Assessment of the PARP inhibitor talazoparib photosafety profile.

Talazoparib (TLZ) is a poly(adenosine diphosphate [ADP]-ribose) polymerase inhibitor employed for the treatment of breast cancer. This drug displays an absorption band in the UVA region, and therefore investigation of the possible phototoxic side-effects associated to its administration results of enormous relevance. In this context, we describe here a photochemical and photobiological study to ascertain the photosafety profile of TLZ. Concerning transient species, the singlet and triplet excited states of TLZ were detected by fluorescence (λmax em = 440 nm) and laser flash photolysis experiments (λmax abs = 400 nm), respectively. Remarkably, TLZ irradiation with UVA light in aqueous solution resulted in formation of a stable photooxidated product, TLZ-P, whose absorption band is extended until the visible region. From in vitro experiments, phototoxicity was revealed for the parent drug by neutral red uptake (NRU) assays, with a PIF value of ca 7; besides, TLZ induced formation of reactive oxygen species (ROS) and produced significant damage to both proteins and DNA. By contrast, the singlet and triplet excited states of TLZ-P were not detected, and no photodamage was observed in the NRU experiments. Overall, the results indicate that TLZ induces phototoxicity, whereas its photoproduct exhibits photosafety.

PhotoSENSIL-18 assay development: Enhancing the safety testing of cosmetic raw materials and finished products to support the in vitro photosensitization assessment?

Although photosensitization remains a major toxicological endpoint for the safety assessment of cosmetic products and their raw materials, there is no validated in vitro method available for the evaluation of this adverse effect so far. Given that previous studies have proposed that the Interleukine-18 (IL-18) plays a key role in keratinocyte-driven pro-inflammatory responses specific of the skin sensitization process, we hypothesize that IL-18 might be used as a specific biomarker for in vitro photosensitization assessment. The aim of the present study was the set-up of a new in vitro assay using IL-18 as a biomarker for the identification of photosensitizers in a reconstructed human epidermis (RHE) model. EpiCS™ RHE were incubated with a set of 16 known sensitising / phototoxic / photosensitizing substances and exposed to ultra-violet (UV) irradiation. Then, the cell viability was analysed by MTT assay, while the IL-18 secretion was quantified by ELISA. Preliminary assays have shown that 1 h of incubation followed by a recovery period of 23 h induced the highest IL-18 production in response to UV exposure. This protocol was used to test 16 substances and a ratio of IL-18 production (UV+/UV- ratio) was then generated. Our data shows that the cut-off of 1.5 (UV+/UV- ratio) is the most predictive model among the tested conditions, being capable of identifying true positive photosensitizers (8 of 9) with a good prediction in comparison with in vivo data. In a nutshell, our data suggests that the PhotoSENSIL-18 is a promising in vitro method for identification of photosensitizing substances. Although further studies are necessary to optimize the model, we foresee that the PhotoSENSIL-18 assay can be used in the context of an Integrative Approach to Testing and Assessment (IATA) of chemicals.

The Assessment of the Phototoxic Action of Chlortetracycline and Doxycycline as a Potential Treatment of Melanotic Melanoma-Biochemical and Molecular Studies on COLO 829 and G-361 Cell Lines.

Melanoma is still one of the most dangerous cancers. New methods of treatment are sought due to its high aggressiveness and the relatively low effectiveness of therapies. Tetracyclines are drugs exhibiting anticancer activity. Previous studies have also shown their activity against melanoma cells. The possibility of tetracycline accumulation in pigmented tissues and the increase in their toxicity under the influence of UVA radiation creates the possibility of developing a new anti-melanoma therapy. This study aimed to analyze the phototoxic effect of doxycycline and chlortetracycline on melanotic melanoma cells COLO 829 and G-361. The results indicated that tetracycline-induced phototoxicity significantly decreased the number of live cells by cell cycle arrest as well as a decrease in cell viability. The simultaneous exposure of cells to drugs and UVA caused the depolarization of mitochondria as well as inducing oxidative stress and apoptosis. It was found that the combined treatment activated initiator and effector caspases, caused DNA fragmentation and elevated p53 level. Finally, it was concluded that doxycycline demonstrated a stronger cytotoxic and phototoxic effect. UVA irradiation of melanoma cells treated with doxycycline and chlortetracycline allows for the reduction of therapeutic drug concentrations and increases the effectiveness of tested tetracyclines.

