Derivation of no significant risk levels for three lower acrylates: Conclusions and recommendations from an expert panel.

A panel of toxicology, mode of action (MOA), and cancer risk assessment experts was engaged to derive no-significant-risk-levels (NSRLs) for three lower acrylates: methyl acrylate (MA), ethyl acrylate (EA), and 2-ethylhexyl acrylate (2EHA) using the best available science, data, and methods. The review was structured as a five-round, modified Delphi format, a systematic process for collecting independent and deliberative input from panel members, and it included several procedural elements to reduce potential sources of bias and groupthink. Input from the panel for key decisions in the dose-response assessments resulted in NSRL values of 530 µg/day (330-800 µg/day), 640 µg/day (280-670 µg/day), and 1700 µg/day (1300-2700 µg/day) for MA, EA, and 2EHA, respectively. Novel to this approach were the use of nonneoplastic lesions reported at point of contact where tumors have been reported in laboratory rodents, along with nonlinear extrapolation to low doses (uncertainty factor approach) based upon panel recommendations. Confidence in these values is considered medium to high for exposures applied to the routes of exposure tested (inhalation for MA and EA, dermal for 2EHA), but confidence is considered lower when applied to other routes of exposure.

Cancer weight of evidence for three lower acrylates: Conclusions and recommendations from an expert panel.

An international panel of experts was engaged to assess the cancer weight of evidence (WOE) for three lower acrylates: methyl acrylate, ethyl acrylate, and 2-ethylhexyl acrylate. The review was structured as a three-round, modified Delphi format, a systematic process for collecting independent and deliberative input from panel members, and it included procedural elements to reduce bias and groupthink. Based upon the available science, the panel concluded: (1) The MOA for point of contact tumors observed in rodent cancer bioassays that is best supported by available data involves increased cell replication by cytotoxicity and regenerative proliferation; (2) The WOE supports a cancer classification of "Not likely to be carcinogenic to humans" a conclusion that is more in line with an IARC classification of Group 3 rather than Group 2 B; (3) Quantitative cancer potency values based on rodent tumor data are not required for these chemicals; and (4) Human health risk assessment for these chemicals should instead rely on non-cancer, precursor endpoints observed at the point of contact (e.g., hyperplasia). The degree of consensus (consensus scores of 0.84-0.91 out of a maximum score of 1) and degree of confidence (7.7-8.7 out of a maximum score of 10) in the WOE conclusions is considered high.

Genotoxicity of methyl acrylate and ethyl acrylate and its relationship with glutathione.

Methyl acrylate (MA) and ethyl acrylate (EA) had previously tested positive for mutagenicity in vitro, but in vivo studies were negative. One of the metabolism pathways of alkyl acrylates is conjugation with glutathione. The glutathione availability is restricted in standard in vitro test systems so that they do not reflect the in vivo metabolism in this respect. We investigated whether the addition of glutathione to the in vitro L5178Y/TK+/- mouse lymphoma mutagenicity test prevents alkyl acrylate's mutagenicity in vitro. We also investigated whether the quantitative relationships support the notion that the GSH supplemented in vitro systems reflect the true in vivo activity. Indeed, glutathione concentrations as low as 1 mM completely negate the mutagenicity of MA and EA in the L5178Y/TK+/- mouse lymphoma mutagenicity test up to the highest concentrations of the two acrylates tested, 35 µg/ml, a higher concentration than that previously found to be mutagenic in this test (14 µg MA/ml and 20 µg EA/ml). 1 mM Glutathione reduced the residual MA and EA at the end of the exposure period in the mutagenicity tests by 96-97%, but in vivo up to 100 mg/kg body weight MA and EA left the glutathione levels in the mouse liver and forestomach completely intact. It is concluded that the in-situ levels of glutathione, 7.55 ± 0.57 and 2.84 ± 0.22 µmol/g mouse liver and forestomach, respectively, can efficiently protect against MA and EA-induced mutagenicity up to the high concentration of 100 mg MA and EA/kg body weight and that the negative in vivo mutagenicity tests on MA and EA reflect the true in vivo situation.

