5. Toxicity
5.1. Acute.
5.1.1. Acute Dermal Toxicity in Rats.
Tinosorb S was applied to the shaved skin of five male and five female Hanlbm:WIST (SPF) rats at a 2000 mg/kg dose, and was covered with a semi-occlusive dressing. It was then suspended in vehicle (PEG 400) at a 0.5 g/ml concentration and was administered at a 4 ml/kg volume. After 24 hours, the dressing was removed, and the treated skin was washed with water. No deaths occurred during the study. Neither clinical signs of systemic toxicity nor local effects of the test article on the skin at the application site were observed during the 15-day observation period. The body weights of the animals were within the range of physiological variability known for rats of this strain and age. No macroscopic organ findings were observed at necropsy. As no deaths occurred during the study, the LD50 was >2000 mg/kg [7].
5.1.2. Acute Oral Toxicity in Rats.
Tinosorb S was administered to five male and five female Hanlbm:WIST (SPF) rats at a 2000 mg/kg dose, by oral gavage. Tinosorb S was suspended in vehicle (PEG 400) at a 0.2 g/ml concentration and was administered at a 10 ml/kg volume. The animals were observed for a 15-day period. No deaths occurred and no clinical signs of toxicity were observed during the study. The body weights of the animals were within the range of physiological variability known for rats of this strain and age. No macroscopic organ findings were observed at necropsy. As no deaths occurred during the study, the LD50 was >2000 mg/kg [8].
5.2. Irritation/Sensitization
5.2.1. Primary Skin Irritatiion in Rabbits.
Tinosorb S was applied to the shaved skin of three young adult New Zealand rabbits for 4 hours using a semi-occlusive dressing. Five hundred milligrams of Tinosorb S was applied to 6cm2 intact dorsal skin. After 4 hours, the dressing was removed, and the application site was washed with water. Scoring of the skin reactions was performed 1, 24, 48, and 72 hours after the removal of the dressing. No effects on the skin, including erythema and edema, were noted at any observation time, with the exception of the reversible light-yellow staining of the treated skin at the 1 hour observation time. The primary irritation score (PIS) was calculated by adding the mean erythema to the mean edema scores at 24, 48, and 72 hours and then dividing the resulting value by the number of figures. The PIS was 0.00 (max. 8.0). Based on the PIS, Tinosorb S was considered non-irritating to the skin [9].
5.2.2. Primary Eye Irritation in Rabbits.
Tinosorb S (0.1 g) was instilled into one eye of each of three young adult New Zealand rabbits. The treated eyes were not rinsed after application. Scoring of the irritation effects was performed approximately 1, 24, 48, and 72 hours after application. The PIS was calculated by totaling the individual cumulative scores at 24, 48, and 72 hours and then dividing the total by the number of figures. The PIS was 0.44 (max. 13). No staining of the cornea, sclera, or conjunctivae of the treated eyes by the test article was observed. Based on the PIS, Tinosorb S was considered minimally irritating to the eye [10].
5.2.3 Skin Sensitization (Guinea Pig Maximiztion Test)
Tinosorb S was administered to 10 male albino guinea pigs using a skin maximization test protocol. Five guinea pigs served as the controls. Induction occurred over the first 10 days. On test day 1, the animals received three intradermal injections (0.1 ml/site) in separate areas of the dorsal skin in the scapular region. The injections consisted of (1) a 1:1 (v/v) mixture of Freund’s complete adjuvant (FCA) and physiological saline; (2) 3% Tinosorb S in PEG 400; and (3) 3% Tinosorb S in an emulsion with a 1:1 (v/v) mixture of FCA and physiological saline. The control animals also received the same three injections, but without Tinosorb S. On test day 7, the injection sites were treated with a 10% solution of sodium lauryl sulfate to enhance the sensitization by provoking a mild inflammatory reaction. On test day 8, approximately 0.3 g of a mixture of 30% Tinosorb S in PEG 400 was topically applied to the injection sites through occlusive exposure for 48 hours. The control animals were treated only with PEG 400. A challenge occurred 2 weeks after the topical induction. Two hundred milligrams of 30% Tinosorb S in PEG 400 was topically applied to the shaved skin on the left flank through 24-hour occlusive exposure. The shaved skin on the right flank received only 200 μl PEG 400. The control animals received the same challenge treatment. The skin reactions were evaluated 24 and 48 hours after the removal of the challenge exposure patch. During the induction phase, slight erythema was noted in several animals in both the treatment and control groups after the topical-induction exposure. During the challenge phase, no erythema or edema was noted in any animal after the challenge exposure. In conclusion, under the test conditions, Tinosorb S was not a skin sensitizer [11].