Absence of phototoxicity/photoirritation potential of bergamottin determined In Vitro using OECD TG 432.

The phototoxic potential of a number of furocoumarins is well established. On the other hand, studies have shown that bergamottin, a furocoumarin containing a bulky, hydrophobic side chain, has significantly less or is even absent of phototoxicity potential. The OECD Test Guideline 432 3T3/Neutral Red Uptake (NRU) in vitro phototoxicity test has shown to be a highly predictive test for identifying compounds that exhibit no phototoxicological potential. In this study using OECD 432, the established phototoxic furocoumarin 5-methoxypsoralen (5-MOP), 8-methoxypsoralen (8-MOP) and psoralen were phototoxic, whereas bergamottin showed no phototoxic potential. When compared to 5-MOP, 8-MOP and psoralen, bergamottin was clearly negative at molar-adjusted concentrations that were more than 9 times higher than those that produced phototoxicity in 8-MOP; nearly 16 times than those for psoralen and more than 36 times higher than those for 5-MOP. These data using in vitro 3T3 NRU Phototoxicity Test (OECD 432) are supportive of earlier studies showing bergamottin does not exhibit phototoxicological properties. The detection and quantification of bergamottin should therefore not contribute to the potential marker furocoumarins for risk management interventions intended to reduce the phototoxicity of natural furocoumarin containing preparations.

A proposed NAM-based tiered phototoxicity testing and human risk assessment framework for agrochemicals.

Phototoxicity testing is required by European regulations for agrochemicals with UV/visible molar extinction/absorption coefficient (MEC) higher than 10 L x mol-1 x cm-1 in the 290-700 nm wavelength range. Furthermore, regulations identify a need of considering human exposure in case of positive results. While in vitro OECD test guidelines are available for hazard characterisation, there is no guidance on how to utilise positive results in human exposure risk assessments. Our goal was to take a first step towards developing a NAM based tiered testing approach and a framework for non-dietary acute human dermal risk assessment for phototoxicity to agrochemicals. The proposed framework can be divided into a few steps: 1) use the OECD updated MEC values of 1000 L x mol-1 x cm-1 as trigger for phototoxicity testing; 2) establish a reference concentration (RfC) from in vitro phototoxicity studies using BMC approach, 3) estimate potential exposure to skin, target organ for phototoxicity, using EFSA exposure models, product specific labels and skin penetration values, and 4) phototoxicity risk assessment; 5) refinement to RfC and/or exposure estimates can be considered. Finally, case studies of a nematicide and an herbicide active substance are provided to illustrate the proposed framework.

RIFM fragrance ingredient safety assessment, l-carvone, CAS Registry Number 6485-40-1.

l-Carvone was evaluated for genotoxicity, repeated dose toxicity, reproductive toxicity, local respiratory toxicity, phototoxicity/photoallergenicity, skin sensitization, and environmental safety. Data show that l-carvone is not genotoxic and provided a No Expected Sensitization Induction Level (NESIL) of 2600 µg/cm2 for the skin sensitization endpoint. Data on l-carvone provided a calculated Margin of Exposure (MOE) >100 for the repeated dose toxicity and reproductive toxicity endpoints. The phototoxicity/photoallergenicity endpoint was completed based on data and ultraviolet/visible (UV/Vis) spectra; l-carvone is not phototoxic/photoallergenic. The local respiratory toxicity endpoint was evaluated using the Threshold of Toxicological Concern (TTC) for a Cramer Class II material (0.47 mg/day); the exposure to l-carvone is below the TTC. The environmental endpoints were evaluated; l-carvone was found not to be persistent, bioaccumulative, and toxic (PBT) as per the International Fragrance Association (IFRA) Environmental Standards, and its risk quotients, based on its current volume of use in Europe and North America (i.e., Predicted Environmental Concentration/Predicted No Effect Concentration [PEC/PNEC]), are <1.

