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Subchronic inhalation and oral toxicity of N-vinylpyrrolidone-2. Studies in rodents
Abstract
N-Vinylpyrrolidone-2 (NVP) is a monomeric compound used as an industrial intermediate. Nine of 11 studies previously reported involved exposure of rats (two different strains), mice or hamsters to NVP by the inhalation route at concentrations of up to 120 ppm (6 hr/day, 5 days/wk) over a period of 1 wk to 12 months. The remaining two studies involved exposure of rats to NVP through the drinking water or by gavage at dose levels of up to 100 mg/kg body weight/day. Reduced body weight gain was seen in rats exposed by inhalation to 5 ppm or more for 3 months and in mice and hamsters exposed to 45 ppm for only 1 day. Effects were seen on haematological (reduced haemoglobin, erythrocyte count, haematocrit) and clinical chemistry parameters (specially raised gamma-glutamyltransferase activity and decreases in plasma protein), liver weight increase and liver lesions (centrilobular single-cell necrosis and foci of hepatocellular alteration) in rats and mice but not hamsters. Rats exposed to 40 mg/kg body weight/day NVP or more for 3 months by gavage developed similar liver changes. Atrophy of olfactory epithelium and hyperplasia of nasal respiratory epithelium was seen in rats exposed by inhalation to 5 ppm NVP for 7 wk but not in response to 1 ppm for 13 wk (no observed-adverse-effect level, NOAEL). These studies indicated that the upper respiratory tract and the liver are the main targets for NVP toxicity.
... Previous studies showed toxicity of NVP especially to the target organs liver (increased gamma-glutamyl transpeptidase and glutathione: LOAEC in rats 5 ppm, in mice 10 ppm; foci of altered hepatocytes in rats at 5 ppm) and nasal mucosa (nasal cavity inflammation, olfactory epithelium atrophy as well as hyperplasia of the olfactory and respiratory epithelium basal cells: LOAEC in rats and mice 5 ppm). In addition, the number of erythrocytes, hematocrit and hemoglobin were reduced in rats and mice at 15 ppm (Klimisch et al. 1997b). Upon inhalation NVP was carcinogenic in the rat liver, nasal cavity and larynx (Table 1). ...
... However, the weakness of the effect precludes a firm conclusion. Yet, previous studies (Klimisch et al. 1997b) already had shown a decrease in the hemoglobin, the hematocrit and the erythrocytes after treatment of rats (two strains: Sprague Dawley and Fischer 344) as well as mice (C57BL/6NCrl) after NVP inhalation starting at 15 ppm and starting at an exposure time of 6 weeks indicating presence and toxicological activity of inhaled NVP in the bone marrow. ...
... In apparent contrast to the present study (treatment of rats with NVP for 5 days) previous studies of the same laboratory, in which GSH was not specifically determined, but rather as total non-protein-bound sulfhydryls, reported an increase of these total non-protein-bound sulfhydryls (after treatment of Sprague-Dawley rats by inhalation for 3 months with 10 ppm NVP, after 6 months in C57BL mice and F344 rats and after 1 week treatment with 15 ppm NVP) (Klimisch et al. 1997b). As a speculation, a somewhat longer treatment of rats with NVP than the 5 days of the present study may lead to a compensatory increase of non-protein-bound sulfhydryls. ...
N -vinyl pyrrolidone (NVP) is produced up to several thousand tons per year as starting material for the production of polymers to be used in pharmaceutics, cosmetics and food technology. Upon inhalation NVP was carcinogenic in the rat, liver tumor formation is starting already at the rather low concentration of 5 ppm. Hence, differentiation whether NVP is a genotoxic carcinogen (presumed to generally have no dose threshold for the carcinogenic activity) or a non-genotoxic carcinogen (with a potentially definable threshold) is highly important. In the present study, therefore, the existing genotoxicity investigations on NVP (all showing consistently negative results) were extended and complemented with investigations on possible alternative mechanisms, which also all proved negative. All tests were performed in the same species (rat) using the same route of exposure (inhalation) and the same doses of NVP (5, 10 and 20 ppm) as had been used in the positive carcinogenicity test. Specifically, the tests included an ex vivo Comet assay (so far not available) and an ex vivo micronucleus test (in contrast to the already available micronucleus test in mice here in the same species and by the same route of application as in the bioassay which had shown the carcinogenicity), tests on oxidative stress (non-protein-bound sulfhydryls and glutathione recycling test), mechanisms mediated by hepatic receptors, the activation of which had been shown earlier to lead to carcinogenicity in some instances (Ah receptor, CAR, PXR, PPARα). No indications were obtained for any of the investigated mechanisms to be responsible for or to contribute to the observed carcinogenicity of NVP. The most important of these exclusions is genotoxicity. Thus, NVP can rightfully be regarded and treated as a non-genotoxic carcinogen and threshold approaches to the assessment of this chemical are supported. However, the mechanism underlying the carcinogenicity of NVP in rats remains unclear.