5.2.4. Phototoxicity in Guinea Pigs
Tinosorb S was tested in a phototoxicity study according to the Cosmetic, Toiletry, and Fragrance Association (CTFA) Safety Testing Guidelines. Tinosorb S in PEG 400 was applied to four separate 2cm2 sites on the shaved skin of the left flank of 10 female Dunkin Hartley guinea pigs at the following concentrations: 10, 15, 25, and 30%. Due to the high viscosity of the test material, a fixed volume could not be applied to each site. Instead, a thin layer of the test article was applied to saturate each test site. Five control female guinea pigs received only PEG 400. Thirty to 50 minutes prior to the test article application, the test sites were pre-treated with 2% DMSO diluted in ethanol (0.0125 ml/cm2) to enhance the skin penetration of the test article. Thirty minutes after the application of the test material, the left flank of each animal in the control and treatment groups was exposed to 20 J/cm2 UVA irradiation. After irradiation, the right flank received the same test material applications as the left flank, but the sites were not exposed to UVA irradiation. The skin reactions were observed 24, 48, and 72 hours after the application. No skin reactions, including erythema and edema, were observed during the experiment. In conclusion, under the test conditions, Tinosorb S was not phototoxic [12].
5.2.5. Photoallergenicity in Guinea Pigs.
Tinosorb S was tested in a photoallergenicity study according to the CTFA Safety Testing Guidelines. Induction occurred over the first 11 days. On test day 1, each of the 20 Dunkin Hartley guinea pigs received four intradermal injections (0.1 ml/site) of a 1:1 (v/v) mixture of Freund’s complete adjuvant (FCA) and physiological saline in the four corners of the 6-8cm2 test site located on the dorsal skin. After the injection, 0.1 ml of 30% Tinosorb S in PEG 400 was topically applied to the test site. The site was then exposed to 1.8 J/cm2 UVB and 10 j/cm2 UVA irradiation. The topical application followed by irradiation was repeated 4 times within 2 weeks on days 3, 7, 9, and 11. The control animals received only the four intradermal FCA injections, without any further treatment, during the induction phase. The challenge phase started on day 22. For both the control and treatment groups, Tinosorb S in PEG 400 was applied to four separate 2cm2 sites on the shaved skin of the left flank at the following concentrations: 10, 15, 25, and 30%. A 0.0125 ml/cm2 dose was applied to each site. After the application, the left flank was exposed only to 10 J/cm2 UVA irradiation. After the irradiation, the right flank was treated as the left flank was, but without UVA irradiation. The skin reactions were assessed after 24-, 48-, and 72-hour exposure. During the topical-induction phase, erythema and edema were observed on test days 9-15 in relationship with the repeated application of 30% Tinosorb S. During the challenge phase, no effects on the skin, including erythema and edema, were noted. In conclusion, under the test conditions, Tinosorb S was not a photosensitizer [13].
5.3. Subchronic Studies.
5.3.1. 14-Day Oral Gavage Range-Finding Study in Rats.
Tinosorb S in PEG 400 (vehicle) was administered to groups of Wistar rats (SPF) (5 animals/sex/group) by oral gavage at 50, 200, 800, and 2000 mg/kg daily doses for 14 days. The controls received only the vehicle. No treatment-related effects on the survival, food consumption, body weight, ophthalmoscopy findings, hematology and clinical chemistry values, organ weight, and macroscopic or microscopic findings were noted. The only clinical sign that was noted was pale feces at 2000 mg/kg from day 12 of the study until the study’s termination. This finding is considered to be due to the yellow color of the test article and to be of no toxicological relevance in the absence of any abnormal clinical laboratory parameters and histopathology findings. In conclusion, under the test conditions, the NOAEL (no-observable-adverse- effect level) for this study was 2000 mg/kg [14].
5.3.2. 90-Day Oral Gavage Toxicity Study in Rats.
