Final Report on the Safety Assessment of 6-Amino-m-Cresol, 6-Amino-o-Cresol, 4-Amino-m-Cresol, 5-Amino-4-Chloro-o-Cresol, 5-Amino-6-Chloro-o-Cresol, and 4-Chloro-2-Aminophenol1

2004 ◽  
Vol 23 (2_suppl) ◽  
pp. 1-22 ◽  
Keyword(s):  
Test Data ◽  
Expert Panel ◽  
Skin Irritation ◽  
Percutaneous Penetration ◽  
Final Report ◽  
Toxicity Data ◽  
Hair Dyes ◽  
Animal Skin

Each of these ingredients function as hair colorants. 5-Amino-4-Chloro-o-Cresol and 5-Amino-6-Chloro-o-Cresol are identified as oxidative hair dyes, that is, they are combined with an oxidizing agent before being applied to the hair. 6-Amino-m-Cresol, 6-Amino-o-Cresol, 4-Amino-m-Cresol, and 5-Amino-4-Chloro-o-Cresol are used in oxidative hair dyes, but it is not known if they are also used in nonoxidative (semipermanent) hair dyes. No toxicologically significant impurities are present with these two ingredients. To supplement the safety test data on these ingredients, available data on related ingredients (4-amino-2-hydroxytoluene and p-, m-, and o-aminophenol) previously found safe as used by the Cosmetic Ingredient Review (CIR) Expert Panel were summarized. 5-Amino-4-Chloro-o-Cresol and 5-Amino-6-Chloro-o-Cresol do not absorb significant ultraviolet radiation in the UVB region and none in the UVA region, although 4-Amino-m-Cresol had a symmetrical UV absorption peak at 300 nm. Percutaneous penetration of 5-Amino-4-Chloro-o-Cresol and 5-Amino-6-Chloro-o-Cresol alone was significant, but when combined with oxidative developer, skin absorption was extremely low. Both of these dyes are excreted rapidly via the urine. Repeated exposure of animal skin to 5-Amino-4-Chloro-o-Cresol and 5-Amino-6-Chloro-o-Cresol failed to produce any cumulative irritation and single exposures up to 10% were not irritating to animal skin. 5-Amino-4-Chloro-o-Cresol and 5-Amino-6-Chloro-o-Cresol combined with oxidizer were not sensitizers in guinea pig maximization tests. Ocular irritation resulted from exposure of animals to undiluted 5-Amino-4-Chloro-o-Cresol, but not to a 5% solution. Only minor irritation was observed with 5% 5-Amino-6-Chloro-o-Cresol. Subchronic toxicity testing in animals using 5-Amino-4-Chloro-o-Cresol, 5-Amino-6-Chloro-o-Cresol, and 4-Amino-m-Cresol did not yield any adverse reactions. 6-Amino-m-Cresol and 4-Amino-m-Cresol were generally not mutagenic in in vitro and in vivo tests. Exposure to 5-Amino-4-Chloro-o-Cresol, 5-Amino-6-Chloro-o-Cresol, 6-Amino-m-Cresol and 4-Amino-m-Cresol from cosmetics were several orders of magnitude below developmental toxicity no-observed-adverse-effect levels (NOAELs). Although irritation data on several ingredients are absent, products containing these ingredients must include a caution statement and patch test instructions for determining whether the product causes skin irritation. The Expert Panel expects that following this procedure would identify individuals who would have an adverse reaction and allow them to avoid significant exposures. These compounds, when tested alone, are moderate skin sensitizers, but when combined with the developer, these ingredients are not sensitizers in animal tests. This information, coupled with the available animal test data, supports the safety of these ingredients in oxidative hair dyes. In the absence of systemic toxicity data, however, the available data are insufficient to support the safety of 6-Amino-o-Cresol and 4-Chloro-2-Aminophenol in semipermanent hair dyes. The types of data required for these two ingredients for this use include (1) physical and chemical properties, including the octanol/water partition coefficient; (2) impurities data, especially regarding the presence of m-cresol, other organic molecules, and heavy metals; (3) data demonstrating that the metabolism is similar to that of 4-amino-2-hydroxytoluene and/or p-, m-, and o-aminophenol, or 28-day dermal toxicity with histopathology, dermal reproductive toxicity data, and an in vitro genotoxicity study for 6-Amino-o-Cresol and one genotoxicity study in a mammalian system; if positive, a 2-year dermal carcinogenicity study using National Toxicology Program methods may be needed.