... The classifications are based among others on long-term inhalation exposure studies with Sprague-Dawley rats by Klimisch et al, in which adenocarcinoma of the nasal cavity and liver cell carcinoma occurred. 18,19 The metabolism is only described roughly in a theoretical model in the technical rules for hazardous substances (TRGS 900) of the commission on hazardous substances by the DFG. 20 Isotope-labeled VP given to rats was excreted to 75 % in the first 12 h after gavage. ...
Rationale:
The monomer 1-vinyl-2-pyrrolidone (VP) is a substance with excellent solvent features. It is used in a wide variety of pharmaceutical, cosmetic, food industrial or technical applications and produced in industrial scale. Since VP has caused adenocarcinoma of the nasal cavity and liver cell carcinoma in long term experiments with rats, a human biomarker would be appreciated for risk assessment.
Methods:
A sensitive analytical electron ionization GCMSMS method for the determination of six possible biomarkers for VP in urine was established and validated. Two isotope labeled internal standards (ISTD) were used for quantification. A simple and easy to use freeze drying step was performed prior to derivatization with N-tert-butyldimethylsilyl-N-methyltrifluoracetamide (MTBSTFA) and following sample extraction for cleanup purposes.
Results:
A calibration curve with 6 calibration standards ranging from 50 μg/L to 2000 μg/L (10 fold higher for H-OPAA) in urine was prepared. Validation results were satisfying with recoveries ranging from 88.2 to 110.2 % with two exceptions for the lowest quality control for two substances without ISTD (126.4 % and 139.3 %). Three of the substances could be identified as VP metabolites in an exposure study with Sprague-Dawley (SD) rats.
Conclusions:
The paper provided describes a quick and easy to use method of six target molecules investigated for better understanding of the VP metabolization. Two of three substances identified as metabolites of VP might serve as a nonspecific human biomarker for a VP exposure as shown with an excerpt of an exposure study performed in SD rats.
... Klimisch et al. (1997) a NOAEC for 6 h/day exposure corrected to a value for chronic exposure and for 5 days per week. ...
The inhalation toxicology studies available in the public domain have been reviewed to establish a database for inhalation toxicology and derive thresholds of toxicological concern (TTC) for effects in the respiratory tract and systemically for Cramer class 1 and 3 chemicals. These TTCs can be used as the basis for developing an exposure based waiving (EBW) approach to evaluating the potential for adverse effects from exposure to ingredients in aerosol products, used by consumers. The measurement of consumer exposure in simulated product use is key to the application of an exposure based waiving approach to evaluating potential consumer risk. The detailed exposure evaluation for aerosol ingredients with defined use scenarios, in conjunction with an evaluation of the potential structure activity relationship for toxicity and the TTCs for inhalation exposure could be used to waive undertaking inhalation toxicology studies under REACH. Not all classes of chemicals are suitable for such an approach, but for chemicals with a predictable low potential toxicity, and very low levels of exposure, this approach, could reduce the amount of inhalation toxicology studies required for the implementation of the European REACH legislation. Such an approach is consistent with the concept of developing 'intelligent testing strategies' for REACH.