Tinosorb S in PEG 400 (vehicle) was administered to groups of Wistar rats (SPF) (20 animals/sex/group) by oral gavage at 100, 500, and 1000 mg/kg daily doses for at least 92 days. The controls received only the vehicle. No treatment-related effects on the clinical appearance, functional observational battery testing and grip strength, survival, food consumption, body weight, ophthalmoscopy findings, hematology/clinical chemistry/ urinalysis values, organ weight, and macroscopic or microscopic findings were noted. Any significant difference in the various parameters was not considered treatment-related because it was not correlated with any morphological change and was within the range of normal biological variability for the strain and age of the rats used in this study, and/or did not exhibit a dose response. In conclusion, under the test conditions, the NOEL for this study was 1000 mg/kg [15].
5.3.3. Range Finding Developmental Toxicity Study in Rats.
Tinosorb S in PEG 400 (vehicle) was administered by oral gavage to groups of pregnant female Wistar rats (5 animals/group) on gestation days 6-17 at 100, 300, and 1000 mg/kg. The controls received only the vehicle. The animals were sacrificed on gestation day 21, and the fetuses were removed by Caesarian section. No treatment-related effects on the clinical appearance, survival, food consumption, body weight gain, or macroscopic findings were noted in any dam. No treatment-related reproductive effects (mean numbers of corpora lutea and implantation sites, and pre- and post-implantation loss percentages) were noted. No treatment-related fetal effects (external abnormality, sex ratio, and body weight) were noted either, with the exception of an incidental increase in fetal body weight (on an individual basis) at 1000 mg/kg. In conclusion, under the test conditions, the maternal and fetal NOELs were both 1000 mg/kg [16].
5.3.4. Developmental Toxicity Study in Rats.
Tinosorb S in PEG 400 (vehicle) was administered by oral gavage to groups of pregnant female Wistar rats (22 animals/group) on gestation days 6-17 at 100, 300, and 1000 mg/kg. The controls received only the vehicle. The animals were sacrificed on gestation day 21, and the fetuses were removed by Caesarian section. No treatment-related effects on the survival, food consumption, body weight gain, or macroscopic findings were noted in any dam. No treatment-related clinical signs were noted either, with the exception of soft feces. The soft feces, however, was determined to be a vehicle-related effect because it was observed in all the groups, including the vehicle controls, and because it was seen in all the animals that had been treated with PEG 400. The only significant differences in the reproductive parameters were an increase in post-implantation loss and a reduction in the number of fetuses in the 100 and 1000 mg/kg groups. The effects, however, were not considered treatment-related because a dose relationship was not evident and the parameters were within the ranges of the historical control data. No treatment-related effects were noted for the other reproductive parameters (mean numbers of corpora lutea and implantation sites, and pre-implantation loss percentages). No treatment-related fetal effects (external/visceral/ skeletal abnormalities, sex ratio, and body weight) were noted. In conclusion, under the test conditions, the maternal and fetal NOELs were both 1000 mg/kg [17].
5.4. Genotoxicity Studies.
5.4.1. S.typhimurium Reverse Mutation Assay
Tinosorb S was tested in the Ames assay (Salmonella typhimurium reverse mutation assay) to determine if it induces base pair or frame shift mutations in the Salmonella typhimurium strains TA 98, TA 100, TA 1535, and TA 1537. The assay was performed using the plate incorporation method (experiment I) and was repeated in an independent experiment using the pre-incubation method (experiment II). The test article, dissolved in dimethyl sulfoxide, was tested at the following concentrations in all the experiments: 33, 100, 333, 1000, 2500, and 5000 μg/plate. Each concentration, including the controls, was tested in triplicate and was with and without exogenous rat liver microsomal (S9 mix) activation. Normal background bacterial growth was observed at up to 5000 μg/plate with and without S9 mix. In experiment I, a reduction in the number of revertants was observed in strain TA 1537 at 5000 μg/plate without S9 mix, at ≥2500 μg/plate with S9 mix, and in strain TA 98 at 1000 and 5000 μg/plate with S9 mix. In both experiments, no significant increase in the revertant colony numbers of any of the four tester strains was observed following the treatment with Tinosorb S at any dose level, with or without S9 mix. Appropriate reference mutagens were used as positive controls and produced a distinct increase of the induced revertant colonies. In conclusion, under the test conditions, Tinosorb S did not induce base pair or frame shift mutations [18].
