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Toxicity Effects

CAS Registry Number: 2835-95-2

Selected toxicity information from HSDB, one of the National Library of Medicine's databases. 2.

Names 1

  • 3-Amino-6-Methylphenol
  • 3-Hydroxy-4-Methylaniline
  • 4-Amino-2-Hydroxy-1-Methylbenzene
  • 4-Amino-2-Hydroxytoluene
  • 5-Amino-2-methylphenol
  • 5-Amino-o-cresol

Human Toxicity Excerpts

  • HUMAN EXPOSURE STUDIES: A modified Draize repeat insult patch test (RIPT) procedure was used to evaluate the irritation and sensitization potential of two aqueous solutions, each containing 2% of 4-amino-2-hydroxytoluene as supplied. An initial challenge (100% applied for 1 hr) was made to aid in the interpretation of the challenge following the rest period. For the induction exposure, semiocclusive patches containing 0.3 ml of the solution were applied to the same site on the upper arm of each subject on Mondays, Wednesdays, and Fridays for 3 consecutive weeks. The first solution for induction was a 3.0% v/v aqueous solution and the second was a 10% w/v aqueous solution. Patches were left in place for 24 hr and scored 48 or 72 hr after application. The challenge was made after a 2 wk nontreatment period. A patch containing 100% of the test solution was applied to a previously untreated site for 1 hr. Sites were scored 48 and 96 hr after application. Another challenge patch was also applied simultaneously to the induction site using the induction concentration. Twenty-three of the 27 subjects completed testing with the first solution. The initial challenge produced 21 negative and 5 slight reactions; the induction period elicited reactions from one subject only, who had a score of 4 (maximum=7) at the sixth induction patch and was subsequently patched on a different site. The challenge solution produced 20 negative, 2 slight (score of 1), and 1 significant (score of 3) reactions. The significant reaction was seen in the same subject who had reacted during the induction phase. No reactions were produced by the challenge patch applied to the induction site. A rechallenge was conducted with 11 of the subjects at a naive site on the upper back using a concentration of 25% of the test solution; 10 negative (including the 1 patient with the significant reaction at challenge) and 1 slight reactions were observed. /It was/ concluded that the test solution had produced one case of significant dermatitis, although it was not reproduced at rechallenge. Thirty-one subjects completed testing with the second solution. The initial challenge failed to produce a reaction in any of the subjects. During the induction period, very slight reactions (scores of 1 or less) were observed in 4 subjects and strong reactions (scores of up to 3 and 5) in two subjects. Challenge at a previously untreated site produced two slight reactions and one strong reaction (scores of 5 at both 48 and 96 hr), the latter being a delayed challenge due to residual reactions from the induction phase. The challenge patches applied to the induction site produced three slight and two strong reactions; however, only one of these five subjects had a reaction when challenged at a previously untreated site. A rechallenge of two subjects produced one negative and one significant response, the latter being from one of those with a strong reaction to challenge at the induction site. In the investigator's opinion, two cases of significant dermatitis had been observed, one each during challenge and rechallenge; therefore, these were cases of induced contact allergic eczema.[Christian MS, ed; Journal of the American College of Toxicology V8 No.4 p.581-2 (1989)] **PEER REVIEWED**
  • HUMAN EXPOSURE STUDIES: Ten volunteers (males and females) each had their hair dyed 13 times at intervals of 3-6 wk. Each volunteer used a single commercial preparation throughout the study. /Five of the preparations contained 2-hydroxy-4-aminotoluene./ ...Lymphocytes of the hair-dyed volunteers and of ten controls matched for age and sex were scored for chromosomal aberrations. The incidence of aberrations did not differ significantly between the controls and the hair-dyed volunteers at any of the nine sampling times.[Hofer H et al; Food Chem Toxicol 21 (6): 785-9 (1983)] **PEER REVIEWED** PubMed Abstract

