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1.
Food Chem Toxicol ; 81: 71-80, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25846501

RESUMO

Systemic exposure was measured in humans after hair dyeing with oxidative hair dyes containing 2.0% (A) or 1.0% (B) [(14)C]-p-phenylenediamine (PPD). Hair was dyed, rinsed, dried, clipped and shaved; blood and urine samples were collected for 48 hours after application. [(14)C] was measured in all materials, rinsing water, hair, plasma, urine and skin strips. Plasma and urine were also analysed by HLPC/MS/MS for PPD and its metabolites (B). Total mean recovery of radioactivity was 94.30% (A) or 96.21% (B). Mean plasma Cmax values were 132.6 or 97.4 ng [(14)C]-PPDeq/mL, mean AUC(0-∞) values 1415 or 966 ng [(14)C]-PPDeq/mL*hr in studies A or B, respectively. Urinary excretion of [(14)C] mainly occurred within 24 hrs after hair colouring with a total excretion of 0.72 or 0.88% of applied radioactivity in studies A or B, respectively. Only N,N'-diacetylated-PPD was detected in plasma and the urine. A TK-based human safety assessment estimated margins of safety of 23.3- or 65-fold relative to respective plasma AUC or Cmax values in rats at the NOAEL of a toxicity study. Overall, hair dyes containing PPD are unlikely to pose a health risk since they are used intermittently and systemic exposure is limited to the detoxified metabolite N,N'-diacetyl-PPD.


Assuntos
Tinturas para Cabelo/química , Fenilenodiaminas/farmacocinética , Adulto , Área Sob a Curva , Isótopos de Carbono , Cromatografia Líquida de Alta Pressão , Qualidade de Produtos para o Consumidor , Feminino , Cabelo/química , Cabelo/efeitos dos fármacos , Humanos , Masculino , Nível de Efeito Adverso não Observado , Fenilenodiaminas/sangue , Fenilenodiaminas/urina , Espectrometria de Massas em Tandem , Adulto Jovem
2.
Regul Toxicol Pharmacol ; 71(3): 515-28, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25659490

RESUMO

In the European Union animal testing has been eliminated for cosmetic ingredients while the US Cosmetic Ingredient Review Expert Panel may request data from animal studies. The use of read-across and predictive toxicology provides a path for filling data gaps without additional animal testing. The PEG cocamines are tertiary amines with an alkyl group derived from coconut fatty acids and two PEG chains of varying length. Toxicology data gaps for the PEG cocamines can be addressed by read-across based on structure-activity relationship using the framework described by Wu et al. (2010) for identifying suitable structural analogs. Data for structural analogs supports the conclusion that the PEG cocamines are non-genotoxic and not expected to exhibit systemic or developmental/reproductive toxicity with use in cosmetics. Due to lack of reliable dermal sensitization data for suitable analogs, this endpoint was addressed using predictive software (TIMES SS) as a first step (Laboratory of Mathematical Chemistry). The prediction for PEG cocamines was the same as that for PEGs, which have been concluded to not present a significant concern for dermal sensitization. This evaluation for PEG cocamines demonstrates the utility of read-across and predictive toxicology tools to assess the safety of cosmetic ingredients.


Assuntos
Aminas/toxicidade , Simulação por Computador , Cosméticos/toxicidade , Irritantes/toxicidade , Modelos Teóricos , Polietilenoglicóis/toxicidade , Testes de Toxicidade/métodos , Aminas/química , Animais , Cosméticos/química , Dermatite de Contato/etiologia , Olho/efeitos dos fármacos , Humanos , Irritantes/química , Camundongos , Estrutura Molecular , Testes de Mutagenicidade , Polietilenoglicóis/química , Medição de Risco , Pele/efeitos dos fármacos , Testes de Irritação da Pele , Software , Relação Estrutura-Atividade
3.
Mutagenesis ; 25(1): 17-23, 2010 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-19892773

RESUMO

Hair dye ingredients frequently produce positive results in short-term in vitro genotoxicity tests, although results from in vivo assays are typically negative, especially for ingredients in use today. The use of hair dyes is quite widespread resulting in the exposure both for persons working in hairdressing salons and for individuals who have their hair dyed. This provides the opportunity to add to the data from standard in vitro and in vivo genotoxicity tests by investigating whether or not genotoxic responses are detected in such exposed individuals. A number of biomonitoring studies of humans exposed to hair dyes have been conducted using either cytogenetic alterations or DNA damage as measures of genotoxicity, or urine mutagenicity as a measure of exposure to genotoxic compounds. In this paper, each study is critically reviewed and interpreted. Overall, there is no consistent evidence of genotoxicity in humans exposed to hair dyes occupationally or through individual use.