5.4.2. In Vitro Chromosome Aberration Assay in Chinese Haster V79 Cells.
Tinosorb S was assessed for its potential to induce structural chromosome aberrations in Chinese hamster V79 cells. Two independent experiments were performed with and without exogenous rat liver microsomal (S9 mix) activation. A stock solution was prepared by dissolving Tinosorb S in acetone at a 21 mg/ml concentration. The stock solution was diluted with a culture medium to produce the appropriate exposure concentrations. Based on the limited solubility of the test material in the solvent, the following Tinosorb S concentrations were tested: 6.5, 13.1, 26.3, 52.5, 105.0, and 210.0 μg/ml without S9 mix and 3.3, 6.5, 13.1, 26.3, 52.5, and 210.0 μg/ml with S9 mix. Precipitation of the test material was noted at ≥52.5 μg/ml with and without S9 mix. In experiment I, duplicate plates of exponentially growing cells were exposed to each concentration of the test material for 4 hours with and without S9 mix. In experiment II, the cells were exposed to the test material for 4 hours with S9 mix and 18 and 28 hours without S9 mix. Approximately 2.5 hours prior to harvesting, colcemid was added to the cultures to arrest the cells in metaphase. The cells that had been exposed for 4 hours were harvested 14 hours after the exposure period. The cells that had been exposed for 18 and 28 hours were harvested upon the completion of their exposure. The cells from the four highest-dose groups were fixed, stained, and analyzed for structural chromosome aberrations. The chromosome gaps and numerical aberrations were recorded but were not included in the analysis. A single significant increase in the aberrations of the treated cells compared to the solvent controls (3.5% aberrant-cell exclusive gaps) was observed in experiment II (210 μg/ml, 28-hour exposure, without S9 mix), but this increase was considered biologically irrelevant because its value was within the historical control range (0.0-4.0%). The positive control treatments produced a distinct increase in the cells with structural chromosome aberrations in both experiments. In conclusion, under the test conditions, Tinosorb S did not induce structural chromosome aberrations [19].
5.4.3. Photomutagenicity: S.typhimurium and E.coil Reverse Mutation Assy
Tinosorb S was tested in the Ames assay (Salmonella typhimurium and Escherichia coli reverse mutation assays) to determine if it induces base pair mutations in the S. typhimurium strain TA 102 and the E. coli strain WP2 after UV irradiation. These strains were chosen because they can tolerate relatively high doses of UV irradiation. The assay was performed using the plate incorporation method (experiment I) and was repeated in an independent experiment using the pre-incubation method (experiment II). The test article was tested at the following concentrations in both experiments: 33, 100, 333, 1000, 2500, and 5000 μg/plate. Each concentration, including the controls, was tested in triplicate. Immediately after the cells’ treatment with the test material, the cells were exposed to the UVA/ UVB irradiation doses that were determined in the preliminary experiments to produce a doubling in the background revertant frequency. The WP2 cells were exposed for 10 seconds to 20 ml/cm2 UVA and 1 mJ/cm2 UVB irradiation. The TA 102 cells were exposed for 40 seconds to 80 mJ/cm2 UVA and 4 mJ/cm2 UVB irradiation. Normal background bacterial growth was observed at up to 5000 μg/plate. Slight toxic effects, evident as a reduction in the number of revertants, occurred in both strains in experiment II. In both experiments, no significant increase in the revertant colony numbers of either tester strain was observed following the treatment with Tinosorb S at any dose level. Appropriate reference mutagens were used as positive controls and produced a distinct increase of the induced revertant colonies. In conclusion, under the test conditions, Tinosorb S did not induce base pair mutations after exposure to UVA/UVB irradiation [20].