The Saussurea lappa (Sc), traditionally known as Costus, is a perennial effective root extensively used to treat various ailments. This study intends to evaluate the anticancer effect of Sc- Root Extract (Sc-RE) against cancer induced by intraperitoneal injection of Polyvinyl pyrrolidone K-30 (PVP) in mice. 72 mice divided randomly into eight groups (G1, control group; G2, Sc-RE group; G3, chemotherapy alone; G4 cancer- group without treatment, G5, cancer-induced + chemotherapy; G6, cancer induced+ Sc-RE/ low dose; G7, cancer induced+ Sc-RE/ moderate
dose; G8, cancer induced+ Sc-RE/ high dose). Liver and kidney samples were collected from all mice during different
experiment periods, kept in 10% neutral buffered formalin, and sent for histological analysis. No abnormal histological
features were seen in liver and kidney sections from the control and other mice groups before various treatments. The
various treatment groups revealed diverse histopathological changes compared to the control groups. Various histological
features were also seen in low, moderate, and high-dose Sc-RE treatment groups, accompanied by regeneration related
to the treatment dose. Severe damage comprising necrosis of the hepatic cells, renal tubules, congestion, and infiltration
of inflammatory cells was seen in the chemotherapy-treated group and mice suffering from cancer without treatment.
This study also revealed variations in serum liver enzyme values between treatment groups. The values of ALT, AST,
and ALP (U/L) evaluation in control groups were ˃ 29.01±1.8, 87.55±2.9 and ˃ 98.12±8.8, respectively. In conclusion,
this study investigated that the ethanolic extract of Sc-RE has an anticancer effect that reduces the proliferation of
cancer cells caused by the carcinogenic substance.
Half Title Series Info Title Copyright Preface Acknowledgements Contents
N-vinyl-2-pyrrolidone (NVP) is mainly used as a monomer in the production of polyvinylpyrrolidone or copolymers. Percutaneous absorption is an important source of exposure in the work environment. However, few studies have investigated this route of absorption. In this study, percutaneous absorption of neat or aqueous NVP solutions was measured in vivo and ex vivo in rats, and ex vivo in humans. Penetration and absorption fluxes were very similar following in vivo exposure to neat NVP (0.54 and 0.43 mg/cm(2)/h, respectively). Exposing rats to a 50 % aqueous solution of NVP increased both fluxes threefold (to 1.48 and 1.55 mg/cm(2)/h, respectively). Ex vivo, the absorption flux increased with solutions from 10 to 25 % of NVP, reached a plateau (between 25 and 50 % in rat, 25 and 75 % in human) and then decreased with neat NVP. In vivo and ex vivo absorption fluxes measured using rat skin were similar, supporting the hypothesis that the ex vivo measurements were a good representation of what was observed in vivo. Thus, for humans, the ex vivo measurements are likely the same as would be determined in vivo.
We have become progressively more concerned about the quality of some published ecotoxicology research. Others have also expressed concern. It is not uncommon for basic, but extremely important, factors to apparently be ignored. For example, exposure concentrations in laboratory experiments are sometimes not measured, and hence there is no evidence that the test organisms were actually exposed to the test substance, let alone at the stated concentrations. To try to improve the quality of ecotoxicology research, we suggest twelve basic principles that should be considered, not at the point of publication of the results, but during the experimental design. These principles range from carefully considering essential aspects of experimental design through to accurately defining the exposure, as well as unbiased analysis and reporting of the results. Although not all principles will apply to all studies, we offer these principles in the hope that they will improve the quality of the science that is available to regulators. Science is an evidence-based discipline and it is important that we and the regulators can trust the evidence presented to us. Significant resources often have to be devoted to refuting the results of poor research when those resources could be utilised more effectively.
The aim of this study was to investigate the feasibility of eliminating organic solvent consumption for the synthesis of biodegradable poly(lactide ethylene oxide fumarate) (PLEOF). A gas expanded solution comprised of high pressure carbon dioxide (CO2) and dichloromethane (DCM) or poly(ethylene glycol) (PEG) was used as an alternative medium for the synthesis of PLEOF. The effect of pressure (50–150 bar), temperature (25–50 °C) and the amount of DCM on the yield, molecular weight and thermal properties of PLEOF was examined. The results of 1H NMR and ATR-FTIR analysis confirmed that it is possible to conduct the PLEOF synthesis in a high pressure CO2 expanded solution as a reaction medium and acquire similar characteristics compared to the conventional method using neat DCM. A comparable yield was achieved in a high pressure CO2 expanded solution process even when DCM was decreased to only 14% of the amount used in the conventional method. Increasing the pressure from 50 to 150 bar had no significant effect on the yield. In addition, DCM could be completely eliminated from the polymerisation by increasing the temperature to 50 °C and pressure to 100 bar. Under these conditions, the synthesis was carried out in PEG expanded solution due to the melting point depression effect of CO2. It is, therefore, viable to conduct the polymerisation of PLEOF in gas expanded solution as a benign solvent and can either substantially reduce or eliminate the consumption of volatile organic solvents. The synthesised PLEOF was also crosslinked with poly(ethylene glycol) diacrylate (PEGDA) as a non-toxic crosslinker to produce an injectable hydrogel. The hydrogel prepared from PLEOF that was synthesised by gas expanded solution had better mechanical properties and less toxicity to primary human osteoblast cells. This study demonstrated that the synthesis process can have a significant impact on improving the physical properties and biological activity of the PLEOF polymer.
