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Journal of Toxicology and Environmental... 2018N-nitrosamines and their precursors found in cosmetics may be carcinogenic in humans. Thus the aim of this study was to carry out risk assessment for N-nitrosamines...
N-nitrosamines and their precursors found in cosmetics may be carcinogenic in humans. Thus the aim of this study was to carry out risk assessment for N-nitrosamines (N-nitrosodiethanolamine [NDELA], N-nitrosodiethylamine [NDEA]) and amines (triethanolamine [TEA], diethanolamine [DEA]) levels in cosmetics determined using validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) procedures. NDELA and NDEA concentrations were present at levels of "not detected" (N.D.) to 596.5 μg/kg and N.D. to 40.9 μg/kg, respectively. TEA and DEA concentrations ranged from N.D. to 860 μg/kg and N.D. to 26.22 μg/kg, respectively. The nitrite concentration (3-2250 mg/l), number of nitrosating agents to a maximum 5, and pH (3.93-10.09) were also assessed. The impact of N-nitrosamine formation on the levels of TEA, DEA, nitrite, and other nitrosating agents was also examined. N-nitrosamine concentrations correlated with the number of nitrosating agents and nitrite concentrations. Data demonstrated that higher nitrite concentrations and a greater number of nitrosating agents increased NDELA and NDEA yields. Further, the presence of TEA and DEA exerted a significant influence on N-nitrosamine formation. Risk assessments, including the margin of exposure (MOE) and lifetime cancer risk (LCR) for N-nitrosamines and margin of safety (MOS) for amines, were calculated using product type, use pattern, and concentrations. Exposure to maximum amounts of NDELA and NDEA resulted in MOE > 10,000 (based upon the benchmark dose lower confidence limit 10%) and LCR <1 × 10, respectively. In addition, TEA and DEA concentrations in cosmetic samples resulted in MOS values >100. Therefore, no apparent safety concerns were associated with cosmetic products containing NDELA, NDEA, TEA, and DEA in this study. However, since amines and nitrosating agents produce carcinogenic nitrosamines, their use in cosmetics needs to be minimized to levels as low as technically feasible.
Topics: Carcinogens; Chromatography, Liquid; Cluster Analysis; Cosmetics; Diethylnitrosamine; Ethanolamines; Multivariate Analysis; Nitrates; Nitrites; Risk Assessment; Tandem Mass Spectrometry
PubMed: 29694274
DOI: 10.1080/15287394.2018.1460782 -
Mutation Research Mar 1981Following matings of DEN-treated Xc2/BSYy+ males with repair-deficient mei-9 alpha females and ordinary females, significant increases in complete and partial sex...
Following matings of DEN-treated Xc2/BSYy+ males with repair-deficient mei-9 alpha females and ordinary females, significant increases in complete and partial sex chromosome loss as well as dramatic shifts in sex ratio were found with mei-9 alpha but not ordinary females. Accordingly, the mei-9 alpha female enhances the detection of chromosome lesions leading to chromosome loss induced in the male genome by DEN. To date, the 4 compounds tested in this way (DMN, DEN, MMS and procarbazine) exhibit strong potentiation of chromosome loss with mei-9 alpha females suggesting the possibility that a protocol involving treatment (or not) or Xc2/BSYy+ males mated with mei-9 alpha females may hold promise as an alternative to traditional tests for chromosome loss using repair-proficient females. Comparison with published translocation data on the 4 compounds indicated above suggests an overall greater sensitivity of the described mei-9 alpha chromosome-loss test compared with the traditional translocation test in the detection of chemically induced chromosome lesions.
Topics: Animals; Chromosome Deletion; Chromosomes; Crosses, Genetic; DNA Repair; Diethylnitrosamine; Drosophila melanogaster; Female; Male; Phenotype
PubMed: 6789198
DOI: 10.1016/0165-7992(81)90085-3 -
Journal of the National Cancer Institute Jul 1986Carcinogen-mediated alterations in hepatic membrane growth factor receptor activity were investigated with the use of the hepatocarcinogen diethylnitrosamine [(DENA)...
