolation of hepatocytes were observed in the PNF gel 0.8 mg/kg/day and above groups. These changes were also observed in the PN gel group and were reversible changes which are commonly observed with administration of adrenal cortex steroids. Therefore, it was concluded that the non-toxic dose level was 0.2 mg/kg/day for both males and females and the overt toxic dose level was 3.2 mg/kg/day in this 13-week toxicity study by percutaneous administration in beagle dogs.
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  • Yoshikazu Nagashima, Makoto Ide, Hiroyuki Akai, Kazutoshi Tamura, Kats ...
    1992 Volume 17 Issue SupplementIII Pages 161-199
    Published: November 30, 1992
    Released: February 21, 2008
    JOURNALS FREE ACCESS
    The toxicity of Prednisolone farnesylate (PNF) gel, a synthetic glucocorticoid, was investigated in the Beagle dog. PNF gel was administered percutaneously at doses of 0.05, 0.2 and 0.8 mg/kg/day for 52 weeks, then the drug was with held for 8 weeks to evaluate reversibility. The results are summarized in the following. 1. In the 0.05 mg/kg/day and above groups, hypotrichosis in the application site of the skin, thinning of the skin and atrophy of the appendages, and in the 0.2 mg/kg/day and above groups a tendency toward retarded body weight gain, were observed. 2. In the 0.2 mg/kg/day and above groups, a drop in the lymphocyte ratio, a rise in GOT activity and AlP level, and in the 0.8 mg/kg/day group a rise in free fatty acid were observed. 3. In the 0.2 mg/kg/day group and above groups, atrophy of the zona fasciculata and zona reticularis were observed. In the 0.8 mg/kg/day group, a decrease in the weight of the thymus and adrenal glands, and a increase in the weight of the liver, were observed. 4. At the end of the recovery period, most of the changes disappeared, except for those in the adrenals and treated area. From the above results, under the conditions of this study, it was concluded that when the changes observed in the application site of the skin in each group were not taken into consideration, the toxicologocal no effect level was 0.05 mg/kg/day for both males and females and the overt toxic dose level was 0.8 mg/kg/day.
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  • Hidemi TANIGUCHI, Hitoshi YOSHITOMI, Katsuyoshi MIYAZAKI, Nobuo KOGA, ...
    1992 Volume 17 Issue SupplementIII Pages 201-215
    Published: November 30, 1992
    Released: February 21, 2008
    JOURNALS FREE ACCESS
    A fertility study of Prednisolone farnesylate (PNF), a newly synthesized corticosteroid, was conducted in Sprague-Dawley rats. This compound was administrated subcutaneously at dose levels of 0(control), 0.04, 0.2 and l mg/kg/day to males for 63 days before mating and during the mating period, and to females for 14 days before mating, through the mating period and until day 7 of pregnancy. Each 24 male and female rats were mated, and females were killed on day 20 of pregnancy to examine their fetuses. 1. In the parental animals, loss of fur or thin fur and incrustation of treated site occurred in male rats treated at doses of 0.2 mg/kg or more and female rats treated at dose of l mg/kg, and at the same dose groups, the thinning of skin, atrophy of the thymus and intention of the substance at the injected site were noted. Moreover, body weight gains and food consumption were suppressed in both sexes treated at the dose of 1 mg/kg. 2. Fertility and reproductive ability in both sexes, and estrus cycles in female rats were not affected by administration of PNF. 3. In the fetuses, no embryonic or fetal lethal effect and teratogenic effect were noted. From these results, the no-effect dose levels of PNF on the parental general states, the parental reproductive ability and those of the fetuses are thought to be 0.04 mg/kg/day, l mg/kg/day or more and l mg/kg/day or more, respectively, under the experimental conditions of this study.
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  • Hidemi TANIGUCHI, Yoshifumi HIMENO, Masayuki CHONO, Eiki ARAKI, Masaru ...