RIFM fragrance ingredient safety assessment, ß-caryophyllene, CAS Registry Number 87-44-5.

The existing information supports the use of this material as described in this safety assessment. ß-Caryophyllene was evaluated for genotoxicity, repeated dose toxicity, reproductive toxicity, local respiratory toxicity, phototoxicity/photoallergenicity, skin sensitization, and environmental safety. Data show that ß-caryophyllene is not genotoxic. Data on ß-caryophyllene provided a calculated Margin of Exposure (MOE) > 100 for the repeated dose toxicity and fertility endpoints. The developmental and local respiratory toxicity endpoints were evaluated using the Threshold of Toxicological Concern (TTC) for a Cramer Class I material, and the exposure to ß-caryophyllene is below the TTC (0.03 mg/kg/day and 1.4 mg/day, respectively. Data show that there are no safety concerns for ß-caryophyllene for skin sensitization under the current declared levels of use. The phototoxicity/photoallergenicity endpoints were evaluated based on data and ultraviolet/visible (UV/Vis) spectra; ß-caryophyllene is not expected to be phototoxic/photoallergenic. The environmental endpoints were evaluated; ß-caryophyllene was found not to be Persistent, Bioaccumulative, and Toxic (PBT) as per the International Fragrance Association (IFRA) Environmental Standards, and its risk quotients, based on its current volume of use in Europe and North America (i.e., Predicted Environmental Concentration/Predicted No Effect Concentration [PEC/PNEC]), are <1.

RIFM fragrance ingredient safety assessment, phenethyl phenylacetate, CAS Registry Number 102-20-5.

The existing information supports the use of this material as described in this safety assessment. Phenethyl phenylacetate was evaluated for genotoxicity, repeated dose toxicity, reproductive toxicity, local respiratory toxicity, phototoxicity/photoallergenicity, skin sensitization, and environmental safety. Data show that phenethyl phenylacetate is not genotoxic. Data provide a calculated MOE >100 for the repeated dose toxicity endpoint. Data on read-across analog benzyl benzoate (CAS # 120-51-4) provide an MOE >100 for the developmental toxicity endpoint. The fertility and local respiratory toxicity endpoints were evaluated using the TTC for a Cramer Class I material, and the exposure to phenethyl phenylacetate is below the TTC (0.03 mg/kg/day, and 1.4 mg/day, respectively). Data from analog benzyl phenylacetate (CAS # 102-16-9) show that there are no safety concerns for phenethyl phenylacetate for skin sensitization under the current declared levels of use. The phototoxicity/photoallergenicity endpoints were evaluated based on UV/Vis spectra; phenethyl phenylacetate is not expected to be phototoxic/photoallergenic. The environmental endpoints were evaluated; phenethyl phenylacetate was found not to be PBT as per the IFRA Environmental Standards and its risk quotients, based on its current volume of use in Europe and North America (i.e., PEC/PNEC), are <1.

RIFM fragrance ingredient safety assessment, tetrahydro-6-(3-pentenyl)-2H-pyran-2-one, CAS Registry Number 32764-98-0.

The existing information supports the use of this material as described in this safety assessment. Tetrahydro-6-(3-pentenyl)-2H-pyran-2-one was evaluated for genotoxicity, repeated dose toxicity, reproductive toxicity, local respiratory toxicity, phototoxicity/photoallergenicity, skin sensitization, and environmental safety. Data show that tetrahydro-6-(3-pentenyl)-2H-pyran-2-one is not genotoxic. The repeated dose, reproductive, and local respiratory toxicity endpoints were evaluated using the Threshold of Toxicological Concern (TTC) for a Cramer Class II material, and the exposure to tetrahydro-6-(3-pentenyl)-2H-pyran-2-one is below the TTC (0.009 mg/kg/day, 0.009 mg/kg/day, and 0.47 mg/day, respectively). Data and read-across to 5-hydroxy-7-decenoic acid δ-lactone (CAS # 25,524-95-2) show that there are no safety concerns for tetrahydro-6-(3-pentenyl)-2H-pyran-2-one for skin sensitization under the current declared levels of use. The phototoxicity/photoallergenicity endpoints were evaluated based on data and ultraviolet/visible (UV/Vis) spectra; tetrahydro-6-(3-pentenyl)-2H-pyran-2-one is not expected to be phototoxic/photoallergenic. The environmental endpoints were evaluated; tetrahydro-6-(3-pentenyl)-2H-pyran-2-one was found not to be Persistent, Bioaccumulative, and Toxic (PBT) as per the International Fragrance Association (IFRA) Environmental Standards, and its risk quotients, based on its current volume of use in Europe and North America (i.e., Predicted Environmental Concentration/Predicted No Effect Concentration [PEC/PNEC]), are <1.