Final Report on the Safety Assessment of 3-Methylamino-4-Nitrophenoxyethanol as Used in Hair Dyes

2008 ◽  
Vol 27 (2_suppl) ◽  
pp. 41-51 ◽  
Keyword(s):  
Human Skin ◽  
Expert Panel ◽  
Chinese Hamster Ovary Cells ◽  
High Dose ◽  
Final Report ◽  
Toxicity Data ◽  
Hair Dyes ◽  
Hair Dye ◽  
Skin Contact

3-Methylamino-4-Nitrophenoxyethanol is a semipermanent (direct) hair colorant used in 21 hair dyes and colors at use concentrations up to 0.15%. When applied to human skin in vitro, 0.42% of the applied 3-Methylamino-4-Nitrophenoxyethanol was recovered in the receptor fluid. In an acute toxicity study using rats, 3-Methylamino-4-Nitrophenoxyethanol at 1000 mg/kg resulted in hypoactivity, piloerection, dyspnea, and lateral recumbency in animals that later died. The surviving rats exhibited none of these signs. No abnormalities were found at necropsy. Subchronic toxic-ity tests using rats fed 25, 100, or 400 mg/kg day-1 3-Methylamino-4-Nitrophenoxyethanol for up to 93 days resulted in yellow urine and tails with all three dose levels and yellow fur occurred in the two high-dose groups. The no observed adverse effect level (NOAEL) for 3-Methyl-amino-4-Nitrophenoxyethanol was 100 mg/kg day-1. Two percent 3-Methylamino-4-Nitrophenoxyethanol was a slight ocular irritant but not a dermal irritant using rabbits and it was not a sensitizer using the murine local lymph node Assay. There were no embryotoxic or teratogenic effects observed in doses up to 750 mg/kg day-1 in rats; the NOAEL was defined as 100 mg/kg. 3-Methylamino-4-Nitrophenoxyethanol was not genotoxic in in vitro assays including multiple strains of Salmonela typhimurium and Escherichia coli, Chinese Hamster ovary cells, and human lymphocyte cultures. No carcinogenicity studies were available, nor were any clinical tests reported. As reviewed by the Cosmetic Ingredient Review (CIR) Expert Panel, there are gaps in the data available for of 3-Methylamino-4-Nitrophenoxyethanol. In particular, there is an absence of data from chronic animal studies. The Expert Panel considered that the low percutaneous absorption and that the available developmental toxicity data and the subchronic toxicity data, both of which resulted in relatively high NOAEL values, alleviate concern about the absence of chronic exposure data. In addition, several studies demonstrated that 3-Methylamino-4-Nitrophenoxyethanol is not genotoxic. Direct hair dyes, of which 3-Methylamino-4-Nitro-phenoxyethanol is one, although not the focus in all investigations, appear to have little evidence of an association with adverse events as reported in hair dye epidemiology studies. The lack of phototoxicity data was not considered to be a concern because this is a direct hair dye ingredient, which has little skin contact and residual color is attached to hair, not normally to skin. No human skin sensitization or irritation data were available. However, hair dyes containing 3-Methylamino-4-Nitrophenoxyethanol, as coal tar hair dye products, are exempt from the principal adulteration provision and from the color additive provisions in sections 601 and 706 of the Federal Food, Drug, and Cosmetic Act, when the label bears a caution statement and patch test instructions for determining whether the product causes skin irritation. The Expert Panel expects that following this procedure will prospectively identify individuals who would have an irritation/sensitization reaction and allow them to avoid significant exposures and concluded that 3-Methylamino-4-Nitrophenoxyethanol is safe as a cosmetic ingredient in the practices of use and use concentrations described in this safety report.

2 Final Report on the Safety Assessment of p-Aminophenol, m-Aminophenol, and o-Aminophenol

1988 ◽  
Vol 7 (3) ◽  
pp. 279-333 ◽  
Keyword(s):  
Topical Application ◽  
Guinea Pigs ◽  
Safety Assessment ◽  
Mutagenic Activity ◽  
Skin Irritation ◽  
Final Report ◽  
Hair Dyes ◽  
Hair Dye ◽  
Mutagenicity Tests