5.4.4. Photomutagenicity: In Vitro Chrom Ab Assay in Chinese Hamster V79 Cells.
Tinosorb S was assessed for its potential to induce structural chromosome aberrations in Chinese hamster V79 cells with and without UVA/UVB irradiation in two independent experiments. Based on the limited solubility of the test material in the phosphate-buffered saline (PBS) solution (containing 1% (v/v) acetone with the test material), the following Tinosorb S concentrations were tested: 6.25, 12.5, 25.0, 50.0, 75.0, and 100.0 μg/ml with and without UVAJUVB irradiation. Precipitation of the test material was noted at ≥25.0 μg/ml. In both experiments, duplicate plates of exponentially growing cells were exposed to each concentration of the test material in a PBS solution for 30 minutes, followed by irradiation with 200 mJ/cm2 UVA and 22 mJ/cm2 UVB for 30 minutes. Additional groups in experiment II were exposed to 300 mJ/cm2 UVA and 33 mJ/cm2 UVB for 30 minutes. After irradiation, the PBS solution was replaced with a culture medium. Concurrent solvent and positive controls were run in parallel. In experiments I and II, the cells were harvested 18 and 28 hours after the start of the experiment, respectively. Approximately 2 hours prior to harvesting, colcemid was added to the cultures to arrest the cells in metaphase. In experiments I and II, the cells were fixed, stained, and analyzed for structural chromosome aberrations from the 6.25, 12.5, 25.0, and 100.0 μg/rnl groups and the 12.5, 25.0, 50.0, and 100.0 μg/ml groups, respectively. The chromosome gaps and numerical aberrations were recorded but were not included in the analysis. In both experiments, with and without UVA/UVB irradiation, the test material did not increase the frequency of the cells with structural chromosome aberrations. The positive control treatments produced a distinct increase in the cells with structural chromosome aberrations in both experiments. In conclusion, under the test conditions, Tinosorb S did not induce structural chromosome aberrations in the presence or absence of UVA/UVB irradiation [24].
5.5. Absorption Studies.
5.5.1. In Vitro Human Skin Penetration.
This study was designed to determine the in-vitro skin penetration and distribution of Tinosorb S (10% w/w in a representative sunscreen formulation) over a 24-hour period after application to the epidermal sections of the human skin. The sunscreen formulation containing 10% Tinosorb S was applied to human epidermal-skin membranes mounted in Franz-type diffusion cells at a target dose of 2 mg/cm2. The receptor phase consisted of 6% Oleth 20 in phosphate-buffered saline (pH 7.4). Of the 12 skin samples treated with Tinosorb S, four showed some permeation of Tinosorb S through the skin and into the receptor phase, but one of the samples was excluded from further analysis based on the anomalously early and high permeation. The overall permeation through the skin was very low (15±8 mg/cm2, representing 0.006±0.003% of the applied dose after 24 hours) [21].
5.5.2. In Vitro Human Skin Penetration and Distribution
This study was designed to determine the in-vitro skin penetration and distribution of Tinosorb S (10% w/w in a representative sunscreen formulation) over a 24-hour period after application to the epidermal sections of the human skin. The sunscreen formulation containing 10% Tinosorb S was applied to human epidermal-skin membranes mounted in Franz-type diffusion cells at a target dose of 2 mg/cm2. The receptor phase consisted of 6% Oleth 20 in phosphate-buffered saline (pH 7.4). Of the 12 skin samples treated with Tinosorb S, six showed some permeation of Tinosorb S through the skin and into the receptor phase, but one of the samples was excluded from further analysis based on the anomalously early and high permeation. The overall permeation through the skin was very low (40±20 mg/cm2, representing 0.02±0.01% of the applied dose after 12 hours, and an extrapolated level of 80 mg/cm2, representing 0.04±0.01% of the applied dose after 24 hours). Linear extrapolation to 24 hours was necessary because the permeation profile plateaued between 12 and 24 hours. This plateauing effect was due to the large errors associated with the very low levels of permeation that occurred. The assessment of the Tlnosorb 5 levels on and in the skin after 24 hours revealed that the majority of the recovered material (>80% of the applied dose) was found either on the skin surface or on the first three tape strips. The remaining material was recovered in tape strips 4-20 (10.2% of the applied dose), the remaining skin sample (7.3%), or the receptor phase (<0.1%). In conclusion, under the test conditions, less than 0.1% of the applied Tinosorb S penetrated the epidermal sections of the human skin over a 24-hour period [21].