Assuntos
Dano ao DNA/genética , Monitoramento Ambiental/estatística & dados numéricos , Tinturas para Cabelo/toxicidade , Exposição Ocupacional/estatística & dados numéricos , Humanos , Testes de Mutagenicidade/estatística & dados numéricos , New York
4.
J Chromatogr A ; 1216(41): 6970-3, 2009 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-19733358

RESUMO

The assessment of human exposure to specific isomers of dimethylanilines (DMA's) is of interest for the evaluation of potential exposure-health outcome relationships. Improved analytical methods will help in identifying the environmental sources of such exposures. The separation of all six DMA isomers by supercritical fluid chromatography (SFC), without derivatization, is reported within. Further, the combination of SFC with electrospray ionization/tandem mass spectrometry provides selective detection in crude extracts of spiked (40 ppb of 3,5-dimethylaniline) raw materials. The raw materials chosen for analysis are commonly used in the manufacture of consumer hair-dye products.


Assuntos
Compostos de Anilina/análise , Cromatografia com Fluido Supercrítico/métodos , Diaminas/análise , Fenóis/análise , Pirazóis/análise , Compostos de Anilina/isolamento & purificação , Misturas Complexas/química , Tinturas para Cabelo/química , Isomerismo , Mutagênicos/química , Espectrometria de Massas por Ionização por Electrospray , Espectrometria de Massas em Tandem
5.
Toxicol Lett ; 188(2): 119-29, 2009 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-19446244

RESUMO

To address the provision of the 7th Amendment to the EU Cosmetics Directive banning the use of in vivo genotoxicity assays for testing cosmetic ingredients in 2009, the 3D EpiDerm reconstructed human skin micronucleus assay has been developed. To further characterise the EpiDerm tissue for potential use in genotoxicity testing, we have evaluated the dermal penetration and metabolism of two hair dye ingredients, p-aminophenol (PAP) and p-phenylenediamine (PPD) in this reconstructed epidermis model. When EpiDerm tissue was topically exposed to PAP or PPD for 30 min (typical for a hair dye exposure), the majority (80->90%) of PAP or PPD was excluded from skin tissue and removed by rinsing. After a 23.5h recovery period, the PAP fraction that did penetrate was completely N-acetylated to acetaminophen (APAP). Similarly, 30 min topical application of PPD resulted in the formation of the N-mono- and N,N'-diacetylated metabolites of PPD. These results are consistent with published data on the dermal metabolism of these compounds from other in vitro systems as well as from in vivo studies. When tissue was exposed topically (PAP) or via the culture media (PPD) for 24h, there was good batch-to-batch and donor-to-donor reproducibility in the penetration and metabolism of PAP and PPD. Overall, the results demonstrate that these two aromatic amines are biotransformed in 3D EpiDerm tissue via N-acetylation. Characterising the metabolic capability of EpiDerm tissue is important for the evaluation of this model for use in genotoxicity testing.


Assuntos
Aminofenóis/metabolismo , Epiderme/metabolismo , Modelos Biológicos , Fenilenodiaminas/metabolismo , Absorção Cutânea , Aminofenóis/farmacocinética , Biotransformação , Calibragem , Cromatografia Líquida de Alta Pressão , Qualidade de Produtos para o Consumidor , Tinturas para Cabelo/química , Tinturas para Cabelo/farmacocinética , Tinturas para Cabelo/toxicidade , Humanos , Espectrometria de Massas , Técnicas de Cultura de Órgãos , Fenilenodiaminas/farmacocinética , Soluções
6.
Toxicol Appl Pharmacol ; 208(1): 1-20, 2005 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-16164957

RESUMO

In April 2004, the Health and Environmental Sciences Institute, a branch of the International Life Sciences Institute, with support from the National Institute of Environmental Health Sciences, organized a workshop to discuss the biological significance of DNA adducts. Workshop speakers and attendees included leading international experts from government, academia, and industry in the field of adduct detection and interpretation. The workshop initially examined the relationship between measured adduct levels in the context of exposure and dose. This was followed by a discussion on the complex response of cells to deal with genotoxic insult in complex, interconnected, and interdependent repair pathways. One of the major objectives of the workshop was to address the recurring question about the mechanistic and toxicological relevance of low-concentration measured adducts and the presentations in the session entitled "Can low levels of DNA adducts predict adverse outcomes?" served as catalysts for further discussions on this subject during the course of the workshop. Speakers representing the regulatory community and industry reviewed the value, current practices, and limitations of utilizing DNA adduct data in risk assessment and addressed a number of practical questions pertaining to these issues. While no consensus statement emerged on the biological significance of low levels of DNA adducts, the workshop concluded by identifying the need for more experimental data to address this important question. One of the recommendations stemming from this workshop was the need to develop an interim "decision-logic" or framework to guide the integration of DNA adduct data in the risk assessment process. HESI has recently formed a subcommittee consisting of experts in the field and other key stakeholders to address this recommendation as well as to identify specific research projects that could help advance the understanding of the biological significance of low levels of DNA adducts.


