Final Report On the Safety Assessment of m-Phenylenediamine and m-Phenylenediamine Sulfate1

1997 ◽  
Vol 16 (1_suppl) ◽  
pp. 59-115 ◽  
Author(s):  
F. Alan Andersen
Keyword(s):  
Animal Studies ◽  
Skin Irritation ◽  
Kidney Injury ◽  
Dermal Exposure ◽  
Female Rats ◽  
Final Report ◽  
Hair Dyes ◽  
Hair Dye ◽  
Kidney Toxicity ◽  
Negative Results

The ingredients m-Phenylenediamine and m-Phenylenediamine Sulfate are aromatic amines that function as hair colorants in cosmetic products. Both are currently used in hair dye products at concentrations of up to 3%. Percutaneous absorption of m-Phenylenediamine has been demonstrated in animals. Three metabolites excreted in urine have been identified. The oral LD50 of m-Phenylenediamine in rats is between 360 and 650 mg/kg. Subchronic studies in rats (oral) indicated some lesions in the liver but no kidney injury, while one study in rabbits (dermal) indicated some liver and kidney toxicity. Another dermal study in rabbits failed to show any liver or kidney toxicity. Skin irritation and sensitization were found in guinea pigs exposed to m-Phenylenediamine. Clinical data indicated some evidence of sensitization. A short-term study in rats (oral) reported an absence of any neurotoxicity. One study in female rats identified fetotoxicity but no evidence of terata. Other studies reported neither birth defects nor fetal deaths. Both positive and negative results were found in various mutagenesis assay systems. In studies with mice and rats, neither m-Phenylenediamine (both oral and dermal exposure) nor hair dye formulations (dermal exposure only) containing m-Phenylenediamine were carcinogenic. Based on the concentrations of m-Phenylenediamine shown to produce sensitization in animal studies, it was concluded that these ingredients can be used safely in hair dyes at concentrations of up to 10%.

Final Report on the Safety Assessment of HC Blue No. 1

1994 ◽  
Vol 13 (5) ◽  
pp. 344-360
Keyword(s):  
Animal Studies ◽  
Current Data ◽  
Female Rats ◽  
Male Rats ◽  
Final Report ◽  
Positive Trend ◽  
Hair Dyes ◽  
Pregnant Rats ◽  
Hepatocellular Carcinomas ◽  
Dose Dependent

The aromatic amine HC Blue No. 1 is a hair colorant intended exclusively for use in hair dyes. While this colorant had previously been used in concentrations up to 1.6%, current information indicates it is not presently used in any hair dyes. Animal studies indicate this ingredient is absorbed slowly through the skin. Short-term and subchronic animal toxicity studies show a dose-dependent reduction in weight gain. HC Blue No. 1 was mutagenic in some, but not all, test systems, and was associated with fetal bone malformations when given orally to pregnant rats at levels that were maternally toxic. In a National Toxicology Program feeding study, dosed male rats had a positive trend in incidence of hepatic neoplastic nodules, but not in hepatic carcinomas; dosed female rats showed a positive trend in the incidence of alveolar/bronchiolar neoplasms; and mice of both sexes showed an increase in hepatocellular carcinomas. Although it is recognized that further dermal carcinogenicity data would help clarify the different findings in the current data, such information is not expected, and it is concluded on the basis of the data that are available in this report that HC Blue No. 1 is unsafe for use in cosmetic formulations (hair dyes).

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 HC Red #3

1992 ◽  
Vol 11 (4) ◽  
pp. 509-519
Keyword(s):  
Coal Tar ◽  
Metabolic Activation ◽  
Female Rats ◽  
Final Report ◽  
Male Mice ◽  
Hair Dyes ◽  
Hair Dye ◽  
Feeding Study ◽  
Body Weights ◽  
The Mean

HC Red #3, also known as N1(2-hydroxyethyl)-2-nitro-p-phenylenediamine, is a colorant used in semipermanent hair dyes. Unidentified nitrosamines were found in two lots of HC Red #3, at concentrations of 20 ± 5 ppm and 11 ± 8 ppm. The LD50 for HC Red #3 was >500 mg/kg in mice and >1000 mg/kg in rats. In a subchronic feeding study, the mean body weights of male mice and rats were reduced. Other than a pigmentation of the urine and some organs of these animals, no gross or microscopic changes due to HC Red #3 were noted. HC Red #3 was mutagenic in the Ames assay; the mutagenicity was greatly increased by metabolic activation. In a two-year feeding study, there was no evidence of carcinogenicity produced in either male or female rats. There was equivocal evidence for the carcinogenicity of HC Red #3 in male mice and inadequate evidence to make a judgement of carcinogenicity in female mice. On the basis of the available data presented in this report, it is concluded that HC Red #3, which does not contain nitrosamines and used in products not containing N-nitrosating agents, is safe as a “coal tar” hair dye ingredient at the current concentrations of use.