Oxidative stress responses in two marine diatoms during acute n-butyl acrylate exposure and the toxicological evaluation with the IBRv2 index.

n-Butyl acrylate (nBA), a typical hazardous and noxious substance (HNS), is the largest-volume acrylate ester used to produce various types of polymers. With the increasing volume of nBA subject to maritime transportation, its accidental leakage poses a great risk to the marine organisms. Therefore, it is necessary to evaluate the ecological risk of nBA in marine environments. In this study, two species of marine microalgae, Skeletonema costatum and Phaeodactylum tricornutum, were used to explore the toxic effects of nBA based on their growth, pigment content, and oxidative stress. The growth of each species was significantly inhibited by nBA, showing a 96 h-EC50 value of 2.23 mg/L for P. tricornutum and 8.19 mg/L for S. costatum, respectively. Although chlorophylls a and c exerted a hormesis effect in P. tricornutum, contents of pigments generally decreased at high concentrations. In P. tricornutum, all detected antioxidants (reduced glutathione, GSH; superoxide dismutase, SOD; catalase, CAT; and glutathione peroxidase, GPx) were stimulated at concentrations ranging from 1.50 to 3.82 mg/L. However, these elevations were not enough to reduce the oxidative damage caused by nBA, because the content of malondialdehyde (MDA) increased continuously during 96-h exposure. For S. costatum, the activities of only two antioxidants (GSH and CAT) were enhanced, which is enough to prevent the MDA content from rising, even at higher concentrations of nBA (5-10 mg/L). The Integrated Biomarker Response Version 2 (IBRv2) index that combines responses of the above five oxidative stress biomarkers, was not only correlated positively with nBA concentration but could also indicate the occurrence of oxidative stress caused by acute concentration of nBA. These findings showed that P. tricornutum was sensitive to nBA compared to S. costatum, and the IBRv2 index was an effective tool for evaluating ecotoxicological effects on marine microalgae due to nBA spills.

Sunscreen filter octocrylene is a potential obesogen by acting as a PPARγ partial agonist.

Octocrylene (OC) is an extensively prescribed organic ultraviolet B filter used in sunscreen products. Due to its extensive use, a significant level of OC is detected in marine and freshwater environments. Notably, the bioaccumulation of OC in aquatic biota may affect human health. In this study, the effect of OC on metabolism was investigated using the adipogenesis model of human bone marrow mesenchymal stem cells (hBM-MSCs). OC promoted adiponectin production during adipogenesis in hBM-MSCs compared to the vehicle-treated control (EC50, 29.6 µM). In target identification, OC directly bound to peroxisome proliferator-activated receptor (PPAR) γ (Ki, 37.8 µM). OC-bound PPARγ also significantly recruited nuclear receptor coactivator proteins SRC-1 (EC50, 54.1 µM) and SRC-2 (EC50, 58.6 µM). In the molecular docking simulation study, the optimal ligand-binding mode of OC suggested that OC is a PPARγ partial agonist. A competitive analysis with a PPARγ full agonist pioglitazone revealed that OC acted as a PPARγ partial agonist. OC altered the gene transcription profile of lipid-metabolism associated enzymes in normal human keratinocytes, primarily exposed human cells after the application of sunscreens. In conclusion, OC is a potential metabolic disrupting obesogen.

Curing of UV prints - Assessment of possible toxicological hazard for consumers.

In an experimental setting a laboratory analysis of substances migrating from UV prints under mechanical stress into sweat and saliva simulant was performed. The influence of paper type and curing degree on UV prints was investigated. Five substances were identified at concentrations above the limit of detection in the simulants PPG-3 glyceryl triacrylate, ethoxylated trimethylolpropane triacrylate, trimethylolpropane triacrylate, 2/4-isopropylthioxanthone (ITX), and 2,4-diethylthioxanthone (DETX). Migration of the acrylates and photoinitiators into saliva and sweat simulants were increased when the UV inks were printed on uncoated paper in comparison to coated paper. With an exposure scenario considering a person to leaf through 80 pages of UV-printed paper per day while touching each page with a licked fingertip, Risk Characterisation Ratios (RCR) for oral exposure well below 1 were obtained for all five substances indicating no risk for the general population. The three acrylates are classified for skin sensitisation. The migrated amounts per skin surface area of these three were compared with the EC3 value for a hypothetical substance that could be categorised as strong sensitiser (EC3 = 0.1%). The results show that the risk of skin sensitisation even under worst case conditions can be considered as negligible.