p-Aminophenol (PAP), m-Aminophenol (MAP), and o-Aminophenol (OAP) are used in permanent (oxidative) hair dyes at concentrations from 0.1 to 5%. In vivo and in vitro skin absorption studies indicated that 11% of the dermally applied 14C-PAP was detected in the excreta, viscera, and skin of the test animals. The oral LD50s of PAP, MAP, and OAP in rats ranged from 600 to 1300 mg/kg. Topical application of PAP at concentrations up to 8.00 g/kg to the skin of New Zealand white (NZW) rabbits produced no skin irritation and no mortality. PAP, MAP, and OAP were irritating to eyes of NZW rabbits at a concentration of 2.5%. MAP at 3% was nonsensitizing in guinea pigs; PAP at 2% sensitized 9 of 10 guinea pigs. Neither PAP nor MAP produced photosensitization in guinea pigs. No treatment-related toxicity was found in three separate four-generation chronic dermal toxicity and reproduction studies of hair dye formulations containing the three Aminophenols. Additional studies on the pure ingredients were also nonteratogenic; embryotoxicity was reported. A range of results was obtained from studies assessing the mutagenic activity of the Aminophenols. PAP tested positive in six of eight mutagenicity tests. MAP and OAP gave positive results in two of eight and five of seven mutagenicity tests, respectively. Oxidative hair dye formulations containing PAP, MAP, and OAP did not produce gross or microscopic alterations or have carcinogenic effects after chronic topical application to mice. Feeding of OAP-HCl and PAP to rats at a dose of 8 mmol/kg produced neither hepatic cirrhosis nor neoplastic lesions. A 3% solution of MAP in an aqueous vehicle was neither a significant irritant nor sensitizer in two clinical studies. A variety of epidemiological studies have not indicated that occupational exposure to, and personal use of, hair dyes containing the Aminophenols presented a carcinogenic risk. A discussion of the significance of the mutagenic data in the safety assessment and the potential for human effects is presented. On the basis of the available animal and clinical data presented in this report it is concluded that p-, m-, and o-Aminophenols are safe as cosmetic ingredients in the present practices of use and concentrations.

Final Report on the Safety Assessment of Disperse Blue 1

1995 ◽  
Vol 14 (6) ◽  
pp. 433-451 ◽  
Keyword(s):  
Urinary Bladder ◽  
Skin Irritation ◽  
Bladder Neoplasms ◽  
Urinary Bladder Neoplasms ◽  
Female Rats ◽  
Final Report ◽  
Hair Dyes ◽  
Bladder Calculi ◽  
Male And Female Rats

The anthraquinone color Disperse Blue 1 is used in many nonoxidative hair dyes, colors and rinses. In vitro dermal penetration studies using skin from miniature pigs indicate this ingredient is poorly absorbed. All rats given Disperse Blue 1 orally at concentrations up to 3 g/kg survived. Reduced body weights and blue tissue samples were observed in short-term, subchronic, and chronic animal studies. No skin irritation was observed with concentrations up to 10%, but Disperse Blue 1 was a moderate sensitizer in guinea pigs. Disperse Blue 1 was mutagenic in several test systems. In feeding studies, the ingredient produced a significant increase in urinary bladder neoplasms in male and female rats. Equivocal results were reported in studies with male mice and negative results were reported for female mice. A dermal carcinogenesis study in mice was negative. Further evaluation of the carcinogenesis data suggests that the urinary bladder neoplasms appear to be associated with bladder calculi rather than arising from a genotoxic mechanism. Such bladder calculi do not appear to form in humans. Based upon these data and the facts that dermal exposure produced no evidence of carcinogenesis, that the ingredient is poorly absorbed, and that exposure to hair dyes is brief, it was concluded that Disperse Blue 1 is safe for use in hair dyes at concentrations up to 1%.

Final Report on the Safety Assessment of Glutaral

1996 ◽  
Vol 15 (2) ◽  
pp. 98-139 ◽  
Keyword(s):  
Drinking Water ◽  
Safety Assessment ◽  
Animal Studies ◽  
Skin Irritation ◽  
Blood Chemistry ◽  
Lymphocytic Leukemia ◽  
Final Report ◽  
Carcinogenicity Study ◽  
Animal Skin