Final Report on the Safety Assessment of Hydroxybenzomorpholine

1991 ◽  
Vol 10 (1) ◽  
pp. 205-213 ◽  
Keyword(s):  
Safety Assessment ◽  
Micronucleus Test ◽  
Coal Tar ◽  
Skin Irritation ◽  
High Dose ◽  
Final Report ◽  
Oral Toxicity ◽  
Hair Dyes ◽  
Hair Dye ◽  
Rabbit Eye

Hydroxybenzomorpholine (HBM) is a heterocyclic compound that is used in cosmetics as a coupler in coal tar hair dyes. No deaths were reported in a subchronic oral toxicity study in rats. Some degenerative changes in the cortical tubules of the kidneys were observed in the mid and high-dose groups. HBM was considered to be practically nonirritating to the rabbit eye and produced only slight skin irritation. HBM was neither a sensitizer nor a photoallergen. HBM was not mutagenic in either the Ames assay or in the mouse micronucleus test. On the basis of the data included in the report, Hydroxybenzomorpholine is considered to be safe as a hair dye ingredient at the current concentrations of use.

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 N-Phenyl-p-Phenylenediamine, N-Phenyl-p-Phenylenediamine Hydrochloride, and N-Pheny 1-p-Phenylenediamine Sulfate

1994 ◽  
Vol 13 (5) ◽  
pp. 374-394
Keyword(s):  
Patch Test ◽  
Developmental Toxicity ◽  
Female Rats ◽  
Final Report ◽  
Similar Response ◽  
Hair Dyes ◽  
Hair Dye ◽  
Female Mice ◽  
Dose Dependent ◽  
Dermal Application

N-Phenyl-p-Phenylenediamine and its sulfate and hydrochloride salts are aromatic amines. Whereas N-Phenyl-p-Phenylenediamine Sulfate is not currently reported to be used in cosmetics, N-Phenyl-p-Phenylenediamine and N-Phenyl-p-Phenylenediamine Hydrochloride are used as colorants in hair dyes/colors. Data evaluated are for N-Phenyl-p-Phenylenediamine and are extended to the sulfate and hydrochloride salts. The oral median lethal dose (LD50) in rats ranged from 464 mg/kg to 1,000 mg/kg. Acute oral toxicity studies in cats showed increased methemoglobin and Heinz body formation ≥25 mg/kg. Dose-dependent weight reductions were seen in rats fed ≥2,200 ppm for 90 days. Mice fed 14,700 ppm showed a similar response. CNS damage was observed in mice fed ≥5,000 ppm for 91 weeks. Irritation and sensitization were both observed in guinea pigs, but no ocular irritation was seen in rabbits. Oral administration to female rats showed no developmental toxicity in one study, but showed maternal and fetal toxicity and an increase in skeletal malformations in another. Dermal application of a hair dye formulation containing 2.0% N-Phenyl-p-Phenylenediamine to female rats and mice showed no developmental toxicity of any sort. No evidence of carcinogenicity was found in either male or female rats fed N-Phenyl-p-Phenylenediamine for 78 weeks, or in female mice fed up to 10,000 ppm for 48 weeks. Male mice, however, showed a non-dose-dependent increased incidence of hepatocellular neoplasms. In another study, dermal application of a hair dye formulation containing 2.0% N-Phenyl-p-Phenylenediamine to male and female mice once a week for 23 months resulted in no increase in neoplasms compared to controls. Clinical data indicate that N-Phenyl-p-Phenylenediamine is a skin irritant and can be a sensitizer. Sensitization reactions were more common among dermatitis patients who work as hairdressers. Products containing these ingredients are exempt from the principal adulteration provision of the Federal Food, Drug, and Cosmetic Act when the label bears a caution statement and instructions to perform a patch test to ascertain if the user is sensitive to them. Because this ingredient is a sensitizer, users should be screened with a patch test. On the basis of the information in this report, it is concluded that N-Phenyl-p-Phenylenediamine, N-Phenyl-p-Phenylenediamine Sulfate, and N-Phenyl-p-Phenylenediamine Hydrochloride are safe for use in hair dyes at concentrations up to 1.7% (as the free base).