Toxic effects of octocrylene on zebrafish larvae and liver cell line (ZFL).

Octocrylene (OC) is a broad-spectrum ultraviolet-absorbing chemical used in sunscreen and other personal care products. Its health effects are a concern because it has been detected in water, fish, humans, and food chains. In vivo and in vitro investigations were performed in zebrafish (Danio rerio) larvae and a zebrafish liver cell line (ZFL), respectively, to understand the potential risks and molecular mechanisms of OC toxicity. The 96-h median lethal concentration (LC50) of OC was determined to be 251.8 µM in larvae and 5.5 µM in ZFL cells. Quantitative real-time PCR (qRT-PCR) showed that OC induced the expression of genes for CYPs (CYP1A, CYP3A65), estrogen receptors (ERα, ERß1, GPER), vitellogenin (VTG1), and sex determination (BRCA2, CYP19A, DMRT1, SOX9A), both in vitro and in vivo. A whole-transcriptome sequencing method was used to evaluate the gene expression profile of larvae exposed to OC. OC was found to mediate the biosynthesis of estrogens (such as estriol) and affect the antioxidant pathway (glutathione transferases and peroxisome). These findings clarify the toxic effects and molecular mechanisms of OC and support banning its use in cosmetics.

Ethyl acrylate (EA) exposure and thyroid carcinogenicity in rats and mice with relevance to human health.

Ethyl acrylate (EA) was classified by IARC as a Group-2B Carcinogen based, in part, on data suggesting increased incidence of thyroid neoplasia in rats and mice exposed chronically to EA vapors. We examined chronic exposure of rats and mice to EA vapors, evaluated the data on the incidence of thyroid follicular neoplasia, and determined the relevance of thyroid tumors to human health risk. The data revealed a small statistically significant increase in thyroid tumors in EA-exposed male rats and mice. The tumor incidences were within the range of historical controls and were not consistently dose-dependent. Most thyroid tumors in exposed animals were benign. Chronic exposure of EA to rats and mice (drinking water or gavage) and dogs (capsules) had no evidence of thyroid neoplasia. Results from chronic studies, in vivo and in vitro data, and ToxCastTM/Tox 21 HTPS did not support genotoxic/mutagenic potential for EA. This suggests that the associations between EA exposure and thyroid neoplasia represent chance or random observations rather than a compound-mediated effect. Due to species-specific physiological differences, the hypothalamic-pituitary-thyroid axis of rodents is more sensitive to endocrine disruptive chemicals than that of humans which further suggests that findings in rodents have questionable relevance to human health.

Acute toxic effect of typical chemicals and ecological risk assessment based on two marine microalgae, Phaeodactylum tricornutum and Platymonas subcordiformis.

With the increasing demand for typical hazardous and noxious substances (HNS) in chemical industry, there is an increased leakage risk of these HNS during transportation by vessel and storage nearby seashore. In this study, the acute toxicity of nonylphenol, butyl acrylate and 1, 2-dichloroethane to Phaeodactylum tricornutum (P. tricornutum) and Platymonas subcordiformis (P. subcordiformis), was investigated to assess their ecological risk. The results showed that the three kinds of HNS showed significant time- and dose-dependent patterns on the growth inhibition of two marine microalgae. The 96 h-EC50 of nonylphenol, butyl acrylate and 1, 2-dichloroethane on P. tricornutum was 1.088, 45.908 and 396 mg L-1, respectively, and the 96 h-EC50 of that on P. subcordiformis was 0.851, 52.621 and 389 mg L-1, respectively. It was a common method to evaluate the harm of pollutants to organisms by calculating HC5 value (the minimum pollutant concentration value harmful to 95 % of the studied species, which was no-effect concentration) with Species Sensitivity Distribution (SSD). On the basis of EC50, the ecological risk assessment was further carried out, and HC5 value of nonylphenol and 1, 2-dichloroethane to aquatic organism was 0.079 and 44 mg L-1, respectively.