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Non-Human Toxicity Excerpts

  • GENOTOXICITY: /5-amino-o-cresol tested positive in the Salmonella mutagenicity test using S. typhimurium TA97, TA98, TA100 with S9 activation; and negative in S.typhimurium TA1535 with or without S9 activation./[Zeiger E et al; Environ Mol Mutagen 11 (Supp 12): 1-158 (1988)] **PEER REVIEWED**
  • LABORATORY ANIMALS: Acute Exposure: Groups of 5 male and 5 female /CFY strain/ rats were /given a 10% suspension of 4-amino-2-hydroxytoluene in 0.5% aqueous gum tragacanth containing 0.05% anhydrous sodium sulfite./ ...All animals that died as well as those killed at the end of the study were subjected to autopsy exam. ...At necropsy of the rats that died, some darkening of liver and kidneys, darkening or pallor of the spleen, hemorrhages of the lungs and intestines, and injection of intestinal and mesenteric blood vessels were observed. The survivors did not have any abnormalities indicative of residual systemic effects.[Christian MS, ed; Journal of the American College of Toxicology V8 No.4 p.574 (1989)] **PEER REVIEWED**
  • LABORATORY ANIMALS: Acute Exposure: The acute dermal toxicity of 4-amino-2-hydroxytoluene was evaluated using six male and six female New Zealand white rabbits. The back of each rabbit was clipped free of hair and the animals were fitted with plastic collars to prevent oral ingestion of the compound. A dose of 5 g/kg 4-amino-2-hydroxytoluene (as a slurry with 3.0% acacia) was applied to the back of each rabbit with a gauze pad. The pads were left in place under semiocclusive conditions for 24 hr. The rabbits were observed for 7 days after patch removal. The 4-amino-2-hydroxytoluene did not produce any systemic/dermal toxicity at a dosage of 5 g/kg.[Christian MS, ed; Journal of the American College of Toxicology V8 No.4 p.575 (1989)] **PEER REVIEWED**
  • LABORATORY ANIMALS: Acute Exposure: The irritant effects on rabbit skin and eye mucosa, and the acute oral toxicity in rats were assessed for twelve compounds which are hair-dye constituents or chemically related aromatic amines, aminophenols, nitro derivatives or aromatic hydroxy derivatives. .../4-amino-2-hydroxytoluene was/ non-irritant /to rabbit skin/ at the concentrations studied. ...Only mild conjunctival reaction followed treatment with /4-amino-2-hydroxytoluene/... .[Lloyd GK et al; Food and Cosmetic Toxicology 15 (6): 607-10 (1977)] **PEER REVIEWED**
  • LABORATORY ANIMALS: Developmental or Reproductive Toxicity: ...Groups of /Sprague-Dawley/ rats were fed diets containing 0, 0.3, 1.0 and 3.0% 4-amino-2-hydroxytoluene for a period of about 20 weeks. At that time, 20 male rats from each dose group were removed from the test diet, placed on a basal diet, and mated to two untreated females each week for two weeks. All of the rats were observed daily and the body weights were recorded weekly for the males and on days 0, 12, and 17 of gestation for the females. The females were killed on day 17 of gestation and the fetuses removed by cesarean section. The numbers of live and dead fetuses, early and late resorptions, and the total number of corpora lutea on each ovary were recorded. The males fed the 3.0% diet of 4-amino-2-hydroxytoluene weighed significantly less than the controls at the start of the mating period. Although these rats gained weight more rapidly than the controls when fed the basal diet, the significant difference in weight persisted. All of the males, with the exception of one male in the middose group, sired at least one litter. There were no significant differences in the body weights of the pregnant females from either mating period and no significant dose-related differences were noted in any of the reproductive parameters studied. 4-Amino-2-hydroxytoluene, at concentrations toxic to males, produced no adverse effects on reproductive performance and no dominant lethal effect.[Christian MS, ed; Journal of the American College of Toxicology V8 No.4 p.579-80 (1989)] **PEER REVIEWED**
  • LABORATORY ANIMALS: Developmental or Reproductive Toxicity: Groups of 25 female Sprague-Dawley rat were fed diets containing 0, 0.3, 1.0, or 3.0% 4-Amino-2-hydroxytoluene for 14 weeks. These rats were then removed from the test diet and mated with untreated males of the same strain and age. The feeding was then resumed for the duration of gestation at the same dietary doses. ...Statistically significant decreases in the mean body weights were observed for the mid- and high-dose groups throughout gestation (with the exception of the mid-dose group at day 0). Rate of weight gain was significantly less for rats of both dose groups. There were no significant differences in gravid uterus weights. Feed consumption was significantly reduced in the high-dose group. No significant differences were noted in any of the reproductive parameters studied. No visceral abnormalities or skeletal malformations were noted; however, there was a statistically significant increase in rudimentary 14th ribs in the rats of the 1.0 and 3.0% groups. An insignificant increase was also noted in the number of full 14th ribs in the fetuses of the same groups. The investigators stated that a high degree of variability exists in the occurrence of extra 14th ribs and that they may be an indication of teratogenic potential at higher dosages; however, the current dosages of 1.0 and 3.0% 4-amino-2-hydroxytoluene produced maternal toxicity and higher dosages would probably be lethal. 4-Amino-2-hydroxytoluene, at maternally toxic dosages, did not affect the animals' ability to reproduce and did not produce a teratogenic effect in the Sprague-Dawley rat.[Christian MS, ed; Journal of the American College of Toxicology V8 No.4 p.575 (1989)] **PEER REVIEWED**
  • LABORATORY ANIMALS: Subchronic or Prechronic Exposure: ...The dietary administration of 4-amino-2-hydroxytoluene to rats at concentrations up to 3.0% for periods of 3-6 months can cause reduction in body weight, a slight anemia, and sporadic microfollicular goiter.[Christian MS, ed; Journal of the American College of Toxicology V8 No.4 p.577 (1989)] **PEER REVIEWED**