Final Report on the Safety Assessment of Disperse Blue 71

2007 ◽  
Vol 26 (2_suppl) ◽  
pp. 51-63
Keyword(s):  
Patch Test ◽  
Skin Irritation ◽  
Point Mutations ◽  
Metabolic Activation ◽  
Final Report ◽  
Textile Dye ◽  
Hair Dyes ◽  
Hair Dye ◽  
Anthraquinone Dye ◽  
Study Results

Disperse Blue 7 is an anthraquinone dye used in cosmetics as a hair colorant in five hair dye and color products reported to the Food and Drug Administration (FDA). Hair dyes containing Disperse Blue 7, as “coal tar” hair dye products, are exempt from the principal adulteration provision and from the color additive provision in sections 601 and 706 of the Federal Food, Drug, and Cosmetic Act of 1938 when the label bears a caution statement and “patch test” instructions for determining whether the product causes skin irritation. Disperse Blue 7 is also used as a textile dye. The components of Disperse Blue 7 reportedly include Disperse Turquoise ALF Granules, Disperse Turquoise LF2G, Reax 83A, Tamol SW, and Twitchell Oil. No data were available that addressed the acute, short-term, or chronic toxicity of Disperse Blue 7. A mouse lymph node assay used to predict the sensitization potential of Disperse Blue 7 was negative. Although most bacterial assays for genotoxicity were negative in the absence of metabolic activation, consistently positive results were found with metabolic activation in Salmonella strains TA1537, TA1538, and TA98, which were interpreted as indicative of point mutations. Studies using L5178Y mouse lymphoma cells appeared to confirm this muta-genic activity. Mammalian assays for chromosome damage, however, were negative and animal tests found no evidence of dominant lethal mutations. Cases reports describe patients patch tested with Disperse Blue 7 to determine the source of apparent adverse reactions to textiles. In most patients, patch tests were negative, but there are examples in which the patch test for Disperse Blue 7 was positive. In general, anthraquinone dyes are considered frequent causes of clothing dermatitis. The Cosmetic Ingredient Review Expert Panel determined that there was a paucity of data regarding the safety of Disperse Blue 7 as used in cosmetics. The following data are needed in order to arrive at a conclusion on the safety of Disperse Blue 7 in cosmetic products: (1) methods of manufacture, including clarification of the relationship between Disperse Blue 7 and Disperse Turquoise ALF and Disperse Turquoise LF2G mixed with Reax 83A, Tamol SW, and Twitchell Oil; (2) analytical methods by which Disperse Blue 7 is measured; (3) impurities; (4) concentration of use as a function of product type; (5) confirmation that this is a direct hair dye; and (6) clarification of genotoxicity study results (e.g., Disperse Turquoise ALF and Disperse Turquoise LF2G were genotoxic in bacteria—what is the specific relation to Disperse Blue 7? Disperse Blue 7 at 60% purity was genotoxic in bacteria—is the other 40% the inert Reax 83A, Tamol SW, and Twitchell Oil?). Until such data are provided, the available data are insufficient to support the safety of Disperse Blue 7 as a hair dye ingredient in cosmetic formulations.

Final Report on the Safety Assessment of HC Yellow No. 2

1994 ◽  
Vol 13 (3) ◽  
pp. 157-166 ◽  
Keyword(s):  
Body Weight Gain ◽  
Clinical Chemistry ◽  
Metabolic Activation ◽  
Female Rats ◽  
Male Rats ◽  
Final Report ◽  
Test Substance ◽  
Hair Dyes ◽  
Hair Dye ◽  
Reduced Body

HC Yellow No. 2 is used in oxidative or semipermanent hair dye formulations in concentrations up to 1%. The LD50 for HC Yellow No. 2 administered via gavage was between 1.2 and 2.5 g/kg in male rats and between 0.6 and 1.2 g/kg in female rats. In the subchronic and chronic feeding studies, 1.25% HC Yellow No. 2 reduced body weight gain and induced changes in various organ sizes and clinical chemistry values. The only histologic change attributed to this hair dye was a small increase in the pigment of the spleen. The compound was only a minor ocular irritant when tested at a concentration of 10%. It was neither a sensitizer nor photosensitizing agent in guinea pigs at 10%. It was not a teratogenic compound in rats. HC Yellow No. 2 was negative in a dominant lethal assay and it was not mutagenic in the four S. typhimurium strains tested, both with or without S9 metabolic activation. In a repeated insult patch test (RIPT) using 3% HC Yellow No. 2, two volunteers of 98 had a positive reaction to the test substance. In another RIPT study, 1 of 104 volunteers had a sensitization reaction to 3% HC Yellow No. 2. It is concluded that HC Yellow No. 2 is safe for use in hair dyes at concentrations up to 3%.