The presence of benzophenone in sunscreens and cosmetics containing the organic UV filter octocrylene: A laboratory study.

BACKGROUND: The reason why patients photosensitized to the drug ketoprofen (KP) may develop severe photoallergic skin reactions to octocrylene (OCT), an organic ultraviolet filter in sunscreens and cosmetics, remains largely unknown. OCT can be synthesized by using unsubstituted benzophenone (BP), a possible human carcinogen. OBJECTIVES: To verify if, and to what extent, BP residues are present in OCT-containing consumer products. METHODS: The raw material of OCT and 39 skincare products, of which 28 contain OCT, were chemically analysed for the presence of BP by means of liquid chromatography. RESULTS: In the OCT raw material and in all 28 OCT-containing products the presence of BP could be demonstrated, mostly in concentrations above 10 ppm (0.001%), whereas a majority of OCT-free products (8/11, 73%) did not contain BP. Moreover, BP concentrations significantly increased, in a time- and temperature-dependent manner, likely due to the additional degradation of OCT. CONCLUSIONS: Photoallergic contact dermatitis from OCT in patients photosensitized to KP might rely on residual BP impurities. Toxicological and ecological studies that evaluate the safety of OCT might also need to consider the concomitant presence of BP.

Comprehensive analysis of chronic rodent inhalation toxicity studies for methyl acrylate with attention to test conditions exceeding a maximum tolerated concentration.

MA is a chemical intermediate, manufactured and processed within closed systems. While so far available subacute to chronic inhalation toxicity studies performed in compliance with OECD TG principles gave no indication of any carcinogenic potential for MA, a recent 2-year inhalation study with F344/DuCrlCrlj rats published in 2017 by the JBRC showed a statistically significant increase of squamous cell carcinoma in the nasal cavity of male rats at the highest tested concentration of 160 ppm. However, the results of the different studies in total indicate that this high concentration exceeded the MTC. As MA has a low potential for genotoxic and mutagenic activity, the increased tumour incidence can be attributed to a non-genotoxic mechanism, namely to a strong inflammatory response observed in this study. Together with mechanistic and epidemiologic data for other compounds related to nasal carcinogenesis via this mode of action, it can be concluded that the relevance of this increased tumour incidence in male rats for humans is questionable. Also, a long-term exposure to higher concentrations of MA is highly unlikely to be reached in the environment or at workplaces. Therefore, a risk for humans including cancer hazard is considered implausible.

Toxic effect of p-chloroaniline and butyl acrylateon Nannochloropsis oculata based on water samples from two sea areas.

To compare the influence of water samples collected from various areas on toxic effect of HNS, we examined the toxic effect of two commonly found HNS: p-chloroaniline and butyl acrylate, on Nannochloropsis oculata cultured in seawater collected from Laizhou bay and Jiaozhou bay (China). The results showed that both p-chloroaniline and butyl acrylate had significant toxic effect on N. oculata cultured in both water samples. P-chloroaniline inhibited its net oxygenation rate and oxygen consumption rate. Butyl acrylate inhibited the net oxygenation rate whereas significantly stimulated oxygen consumption rate. Performance of N. oculata changed between two water samples under same level of p-chloroaniline and butyl acrylate. The net oxygenation rate of N. oculata cultured in the seawater from the Jiaozhou bay increased by 11.60 %, the oxygen consumption rate increased by 26.91 %, algae cell growth decreased by 16.83 %, compared to those from Laizhou bay. The Fv/Fm of N. oculata cultured in Jiaozhou bay was more significantly inhibited at 0.5 and 2.0 mg L-1 p-chloroaniline, while it was significantly inhibited at 5. 0 mg L-1 of butyl acrylate, compared to those from Laizhou bay. Moreover, the toxic effect of both HNS on net oxygenation rate and oxygen consumption rate were significantly attenuated as the concentration increased. The growth inhibition of microalgae cultured in two seawater samples was more evident at 0.5 and 5.0 mg L-1 p-chloroaniline than at 2.0 mg L-1 p-chloroaniline,and the growth inhibition of microalgae cultured in two seawater samples was more evident at 2.0 and 5.0 mg L-1 butyl acrylate than at 0.5 mg L-1 butyl acrylate. These results indicated that toxic effect of p-chloroaniline and butyl acrylate on the growth of N. oculata was influenced by the pollutants in the two water samples. Consequently, a corresponding research on water sample is required in advance to increase accuracy of future ecological risk assessment of HNS.