N ‐vinyl‐2‐pyrrolidone was plasma‐polymerized on glass substrates using a pulsed AC plasma. Pulsed AC plasma produces a chemical surface structure different from that produced by conventional RF plasma; this is ascribed to the different power regimes used. A high degree of control over the structure of the chemical surface was obtained using pulsed AC plasma, as shown by ToF‐SIMS. It is demonstrated how the experimental conditions to some extent control the chemical structure of the plasma‐polymerized film, e.g., film thickness, density of post‐plasma‐polymerized oligomeric chains, and the density of intact pyrrolidone rings.
Electrode configuration and gas flow in the two‐phase AC plasma chamber.
magnified image Electrode configuration and gas flow in the two‐phase AC plasma chamber.
N-vinylpyrrolidone dimer (VPD), a novel vehicle for preclinical toxicity studies, was evaluated in a standard 28-day oral toxicity study in rats including a 4 week recovery period. In addition, a subgroup of animals was dosed for 13 weeks. In the 28-day study arm, daily dosages of 0 (saline control, 3 mL/kg), 300, 1000 or 3000 mg/kg at respective dose volumes of 0.3, 1 and 3 mL/kg were administered. In the 13 week study arm, animals received daily doses of 0 or 300 mg/kg. No test item related mortality or changes in body weight, food consumption, ophthalmology and clinical pathology parameters were observed after 28-days or 13 weeks of administration. VPD induced transient salivation at all tested dose levels after each dose and increased water consumption at doses ≥1000 mg/kg (28-day arm).
Porous nanocomposites based on poly(ε-caprolactone fumarate) (PCLF) resin matrix; N-vinyl pyrrolidone (NVP) as a reactive diluents and nanohydroxyapatite (nHA) filler were developed for bone tissue engineering applications. Nanocomposite scaffolds with three different contents of nHA [5, 10, and 20 (w/w %)] were prepared by thermal crosslinking of PCLF followed by particulate leaching and characterized in terms of mechanical properties (cyclic loading) and in vitro cell-material interaction by MTT assay and alkaline phosphatase activity measurements. Five osteoblastic cell lines were used to investigate the ability of the nanocomposites to support cell attachment, spreading, and proliferation after 3, 7, and 14 days. By adding the nHA filler phase, elastic modulus of the nanocomposites increased significantly. Scaffolds showed comparable biocompatibility to neat nHA particles, commercial bone graft (Bio-Oss) and tissue culture polystyrene as control groups. According to the results it can be concluded that these scaffolds are potential candidates for bone substitution because of their mechanical strength and bioactivity.
In the absence of toxicological data on a chemical, the threshold of toxicological concern (TTC) approach provides a system to estimate a conservative exposure below which there is a low probability of risk for adverse health effects. The original toxicology dataset underlying the TTC was based on NOELs from repeat dose studies. Subsequently there have been several efforts to assess whether or not these limits are also protective for reproductive/developmental effects. This work expands the database of chemicals with reproductive and developmental data, presents these data in a comprehensive and transparent format and groups the chemicals according to the TTC "Cramer Class" rules. Distributions of NOAELs from each of these classes were used to assess whether the previously proposed TTC values based on repeat dose data are protective for reproductive/developmental toxicity endpoints as well. The present analysis indicates that, for each Cramer Class, the reproductive and developmental endpoints would be protected at the corresponding general TTC tiers derived by Munro et al. (1996).