RIFM fragrance ingredient safety assessment, 5,8-methano-2H-1-benzopyran, 6(or 7)-ethylideneoctahydro-, [4aR,5S,8S,8aS(or 4aR,5R,8S,8aR)]-rel-, CAS Registry Number 943723-15-7.

The existing information supports the use of this material as described in this safety assessment. 5,8-Methano-2H-1-benzopyran, 6(or 7)-ethylideneoctahydro-, [4aR,5S,8S,8aS(or 4aR,5R,8S,8aR)]-rel- was evaluated for genotoxicity, repeated dose toxicity, reproductive toxicity, local respiratory toxicity, phototoxicity/photoallergenicity, skin sensitization, and environmental safety. Data from read-across analog 5,8-methano-2H-1-benzopyran-2-one, 6- ethylideneoctahydro- (CAS # 69486-14-2) show that 5,8-methano-2H-1-benzopyran, 6(or 7)-ethylideneoctahydro-, [4aR,5S,8S,8aS(or 4aR,5R,8S,8aR)]-rel- is not expected to be genotoxic. The repeated dose, reproductive, and local respiratory toxicity endpoints were evaluated using the TTC for a Cramer Class III material, and the exposure to 5,8-methano-2H-1-benzopyran, 6(or 7)-ethylideneoctahydro-, [4aR,5S,8S,8aS(or 4aR,5R,8S,8aR)]-rel- is below the TTC (0.0015 mg/kg/day, 0.0015 mg/kg/day, and 0.47 mg/day, respectively). Data provided 5,8-methano-2H-1-benzopyran, 6(or 7)-ethylideneoctahydro-, [4aR,5S,8S,8aS(or 4aR,5R,8S,8aR)]-rel- a NESIL of 8200 µg/cm2 for the skin sensitization endpoint. The phototoxicity/photoallergenicity endpoints were evaluated based on human study data and UV/Vis spectra; 5,8-methano-2H-1-benzopyran, 6(or 7)-ethylideneoctahydro-, [4aR,5S,8S,8aS(or 4aR,5R,8S,8aR)]-rel- is not expected to be phototoxic/photoallergenic. The environmental endpoints were evaluated; 5,8-methano-2H-1-benzopyran, 6(or 7)-ethylideneoctahydro-, [4aR,5S,8S,8aS(or 4aR,5R,8S,8aR)]-rel- was found not to be PBT as per the IFRA Environmental Standards, and its risk quotients, based on its current volume of use in Europe and North America (i.e., PEC/PNEC), are <1.

RIFM fragrance ingredient safety assessment, cis-3-hexenyl methyl carbonate, CAS Registry Number 67633-96-9.

The following paper presents the method of determination of the percolation threshold in cement composites with expanded graphite by impedance spectroscopy. Most of the applications of cement composites with conductive additives require exceeding the percolation threshold. The ionic conductivity of cement matrix below the percolation threshold has a major impact on the conductivity of the composite, as a result, it significantly hinders the exploitation of these composites. The electric properties of cement composites with expanded graphite were evaluated by DC measurements and impedance spectroscopy (IS). Based on Nyquist plots, two equivalent circuits were adopted for the composites. Next, the values of capacitance and inductance of cement composites with expanded graphite were calculated from the fitted equivalent circuits. The analysis of the results shows that the percolation threshold occurs when the reactance of the composite changes from captative to inductive. Comparison between the values of percolation threshold obtained from DC measurements and IS shows that the method is effective for cement composites with conductive additives.