Single intratracheal administration of cross-linked water-soluble acrylic acid polymer causes acute alveolo-interstitial inflammation and the subsequent fibrotic formation possibly via the TGF-ß1 pathway in the lung of rats.

In a Japanese chemical factory, a lung disease like pneumoconiosis appeared at a high rate among workers handling cross-linked water-soluble acrylic acid polymer (CWAAP). To our knowledge, no such case was known in the world until very recently. The present study was designed to elucidate the effect of single intratracheal CWAAP instillation on the lung of rats. The CWAAP group had a significant increase in relative lung weight accompanied by a significant elevation in the number of total cells, total protein concentrations, and myeloperoxidase concentrations in bronchoalveolar lavage fluid when compared to the control group. The histopathological study revealed acute lung inflammation with the destruction of alveoli. The factors promoting fibrosis, macrophages, TGF-ß1, collagen and fibronectin vs. the factors suppressing fibrosis, matrix metalloproteinases were more powerfully driven in the CWAAP group, resultantly leading to fibrotic formation. In turn, we examined if acute lung inflammation and the subsequent fibrotic formation seen in the CWAAP group appeared in the other water-soluble polymer groups. Their histopathological findings were observed only in the polyacrylic acid sodium (PAAS), a monomer of CWAAP, group. The degree of inflammation and fibrogenesis was stronger in the CWAAP group than in the PAAS group. In conclusion, the present study demonstrated the induction of acute lung inflammation and the subsequent fibrotic formation by single intratracheal CWAAP instillation. The structural features of CWAAP that contains many carboxyl groups and cross-linked chains may be responsible for enhanced inflammation and fibrogenesis in the lung.

Impact of solvents on the in vitro genotoxicity of TMPTA in human HepG2 cells.

Small hydrophobic chemical compounds require solvents to produce suitable solutions for toxicological studies. However, some solvents can modify the biological properties of substances and therefore their toxicity. This specific issue has been raised for PEG-400 as an anti-inflammatory and anti-oxidative compound. Recently, in the context of the REACH Regulation, PEG-400 was used to test the in vivo genotoxicity of trimethylolpropane triacrylate (TMPTA) in the comet assay. TMPTA failed to increase DNA damage whereas it induces genotoxicity in vitro in DMSO. Therefore, we questioned whether PEG-400 could modify the genotoxicity of TMPTA. The aim of this study was to determine the potential impact of PEG-400 on the in vitro genotoxicity of TMPTA, compared to DMSO. TMPTA was dissolved in either PEG-400 or DMSO, and the induction of γH2AX and Caspase-3 was analyzed in HepG2 cells. TMPTA induced γH2AX and Caspase-3 with both PEG-400 and DMSO. However, TMPTA induced effects at 4-fold lower concentrations when PEG-400 is used as the solvent compared to DMSO. While genotoxic effects are observed at much lower concentrations with PEG-400, it does not modify the in vitro genotoxicity of TMPTA. However, further in vitro studies with small hydrophobic compounds should be done to clarify the effect of PEG-400. Moreover, in vivo studies should be performed to confirm that PEG-400 remains suitable for in vivo genotoxicity tests.

Unveiling complex responses at the molecular level: Transcriptional alterations by mixtures of bisphenol A, octocrylene, and 2'-ethylhexyl 4- (dimethylamino)benzoate on Chironomus riparius.

