SCCS scientific opinion on Butylated hydroxytoluene (BHT) - SCCS/1636/21.

OPINION TO BE CITED AS: SCCS (Scientific Committee on Consumer Safety), scientific opinion on Butylated hydroxytoluene (BHT), preliminary version of September 27, 2021, final version of December 2, 2021, SCCS/1636/21.

SCCS Scientific Opinion on Acid Yellow 3 (submission II) - SCCS/1631/21.

Opinion to be cited as: SCCS (Scientific Committee on Consumer Safety), Opinion on Acid Yellow 3 - C054 (CAS Number 8004-92-0, EC No 305-897-5), submission II, preliminary version of 7 May 2021, final version of 23 July 2021, SCCS/1631/21.

SCCS scientific opinion on HAA299 (nano) - SCCS/1634/21.

Opinion to be cited as: SCCS (Scientific Committee on Consumer Safety), Opinion on HAA299 (nano), preliminary opinion July 22, 2021, final opinion 26-27 October 2021, SCCS/1634/2021. HAA299 is a UV filter active intended to be used in sunscreen products as skin protectant against UVA-1 rays. Its chemical name is '2-(4-(2-(4-Diethylamino-2 hydroxy-benzoyl)-benzoyl)-piperazine-1-carbonyl)-phenyl)-(4-diethylamino-2-hydroxyphenyl)-methanone' and INCI name 'Bis-(Diethylaminohydroxybenzoyl Benzoyl) Piperazine' (CAS 919803-06-8). This product was designed and developed to deliver to the consumer stronger UV protection on skin and is most effective as a UV filter when it is milled to a smaller particle size, a process we refer to as micronization. Currently HAA299 normal form and nano form is not regulated under the Cosmetic Regulation (EC) No. 1223/2009. In 2009, Commission' services received a dossier from industry to support the safe use of HAA299 (micronised and non-micronised) in cosmetic products, which was further substantiated with additional information in 2012. In its corresponding opinion (SCCS/1533/14), the SCCS concluded that "the use of non-nano HAA299 (micronised or non-micronised, with median particle size distribution around 134 nm or larger, as measured by FOQELS) at a concentration up to 10% as an UV-filter in cosmetic products, does not pose a risk of systemic toxicity in humans". In addition, SCCS stated that "[the Opinion] … covers the safety evaluation of HAA299 in non-nano form. The opinion does not cover the safety evaluation of HAA299 which is composed of nano particles' and highlighted that '[the Opinion] … does not apply to inhalation exposure of HAA299 since no information on chronic or sub-chronic toxicity after inhalation is provided". With the current submission, received in September 2020, and in view of the previous SCCS opinion (SCCS/1533/14) on the normal form of HAA299, the applicant requests to assess the safety of HAA299 (nano) intended to be used as UV-filter up to a maximum concentration of 10%.

The SCCS scientific advice on the safety of nanomaterials in cosmetics.

The Cosmetic Regulation (EC) No 1223/2009 specifically covers the risk of nanomaterials used in cosmetic products. If there are concerns regarding the safety of a nanomaterial, the European Commission refers it to the SCCS for a scientific opinion. The Commission mandated the SCCS to identify the scientific basis for safety concerns that could be used as a basis for identifying and prioritising nanomaterials for safety assessment, and to revisit previous inconclusive SCCS opinions on nanomaterials to identify any concerns for potential risks to the consumer health. The SCCS Scientific Advice identified the key general aspects of nanomaterials that should raise a safety concern for a safety assessor/manager, so that the nanomaterial(s) in question could be subjected to safety assessment to establish safety to the consumer. The Advice also developed a list of the nanomaterials notified to the Commission for use in cosmetics in an order of priority for safety assessment, and revisited three previous inconclusive opinions on nanomaterials to highlight concerns over consumer safety that merited further safety assessment.

Opinion of the Scientific Committee on Consumer Safety (SCCS) - Final Opinion on propylparaben (CAS No 94-13-3, EC No 202-307-7).