  • LABORATORY ANIMALS: Subchronic or Prechronic Exposure: 4-Amino-2-hydroxytoluene (1 of 12 hair dye ingredients) was evaluated for sensitization in 19 albino guinea pigs of the Prilbright white strain. 4-Amino-2-hydroxytoluene was administered at a concentration of 3% in a vehicle consisting of Natrosol 250HR (2.0%), Tween 80 (2.0%), sodium sulfite (0.05%), deionized water (82.95%), and isopropanol (10.0%). An open epicutaneous method was used. The 4-amino-2-hydroxytoluene was applied daily for 3 weeks (except Sundays) on a 6 sq cm shaven area of the flank of each guinea pig and rubbed carefully with a glass bar. Two weeks after the last administration, a challenge application was made on the opposite untreated flank of each animal. Reactions were scored on a scale of 0-4. Four of the 19 guinea pigs had a reaction, with the total point score (for all four) being 4. /It was/ concluded that very weak sensitization was produced by 4-amino-2-hydroxytoluene.[Christian MS, ed; Journal of the American College of Toxicology V8 No.4 p.578-9 (1989)] **PEER REVIEWED**
  • LABORATORY ANIMALS: Subchronic or Prechronic Exposure: 4-Amino-2-hydroxytoluene was evaluated for photosensitization potential using 16 Hartley guinea pigs (8 males and 8 females). Concentrations of 5 and 10% were used for the induction and challenge applications, respectively, in a vehicle consisting of 32% dimethylacetamide, 24% acetone, 24% ethanol, and 20% physiological saline. ...For the first week of induction, 0.1 ml of the test material was applied to a shaved nuchal site (1.8 cm diameter) daily for 4 consecutive days. One hour after each application the animals were irradiated with one-half of the /minimal erythemal dose/ (MED) of UVA... . Sites were scored for irritation 24 hr after each application. The second and third weeks of induction consisted of similar applications but sites were irradiated with the MED of UVB and each animal received an intradermal injection of Freund's complete adjuvant on the first and third days of each week (total of four injections). After a 2 wk nontreatment period, the animals were challenged in three different manners. Samples of 0.1 ml of the test material were applied to three new sites daily for 3 consecutive days. One hour after each application, the sites were irradiated with one-half of the MED of UVA, one-half of the MED of UVB, or not irradiated at all. Sites were scored for irritation 24 hr after each application. No evidence of erythema or edema was observed in any of the animals during the induction period; discoloration (dark brown color) was noted at test sites. No reactions were noted at any of the three challenge sites over the 72 hr observation period. ...4-Amino-2-hydroxytoluene did not induce photosensitization in the guinea pig under conditions of this test.[Christian MS, ed; Journal of the American College of Toxicology V8 No.4 p.575 (1989)] **PEER REVIEWED**
  • LABORATORY ANIMALS: Subchronic or Prechronic Exposure: Groups of 40 male and 35 female weanling Sprague-Dawley rats were administered 0, 0.3, 1.0, or 3.0% 4-amino-2-hydroxytoluene in the diet. ...After 13 weeks, 10 males and 10 females randomly chosen from each group were killed and the blood was collected for hematologic and clinical chemistry tests. A necropsy was conducted and the major organs weighed and placed in fixative. ...The administration of 4-amino-2-hydroxytoluene in the diet for 90 days produced no deaths and no signs of toxicity, although discoloration of the fur was noted in all animals in the high-dose group. This discoloration began as a brown-stained anogenital area at about 2 weeks and gradually led to general discoloration of the whole coat. Significant reductions were noted in the body weight of all animals fed 3% and of the males fed 1%. Sporadic significant reductions were noted for the females fed 1% and all animals in the low-dose group. This was accompanied by decreased feed consumption that was most consistent for the rats of the 3% group and sporadically significant for the rats of the 1% group. No significant differences were noted between the concentrations of methemoglobin and T3 in the high-dose and control rats; however, the T4 hormone and the free thyroxin index were significantly decreased in the high-dose rats. ...This reduction of T4 hormone without effect on the T3 hormone was indicative of a hypothyroid state; this conclusion was further supported by the observance of enlarged thyroids, both visually and with increased weights and relative weights in the animals fed 1.0 and 3.0% diets (considered a toxic response). Changes in the other absolute and relative organ weights were "probably related" to the changes in body weight noted; significant increases in liver weight or relative liver weight noted in rats fed 1.0 and 3.0% diets were considered either a normal adaptive response to a xenobiotic or a toxic response. ... Significant dose-dependent decreases in erythrocyte count and hemoglobin and hematocrit concentration were observed in the females. The high-dose males and females had significant increases in the mean corpuscular volume. These hematologic results were suggestive of anemia and may be related to nutritional deficiency caused by reduced feed consumption. Serum protein levels were increased in the high-dose males and females. The high-dose females also had a significant increase in albumin levels, while the high- and middose males had a significant increase in the activity of serum glutamic pyruvic transaminase (SGPT). The high- and middose males and females had significantly increased concentrations of cholesterol; this was attributed to the hypothyroid state. The thyroid lesions were moderate follicular cell hyperplasia and misshapen and small follicles. These changes were noted in all rats fed the 3.0% diet and all but one of the rats fed the 1.0% diet. Rats fed the 0.3% diet were less severely affected. This disease was characterized as a "sporadic microfollicular goiter" and was attributed to an increase in the cell size of the epithelium surrounding the follicles in the thyroid. ...4-Amino-2-hydroxytoluene may have produced a toxic effect in the liver. Several test rats and one female control rat had a centrilobular hepatocytomegaly of the liver. Increased SGPT activities were dose-related, although serum glutamic oxaloacetic transaminase (SGOT) and alkaline phosphatase activities were not increased. An increase in liver weights of the middose rats was noted.[Christian MS, ed; Journal of the American College of Toxicology V8 No.4 p.575-6 (1989)] **PEER REVIEWED**