    1992 Volume 17 Issue SupplementIII Pages 217-239
    Published: November 30, 1992
    Released: February 21, 2008
    JOURNALS FREE ACCESS
    A teratogenicity study of Prednisolone farnesylate (PNF), a newly synthesized corticosteroid, was conducted in Sprague-Dawley rats. This compound was administrated subcutaneously to female rats at dose levels of 0(control), 1, 5 and 25 mg/kg/day, once a day, for 11 days from day 7 to day 17 of pregnancy. In each dose group, 26 or 27 dams were killed on day 20 of pregnancy to examine their fetuses. The remaining 14 or 15 dams of each group were allowed to litter naturally, and observations were made on the postnatal growth and development of their offspring. 1. In the dams treated at doses of l mg/kg or more, decreased body weight gains and food consumption and retention of the substance at the injected site were noted. However, general signs, parturition, lactation and nursing behaviors were not affected by the administration of PNF. 2. In the F1 fetuses, no embryonic or fetal lethal effect, fetal retardation and teratogenic effect were noted. 3. In the F1 newborns, the postnatal growth, development, responses, behaviors, learning ability and reproductive ability were not influenced. Additionally, no embryonic or fetal abnormalities of their fetuses (F2) were detected. From these results, the no-effect dose levels of PNF on the parental general states, the parental reproductive ability and those of the F1 offspring are thought to be less than l mg/kg/day, 25 mg/kg/day and 25 mg/kg/day, respectively, under the experimental conditions of this study. Moreover, the F2 fetuses are not affected by doses up to 25 mg/kg/day of PNF.
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  • Sunao ASO, Satoshi MORITA, Yasuhiro KAJIWARA, Shinichi HORIWAKI, Hidet ...
    1992 Volume 17 Issue SupplementIII Pages 241-250
    Published: November 30, 1992
    Released: February 21, 2008
    JOURNALS FREE ACCESS
    The effect of Prednisolone farnesylate (PNF), a newly synthesized corticosteroid, on fetal development of the rabbit was studied. PNF was administered subcutaneously at dose levels of 0(control), 0.01, 0.05 and 0.25 mg/kg/day during the fetal organogenesis period. In the pregnant animals, PNF caused no abnormalities in clinical sign, body weight gain, food consumption, or autopsy findings at 0.0l and 0.05 mg/kg/day groups; the animals at 0.25 mg/kg/day group showed a reduction in body weight gain and food consumption. Two of 13 animals at 0.25 mg/kg/day group aborted. And hydrothorax, mucosal hemorrhage of the stomach, or fading of the liver were observed in some animals. In the fetuses, PNF was observed no abnormalities in external, visceral, or skeletal examination; slight increase of embryofetal mortality, or reduction of live fetal body weight and placental weight were observed at 0.25 mg/kg/day. The results suggest that the non-effective dose level of PNF is 0.05 mg/kg/day for pregnant females in general and reproductive toxicity, and for fetuses under the condition of this study.
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  • Hidemi TANIGUCHI, Eiki ARAKI, Motohiro NAGAI, Katsunori MASAKI, Shigem ...
    1992 Volume 17 Issue SupplementIII Pages 251-267
    Published: November 30, 1992
    Released: February 21, 2008
    JOURNALS FREE ACCESS
    The effects of Prednisolone farnesylate (PNF), a newly synthesized corticosteroid, administrated during the perinatal and postnatal periods were studied in Sprague-Dawley rats. This compound was injected subcutaneously to female rats at does levels of 0(control), 0.05, 0.5 and 5 mg/kg/day, once a day, for the period from day 17 of pregnancy to day 21 after parturition. Twenty-two to 25 dams in each dose group were allowed to litter naturally, and obserbations were made on the postnatal growth and development of their offspring. 1. In the dams treated at doses of 0.5 and 5 mg/kg, decreased body weight gains, atrophy of the thymus and retention of the substance at the injected site were noted. However, general signs, food consumption, parturition, lactation and nursing behaviors were not affected by the administration of PNF. 2. In the F1 newborns, the postnatal growth, development, rosponses, behaviors, learning ability and reproductive ability were not influenced. Additionally, no embryonic or fetal abnormalities of their fetuses (F2) were detected. From these results, the no-effect dose levels of PNF on the parental general states, the parental reproductive ability and those of the F1 offspring are thought to be 0.05 mg/kg/day, 5 mg/kg/day or more and 5 mg/kg/day or more, respectively, under the experimental conditions of this study. Moreover, the F2 fetuses are not affected by doses up to 5 mg/kg/day of PNF.
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  • Masanori OTSUKA, Shozo AJIMI, Yoshitsugu KAJIWARA, Shozo OGURA, Keijir ...