RIFM fragrance ingredient safety assessment, 6,6-dimethylbicyclo[3.1.1]hept-2-ene-2-propionaldehyde, CAS Registry Number 33885-51-7.

No treatment-related effects at the low and mid doses were observed in gestation, viability and lactation indices, duration of gestation, parturition, sex ratio, maternal care, litter size, and early postnatal pup development consisting of mortality, clinical signs, anogenital distance, areola/nipple retention, T4 thyroid hormone levels, or macroscopic examination. However, the number of litters (N = 5) at the high dose was considered too low for toxicological evaluation. Thus, based on insufficient data at 120 mg/kg/day, the NOAEL for this study was considered to be 60 mg/kg/day (RIFM, 2020d).

RIFM fragrance ingredient safety assessment, cis-3-hexenyl tiglate, CAS Registry Number 67883-79-8.

The existing information supports the use of this material as described in this safety assessment. cis-3-Hexenyl tiglate was evaluated for genotoxicity, repeated dose toxicity, reproductive toxicity, local respiratory toxicity, phototoxicity/photoallergenicity, skin sensitization, and environmental safety. Data from read-across analogs 2-methyl-trans-2-butenoic acid (CAS # 80-59-1) and cis-3-hexenol (CAS # 928-96-1) show that cis-3-hexenyl tiglate is not expected to be genotoxic. The repeated dose, reproductive, and local respiratory toxicity endpoints were evaluated using the Threshold for Toxicological Concern (TTC) for a Cramer Class I material; exposure to cis-3-hexenyl tiglate is below the TTC (0.03 mg/kg/day, 0.03 mg/kg/day and 1.4 mg/day, respectively). Data from analog 2-hexenoic acid, 2-methyl-, methyl ester, (2E)- (CAS # 16493-96-2) provided cis-3-hexenyl tiglate a No Expected Sensitization Induction Level (NESIL) of 1100 µg/cm2 for the skin sensitization endpoint. The phototoxicity/photoallergenicity endpoints were evaluated based on ultraviolet/visible (UV/Vis) spectra; cis-3-hexenyl tiglate is not expected to be phototoxic/photoallergenic. The environmental endpoints were evaluated; cis-3-hexenyl tiglate was found not to be Persistent, Bioaccumulative, and Toxic (PBT) as per the International Fragrance Association (IFRA) Environmental Standards, and its risk quotients, based on its current volume of use in Europe and North America (i.e., Predicted Environmental Concentration/Predicted No Effect Concentration [PEC/PNEC]), are <1.

RIFM fragrance ingredient safety assessment, dihydrocarvyl acetate, CAS Registry Number 20777-49-5.

The existing information supports the use of this material as described in this safety assessment. Dihydrocarvyl acetate was evaluated for genotoxicity, repeated dose toxicity, reproductive toxicity, local respiratory toxicity, phototoxicity/photoallergenicity, skin sensitization, and environmental safety. Data from read-across analogs dihydrocarveol (isomer unspecified) (CAS # 619-01-2) and acetic acid (CAS # 64-19-7) show that dihydrocarvyl acetate is not expected to be genotoxic. Data on read-across analogs isopulegol (CAS # 89-79-2) and acetic acid (CAS # 64-19-7 provide a calculated MOE >100 for the repeated dose toxicity endpoint. The reproductive and local respiratory toxicity endpoints were evaluated using the TTC for a Cramer Class I material, and the exposure to dihydrocarvyl acetate is below the TTC (0.03 mg/kg/day and 1.4 mg/day, respectively). Data from read-across analog 4-methyl-8-methylenetricyclo [3.3.1.(3,7)]decan-2-yl acetate (CAS # 122,760-85-4) provided dihydrocarvyl acetate a NESIL of 2500 µg/cm2 for the skin sensitization endpoint. The phototoxicity/photoallergenicity endpoints were evaluated based on UV/Vis spectra; dihydrocarvyl acetate is not expected to be phototoxic/photoallergenic. The environmental endpoints were evaluated; dihydrocarvyl acetate was found not to be PBT as per the IFRA Environmental Standards, and its risk quotients, based on its current volume of use in Europe and North America (i.e., PEC/PNEC), are <1.