In cosmetic products, the ingredient propylparaben (CAS No 94-13-3, EC No 202-307-7) with the chemical names Propyl 4-hydroxybenzoate and 4-Hydroxybenzoic acid propyl ester is currently regulated as a preservative in a concentration up to 0.14% (as acid) (Annex V/12a). In addition, a safe concentration was established for mixtures of parabens, where the sum of the individual concentrations should not exceed 0.8% (as acid). However, in such mixtures the sum of the individual concentrations of butyl- and propylparaben and their salts should not exceed 0.14%. Propylparaben was subject to different safety evaluations in 2005 (SCCP/0874/05), 2006 (SCCP/1017/06), 2008 (SCCP/1183/08), 2010 (SCCS/1348/10), 2011 (SCCS/1446/11), and in 2013 (SCCS/1514/13). On the basis of the safety assessment of propylparaben, and considering the concerns related to potential endocrine disrupting properties, the SCCS has concluded that propylparaben is safe when used as a preservative in cosmetic products up to a maximum concentration of 0.14%. The available data on propylparaben provide some indications for potential endocrine effects. However, the current level of evidence is not sufficient to regard it as an endocrine disrupting substance, or to derive a toxicological point of departure based on endocrine disrupting properties for use in human health risk assessment. The SCCS mandate does not address environmental aspects. Therefore, this assessment did not cover the safety of propylparaben for the environment. Link to the Opinion (SCCS/1623/20): https://ec.europa.eu/health/sites/default/files/scientific_committees/consumer_safety/docs/sccs_o_243.pdf.

The SCCS Notes of Guidance for the testing of cosmetic ingredients and their safety evaluation, 11th revision, 30-31 March 2021, SCCS/1628/21.

The "SCCS Notes of Guidance for the Testing of Cosmetic Ingredients and Their Safety Evaluation, 11 th Revision" (SCCS/1628/21) contains relevant and updated information on the different aspects of testing and safety evaluation of cosmetic substances in Europe. The emphasis is on cosmetic ingredients for which a concern has been expressed for human health. Indirectly, the Guidance also provides some advice on the safety of finished products. A general aim is to improve harmonised compliance with the current cosmetic EU legislation, Regulation (EC) No 1223/2009, for which animal testing and marketing bans fully apply from 2013 onwards. This means that no in vivo testing of ingredients or finished products is allowed in Europe for the purpose of cosmetics. For this reason, the SCCS has closely followed the progress made in regard to the development and validation of alternative replacement methods, also referred to as new approach methodology (NAM). The "SCCS Notes of Guidance" are regularly revised and updated in order to incorporate progress made and experience gained over time, in particular on the use of NAMs, and the new methods and data that became available since previous revision (SCCS/1602/18) formed the basis of the current (11 th) Revision.

Enhancement of Cisplatin Cytotoxicity by Cu(II)-Mn(II) Schiff Base Tetradentate Complex in Human Oral Squamous Cell Carcinoma.

Oral squamous cell carcinoma (SCC) is one of the most predominant tumors worldwide and the present treatment policies are not enough to provide a specific solution. We aimed to assess the cytotoxic effect of Cu(II)-Mn(II) Schiff base tetradentate complex alone or in combination with cisplatin against squamous cell carcinoma cell line (SCCs) in vitro. Oral-derived gingival mesenchymal stem cells (GMSCs) were used as control. The cell viability was assessed by MTT assay. IC50 values were calculated. Evaluation of apoptosis and DNA damage were performed. In addition, the expression of pro-apoptotic and anti-apoptotic genes and proteins were tested. IC50 values indicated less toxicity of the Schiff base complex on GMSCs compared to cisplatin. Schiff base complex treatment resulted in up-regulation of p53 and Bax genes expression and down-regulation of Bcl2 gene expression in SCCs paralleled with increased protein expression of caspase-3 and Bax and down-regulation of Bcl-2 protein. Annexin V-FITC apoptosis kit showed a higher apoptotic effect induced by a Schiff base complex compared to the cisplatin-treated group. These effects were markedly increased on the combination of Schiff base and cisplatin. The present study established that Cu(II)-Mn(II) Schiff base tetradentate complex might induce a cytotoxic effect on SCCs cells via induction of the apoptotic pathway. Moreover, this Schiff base complex augments the anticancer effect of cisplatin.

Lessons learned from SMAD4 loss in squamous cell carcinomas.

SMAD4 is a potent tumor suppressor and a central mediator of the TGFß signaling pathway. SMAD4 genetic loss is frequent in squamous cell carcinomas (SCCs). Reports of SMAD4 expression in SCCs vary significantly possibly due to inter-tumor heterogeneity or technical reasons. SMAD4 loss is an initiation event for SCCs. In tumor epithelial cells, SMAD4 loss causes increased proliferation, decreased apoptosis, and "Brca-like" genomic instability associated with DNA repair defects. SMAD4 loss also plays a role in the expansion of cancer stem cells. Epithelial SMAD4 loss causes overexpression of TGFß that is released into the tumor microenvironment and contributes to SCC progression through proinflammatory and immune evasive mechanisms. SMAD4 loss, while not a direct therapeutic target, is associated with multiple targetable pathways that require further therapeutic studies. Altogether, SMAD4 loss is a potential biomarker in SCCs that should be further studied for its values in prognostic and therapeutic predictions. Such information will potentially guide future biomarker-driven clinical trial designs and improve SCC patient outcomes.