Carcinogen-mediated alterations in hepatic membrane growth factor receptor activity were investigated with the use of the hepatocarcinogen diethylnitrosamine [(DENA) CAS: 55-18-5]. For the separate assessment of carcinogen-induced acute membrane receptor changes from changes associated with carcinogen-mediated alterations in growth, the receptor activity was measured both acutely after, and several months after, a single ip dose of DENA in male F344 rats. An acute dose-dependent decrease was observed in ligand binding and autophosphorylation of the epidermal growth factor (EGF) and insulin receptor. Binding decreased sharply by 36 hours and recovered by 30 days in Golgi fractions and more slowly in plasma membranes. Scatchard analysis revealed a decrease in receptor number but not affinity. Chronic DENA administration also decreased insulin and EGF binding. Hepatocellular carcinomas, induced by single DENA injections 1 year previously, had decreased EGF receptor binding and autophosphorylation compared to those seen in age-matched controls and also less extensive insulin receptor changes. Single DENA doses thus have two effects: an acute reversible receptor change and a delayed, apparently permanent change associated with altered growth.
Topics: Animals; Cell Membrane; Diethylnitrosamine; Dose-Response Relationship, Drug; Electrophoresis, Polyacrylamide Gel; ErbB Receptors; Golgi Apparatus; Liver; Liver Neoplasms, Experimental; Male; Microsomes, Liver; Phosphorylation; Rats; Rats, Inbred F344; Receptor, Insulin; Receptors, Cell Surface
PubMed: 3014198
DOI: No ID Found -
Mutation Research Oct 1976A rat-liver microsomal system in vitro has been used to activate two indirectly acting carcinogens, DMN and DEN. On activation, both compounds were extremely potent in...
Cytogenetic effects of mutagens/carcinogens after activation in a microsomal system in vitro I. Induction of chromosome aberrations and sister chromatid exchanges by diethylnitrosamine (DEN) and dimethylnitrosamine (DMN) in CHO cells in the presence of rat-liver microsomes.
A rat-liver microsomal system in vitro has been used to activate two indirectly acting carcinogens, DMN and DEN. On activation, both compounds were extremely potent in inducing chromosomal aberrations as well as sister chromatid exchanges in Chinese hamster cells. The implications of these findings and the potential utility of this technique to detect mutagens/carcinogens are discussed.
Topics: Carcinogens; Cell Line; Chromatids; Chromosome Aberrations; Diethylnitrosamine; Dimethylnitrosamine; Microsomes, Liver; Mutagens; Nitrosamines
PubMed: 967188
DOI: 10.1016/0027-5107(76)90057-9 -
Carcinogenesis Jun 2003In order to explore a possibility that the custom of drinking green tea infusion is efficacious for reducing the carcinogenic risk of environmental exposure to...
Prevention of dual promoting effects of pentachlorophenol, an environmental pollutant, on diethylnitrosamine-induced hepato- and cholangiocarcinogenesis in mice by green tea infusion.
In order to explore a possibility that the custom of drinking green tea infusion is efficacious for reducing the carcinogenic risk of environmental exposure to pentachlorophenol (PCP), we examined the effects in a hepato- and cholangiocarcinogenesis model in mice exposed to diethylnitrosamine (DEN). In the first experiment, groups of 15 male mice were initially treated with DEN at a dose of 20 p.p.m. in the drinking water for the first 8 weeks followed by a 4 week recovery interval by PCP at concentrations of 0 (basal diet), 300 or 600 p.p.m. in the diet for 23 weeks. Further groups of animals were treated with DEN and PCP in the same manner and received 2% green tea infusion (GT) instead of the drinking water from week 10 until death. PCP exposure at the high dose promoted DEN-induced hepatocarcinogenesis, and also caused progression of cystic hyperplasias of the intrahepatic bile ducts to cholangiocellular tumors. Co-administration of GT was able to prevent the increases of incidences and multiplicities of DEN-induced hepatocellular tumors and also arrest the progression of cholangiocellular tumors. In the second experiment, co-treatment with GT in the drinking water from 1 week before 300 or 600 p.p.m. PCP treatment in the diet to the end of the experiment at week 3 in B6C3F1 male mice suppressed increases of serum ALT activities, 8-oxodeoxyguanosine levels in liver DNA and bromodeoxyuridine labeling indices of hepatocytes and intrahepatic biliary epithelial cells induced by PCP. These findings suggest that regular intake of green tea may reduce the carcinogenic risk posed by an environmental pollutant, PCP, presumably due to effects on oxidative stress.