Living organisms are exposed to mixtures of pollutants in the wild. Inland aquatic ecosystems contain many compounds from different sources that pollute the water column and the sediment. However, majority of toxicological research is focused on the effects of single exposures to toxicants. Furthermore, studies have been principally oriented toward ecologically relevant effects of intoxication, and lack an analysis of the cellular and molecular mechanisms involved in the response to toxicants. Effects of single, binary, and ternary mixtures of three compounds, bisphenol A, octocrylene, and 2'-ethylhexyl 4- (dimethylamino)benzoate, were assessed using a Real-Time PCR array. Forty genes, and additional six reference genes, were included in the array. The genes were selected based on their association with hormone responses, detoxification mechanisms, the stress response, DNA repair, and the immune system. The study was performed on Chironomus riparius, a benthic dipteran with an essential role in the food web. Transcriptional responses were assessed both 24 and 96 h post-exposure, to determinate short- and medium-term cellular responses. Individual fourth instar larvae were exposed to 0.1 and 1 mg/L of each of the toxic compounds and compound mixtures. A weak response was detected at 24 h, which was stronger in larvae exposed to mixtures than to individual toxicants. The response at 96 h was complex and principally involved genes related to the endocrine system, detoxification mechanisms, and the stress response. Furthermore, exposure to mixtures of compounds altered the expression patterns of an increased number of genes than did individual compound exposures, which suggested complex interactions between compounds affected the regulation of transcriptional activity. The results obtained highlight the importance of analyzing the mechanisms involved in the response to mixtures of compounds over extended periods and offer new insights into the basis of the physiological responses to pollution.

Respiratory Toxicity of Azoxystrobin, Pyraclostrobin and Coumoxystrobin on Chlorella vulgaris.

Azoxystrobin (AZ), pyraclostrobin (PYR) and coumoxystrobin (COU) exert negative impacts on Chlorella vulgaris. Thus, in this study, C. vulgaris was used to assess the respiratory toxicity of AZ, PYR and COU by determining the acute toxicity, complex III activity and ATP viability. The 96 h-EC50 values of AZ, PYR and COU for C. vulgaris were 1.85, 2.21 and 1.62 mg/L, respectively. AZ, PYR and COU exerted significant effects on complex III activity and ATP viability after exposure to 0.71, 1.01 and 1.08 mg/L of the fungicides. The binding potentials of AZ, PYR and COU toward ubiquinone were - 10.44, - 9.31 and - 12.98 kcal/mol, respectively, which had adverse effects on amino acids. These results provided new insight into the potential acute respiratory toxicity mechanisms of these strobilurin fungicides in algae.

Evaluation of pyraoxystrobin bioconcentration in zebrafish (Danio rerio) using modified QuEChERS extraction.

Pyraoxystrobin is a novel strobilurin fungicide that is widely used on many crops. The high log Kow of pyraoxystrobin implies that it tends to accumulate in aquatic organisms. This study optimized the sorbents of QuEChERS (quick, easy, cheap, effective, rugged, and safe) using 13C-labelled pyraoxystrobin as the internal standard (IS). It has been established a QuEChERS-LC-MS/MS IS method to study the bioconcentration and elimination of pyraoxystrobin in zebrafish (Danio rerio). The results indicated that the method had satisfactory linearity between 0.234 and 15 µg L-1 (R2 = 0.9996). The limits of detection (LOD) and quantification (LOQ) for pyraoxystrobin were 0.01 and 0.03 µg L-1, respectively. The LOQs of the method for water and zebrafish were 0.05 µg L-1 and 0.01 mg/kg, respectively. The mean recovery of pyraoxystrobin in zebrafish and water at fortification levels of 0.01-0.3 mg kg-1 and 0.05-1.5 µg L-1 ranged from 98.31 to 105.61% and 101.87 to 108.48%, respectively, with a % RSD (relative standard deviation) of 0.94-3.57%. The bioconcentration has been evaluated. The bioconcentration factors for pyraoxystrobin in zebrafish were 1,792 and 3,505 after exposure to 0.5 µg L-1 for 168 h and 0.05 µg L-1 for 216 h, respectively. The half-life of pyraoxystrobin in zebrafish was 9.0-9.5 d.

A short-term inhalation study to assess the reversibility of sensory irritation in human volunteers.