The dialdehyde Glutaral (also commonly called glutaraldehyde) is used in a wide variety of cosmetics as a preservative. In vitro dermal penetration studies of Glutaral indicate low penetration through animal skin and even less through human skin. The oral LD50 of Glutaral for rats ranged from 66 mg/kg up to 733 mg/kg. A 28-day dermal toxicity study of Glutaral produced skin irritation and slight effects on weight and blood chemistry with concentrations as low as 50 mg/kg/day. Animal skin irritation was dose-dependant, with a no-effect concentration of 1%. Ocular exposure to Glutaral caused severe irritation in rabbits at concentrations 1%, with a no-effect level of 0.1%. Glutaral was not embryotoxic, fetotoxic, or teratogenic at concentrations that did not cause severe maternal toxicity. The no observable adverse effects level for reproduction toxicity was > 1,000 ppm. Bacterial mutagenesis tests produced mixed results, as would be expected for a preservative. In most mammalian system mutagenesis tests, Glutaral was not genotoxic. In a 2-year drinking water study in rats, there was an increase in large granular lymphocytic leukemia (LGLL), but only in females administered 50–1,000 ppm Glutaral. The response was not dose dependent. Clinical studies report some evidence of dermal irritation and sensitization, but no photosensitization. Occupational data and animal studies indicate that inhalation of Glutaral can cause respiratory irritation, in addition to skin effects. Evaluation of the increased incidence of LGLL in the 2-year drinking water study indicated that the incidence was within the historical control levels for this spontaneously occurring neoplasm. These data, however, were not considered sufficient to base a finding of safety of Glutaral in products intended for prolonged use. It was concluded that a 2-year dermal carcinogenicity study following National Toxicology Program (NTP) procedures was needed to complete the safety assessment of Glutaral for use in leave-on products. For rinse-off products, it was concluded that the ocular and dermal irritancy of Glutaral could be substantially avoided if the concentration did not exceed 0.5% and exposure was only brief and discontinuous. Because it can cause respiratory irritation, it was concluded that Glutaral should not be used in aerosolized cosmetic products.

Final Report of the Safety Assessment of Methylisothiazolinone

2010 ◽  
Vol 29 (4_suppl) ◽  
pp. 187S-213S ◽  
Author(s):  
Christina L. Burnett ◽  
Wilma F. Bergfeld ◽  
Donald V. Belsito ◽  
Curtis D. Klaassen ◽  
James G. Marks ◽  
...  
Keyword(s):  
Safety Assessment ◽  
Animal Studies ◽  
Expert Panel ◽  
In Vivo Studies ◽  
Final Report ◽  
Dermal Penetration ◽  
The Many ◽  
Threshold Dose Response

Methylisothiazolinone (MIT) is a heterocyclic organic compound used as a preservative in cosmetics and personal care products in concentrations up to 0.01%. MIT is a colorless, clear liquid with a mild odor that is completely soluble in water; mostly soluble in acetonitrile, methanol, and hexane; and slightly soluble in xylene. Consistent with its solubility, dermal penetration is low. The Cosmetic Ingredient Review Expert Panel noted the in vitro evidence of neurotoxicity but concluded that the absence of any neurotoxicity findings in the many in vivo studies, including subchronic, chronic, and reproductive and developmental animal studies, suggests that MIT would not be neurotoxic as used in cosmetics. Although recognizing that MIT was a sensitizer in both animal and human studies, the panel concluded that there is a threshold dose response and that cosmetic products formulated to contain concentrations of MIT at 100 ppm (0.01%) or less would not be expected to pose a sensitization risk. Accordingly, MIT may be safely used as a preservative in cosmetics up to that concentration.

Final Report On the Safety Assessment of Hc Orange No. 11

1998 ◽  
Vol 17 (4_suppl) ◽  
pp. 21-37 ◽  
Author(s):  
Monice Zondlo Fiume
Keyword(s):  
Expert Panel ◽  
Developmental Toxicity ◽  
Skin Irritation ◽  
Skin Penetration ◽  
Oral Exposure ◽  
Final Report ◽  
Clinical Tests ◽  
Hair Dyes ◽  
Hair Dye ◽  
Carcinogenicity Study

HC Orange No. 1 is used as a colorant in semipermanent hair dyes. The highest concentration reported to be used is 0.15%, but information from manufacturers suggested that higher concentrations may be used in the future. Skin penetration through cadaver skin was 1.28% at 24 hours. In studies using rats, acute oral exposure studies produced little toxicity, and short-term toxicity studies produced reduced body weight and increased liver and kidney weights, relative to controls in animals fed 0.5% HC Orange No. 1. There was no evidence of reproductive or developmental toxicity in rats fed up to 1.25% HC Orange No. 1 or in a multigeneration study using rats in which 0.15% HC Orange No. 1 was painted on the skin. While evidence suggests this ingredient is a mild ocular irritant, no skin irritation, sensitization, or photosensitization was seen in animal or clinical tests. The preponderance of data (four out offive studies) indicate that this ingredient is not genotoxic. Hepatocellular and parathyroid hyperplasia were noted in the dermal carcinogenicity study, but the overall findings were clearly negative. Because the highest concentration tested that produced no significant sensitization in clinical tests was 3%, the Expert Panel concluded that safety could be assured only at levels ≤3%. The Expert Panel recognized that this concentration may be greater than that currently used in hair dye formulations.