Topics: Animals; Cholangiocarcinoma; Diethylnitrosamine; Environmental Pollutants; Liver Neoplasms; Pentachlorophenol; Tea
PubMed: 12807750
DOI: 10.1093/carcin/bgg053 -
Chemico-biological Interactions May 1979Effects of diethylnitrosamine (DEN) and dimethylnitrosamine (DMN) on the sedimentation pattern of [3H]thymidine-labelled Sprague-Dawley female rat liver DNA in alkaline... (Comparative Study)
Comparative Study
Persistence and accumulation of (potential) single strand breaks in liver DNA of rats treated with diethylnitrosamine or dimethylnitrosamine: correlation with hepatocarcinogenicity.
Effects of diethylnitrosamine (DEN) and dimethylnitrosamine (DMN) on the sedimentation pattern of [3H]thymidine-labelled Sprague-Dawley female rat liver DNA in alkaline sucrose gradients were studied with regard to time and dose dependency. In experiments at 1--56 days after a single injection it was observed that (potential) single strand breaks induced by DEN were repaired at a low rate. At 56 days the sedimentation pattern was still grossly abnormal. Half-life values of 27 and 46 days were observed after 134 mg/kg DEN (approx. 45% of the LD50) and 13.4 mg/kg DEN, respectively. Identical experiments after DMN (10 mg/kg, corresponding to about 35% of the LD50) showed return to (almost) completely control sedimentation patterns within 56 days after injection (t 1/2 = 8 days). Experiments at 6 or 56 days after the last of a series of 5 or 10 weekly injections of DEN (13.4 mg/kg) showed that a major part of DEN-induced damage (measured as single strand breaks) is of a persistent and accumulating character. No accumulation of DMN-induced rat liver lesions was observed. It is concluded that DNA fragmentation and lack of DNA repair is not a consequence of hepatotoxicity. Since at equimolar doses DEN gives appreciably less DNA alkylation (including O6-alkylguanine) but is much more effective both as an inducer of preneoplastic liver lesions and as a hepatocarcinogen when compared with DMN, we believe that the formation of persistent (and accumulating) DNA damage after DEN administration might be relevant in the process of liver tumour formation.
Topics: Animals; Carcinogens; Centrifugation, Density Gradient; DNA Repair; Diethylnitrosamine; Dimethylnitrosamine; Drug Administration Schedule; Female; Liver; Nitrosamines; Rats
PubMed: 466734
DOI: 10.1016/0009-2797(79)90048-6 -
Regulatory Toxicology and Pharmacology... Jul 2021The ICH M7(R1) guideline describes a framework to assess the carcinogenic risk of mutagenic and carcinogenic pharmaceutical impurities following less-than-lifetime (LTL)...
The ICH M7(R1) guideline describes a framework to assess the carcinogenic risk of mutagenic and carcinogenic pharmaceutical impurities following less-than-lifetime (LTL) exposures. This LTL framework is important as many pharmaceuticals are not administered for a patient's lifetime and as clinical trials typically involve LTL exposures. While there has been regulatory caution about applying LTL concepts to cohort of concern (COC) impurities such as N-nitrosamines, ICH M7 does not preclude this and indeed literature data suggests that the LTL framework will be protective of patient safety for N-nitrosamines. The goal was to investigate if applying the LTL framework in ICH M7 would control exposure to an acceptable excess cancer risk in humans. Using N-nitrosodiethylamine as a case study, empirical data correlating exposure duration (as a percentage of lifespan) and cancer incidence in rodent bioassays indicate that the LTL acceptable intake (AI) as derived using the ICH M7 framework would not exceed a negligible additional risk of cancer. Therefore, controlling N-nitrosamines to an LTL AI based on the ICH M7 framework is thus demonstrated to be protective for potential carcinogenic risk to patients over the exposure durations typical of clinical trials and many prescribed medicines.
Topics: Carcinogens; Diethylnitrosamine; Dose-Response Relationship, Drug; Humans; Mutagenesis; Mutagens; Nitrosamines; Toxicity Tests
PubMed: 33862169
DOI: 10.1016/j.yrtph.2021.104926 -
Carcinogenesis Aug 1984Nitrosodiallylamine has been reported to be non-carcinogenic in rats while nitrosodipropylamine and nitrosodiethanolamine are liver carcinogens. That...
Nitrosodiallylamine has been reported to be non-carcinogenic in rats while nitrosodipropylamine and nitrosodiethanolamine are liver carcinogens. That nitrosodipropylamine is metabolized at the alpha-position by liver microsomes from Fischer-344 rats supports the widely held contention that such metabolism is responsible for the carcinogenicity of nitrosamines. Nitrosodiallylamine is also metabolized at the alpha-position by the same microsomal preparations. Thus, although alpha-oxidation may be responsible for the carcinogenicity of some nitrosamines, this mechanism alone cannot account for tumorigenicity. Nitrosodiethanolamine is not metabolized by rat liver microsomes, but is metabolized by hepatocytes for Fischer-344 rats. In this case, a mechanism other than the oxidation at the alpha-position may be responsible for the carcinogenic action.