Opinion of the Scientific Committee on Consumer safety (SCCS) - Opinion on Ethylzingerone - 'Hydroxyethoxyphenyl Butanone' (HEPB) - Cosmetics Europe No P98 - CAS No 569646-79-3 - Submission II (eye irritation).

Based on the new information provided by the Applicant, the SCCS considers the use of Hydroxyethoxyphenyl Butanone (HEPB) as a cosmetic preservative in rinse-off, oral care and leave-on cosmetic products with a maximum concentration of 0.7% safe with regard to eye irritation.

Opinion of the Scientific Committee on consumer safety (SCCS) - Final opinion on the safety of fragrance ingredient Acetylated Vetiver Oil (AVO) - (Vetiveria zizanioides root extract acetylated) - Submission III.

On the basis of the safety assessment carried out using a conservative approach, the SCCS considers the use of Acetylated Vetiver Oil (AVO) with 1% alpha-tocopherol as a fragrance ingredient in cosmetic leave-on and rinse-off type products safe at the concentrations proposed by IFRA. Acetylated Vetiver Oil (AVO) contains some constituents that belong to the chemical group of aldehydes and ketones that are known to be reactive towards biological entities, such as DNA and proteins. However, the overall health risk of such components is likely to be negligible at the concentrations intended to be used in cosmetics products. The SCCS has noted that Acetylated Vetiver Oil (AVO) is a moderate skin sensitiser in test animals. Considering the results of the HRIPT study and the fact that AVO has been used for years in cosmetics without evidence of sensitising potential, it is unlikely that AVO would be causing contact allergy in humans. Inhalation toxicity of Acetylated Vetiver Oil (AVO) was not assessed in this Opinion because no data were provided. Assessment of the inhalation risk would be needed if Acetylated Vetiver Oil (AVO) was intended to be used in sprayable products.

A data-driven method to detect adverse drug events from prescription data.

Drug safety issues such as Adverse Drug Events (ADEs) can cause serious consequences for the public. The clinical trials that are undertaken to assess medicine efficacy and safety prior to marketing, generally, may provide sufficient samples for discovering common ADEs. However, more samples are needed to detect infrequent and rare events. Additionally, clinical trials may not include all subgroups of patients. For these reasons, post-marketing surveillance of medicines is necessary for identifying drug safety issues. Most regulatory agencies use the Spontaneous Reporting Systems to identify associations between medicines and suspected ADEs. Data mining with effective analytical frameworks and large-scale medical data is potentially an alternative method to discover and monitor ADEs. In the present paper, we aim to detect potential ADEs from prescription data by discovering ADE associated prescription sequences. In an ADE associated prescription sequence 〈Dp→Ds〉, the prior medicine Dp leads to an ADE for which the succeeding medicine Ds is dispensed to treat. We propose a data-driven method which integrates (1) a constrained sequential pattern mining to uncover prescription sequences as potential signals of ADEs, (2) domain constraints to eliminate interference signals and (3) an adapted Self-Controlled Case Series model to evaluate the potential signals of ADEs. Despite ample prior works using Electronic Health Records (EHRs), our method utilises pure prescription data which does not contain additional information, e.g. symptoms or diagnoses as included in EHRs. To assess the performance of the proposed method, we apply it to a real-world dataset from the Pharmaceutical Benefits Scheme of Australia. The dataset contains over 50 million records covering approximately 2 million patients. The results demonstrate the effectiveness of our method in identifying both known ADEs and unknown yet suspicious ADEs with limited detection of false positive signals. Comparing to a recognised gold standard, our method successfully detects 67.4% of the positive adverse events while only 8.78% false positives exist.

Opinion of the Scientific Committee on Consumer Safety (SCCS) - Revision of the Opinion on hydroxyapatite (nano) in cosmetic products.

In response to the concerns of the European Commission about potential absorption and entry of nanoparticles of hydroxyapatite into the cells when used in oral cosmetic products, the Scientific Committee on Consumer Safety (SCCS) was requested to provide a safety assessment of hydroxyapatite (nano). After making a detailed evaluation of the data provided in the submissions and scientific literature, the SCCS considered needle-shaped hydroxyapatite (nano) to be of concern due to its potential toxic effects, and stated that it should not be used in cosmetic products. In terms of other shapes of hydroxyapatite (nano), the available evidence was insufficient to allow drawing a conclusion on the safety of hydroxyapatite (nano) when used in oral cosmetic products up to a concentration of 10%.