This study investigated the toxicity of N-vinyl-2-pyrrolidone-acrylic acid copolymer hydrogels crosslinked with ethylene glycol dimethacrylate or poly(ethylene glycol) dimethacrylate. There is a pressing need to establish the toxicity status of these new copolymers because they may find applications in future wound healing processes. Investigations revealed that the capacity of these hydrogels for swelling permitted the retention of high amounts of water yet still maintaining structural integrity. Reverse phase HPLC analysis suggested that unreacted monomeric base material was efficiently removed post-polymerization by applying an additional purification process. Subsequently, in vitro toxicity testing was performed utilizing direct and indirect contact exposure of the polymers to human keratinocytes (HaCaT) and human hepatoma (HepG2) cells. No indication of significant cell death was observed using the established MTT, neutral red (NR) and fluorescence-based toxicity endpoint indicators. In addition, the alkaline Comet assay showed no genotoxic effects following cell exposure to hydrogel extracts. Investigations at the nucleotide level using the Ames mutagenicity assay demonstrated no evidence of mutagenic activity associated with the polymers. Findings from this study demonstrated that these hydrogels are non-cytotoxic and further work can be carried out to investigate their potential as a wound-healing device that will impact positively on patient health and well-being.
The present study deals with the preparation and characterization of an injectable and in situ forming drug delivery system based on photocrosslinked poly(epsilon-caprolactone fumarate) (PCLF) networks loaded with tamoxifen citrate (TC). Networks were made of PCLF macromers, a photoinitiation system (comprising initiator and accelerator) and the active ingredient N-vinyl-2-pyrrolidone (NVP) as a crosslinker and reactive diluent. Shrinkage behavior, equilibrium swelling and sol fraction ratios of photocrosslinked PCLF gels were determined as functions of NVP content. It was shown that the crosslinking is facilitated up to a certain concentration of NVP and most of NVP remained unreacted above this value. In vitro drug release, biocompatibility evaluation and activity against MCF-7 breast cancer cell line were also investigated. Accurate but simple bipartite expressions were also derived that enable rapid determination of effective diffusion coefficients of TC in photocrosslinked PCLF/NVP disks. Cytotoxicity assay showed that while the photocrosslinked PCLF network with optimum NVP content exhibits no significant cytotoxicity against MCF-7 and L929 cell lines, 40-60% of the MCF-7 cells were killed after incubation with TC-loaded devices.
In previous subchronic studies inhaled N-vinylpyrrolidone-2 (NVP) was haemotoxic, hepatotoxic and irritant to the nose. In the first of two long-term studies, study A, Sprague-Dawley rats were exposed by inhalation to 0, 5, 10 or 20 ppm NVP (6 hr/day, 5 days/wk) for 24 months. Satellite groups were killed after 3, 12 or 24 months. In study B, female Sprague-Dawley rats were exposed to 0 or 45 ppm NVP for 3 months and killed at 3 or 12 and 24 months post-exposure. In study A, survival was unaffected, but reduced body weight gain, haemotoxicity, effects on clinical chemistry parameters indicative of hepatotoxicity, increased liver weight, hepatocellular carcinomas, necrosis, reparative hyperplasia, adenomas and adenocarcinomas of the nasal cavity, and squamous cell carcinomas of the larynx were seen. Increased tumour incidence was seen only in the liver and upper respiratory tract. In study B, the effect of NVP on body weight evident at 3 months disappeared before 1 yr, but effects on liver pathology persisted throughout the subsequent 21-month exposure-free period, and a few liver tumours were seen at 2 yr. As NVP gave negative results in a battery of in vitro and in vivo genotoxicity tests, it appears that the tumours that arose were manifestations of a non-genotoxic mechanism.