Topics: Animals; Carcinogens; Chromatography, Gel; Chromatography, High Pressure Liquid; Diethylnitrosamine; Male; Microsomes, Liver; Nitrosamines; Rats; Rats, Inbred F344
PubMed: 6744511
DOI: 10.1093/carcin/5.8.1015 -
Toxicology 1982Male Syrian golden hamsters were exposed to 10 ppm of formaldehyde (H2CO) 5 times/week for lifetime. Survival of the treated animals was reduced relative to unexposed...
Male Syrian golden hamsters were exposed to 10 ppm of formaldehyde (H2CO) 5 times/week for lifetime. Survival of the treated animals was reduced relative to unexposed controls. No tumors were observed in histologic sections of respiratory tract tissues from either unexposed or treated animals. Only a minimal increase in hyperplastic and metaplastic areas was observed in nasal epithelium of exposed animals. However, there was evidence that H2CO could serve as a cofactor in the incidence of respiratory tumors induced by diethylnitrosamine (DEN). Animals were exposed once per week to 30 ppm H2CO (5 h/day) for lifetime. No tumors were observed in the respiratory tract of the H2CO-only control group exposed to this regimen. Hamsters receiving exposures to H2CO at 2 days prior to each of 10 weekly DEN injections had a higher number of tracheal tumors/tumor-bearing animal at autopsy than those receiving DEN alone.
Topics: Adenoma; Aging; Animals; Carcinogens; Cricetinae; Diethylnitrosamine; Formaldehyde; Male; Mesocricetus; Neoplasms, Experimental; Respiratory Tract Neoplasms
PubMed: 7135407
DOI: 10.1016/0300-483x(82)90058-0 -
Journal of Pharmaceutical and... Nov 2022The probable carcinogenic nitrosamine impurities, such as N-nitrosodiethylamine (NDEA) and N-nitrosodimethylamine (NDMA), have been detected from various pharmaceuticals...
The probable carcinogenic nitrosamine impurities, such as N-nitrosodiethylamine (NDEA) and N-nitrosodimethylamine (NDMA), have been detected from various pharmaceuticals in recent years. The sensitive chromatographic methods, including liquid chromatography (LC) and gas chromatography (GC), have been applied for analyzing nitrosamines in the pharmaceutical substrates, such as sartans, ranitidine and metformin. In comparison of LC, the efficacy of GC for analyzing multiple nitrosamines in diverse pharmaceuticals will be limited or attenuated owing to the chemical properties of target analytes or matrix hinderance of pharmaceutical substrates. To extend the applicability of GC analysis for multiple nitrosamines in pharmaceuticals, this study presented a gas chromatograph tandem mass (GC-MS/MS) method for monitoring 14 nitrosamines within 44 pharmaceuticals, whereas the headspace-solid phase microextraction (HS-SPME) sampling mode was introduced. Chromatographic separation was achieved on a DB-heavyWax column (30 m × 0.25 mm; i.d., 0.25 µm), whereas the HS-SPME sampling mode with a 50/30 µm DVB/CAR/PDMS extracting fiber was applied for comparison of the direct injection mode. Meanwhile, the HS-SPME conditions were optimized to evaluate the effects of the parameters on analyzing total nitrosamines in pharmaceuticals by GC-MS/MS. The optimal conditions of HS-SPME were as follows: extracting solution of 90% NaCl, HS incubation time 1 min, SPME adsorbing at 80 ℃ for 30 min, and desorbing at 250 ℃ for 5 min. The limit of quantification (LOQ) for 14 nitrosamines in pharmaceutical matrices under the optimal conditions was 0.05 μg/g for the optimal HS-SPME, whereas the value was 0.05-0.25 μg/g for direct injection.
Topics: Angiotensin II Type 1 Receptor Blockers; Diethylnitrosamine; Dimethylnitrosamine; Gas Chromatography-Mass Spectrometry; Metformin; Nitrosamines; Pharmaceutical Preparations; Ranitidine; Sodium Chloride; Solid Phase Microextraction; Tandem Mass Spectrometry
PubMed: 36095885
DOI: 10.1016/j.jpba.2022.115003