Opinion of the Scientific Committee on Consumer safety (SCCS) - Final opinion on water-soluble zinc salts used in oral hygiene products.

The SCCS has estimated that exposure to water-soluble zinc salts via toothpaste and mouthwash at the concentrations of 1 and 0.1%, respectively, may lead to a daily intake level of 3.54 mg for adults and children aged 6-17 years. This exposure constitutes between 14 and 35% of the Upper Limit (UL) for these age groups. Therefore, the SCCS considers that the use of zinc in toothpaste and mouthwash per se is safe for adults and children aged 6-17 years. The SCCS has estimated that exposure to water-soluble zinc salts via toothpaste at the concentrations of 1% may lead to a daily intake level of 1.0-2.00 mg for children aged 0.5-5 years. This exposure constitutes between 10 and 29% of the UL for this age group. Therefore, the SCCS considers that the use of zinc in toothpaste per se is safe for children aged 0.5-5 years. Exposure to zinc may also occur from sources other than oral hygiene products. An important source of zinc in the population is the diet. This assessment has not taken into account the daily dietary intake of zinc. The dietary zinc intake (estimated by EFSA in 2014) ranges from 6.8 to 14.5 mg/day in adolescents aged 10 to < 18 years, from 5.5 to 9.3 mg/day in children aged 3 to < 10 years and from 4.6 to 6.2 mg/day in children aged 1 to <3 years. Therefore, exposure to zinc via the diet may already exceed or be close to exceeding the upper limits of 18, 13, 10 and 7 mg/day for the age groups 11-14, 7-10, 3-7 and 1-3 years, respectively. Any additional source of exposure, including cosmetics, may lead to exceeding the upper limits for children. The SCCS cannot advise which portion of the upper limit should be allocated to exposure from cosmetic products. When assessing exposure to chemicals, allocation factors that reflect a reasonable level of exposure while still being protective may be applied. For exposure via toys or drinking water, for example, allocation factors of 10% or 20% of the reference value may be considered as safe. In the case of zinc, the use of 1% in toothpaste and 0.1% in mouthwash constitutes between 10 and 35% of the upper limit depending on the age group. The SCCS is aware that upper limits may be exceeded in some cases because the default values used in this Opinion are based on conservative estimates.

Comparison between Atlantic salmon Salmo salar post-smolts reared in open sea cages and in the Preline raceway semi-closed containment aquaculture system.

The use of closed containment (CCS) or semi-closed containment systems (S-CCS) for Atlantic salmon Salmo salar aquaculture is under evaluation in Norway. One such system is the Preline S-CCS, a floating raceway system that pumps water from 35 m depth creating a constant current through the system. Exposing fish to moderate water currents is considered aerobic exercise and it is often perceived as positive for fish welfare, growth, food utilization, muscle development and cardiac health. The present study compared fish reared in the Preline S-CCS and in a reference open pen. Samples were taken in fresh water before being transferred to the seawater systems and after 1, 2 and 4 months in seawater and analysed for growth, mortality, muscle development and plasma insulin-like growth factor I (IGF-I) levels. Moreover, gene transcription were determined in the skeletal muscle [igf-I, insulin-like growth factor 1 receptor a (igf1ra) and insulin-like growth factor 1 binding protein 1a (igf1bp1a)] and cardiac transcription factors [myocyte-specific enhancer factor 2C (mef2c), gata4 and vascular endothelial growth factor (vegf)]. While the results suggest that post-smolts in Preline S-CCS were smaller than reference fish, fish from Preline S-CCS have less accumulated mortality at the end of the experiment and showed 2.44 times more small muscle fibres than the reference group fish after 4 months in seawater. These results confirmed what was previously observed in the second generation of Preline. Similar levels of big muscle fibres between Preline S-CCS and reference suggest a similar hypertrophy of muscle fibres even with lower IGF-I expression in the Preline S-CCS. Cardiac gene transcription suggests cardiac hypertrophy was observed after 4 months in seawater in the Preline S-CCS group. Altogether, Preline S-CCS is a promising technology able to produce more robust S. salar with a faster growth and lower mortality in the subsequent standard open cage system growth period.

Spline-based self-controlled case series method.