5.6. Clinical Studies.
5.6.1. Phototoxicity In Humans.
Tinosorb S formulated as a 10% O/W lotion was topically applied to 26 human volunteers. Two hundred microliters of the test material, vehicle control (O/W lotion base), and saline were topically applied to separate sites on one side of the spine of each volunteer. Duplicate applications were made on the opposite side of the spine. The treatment sites were covered with an occlusive dressing. After 24-hour exposure, the patches and excess test material from the left paraspinal region were removed. The test sites were then exposed to J 6 J/cm2 UVA irradiation, followed by exposure to 0.75 times the volunteer’s minimum erythemal dose (MED) of UVB irradiation. The patches from the right paraspinal region were then removed. The skin reactions were assessed 1, 24, 48, and 72 hours following the irradiation and patch removal. Only one adverse reaction was reported, and it was determined to be not treatment-related. On a scale of 0-3 (0 representing no reaction and 3 representing strong erythema), grade J reactions were noted at 1, 24, 48, and 72 hours for the irradiated sites in 7, 1, 0, and 0 volunteers for the test material treatment; in 9, 8, 4, and 4 volunteers for the vehicle control treatment; and in 9, 7, 3, and 2 volunteers for the saline treatment, respectively. The remaining skin reactions were all less than grade 1. No skin reactions greater than or equal to grade J were noted for the non-irradiated test material sites. On average, the irradiated test-material-treated sites exhibited lower skin reactions than the irradiated vehicle control and saline treatment sites. In conclusion, under the test conditions, the test material was not phototoxic and was not an irritant to the human skin [22].
5.6.2. Photoallergenicity in Humans.
Tinosorb S was tested for photoallergencitiy using a human repeat insult patch test (HRIPT). The induction phase consisted of two topical applications per week over a 3-week period (total of six topical applications over weeks 1-3) of 200 μl of the test material (10% Tinosorb S in an O/W lotion), vehicle control (O/W lotion base), and saline to separate sites on the body of each of the 33 volunteers. The treatment sites were covered with an occlusive dressing. Twenty four hours after each induction exposure, the patches were removed, and the test sites were exposed to 2 times the volunteer’s UVA/UVB minimum erythemal dose (MED). For a given induction treatment, the same site was used for each exposure unless unacceptable reactions were noted thereon. In that case, a naive site was used for the next induction exposure. After the last induction exposure, the volunteers were not treated for 2 weeks (weeks 4-5). At week 6, duplicate topical applications of 200 μl of the test material, vehicle control, and saline were made to naive sites on both sides of each volunteer's spine. The test sites were covered with an occlusive dressing. After 24-hour exposure, the patches and excess test material from one side of the spine were removed. The test sites were then exposed to 16 J/cm2 UVA irradiation, followed by exposure to 0.75 times the volunteer’s MED of UVB irradiation. The remaining patches were then removed. The skin reactions were assessed 1, 24, 48, and 72 hours following the irradiation and patch removal. Only one adverse reaction was reported, and it was determined to be not treatment-related. The skin reactions were graded on a scale of 0-3 (0 representing no reaction and 3 representing strong erythema). After the challenge phase, grade J reactions were noted at 1, 24, 48, and 72 hours for the irradiated sites in 10, 1, 1, and 0 volunteers for the test material treatment; in 13, 12, 6, and 2 volunteers for the vehicle control treatment; and in 15, 10, 6, and 3 volunteers for the saline treatment, respectively. Grade 2 reactions were noted in two volunteers after 1 hour for all three treatments. The remaining skin reactions were less than grade 1. The average skin reactions for the non-irradiated sites were lower than those for the irradiated sites for all three treatments. On average, the irradiated test-material-treated sites exhibited lower skin reactions than the irradiated vehicle control and saline treatment sites. In conclusion, under the test conditions, the test material was not a photosensitizer or sensitizer to the human skin [23].
5.7. Summary of Pre-Clinical and Clinical Studies.
Study
|
Results
|
Acute
|
|
Acute Dermal Toxicity in Rats
|
LD50<2000mg/kg
|
Acute Oral Toxicity in Rats
|
LD50<2000mg/kg
|
Irritation/Sensitization
|
|
Primary Skin Irritation Study in Rabbits
|
Not Irritating
|
Primary Eye Irritation Study in Rabbits
|
Minimally Irritating
|
Skin Sensitization(Guinea Pig Maximzation Test)
|
Not Sensitizing
|
Phototoxicity in Guinea Pigs
|
Not Phototoxic
|
Photoallergenicity in Guinea Pigs
|
Not Photoallergenic
|
Sub-Chronic
|
|
14-Day Oral Gavage Range Finding Study
|
NOAEL = 2000 mg/kg
|
90-Day Oral Gavage Toxicity Study in the Rat
|
NOEL = 1000 mg/kg
|
Range Finding Developmental Study in Rats
|
NOEL = 1000 mg/kg
|
Developmental Toxicty Study in Rats
|
NOEL = 1000 mg/kg
|
Genotoxicity
|
|
S.typhimurium Reverse Mutation Assay
|
Negative
|
In Vitro Chromosome Aberration Assay in Chinese Hamster V79 Cells
|
Negative
|
Photomutagenicity: S.typhimurium and E.coli Reverse Mutation Assay
|
Negative
|
Photomutagenicity: In Vitro Chromosome Aberration Assay in Chinese Hamster V79 Cells.