scholarly journals In-vitro Antibacterial Activity of Carbopol-Essential Oils hydrogels

2020 ◽  
Vol 7 (2) ◽  
pp. 564-571
Author(s):  
Esam Yahya ◽  
Muhanad Abdullah Abdulsamad
Keyword(s):  
Antibacterial Activity ◽  
Essential Oils ◽  
Skin Irritation ◽  
Diffusion Method ◽  
Disk Diffusion Method ◽  
Tea Tree ◽  
Entire Duration ◽  
Animal Skin

Background and Objectives: The main purpose of the drug therapy of any disease is to maintain the desired therapeutic concen-tration of the drug for the entire duration of the treatment. The aim of this study is to formulate mixed essential oils loaded hydrogel, and evaluate its antibacterial activity against some pathogens. Materials and Methods: Different hydrogels were formulated by using different concentration of essential oils. Antibacterial evaluation was done using disk diffusion method. Screening for antibacterial activity of essential oils were studied prior to hydrogel formulation to compare the changes in activity after incorporation in the hydrogel. Results: Clove oil exhibited the strongest activity towards all the tested pathogens, compared to other tested essential oils (clove > cinnamon > tea tree > rosemary). The formulation containing mixed essential oils showed the best results, with synergistic effect against all tested pathogens. Hydrogels were further subjected to evaluation of physical properties like color, clarity, pH, viscosity and animal skin irritation study. The zone of inhibition of the final formulation containing only 3% from the selected three essential oils was between 18‐23 mm for S. aureus, 17‐20mm for E. coli, and 14‐18mm for P. aeruginosa. The hydrogels were non-irritant, stable, and free of any microbes at room temperature. Conclusion: Activity of essential oils was much affected by incorporation in hydrogel. The loaded hydrogel showed better antimicrobial activity against all the microorganisms used in the study, despite the need for clinical studies to determine of the effectiveness and potential toxic effects in-vivo.

scholarly journals FORMULATION AND IN VITRO, IN VIVO EVALUATION OF PRONIOSOMAL GEL OF NEOMYCIN SULPHATE

2019 ◽  
pp. 156-163
Author(s):  
AMOL SHETE ◽  
PRIYANKA THORAT ◽  
RAJENDRA DOIJAD ◽  
SACHIN SAJANE
Keyword(s):  
Phase Separation ◽  
Skin Irritation ◽  
Entrapment Efficiency ◽  
Separation Method ◽  
Gelling Agent ◽  
In Vivo Evaluation ◽  
Skin Delivery ◽  
Span 60

Objective: The objectives of present investigation were to prepare and evaluate proniosomes of neomycin sulphate (NS) by coacervation phase separation method by using sorbitan monostearate (span 60) and lecithin as a surfactant to increase the penetration through the skin and study the effect of concentration of the same. Methods: Proniosomes of neomycin sulphate (NS) were prepared by coacervation phase separation method by using span 60 and lecithin. The effect of concentration of span 60 and lecithin was studied by factorial design. The prepared proniosomes were converted to gel by using carbopol as a gelling agent. The prepared formulations were evaluated for entrapment efficiency, in vitro drug diffusion, in vitro antibacterial activity and in vivo skin irritation test etc. Results: All Formulation showed the percentage entrapment efficiency in the range 38.31±0.05% to 77.96±0.06%, good homogeneity and gel was easily spreadable with minimal of shear. Optimized formulation showed enhanced rate of diffusion in vitro, increase in zone of inhibition against staphylococcus aureus, no skin irritation and showed good stability. Conclusion: The results of present study indicates that proniosomal gel formulated by using combination of span 60, Lecithin, cholesterol can be used to enhance skin delivery of NS because of excellent permeation of drug. Developed proniosomal gel formulation was promising carrier for NS

Diagnostic and Experimental Methods Skin irritation: tests in vivo and in vitro

1990 ◽  
Vol 23 (4) ◽  
pp. 287-287
Author(s):  
D. P. Bruynzeel ◽  
B. A. M. Gerritsen ◽  
P. De Haan ◽  
E. M. De Boer
Keyword(s):  
Skin Irritation ◽  
Experimental Methods
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