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Human Toxicity Values

  • None found

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Non-Human Toxicity Values

  • LD50 Rat oral 3600 mg/kg[Lewis, R.J. Sax's Dangerous Properties of Industrial Materials. 9th ed. Volumes 1-3. New York, NY: Van Nostrand Reinhold, 1996., p. 166] **PEER REVIEWED**

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Absorption, Distribution And Excretion

  • A: ...series of experiments /compared/ the skin permeability of a number of hair dyes obtained in two different laboratories. /Both pig skin (in vitro) and rat skin (in vivo) are permeable to 5-amino-o-cresol, the latter being more permeable.[Beck H et al; In Vitro Toxicology 7 (4): 305-12 (1994)] **PEER REVIEWED**
  • Percutaneous absorption of 5-amino-o-cresol in a hair dye was studied under the conditions of usage. Radiolabeled 5-amino-o-cresol was added to a commercial dye containing 0.69% non-radioactive 5-amino-o-cresol; the mixture was applied to dry hair of three volunteers, worked in to the hair mass for 5-8 min, and rinsed off after an additional 20 min; the urine samples were collected for as long as radioactivity was detected, approximately 144 hr. The total urinary excretion of radioactivity was 0.2% with 50% of the radioactivity excreted in 24 hr.:[Wolfram LJ, Maibach HI; Arch Dermatol Res 277 (3): 235-41 (1985)] **PEER REVIEWED** PubMed Abstract
  • A 94% recovery of radioactivity (corrected for incomplete excretion from internal application) in human urine after oral administration of radioactive 4-amino-2-hydroxytoluene /was reported/.[Christian MS, ed; Journal of the American College of Toxicology V8 No.4 p.572 (1989)] **PEER REVIEWED**

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Metabolism/Metabolites

  • None found

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Tsca Test Submissions

  • None found

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Footnotes

1 Source: the NTP's CEBS database.

2 Source: the National Library of Medicine's Hazardous Substance Database, 02/28/2017.

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