The self-controlled case series (SCCS) method is an alternative to study designs such as cohort and case control methods and is used to investigate potential associations between the timing of vaccine or other drug exposures and adverse events. It requires information only on cases, individuals who have experienced the adverse event at least once, and automatically controls all fixed confounding variables that could modify the true association between exposure and adverse event. Time-varying confounders such as age, on the other hand, are not automatically controlled and must be allowed for explicitly. The original SCCS method used step functions to represent risk periods (windows of exposed time) and age effects. Hence, exposure risk periods and/or age groups have to be prespecified a priori, but a poor choice of group boundaries may lead to biased estimates. In this paper, we propose a nonparametric SCCS method in which both age and exposure effects are represented by spline functions at the same time. To avoid a numerical integration of the product of these two spline functions in the likelihood function of the SCCS method, we defined the first, second, and third integrals of I-splines based on the definition of integrals of M-splines. Simulation studies showed that the new method performs well. This new method is applied to data on pediatric vaccines. Copyright © 2017 John Wiley & Sons, Ltd.

Do case-only designs yield consistent results across design and different databases? A case study of hip fractures and benzodiazepines.

BACKGROUND: The case-crossover (CXO) and self-controlled case series (SCCS) designs are increasingly used in pharmacoepidemiology. In both, relative risk estimates are obtained within persons, implicitly controlling for time-fixed confounding variables. OBJECTIVES: To examine the consistency of relative risk estimates of hip/femur fractures (HFF) associated with the use of benzodiazepines (BZD) across case-only designs in two databases (DBs), when a common protocol was applied. METHODS: CXO and SCCS studies were conducted in BIFAP (Spain) and CPRD (UK). Exposure to BZD was divided into non-use, current, recent and past use. For CXO, odds ratios (OR; 95%CI) of current use versus non-use/past were estimated using conditional logistic regression adjusted for co-medications (AOR). For the SCCS, conditional Poisson regression was used to estimate incidence rate ratios (IRR; 95%CI) of current use versus non/past-use, adjusted for age. To investigate possible event-exposure dependence the relative risk in the 30 days prior to first BZD exposure was also evaluated. RESULTS: In the CXO current use of BZD was associated with an increased risk of HFF in both DBs, AORBIFAP = 1.47 (1.29-1.67) and AORCPRD = 1.55 (1.41-1.70). In the SCCS, IRRs for current exposure was 0.79 (0.72-0.86) in BIFAP and 1.21 (1.13-1.30) in CPRD. However, when we considered separately the 30-day pre-exposure period, the IRR for current period was 1.43 (1.31-1.57) in BIFAP and 1.37 (1.27-1.47) in CPRD. CONCLUSIONS: CXO designs yielded consistent results across DBs, while initial SCCS analyses did not. Accounting for event-exposure dependence, estimates derived from SCCS were more consistent across DBs and designs.

Opinion of the Scientific Committee on Consumer safety (SCCS) - Opinion on the safety of the use of deoxyarbutin in cosmetic products.

CONCLUSION OF THE OPINION: Although on the basis of the provided scientific data the use of deoxyarbutin as such can be considered safe for consumers in cosmetic products in a concentration up to 3% in face creams, hydroquinone will be formed at levels which raise concerns with regard to the safety of such products during life-cycle of the product (e.g. storage conditions and stability under in-use conditions). Therefore, the overall conclusion of the SCCS is that the use of deoxyarbutin up to 3% in face creams is not safe.

Opinion of the Scientific Committee on Consumer safety (SCCS)--Opinion on the safety of the use of α-arbutin in cosmetic products.

CONCLUSION OF THE OPINION: The SCCS considers the use of α-Arbutin safe for consumers in cosmetic products in a concentration up to 2% in face creams and up to 0.5% in body lotions. A potential combined use of α-Arbutin and other hydroquinone releasing substances in cosmetic products has not been evaluated in this Opinion.

Opinion of the Scientific Committee on Consumer Safety (SCCS) - Final version of the opinion on Phenoxyethanol in cosmetic products.

The SCCS considers 2-phenoxyethanol safe for use as a preservative with a maximum concentration of 1.0%, taking into account the information provided. The toxicokinetics default factor of 4.0 can be reduced to 1.0 yielding a minimum Margin of Safety (MoS) of 25 instead of 100 for the safety assessment of 2-phenoxyethanol. Therefore, the MoS of about 50 for children also covers this specific age group who might be higher exposed to 2-phenoxyethanol than adults. This Opinion does not take into account exposure from sources other than cosmetics.