Assuntos
Biomarcadores/análise , Adutos de DNA/análise , Medição de Risco/métodos , Animais , Dano ao DNA , Exposição Ambiental/análise , Exposição Ambiental/normas , Humanos
7.
Toxicology ; 210(2-3): 147-57, 2005 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-15840428

RESUMO

p-Phenylenediamine (PPD) is a widely used ingredient in permanent hair dyes; however, little has been published on its metabolism, especially with respect to hepatic cytochrome P450 (CYP)-mediated oxidation. This is regarded as a key step in the activation of carcinogenic arylamines that ultimately leads to the development of bladder cancer. Most epidemiology studies show no significant association between personal use of hair dyes and bladder cancer, but one recent study reported an increased risk of bladder cancer in women who were frequent users of permanent hair dyes. The aim of the present study was to use intact human hepatocytes, human liver microsomes, and heterologously expressed human CYPs to determine whether PPD is metabolised by hepatic CYPs to form an N-hydroxylamine. p-Phenylenediamine was N-acetylated by human hepatocytes to form N-acetylated metabolites, but there was no evidence for the formation of mono-oxygenated metabolites or for enzyme-mediated covalent binding of 14C-PPD to microsomal protein. In contrast, 2-aminofluorene underwent CYP-mediated metabolism to > or = 4 different hydroxylated metabolites. The lack of evidence for hepatic CYP-mediated metabolism of PPD is inconsistent with the hypothesis that this compound plays a causal role in the development of bladder cancer via a mode of action involving hepatic metabolism to an N-hydroxyarylamine.


Assuntos
Sistema Enzimático do Citocromo P-450/metabolismo , Hepatócitos/enzimologia , Microssomos Hepáticos/enzimologia , Fenilenodiaminas/metabolismo , Acetilação , Células Cultivadas , Cromatografia Líquida de Alta Pressão , Fluorenos/metabolismo , Humanos , Masculino , Espectrometria de Massas , Ligação Proteica , Proteínas Recombinantes/metabolismo
8.
Food Chem Toxicol ; 42(11): 1885-91, 2004 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-15350687

RESUMO

In the organism of mammals, important detoxification pathways of arylamines are catalysed by N-acetyltransferase 2 (NAT2). A recent case-control epidemiology study suggested that human NAT2 slow acetylators exposed to oxidative hair dyes may be at greater risk to develop bladder cancer. We therefore profiled urinary [(14)C]-metabolites and NAT2 genotype in eight human subjects following treatment with a dark-shade oxidative hair dye containing [(14)C]-para-phenylenediamine (PPD). Genotyping identified three subjects as slow, and five subjects as intermediate NAT2 acetylators. Within 24 h after treatment, the study subjects excreted a mean total of 0.43+/-0.24% of the applied [(14)C] in the urine, where five different metabolites were found. The major urinary metabolites were concluded to be N-mono-acetylated and N,N'-diacetylated PPD. They were present in all urine samples and amounted to 80-95% of the total urinary [(14)C]. Another metabolite, possibly a glucuronic acid conjugate, was found in 6/8 urine samples at 5-13% of the total urinary [(14)C]. All metabolites appeared to be related to PPD, no evidence of the presence of high-molecular weight dye-intermediates or corresponding metabolites was found. The metabolite profile in the study subjects showed no significant differences between the NAT2 intermediate and NAT2 slow acetylator subgroups. Urine of NAT2 slow acetylators contained N-mono-acetylated-PPD at 42.2+/-10.2% and N,N'-di-acetylated-PPD at 54.1+/-7.6% of total urinary radioactivity, while the corresponding values of intermediate acetylators were 46.0+/-8.9% and 45.7+/-9.9%, respectively. Overall, our results suggest that the human acetylation rate of PPD after topical application is independent of the NAT2 genotype status, most likely due to metabolism by epidermal NAT1 prior to systemic absorption.


Assuntos
Arilamina N-Acetiltransferase/genética , Tinturas para Cabelo/efeitos adversos , Tinturas para Cabelo/metabolismo , Fenilenodiaminas/urina , Neoplasias da Bexiga Urinária/etiologia , Absorção , Acetilação , Administração Tópica , Adolescente , Adulto , Arilamina N-Acetiltransferase/metabolismo , Radioisótopos de Carbono , Predisposição Genética para Doença , Genótipo , Humanos , Masculino , Projetos Piloto , Neoplasias da Bexiga Urinária/genética
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