    1992 Volume 17 Issue SupplementIII Pages 269-281
    Published: November 30, 1992
    Released: February 21, 2008
    JOURNALS FREE ACCESS
    Prednisolone farnesylate (PNF) was tested for mutagenicity by Ames test using Salmonella typhimurium (TAl00, TA1535, TA98, TA1537) and Escherichia coli (WP2 uvrA), for clastogenic activity in vitro by the chromosomal aberration test in a Chinese hamster fibroblast cell line (CHL), and for induction of micronuclei by the micronucleus test in male ICR mice. 1) In Ames test, PNF with and without metabolic activation showed no mutagenicity in any strains at any dose levels (312∼5, 000 μg/plate). 2) In the chromosomal aberration test, PNF with metabolic activation produced a slight increase in the incidence of structural chromosomal aberrations in CHL cells at l, 500 μg/ml. 3) In the micronucleus test, a single administration of PNF caused no significant increase of micronucleated polychromatic erythrocytes at any doses (250∼2, 000 mg/kg).
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  • Hidemori UCHIYAMA, Tatsunori TANAKA, Nobuyuki UEHARA, Masaru NAKAMURA, ...
    1992 Volume 17 Issue SupplementIII Pages 283-312
    Published: November 30, 1992
    Released: February 21, 2008
    JOURNALS FREE ACCESS
    Various tests for irritation, phototoxicity, contact sensitivity and photocontact sensitivity of PNF gel were conducted. The results were as follows. 1) In the primary dermal irritation test and trypan blue test, slight erythema was noted in the rabbits treated with 0.8 and l.6% PNF gel, although similar reaction occurred in those treated with the base. 2) In the test for the primary irritation to the ocular mucosa, severe irritant reactions were caused by 0.8 and l.6% PNF gel and its base. However these reactions disappeared 7 days after irritation. 3) In the phototoxicity test and contact sensitivity test, no positive reactions were detected by 0.8 and l.6% PNF gel. On the other hand, in the photocontact sensitivity test, positive reaction were noted in the guinea pig treated with 0.8 and l.6% PNF gel and its base.
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  • Hideo Kaneko, Shinobu Kawaguchi, Yoshinori Misaki, yuichirou Koyama, A ...
    1992 Volume 17 Issue SupplementIII Pages 313-334
    Published: November 30, 1992
    Released: February 21, 2008
    JOURNALS FREE ACCESS
    Acute toxicity: Empenthrin ((RS)-(EZ)-1-ethynyl-2-methyl-2-pentenyl (1R)-cis/trans-chrysanthemate) caused some toxic signs such as muscular fibrillation, tremor, hypersensitivity, decrease of spontaneous activity, ataxic gait, lymb paralysis, irregular respiration, excretion of oily substance, loose stool and urinary incontinence in oral acute toxicity studies at l000 mg/kg and above in rats, and at 2000 mg/kg and above in mice. The oral LD50 value was estimated greater than 5000 mg/kg (male) and greater than 3500 mg/kg (female) in rats and greater than 3500 mg/kg (both sexes) in mice. In both rats and mice, the toxic signs were not found at 2000 mg/kg by dermal administration. The dermal LD50 value was estimated greater than 2000 mg/kg (both sexes) in both rats and mice. The LC50 value in rats for the acute inhalation toxicity of empenthrin was estimated to be greater than 4610 mg/m3 for both sexes. The LC50 value in mice was determined to be 2700 mg/m3 for male and 2300 mg/m3 for female. Mice showed higher sensitivity to empenthrin than rats. 2. Reproductive and developmental toxicity: Empenthrin was orally administered to fetal organogenesis periods of rats at the dose levels of 50, 150 and 500 mg/kg, and of rabbits at 100, 300 and 1000 mg/kg. Maternal toxicity was found at 500 mg/kg in rats and at 300 mg/kg or more in rabbits. There were no teratogenicity, no embryotoxicity and no fetal retardation in rats or rabbits. In addition, there were no adverse effects on Fl pups growth, development or reproductive performanece. 3. Subchronic toxicity: Empenthrin was orally administered to male and female SD rats at dose levels of 0 (corn oil), 10, 100 and 300 mg/kg for 26 weeks. Clinical signs, body weight, food and water consumption were monitered, and hematological, blood biochemical, ophthalmological and histopathological examination were carried out. As a result, changes related to administration of empenthrin were observed mainly in the liver and kidneys in rats receiving l00 mg/kg or more. Therefore, the no-effect-level of empenthrin is determined to be l0 mg/kg in both sexes of rats in this study.
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