|
Negative
|
Absorption
|
|
In Vitro Human Skin Penetration
|
<0.1% Penetrated Across Skin
|
In Vitro Human Skin Penetration and Distribution
|
<0.1% Penetrated Across Skin
|
Clinical
|
|
Phototoxicity in Humans
|
Not Phototoxic
|
Phtoallergenicity in Humans
|
Not Photoallergenic
|
6. Regulatory status
Contents
Country
|
Status
|
Details
|
EU
|
O
|
The SCCNFP concluded Bis-Ethylhexyloxy phenol Methoxyphenyl Triazine is safe for use without restrictions as a UV absorber in cosmetic products, including sunscreen products, at a concentration of up to J 0%. The UV filter is now included for cosmetic under the Twenty-Fourth Commission Directive 2000/6/EC of the Commission of the European Communities on March 1, 2000. Bis-Ethylhexyloxyphenol Methoxyphenyl Triazine is also approved for use in Switzerland.
|
Canada
|
-
|
-
|
Australia
|
O
|
In Australia, UVA-protection may be claimed when the transmission of the sunscreen, measured at an optical pathlength of 8 urn, is below J 0% in the wavelength range between 320 and 360nm. This an absolute criterion whereas the UVA/UVB-ratio as well as the h,-concept are both measured in relation to UVB. A minimum of 2% of Bis-Ethylhexyloxy phenol Methoxyphenyl Triazine is necessary to fulfill this requirement.
|
FDA
|
-
|
-
|
Japan
|
O
|
-
|
China
|
O
|
-
|
Brazil
|
O
|
Approved for use in Brazil.
|
* O indicates that it is under the regulation.
7. Risk assessment
Tinosorb S exhibited very low toxicity via the dermal and oral exposure routes. In addition, it did not exhibit enhanced toxicity upon exposure to UV radiation, which is critical for a UV protectant. Tinosorb S did not exhibit compound or dose-related toxicity in the subchronic- and developmental-toxicity studies. Based on these data, Tinosorb S is safe for use as a human skin UV protectant because it is unlikely to cause any toxic effect after dermal exposure. A >40,000 safety factor exists between the NOELS in the animal toxicity studies and estimated human exposures [6].
8. Conclusion
The review of the toxicity tests of bis-ethylhexyloxyphenol methoxyphenyl triazine showed that no side effects were found in the acute-dermal- and oral-toxicity tests on rats, and no skin and eye irritation in rabbits and skin sensitization in guinea pigs were found in the phototoxicity and photoallergenicity tests. The 14- and 90-day oral-gavage toxicity test and developmental-toxicity study on rats also showed no side effects. The genotoxicity test with Chinese hamster V79 cells also showed no side effects, and no side effect was shown either in the human tests. Europe, Australia, and Brazil allow the substance’s use in cosmetic products, so, bis-ethylhexyloxyphenol methoxyphenyl triazine is safe in cosmetics in the present practices of use and concentration.
9. Korean summary
Bis-Ethylhexyloxyphenol Methoxyphenyl Triazine은 UVA 및 UVB 모두를 폭넓게 차단하며 광안정성이 뛰어나 자외선 차단제의 성분으로 사용되고 있다. 유럽과 호주, 브라질에서는 허용된 물질로, 선크림의 성분으로 사용이 가능하다. 급성독성, 자극성, 아만상독성, 유전독성, 임상시험 등의 결과에서는 독성이 없는 것으로 나타났고, 현재 사용되는 농도의 자외선 차단제로써의 사용은 안전할 것으로 판단된다.
10. References
1) Pubchem. https://Pubchem..ncbi.nlm.nih.gov/
2) Wikipedia. https://en.Wikipedia..org/wiki/Bemotrizinol
6) Ciba Specialty Chemicals Corporation Citizen's Petition, 78N-0038, 9/5/2000.
