Eisei Shikenjo hokoku. Bulletin of National Institute of Hygienic Sciences最新文献

The raw material for prednisolone acetate was tested for preparation of the "Prednisolone Acetate Reference Standard (Control 941)". Analytical data obtained were as follows: melting point, 237.5 degrees C (decomposition); UV and infrared spectra, the same as those for JP Prednisolone Acetate Reference Standard (Control 903), respectively; specific absorbance at lambda max E1%1cm = 379; optical rotation, [alpha]20D = +115.2 degrees; thin-layer chromatography and high-performance liquid chromatography (HPLC), no impurities were detected, respectively; assay, 100.8% by HPLC. Based on the above results, the candidate material was authorized as the Japanese Pharmacopoeia Reference Standard (Control 941).

A 13-week oral toxicity study of beta-cyclodextrin was carried out in F344 rats at the dose levels of 10, 5, 2.5, 1.25, 0.6 and 0% in powdered diet. Each group consisted of 10 males and 10 females. All animals survived at the end of the experiment, while a slight decrease in body-weight gain was observed in males of the 10%- and 5%-groups. Dose-dependent increases in serum levels of GOT, GPT and alkaline phosphatase were observed in treated animals of both sexes, and increases in serum levels of urea nitrogen and relative liver weights in treated males. Histopathologically, a dose-dependent increase in the severity of inflammatory cell infiltration was seen in the liver of treated animals, focal hepatocellular necrosis being detected in both sexes of the 10%-group and females of the 5%-group. These findings indicate that beta-cyclodextrin causes hepatocellular injury to rats when it is orally administered.

Preparation of International Chemical Safety Cards (ICSC) is described. The main characteristics of the ICSC are the use of standard phrases, a compiler's guide and a program for their preparation by personal computer. Standard phrases harmonize expressions on ICSC and also facilitate translation into other languages. In our case more than 900 cards have been translated into Japanese and published. Recently, a new program to aid translation by personal computer has been developed.

Recent progress in both protein drug production technologies including biotechnology and protein characterization methodologies has enabled us to mass-produce and extensively characterize highly purified protein drugs. The quality control of these protein drugs, being based on such a background, should be carried out using various modern protein analytical methodologies. One of the points to be considered regarding control strategies for these protein drugs should be the development and standardization of more specific, precise, simple and economical assay methodology. The replacement of existing in vivo bioassays with certain in vitro assays, including physico-chemical assays, is one possible directions along this line. This paper describes strategies for the replacement of an in vivo bioassay for protein drugs with a physico-chemical assay. Such approaches have been applied for recombinant human growth hormone and recombinant human insulin, the potencies of which have been estimated by in vivo bioassay. Scientific rationale for such approaches are also discussed.

Raw ascorbic acid material was tested for preparation of the "Ascorbic Acid Reference Standard (Control 931)". Analytical data obtained were as follows: infrared spectrum, the same as that of the JP Ascorbic Acid Reference Standard; optical rotation -alpha-20D, + 21.4 degrees; melting point, 190.3 degrees C (decomposition); loss on drying, 0.02%; assay result, 100.1% by iodometry. Based on the above findings, the raw material was authorized as the JP Ascorbic Acid Reference Standard (Control 931).

Raw alprostajil material was examined for preparation of the "Alprostajil Reference Standard (Control 921)". Analytical data obtained were as follows: infrared spectrum, the same as that of the USP Alprostajil Reference Standard; thin-layer chromatography, no impurities were detected up to 20 micro g; high-performance liquid chromatography (HPLC), no impurities were detected; assay result, 99.6% by HPLC. Based on the above findings, this raw material was authorized as the NIHS Alprostajil Reference Standard (Control 921).

Revision of microbial tests in the Pharmacopoeia of Japan has been in progress since 1992. The affected areas include sterility tests, microbial limit tests, antimicrobial preservatives-effectiveness, and methods for strilization. Here, the revision of sterility tests, as well as of microbial limit tests, is discussed in detail. Several problems in JPXII are also described.

Raw cyanocobalamin material was tested for preparation of the "Cyanocobalamin Reference Standard (Control 931)". Analytical data obtained were as follows: loss on drying, 4.2%; infrared spectrum, the same as that of the JP Cyanocobalamin Reference Standard (Control 901); thin-layer chromatography, four impurities were detected; high-performance liquid chromatography (HPLC), seven to eight kinds of impurities were detected, but the total amount of impurities was only 1.0 +/- 0.52% (n = 5); assay results, 100.6% by spectrophotometry in the JP XII and 99.7% by HPLC. Based on the above findings, the raw material was authorized as the JP Cyanocobalamin Reference Standard (Control 931).

Many carcinogens react with DNA and form critical DNA adducts, such as O6-alkylguanine (O6-AG), O4-alkylthymine (O4-AT), and 8-hydroxyguanine (8-OHG). This study provides a database that can be used for molecular dosimetry of these DNA adducts. A literature survey on DNA binding in vivo was done by the Dialog search from the MEDLINE database. We propose a Critical Covalent Binding Index (CCBI) for the assessment of in vivo DNA binding level (expressed as micro mol chemical bound per mol G or T/mmol chemical administered per kg body weight). The number of records and compounds in parenthesis of O6-AG, O4-AT, and 8-OHG were 245(13), 54(4), 79(15), respectively. Since the CCBI values for N-nitrosamine in target organ were higher than for non-target organ, they may provide a useful index for estimation of target organ site and carcinogenic potency. As a case example, CCBI values for O4-AT from animal data were applied for diethylnitrosamine human exposure estimation by diethylnitrosamine.

Tributoxyethyl phosphate (TBEP) is widely used in household materials such as plasticizer, floor polish and flame retardant in plastic resins and synthetic rubbers. This compound has been detected at ppb level in underground water. In order to elucidate the toxicity of TBEP, a 14-week oral toxicity study was conducted. Wistar rats (5-weeks old, male & female, 15 rats/group) were given diet containing 0, 0.03, 0.3 or 3.0% TBEP. Suppression of body weight gain was observed in both sexes of the 3.0% group. Serum cholinesterase activity was significantly decreased in both sexes of the 0.3 and 3.0% groups and serum gamma-glutamyl transferase activity was significantly increased in both sexes of the 3.0% group after 5 and 14 weeks exposure. Amylase in serum was also increased in 0.3 and 3.0% group males and 3.0% group females. Absolute and relative liver weights in both sexes were significantly increased in the 3.0% group after 5 and 14 weeks of exposure. Histopathological examination revealed moderate periportal hepatocyte swelling in male rats of the 3.0% group after 14 weeks exposure but this change was not found in male rats given 0.3% or less of TBEP in the diet or in any of the females. These findings indicated that the liver is a target organ for TBEP toxicity. We concluded a no-observed effect level (NOEL) of TBEP in the diet of 0.03% (male: 20 mg/kg/day, female: 22 mg/kg/day) under the conditions of this toxicity study.