Final Report on the Safety Assessment of 2,4-Diaminophenoxyethanol Dihydrochloride

1991 ◽  
Vol 10 (1) ◽  
pp. 113-134
Keyword(s):  
Animal Studies ◽  
Mutagenic Activity ◽  
Coal Tar ◽  
Skin Irritation ◽  
Final Report ◽  
Hair Dyes ◽  
Federal Food ◽  
Mutagenic Response ◽  
Carcinogenic Effects ◽  
Rats And Mice

2,4-Diaminophenoxyethanol Dihydrochloride (2,4-DAPE) is an aromatic amine that is used as a coupler in permanent (oxidative) hair dyes at concentrations up to 1.0%. 2,4-DAPE was slightly toxic in rats and mice. No significant adverse changes were observed in a subchronic toxicity test. 2,4-DAPE was practically nonirritating when a 4% aqueous solution was instilled into the conjunctival sacs of the eyes of rabbits. 2,4-DAPE was slightly irritating to the skin of rabbits when tested at a concentration of 4.0%. Based on animal studies, 2,4-DAPE was judged to produce low level sensitization in humans. Coal tar hair dyes, including those containing 2,4-DAPE, are exempt from the principal adulteration provision and the color additive provisions in Sections 601 and 706 of the Federal Food, Drug, and Cosmetic Act of 1938 when the label bears a caution statement and patch test instructions for determining whether the product causes skin irritation. No teratogenic effects were observed due to administration of 2,4-DAPE. No mutagenic activity attributable to 2,4-DAPE was observed in 22 mutagenic studies. However, in a few studies, a marginal mutagenic response was reported. In two oral carcinogenic studies, one in which mice were dosed with 0.04 and 0.07% 2,4-DAPE and the second in which rats were dosed with 0.05 and 1.0% 2,4-DAPE, no carcinogenic effects were produced. On the basis of the data presented in this report, it is concluded that 2,4-Diaminophenoxyethanol Dihydrochloride is safe as a cosmetic ingredient in the present practices of use and concentration.

Final Report on the Safety Assessment of Disperse Blue 71

2007 ◽  
Vol 26 (2_suppl) ◽  
pp. 65-77 ◽  
Keyword(s):  
Patch Test ◽  
Skin Irritation ◽  
Point Mutations ◽  
Metabolic Activation ◽  
Final Report ◽  
Textile Dye ◽  
Hair Dyes ◽  
Hair Dye ◽  
Anthraquinone Dye ◽  
Study Results

Disperse Blue 7 is an anthraquinone dye used in cosmetics as a hair colorant in five hair dye and color products reported to the Food and Drug Administration (FDA). Hair dyes containing Disperse Blue 7, as “coal tar” hair dye products, are exempt from the principal adulteration provision and from the color additive provision in sections 601 and 706 of the Federal Food, Drug, and Cosmetic Act of 1938 when the label bears a caution statement and “patch test” instructions for determining whether the product causes skin irritation. Disperse Blue 7 is also used as a textile dye. The components of Disperse Blue 7 reportedly include Disperse Turquoise ALF Granules, Disperse Turquoise LF2G, Reax 83A, Tamol SW, and Twitchell Oil. No data were available that addressed the acute, short-term, or chronic toxicity of Disperse Blue 7. A mouse lymph node assay used to predict the sensitization potential of Disperse Blue 7 was negative. Although most bacterial assays for genotoxicity were negative in the absence of metabolic activation, consistently positive results were found with metabolic activation in Salmonella strains TA1537, TA1538, and TA98, which were interpreted as indicative of point mutations. Studies using L5178Y mouse lymphoma cells appeared to confirm this muta-genic activity. Mammalian assays for chromosome damage, however, were negative and animal tests found no evidence of dominant lethal mutations. Cases reports describe patients patch tested with Disperse Blue 7 to determine the source of apparent adverse reactions to textiles. In most patients, patch tests were negative, but there are examples in which the patch test for Disperse Blue 7 was positive. In general, anthraquinone dyes are considered frequent causes of clothing dermatitis. The Cosmetic Ingredient Review Expert Panel determined that there was a paucity of data regarding the safety of Disperse Blue 7 as used in cosmetics. The following data are needed in order to arrive at a conclusion on the safety of Disperse Blue 7 in cosmetic products: (1) methods of manufacture, including clarification of the relationship between Disperse Blue 7 and Disperse Turquoise ALF and Disperse Turquoise LF2G mixed with Reax 83A, Tamol SW, and Twitchell Oil; (2) analytical methods by which Disperse Blue 7 is measured; (3) impurities; (4) concentration of use as a function of product type; (5) confirmation that this is a direct hair dye; and (6) clarification of genotoxicity study results (e.g., Disperse Turquoise ALF and Disperse Turquoise LF2G were genotoxic in bacteria—what is the specific relation to Disperse Blue 7? Disperse Blue 7 at 60% purity was genotoxic in bacteria—is the other 40% the inert Reax 83A, Tamol SW, and Twitchell Oil?). Until such data are provided, the available data are insufficient to support the safety of Disperse Blue 7 as a hair dye ingredient in cosmetic formulations.

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