RIFM fragrance ingredient safety assessment, 4,8-decadienal, (4Z,8Z)-, CAS Registry Number 1958027-35-4.

The existing information supports the use of this material as described in this safety assessment. 4,8-Decadienal, (4Z,8Z)- was evaluated for genotoxicity, repeated dose toxicity, reproductive toxicity, local respiratory toxicity, phototoxicity/photoallergenicity, skin sensitization, and environmental safety. Data from read-across analogs 4,7-decadienal (CAS # 934534-30-2) and nona-2-trans-6-cis-dienal (CAS # 557-48-2) show that 4,8-decadienal, (4Z,8Z)- is not expected to be genotoxic. Data on analog 10-undecenal (CAS # 112-45-8) provide a calculated Margin of Exposure (MOE) > 100 for the repeated dose toxicity and fertility endpoints and a No Expected Sensitization Induction Level (NESIL) of 1700 µg/cm2 for the skin sensitization endpoint. The developmental toxicity and local respiratory toxicity endpoints were evaluated using the Threshold of Toxicological Concern (TTC) for Cramer Class I materials; exposure is below the TTC (0.03 mg/kg/day and 1.4 mg/day, respectively). The phototoxicity/photoallergenicity endpoints were evaluated based on ultraviolet/visible (UV/Vis) spectra; 4,8-decadienal, (4Z,8Z)- is not expected to be phototoxic/photoallergenic. The environmental endpoints were evaluated; 4,8-decadienal, (4Z,8Z)- was found not to be Persistent, Bioaccumulative, and Toxic (PBT) as per the International Fragrance Association (IFRA) Environmental Standards. Its risk quotients, based on its current volume of use in Europe and North America (i.e., Predicted Environmental Concentration/Predicted No Effect Concentration [PEC/PNEC]), are <1.

A cross-industry survey on photosafety evaluation of pharmaceuticals after implementation of ICH S10.

A cross-industry survey was conducted by EFPIA/IQ DruSafe in 2018 to provide information on photosafety evaluation of pharmaceuticals after implementation of ICH S10. This survey focused on the strategy utilized for photosafety risk assessment, the design of nonclinical (in vitro and in vivo) and clinical evaluations, the use of exposure margins in risk assessment, and regulatory interactions. The survey results indicated that a staged approach for phototoxicity assessment has been widely accepted by regulatory authorities globally. The OECD-based 3T3 NRU Phototoxicity Test is the most frequently used in vitro approach. Modifications to this assay suggested by ICH S10 are commonly applied. For in-vitro-positives, substantial margins from in vitro IC50 values under irradiation to Cmax (clinical) have enabled further development without the need for additional photosafety data. In vivo phototoxicity studies typically involve dosing rodents and exposing skin and eyes to simulated sunlight, and subsequently evaluating at least the skin for erythema and edema. However, no formal guidelines exist and protocols are less standardized across companies. A margin-of-safety approach (based on Cmax at NOAEL) has been successfully applied to support clinical development. Experience with dedicated clinical phototoxicity studies was limited, perhaps due to effective de-risking approaches employed based on ICH S10.

Benzodiazepine-induced photosensitivity reactions: A compilation of cases from literature review with Naranjo causality assessment.

OBJECTIVE: Benzodiazepines have been reported to cause photosensitivity reactions. We characterized the clinical presentation and diagnosis of benzodiazepine-associated photosensitivity and adjudicated these cases for a causal association with benzodiazepines. METHODS: A literature search on PubMed's "MeSH" search feature and CINAHL (1964 to 2019) was performed using search terms: benzodiazepine, photosensitivity, and photosensitivity disorders/chemically induced. We applied the Naranjo scale, a standardized causality assessment algorithm, to identified cases. RESULTS: We identified eight published cases, with 50% of patients being female with a mean age of 46.3 years. Alprazolam, tetrazepam, clobazam, and clorazepate induced phototoxic reactions. Chlordiazepoxide induced one photoallergic reaction. Photosensitivity occurred between 1-3 days (37.5%), 7-14 days (25%), and >14 days (25%). Photosensitivity resolved after drug discontinuation within 2 weeks (62.5%). Benzodiazepine rechallenge confirmed photosensitivity in 75% of cases. Photopatch testing was negative in two patients; however, these patients had positive oral provocation testing. However, an oral photoprovocation test, an ideal diagnostic test, was not administered to several patients. Despite these challenges, the Naranjo scale identified 5 cases as definite benzodiazepine-induced photosensitivity. CONCLUSION: Five benzodiazepines induced photosensitivity reactions. Five patients showed a definite association with the Naranjo scale. Reporting to pharmacovigilance databases may help identify other benzodiazepines causing photosensitivity reactions.