The Carcinogenic Potency Database (CPDB) is a systematic and unifying resource that standardizes the results of chronic, long-term animal cancer tests which have been conducted since the 1950s. The analyses include sufficient information on each experiment to permit research into many areas of carcinogenesis. Both qualitative and quantitative information is reported on positive and negative experiments that meet a set of inclusion criteria. A measure of carcinogenic potency, TD(50) (daily dose rate in mg/kg body weight/day to induce tumors in half of test animals that would have remained tumor-free at zero dose), is estimated for each tissue-tumor combination reported. This article is the ninth publication of a chronological plot of the CPDB; it presents results on 560 experiments of 188 chemicals in mice, rats, and hamsters from 185 publications in the general literature updated through 1997, and from 15 Reports of the National Toxicology Program in 1997-1998. The test agents cover a wide variety of uses and chemical classes. The CPDB Web Site (http://potency.berkeley.edu/) presents the combined database of all published plots in a variety of formats as well as summary tables by chemical and by target organ, supplemental materials on dosing and survival, a detailed guide to using the plot formats, and documentation of methods and publications. The overall CPDB, including the results in this article, presents easily accessible results of 6153 experiments on 1485 chemicals from 1426 papers and 429 NCI/NTP (National Cancer Institute/National Toxicology program) Technical Reports. A tab-separated format of the full CPDB for reading the data into spreadsheets or database applications is available on the Web Site.
Intraocular drug delivery systems made from biodegradable polymers hold great potential to effectively treat chronic diseases of the posterior segment of the eye. This study is based on the hypothesis that crosslinked poly(propylene fumarate) (PPF)-based matrices are suitable long-term delivery devices for the sustained release of the anti-inflammatory drug fluocinolone acetonide (FA) due to their hydrophobicity and network density. FA-loaded rods of 10 mm length and 0.6 mm diameter were fabricated by photo-crosslinking PPF with N-vinyl pyrrolidone (NVP). The released amounts of FA and NVP were determined by HPLC analysis. The effects of drug loading and the ratio of PPF to NVP on the release kinetics were investigated using a 2(3-1) factorial design. Overall, FA release was sustained in vitro over almost 400 days by all tested formulations. Low burst release was followed by a dual modality release controlled by diffusion and bulk erosion with release rates up to 1.7 microg/day. The extent of the burst effect and the release kinetics were controlled by the drug loading and the matrix composition. Matrix water content and degradation were determined gravimetrically. Micro-computed tomography was used to image structural and dimensional changes of the devices. The results show that photo-crosslinked PPF-based matrices are promising long-term delivery devices for intraocular drug delivery.
Copolymers of N-vinylpyrrolidinone and acrylic acid, crosslinked with ethylene glycol dimethacrylate and polyethylene glycol 600 dimethacrylate were prepared by UV-polymerisation. These polymers were analysed for their extractable content by Soxhlet extraction of the samples at 100 degrees C for 72 h. Aspirin and paracetamol were incorporated into the polymer structure at 25 wt.% during the curing process and their presence confirmed by Fourier transform infrared spectroscopy. It was found that the release rate of the drug from the polymer matrix was dependent on intermolecular bonding between the polymer and active agent with aspirin being released slower than paracetamol in all cases. Results showed that paracetamol was completely released after 24h whereas complete release of aspirin took up to 70 h. Finally preliminary in vitro biocompatibility testing was performed for crosslinked polyvinylpyrrolidinone, by determining human hepatoma HepG2 cell viability in the MTT assay and DNA damage in the comet assay following direct contact with various concentrations of polyvinylpyrrolidinone-containing media. Cytotoxicity data suggests a dose-dependent effect for both crosslinkers, with concentrations in the range 0.025-2.5 mg ml(-1) showing a marginal decrease in viability to, at most, 70% that of untreated cells. Again DNA migration in the comet assay following short-term exposure to EGDMA crosslinked hydrogels correlates with MTT data.
The function of a photocrosslinked poly(propylene fumarate) (PPF)/poly(N-vinyl pyrrolidone) (PVP) matrix for the sustained release of three ophthalmic model drugs, acetazolamide (AZ), dichlorphenamide (DP), and timolol maleate (TM), was investigated. The drugs differ in molecular weight and degree of dissociation in aqueous environments; both are parameters that significantly influence drug diffusivity. AZ, DP, and TM-loaded cylindrical rods (10 mm length, 0.6 mm diameter) were fabricated by photoinduced cross-copolymerization of PPF and N-vinyl pyrrolidone (NVP) in molds. The released amounts of AZ, DP, TM, and NVP were determined by high-performance liquid chromatography (HPLC). The effects of drug properties and loading on the release kinetics were investigated. The in vitro release of AZ, DP, and TM was well sustained from the polymer matrices over a period of approximately 210, 270, and 250 days, respectively. The release kinetics correlated with the HPLC retention profiles of the different drugs. Following a small initial burst release (<10%), a dual modality release controlled by diffusion and bulk erosion was found for all drugs. Drug release rates of up to 4 microg/day were reached. Matrix drug loading generally affected the extent of the burst release, release kinetics, as well as the matrix water content and matrix degradation that were determined gravimetrically. Microcomputed tomography was used to image structural and dimensional changes of the devices. A preliminary rabbit implantation study revealed promising ocular biocompatibility of drug-free PPF/PVP matrices. All results indicate the potential of photocrosslinked PPF-based matrices as polymeric carriers for long-term ophthalmic drug delivery.