Sensory irritation is an acute adverse effect caused by chemicals that stimulate chemoreceptors of the upper respiratory tract or the mucous membranes of the outer eye. The avoidance of this end point is of uttermost importance in regulatory toxicology. In this study, repeated exposures to ethyl acrylate were analyzed to investigate possible carryover effects from day to day for different markers of sensory irritation. Thirty healthy subjects were exposed for 4 h on five subsequent days to ethyl acrylate at concentrations permitted by the German occupational exposure limit at the time of study. Ratings of eye irritation as well as eye blinking frequencies indicate the elicitation of sensory irritation. These markers of sensory irritation showed a distinct time course on every single day. However, cumulative carryover effects could not be identified across the week for any marker. The rhinological and biochemical markers could not reveal hints for more pronounced sensory irritation. Neither increased markers of neurogenic inflammation nor markers of immune response could be identified. Furthermore, the performance on neurobehavioral tests was not affected by ethyl acrylate and despite the strong odor of ethyl acrylate the participants improved their performances from day to day. While the affected physiological marker, the increased eye blinking frequency stays roughly on the same level across the week, subjective markers like perception of eye irritation decrease slightly from day to day though the temporal pattern of, i.e., eye irritation perception stays the same on each day. A hypothetical model of eye irritation time course derived from PK/PD modeling of the rabbit eye could explain the within-day time course of eye irritation ratings repeatedly found in this study more precisely.

Proteomic analysis of haptenation by skin sensitisers: Diphencyprone and ethyl acrylate.

The potential risk of skin sensitisation, associated with the development of allergic contact dermatitis (ACD), is a consideration in the safety assessment of new ingredients for use in personal care products. Protein haptenation in skin by sensitising chemicals is the molecular initiating event causative of skin sensitisation. Current methods for monitoring skin sensitisation rely on limited reactivity assays, motivating interest in the development of proteomic approaches to characterise the skin haptenome. Increasing our mechanistic understanding of skin sensitisation and ACD using proteomics presents an opportunity to develop non-animal predictive methods and/or risk assessment approaches. Previously, we have used a novel stable isotope labelling approach combined with data independent mass spectrometry (HDMSE) to characterise the haptenome for a number of well-known sensitisers. We have now extended this work by characterising the haptenome of the sensitisers Diphenylcyclopropenone (DPCP) and Ethyl Acrylate (EA) with the model protein Human Serum Albumin (HSA) and the complex lysates of the skin keratinocyte, HaCaT cell line. We show that haptenation in complex nucleophilic models is not random, but a specific, low level and reproducible event. Proteomic analysis extends our understanding of sensitiser reactivity beyond simple reactivity assays and offers a route to monitoring haptenation in living cells.

Review of the safety of octocrylene used as an ultraviolet filter in cosmetics.

Octocrylene or octocrilene is an organic ultraviolet (UV) filter which absorbs mainly UVB radiation and short UVA wavelengths. It is used in various cosmetic products to either provide an appropriate sun protection factor in sunscreen products or to protect cosmetic formulations from UV radiation. There is no discussion that UV filters are beneficial ingredients in cosmetics since they protect from skin cancer, but octocrylene has been recently incriminated to potentially induce adverse effects on the endocrine system in addition to having allergic and/or photoallergic potential. However, the substance has the advantage to work synergistically with other filters allowing a beneficial broad photoprotection, e.g. it stabilizes the UVA filter avobenzone (i.e. butylmethoxydibenzoylmethane). Like all chemicals used in cosmetics, the safety profile of octocrylene is constantly under assessment by the European Chemical Agency (ECHA) since it has been registered according to the European regulation Registration, Evaluation, Authorisation and Restriction of Chemicals. Summaries of safety data of octocrylene are publicly available on the ECHA website. This review aims to present the main safety data from the ECHA website, as well as those reported in scientific articles from peer-reviewed journals. The available data show that octocrylene does not have any endocrine disruption potential. It is a rare sensitizer, photocontact allergy is more frequent and it is considered consecutive to photosensitization to ketoprofen. Based on these results, octocrylene can be considered as safe when used as a UV filter in cosmetic products at a concentration up to 10%.