Integrated approaches to testing and assessment as a tool for the hazard assessment and risk characterization of cosmetic preservatives.

The safety assessment of cosmetic products is based on the safety of the ingredients, which requires information on chemical structures, toxicological profiles, and exposure data. Approximately 6% of the population is sensitized to cosmetic ingredients, especially preservatives and fragrances. In this context, the aim of this study was to perform a hazard assessment and risk characterization of benzalkonium chloride (BAC), benzyl alcohol (BA), caprylyl glycol (CG), ethylhexylglycerin (EG), chlorphenesin (CP), dehydroacetic acid (DHA), sodium dehydroacetate (SDH), iodopropynyl butylcarbamate (IPBC), methylchloroisothiazolinone and methylisothiazolinone (MCI/MIT), methylisothiazolinone (MIT), phenoxyethanol (PE), potassium sorbate (PS), and sodium benzoate (SB). Considering the integrated approaches to testing and assessment (IATA) and weight of evidence (WoE) as a decision tree, based on published safety reports. The hazard assessment was composed of a toxicological matrix correlating the toxicity level, defined as low (L), moderate (M), or high (H) and local or systemic exposure, considering the endpoints of skin sensitization, skin irritation, eye irritation, phototoxicity, acute oral toxicity, carcinogenicity, mutagenicity/genotoxicity, and endocrine activity. In a risk assessment approach, most preservatives had a margin of safety (MoS) above 100, except for DHA, SDH, and EG, considering the worst-case scenario (100% dermal absorption). However, isolated data do not set up a safety assessment. It is necessary to carry out a rational risk characterization considering hazard and exposure assessment to estimate the level of risk of an adverse health outcome, based on the concentration in a product, frequency of use, type of product, route of exposure, body surface location, and target population.

RIFM fragrance ingredient safety assessment, 2-benzyl-2-methylbut-3-enenitrile, CAS Registry Number 97384-48-0.

The existing information supports the use of this material as described in this safety assessment. 2-Benzyl-2-methylbut-3-enenitrile was evaluated for genotoxicity, repeated dose toxicity, reproductive toxicity, local respiratory toxicity, phototoxicity/photoallergenicity, skin sensitization, and environmental safety. Data show that 2-benzyl-2-methylbut-3-enenitrile is not genotoxic. The repeated dose, reproductive, and local respiratory toxicity endpoints were evaluated using the Threshold of Toxicological Concern (TTC) for a Cramer Class III material, and the exposure to 2-benzyl-2-methylbut-3-enenitrile is below the TTC (0.0015 mg/kg/day, 0.0015 mg/kg/day, and 0.47 mg/day, respectively). Data show that there are no safety concerns for 2-benzyl-2-methylbut-3-enenitrile for skin sensitization under the current declared levels of use. The phototoxicity/photoallergenicity endpoints were evaluated based on ultraviolet (UV) spectra; 2-benzyl-2-methylbut-3-enenitrile is not expected to be phototoxic/photoallergenic. The environmental endpoints were evaluated; 2-benzyl-2-methylbut-3-enenitrile was found not to be Persistent, Bioaccumulative, and Toxic (PBT) as per the International Fragrance Association (IFRA) Environmental Standards, and its risk quotients, based on its current volume of use in Europe and North America (i.e., Predicted Environmental Concentration/Predicted No Effect Concentration [PEC/PNEC]), are <1.