Abnormal platelet counts have been observed in patients with iron deficiency anemia. To study this relationship, rats were made iron deficient, and platelet production was estimated by radiosulfate incorporation into platelets. With progressive iron deficiency anemia, both platelet counts and the rate of platelet production increased significantly. Platelet survival was normal. Injection of iron was followed by a fall in platelet counts and platelet production to normal levels within 72 hr, at which time stainable iron had appeared in the bone marrow. An inverse relationship between platelet counts and hematocrit was also seen. It appears that platelet homeostasis in iron deficiency anemia is influenced by the duration and severity of anemia.
In previous subchronic studies inhaled N-vinylpyrrolidone-2 (NVP) was haemotoxic, hepatotoxic and irritant to the nose. In the first of two long-term studies, study A, Sprague-Dawley rats were exposed by inhalation to 0, 5, 10 or 20 ppm NVP (6 hr/day, 5 days/wk) for 24 months. Satellite groups were killed after 3, 12 or 24 months. In study B, female Sprague-Dawley rats were exposed to 0 or 45 ppm NVP for 3 months and killed at 3 or 12 and 24 months post-exposure. In study A, survival was unaffected, but reduced body weight gain, haemotoxicity, effects on clinical chemistry parameters indicative of hepatotoxicity, increased liver weight, hepatocellular carcinomas, necrosis, reparative hyperplasia, adenomas and adenocarcinomas of the nasal cavity, and squamous cell carcinomas of the larynx were seen. Increased tumour incidence was seen only in the liver and upper respiratory tract. In study B, the effect of NVP on body weight evident at 3 months disappeared before 1 yr, but effects on liver pathology persisted throughout the subsequent 21-month exposure-free period, and a few liver tumours were seen at 2 yr. As NVP gave negative results in a battery of in vitro and in vivo genotoxicity tests, it appears that the tumours that arose were manifestations of a non-genotoxic mechanism.
1-20. Lieferung 1994, pp. NI-14. VCH-Verlagsgesellschaft mbH) Ohrt~.towierungstechnik zur indivi-duellen Kennzeichnung yon wei~n Kleintiernagem
- Toxikologisch
Toxikologisch-arbeitsmedizinische Begriindung von MAK-Werten. 1-20. Lieferung 1994, pp. NI-14. VCH-Verlagsgesellschaft mbH, Weinheim. Klimisch H.-J. (1986) Ohrt~.towierungstechnik zur indivi-duellen Kennzeichnung yon wei~n Kleintiernagem. Zeitschrift ffir Versuchstierkund 28, 277-281.
Proposed Guidelines Grunddatensatz "N-Vinyl-2-pyrrolidion'. CAS no
- Chemicals Testing
- Paris Oecd
- Us
OECD (1981) Guidelines for Testing of Chemicals. OECD, Paris. US EPA (1979) Proposed Guidelines. Federal Register 44, No. 91, p. 27354, 9 May. VCI (1992) Grunddatensatz "N-Vinyl-2-pyrrolidion'. CAS no. 88-12.0 (06.07.1992). Verband der Chemischen lndustrie e.V. D-60054 Frankfurt.
Ohrtätowierungstechnik zur individuellen Kennzeichnung von weiβen Kleintiernagern
- Klimisch
Grunddatensatz “N-Vinyl-2-pyrrolidion”
- VCI
Verordnung über Trinkwasser und Wasser für Lebensmittelbetriebe (Trinkwasserverordnung-Trink V)
- Bundesgesetzblatt
Gesundheitsschädliche Arbeitsstoffe; Toxikologisch-arbeitsmedizinische Begründung von MAK-Werten
- Greim