7) Arcelin, G. (J997a). Acute dermal toxicity study with CGF-C-1607 in rats. RCC Project 651420. Sponsored by Ciba Chemikalien GmbH.
8) Arcelin, G. (J997b). Acute oral toxicity study with CGF-C-1607 in rats. RCC Project 651407. Sponsored by Ciba Chemikalien GmbH.
9) Braun, W.H. (1997b). Primary skin irritation study with GCF-C-1607 in rabbits (4-hour semiocclusive application). RCC Project 651431. Sponsored by Ciba Chemikalien GmbH.
10) Braun, W.H. (1997a). Primary eye irritation study with CGF-C-1607 in rabbits. RCC Project 651442. Sponsored by Ciba Chemikalien GmbH.
11) Arcelin, G. (1997c). Contact hypersensitivity to CGF-C-1607 in albino guinea pigs maximizationtest. RCC Project 651453. Sponsored by Ciba Chemikalien GmbH.
12) Arcelin, G. (1997e). Determination of phototoxicity with CGF-C-1607 in albino guinea pigs. RCC Project 651475. Sponsored by Ciba Chemikalien GmbH.
13) Arcelin, G. (1997d). Determination of photoallergenicity with CGF-C-1607 in albino guinea pigs (including information about allergenicity, photoirritation, and irritation). RCC Project 651497. Sponsored by Ciba Chemikalien GmbH.
14) Schmid, H., Luetkemeier, H., and Wilson, J. (1998) 14-Day dose range-finding (gavage) study with CGF-C-1607 in the rat. RCC Project 667530. Sponsored by Ciba Chemikalien GmbH.
15) Hamann, H-J., Schmid, H., Luetkemeier, H., Biedermann, K., nad Chevalier, H-J. (1998). 13-Week oral toxicity (gavage) study with CGF-C-1607 in the rat. RCC Project 667541. Sponsored by Ciba Chemikalien GmbH.
16) Becker, H. (1998). Dose range-finding prenatoal toxicitzy study with CGF-C1607/6 in the rat. RCC Project 681480. Sponsored by Ciba Chemikalien GmbH.
17) Becker, H. and Biedermann, K. (1998). Prenatal toxicity study with CGF-C-1607 in the rat. RCC Project 681491. Sponsored by Ciba Chemikalien GmbH.Czich, A. (1998a). Chromosome aberration assay in vitro: photomutagenicity in Chinese hamster V79 cells with CGF-C-1607. RCC-CCR Project 615904. Project ID of contracting institute RCC 701853. Sponsored by Ciba Chemikalien GmbH.
18) Wollny, H. (1997). Salmonella typhimurium reverse mutation assay with CGF-C-1607. CCR Project 582800. Project ID of the contracting institute- RCC 651508. Sponsored by Ciba Chemikalien GmbH.
19) Czich, A. (1998b). In Vitro chromosome aberration assay in Chinese hamster V79 cells with CGFC-1607. RCC-CCR Project 597700. Project ID of contracting institute RCC 672017. Sponsored by Ciba Chemikalien GmbH.
20) Wollny, H.E. (1998). Photomutagenicity in a Salmonella typhimurium and Escherichia coli reverse mutation assay with CGF-C-J 607. RCC-CCR Project 609003. Project ID of the contracting institute RCC 689354. Sponsored by Ciba Chemikalien GmbH.
21) Watkinson, A.C. (1998). In Vitro human skin penetration and distribution of the UV absorber CGF-CJ 607. An-eX Analytical Services, Ltd. Report Number CSC/8/98. Sponsored by Ciba Spezialitatenchemie Crenzach GmbH.
22) Parisse, A.J. (1998b). Evaluation of phototoxicity in humans. HTR Project No. 100243A. Sponsor Number CGF-C-1607/7. Sponsored by Ciba Specialty Chemicals Corporation.
23) Parisse, A.J. (1998a). Evaluation of human photoallergy by repeated insult patch test. HTR Project No. 1002438. Sponsor Number CGF-C-J 607/7. Sponsored by Ciba Specialty Chemicals Corporation.
24) Czich, A. (1998a). Chromosome aberration assay in vitro: photomutagenicity in Chinese hamster V79 cells with CGF-C-J 607. RCC-CCR Project 615904. Project ID of contracting institute RCC 701853. Sponsored by Ciba Chemikalien GmbH.
