Testing Information

Testing Status of Agents at NTP

CAS Registry Number: 90-04-0 Toxicity Effects

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Selected toxicity information from HSDB, one of the National Library of Medicine's databases. 1

Names (NTP)

  • o-Anisidine
  • 2-METHOXYBENZENAMINE (9CI)

Human Toxicity Excerpts

  • WORKMEN EXPOSED TO AIR CONCN OF 0.4 PPM FOR 3.5 HR/DAY FOR 6 MONTHS DEVELOPED NO ANEMIA OR CHRONIC POISONING. THERE WERE ... SOME COMPLAINTS OF HEADACHE AND VERTIGO ... AND INCREASED SULFHEMOGLOBIN AND METHEMOGLOBIN AND FREQUENT OCCURRENCE OF ERYTHROCYTIC INCLUSION BODIES (HEINZ BODIES). /ANISIDINE, O-, P-ISOMERS/ [American Conference of Governmental Industrial Hygienists, Inc. Documentation of the Threshold Limit Values and Biological Exposure Indices. 6th ed. Volumes I, II, III. Cincinnati, OH: ACGIH, 1991., p. 71]**PEER REVIEWED**
  • O-ANISIDINE IS: A SKIN IRRITANT /&/ SENSITIZER. [The Merck Index. 10th ed. Rahway, New Jersey: Merck Co., Inc., 1983., p. 97]**PEER REVIEWED**
  • In the absence of data on humans, ortho-anisidine should be regarded, for practical purposes, as if it presented a carcinogenic risk to humans. [IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work)., p. V27 77 (1982)]**PEER REVIEWED**

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Non-Human Toxicity Excerpts

  • ... ORTHO-ANISIDINE /HYDROCHLORIDE/ ... INDUCED CANCER IN URINARY BLADDER /OF EXPERIMENTAL ANIMALS/ ... AT HIGH DOSE LEVELS. /ORTHO-ANISIDINE HYDROCHLORIDE/ [Doull, J., C.D.Klassen, and M.D. Amdur (eds.). Casarett and Doull's Toxicology. 3rd ed., New York: Macmillan Co., Inc., 1986., p. 110]**PEER REVIEWED**
  • Groups of 55 male & 55 female B6C3F1 mice, 6 wk of age, were fed diets containing 2500 or 5000 mg/kg ortho-anisidine hydrochloride (purity >99% ... ) for 103 wk; surviving mice were sacrificed at 105 wk. ... A group of 55 mice of each sex served as matched controls. Mean body wt gain of treated male & female mice was depressed as compared with that of controls throughout the study. By the end of the study, 78% of treated male mice, 80% of control males, 69-76% of treated females & 80% of control females were still alive. Transitional cell carcinomas of the urinary bladder were found in 0/48 control males, 0/55 low dose males, 15/53 high dose males (p<0.001), 0/50 control females, 0/51 low dose females & 18/50 high dose females (p<0.001). Transitional cell papilloma were found in 0/48 control males, 2/55 low dose males, 7/53 high dose males, 0/50 control females, 1/51 low dose females & 4/50 high dose females. Bladder hyperplasia was found in 1/48 control males, 2/55 low dose males, 21/53 high dose males, 0/50 control females, 1/51 low dose females & 12/50 high dose females. /ortho-Anisidine hydrochloride/ [IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work)., p. V27 72 (1982)]**PEER REVIEWED**
  • IN SUBACUTE ADMIN, /O-, & P-ANISIDINE/ CAUSED HEMATOLOGICAL CHANGES & INDUCED ANEMIA, WERE NEPHROTOXIC, & INCR HEPATIC VITAMIN C CONTENT. [PROSOLENKO NV; TR KHARK MED INST 124: 11-14 (1976)]**PEER REVIEWED**
  • In 7 wk subchronic feeding studies, male and female B6C3F, mice were fed diets containing up to 30000 mg/kg ortho-anisidine hydrochloride. A dose dependent depression in mean body wt gain of up to 40% was observed. The spleens of animals given >10000 mg/kg of diet were black and enlarged. When chronic doses of 2500 or 5000 mg/kg of diet were given in long term tumor induction studies, female mice developed more cystic hyperplasia of the uterus and endometrium than did control animals. At the higher dose level, animals of both sexes had an increased incidence of hyperplasia of the bladder. /ortho-Anisidine hydrochloride/ [IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work)., p. V27 74 (1982)]**PEER REVIEWED**
  • Subchronic feeding of diets containing up to 30,000 mg/kg of ... ortho-anisidine hydrochloride to Fischer 344 rats for 7 wk led to reductions in weight gain of up to 52% in males and 27% in females. Feeding of diets containing 1000 or 3000 mg/kg resulted in granular spleens in males but not in females: with >10000 mg/kg, the spleens of animals of both sexes were dark and granular. In carcinogenicity experiments, a dose of 10,000 mg/kg of diet resulted in depressions of weight gain of 21% for males and 11% for females. Male and female rats fed diets containing 5000 or 10,000 mg/kg ortho-anisidine hydrochloride developed non-neoplastic lesions of the thyroid gland and kidney more frequently than did control animals. /ortho-Anisidine hydrochloride/ [IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work)., p. V27 74 (1982)]**PEER REVIEWED**
  • ortho-Anisidine induced methemoglobinemia in CBA mice and Alpk:APfSD rats after oral administration. [IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work)., p. V73 52 (1999)]**PEER REVIEWED**
  • ortho-Anisidine hydrochloride ... induced reverse mutations in Salmonella typhimurium strains TA1538, TA98 & TA100 in the presence of liver microsomes from Aroclor-induced and uninduced mice, rats and hamsters at concentrations of ... /approx/ 333 ug/plate. /ortho-Anisidine hydrochloride/ [IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work)., p. V27 75 (1982)]**PEER REVIEWED**
  • An assay for the measurement of chemically induced DNA repair as unscheduled DNA synthesis in isolated rat kidney cells following in vivo treatment was developed. Treatment with o-anisidine, a weak renal carcinogen, did not induce unscheduled DNA synthesis in the kidney, suggesting that it may be acting as a tumor promoter. [Tyson CK, Mirsalis JC; Environ Mutagen 7 (6): 889-99 (1985)]**PEER REVIEWED**
  • In a model of urinary bladder carcinogenesis, groups of 15 male Fischer 344 rats , six weeks of age, were given 0.05% N-nitroso-N,4-hydroxybutylamine (NHBA) in the drinking water for four weeks. They were then fed diets with or without a supplement of 1700 mg/kg diet (ppm) ortho-anisidine for the first two weeks and 425 ppm thereafter for an additional 30 weeks. Ten animals received ortho-anisidine without prior NHBA administration. The incidence of papillary or nodular hyperplasia in the urinary bladder, derived by assessing the number of lesions per unit length of mucosa, was significantly higher (p < 0.01) in the group receiving ortho-anisidine plus NHBA (13/16) than in the group given NHBA alone (2/13). No lesions were observed in animals receiving ortho-anisidine alone. [IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work)., p. V73 51 (1999)]**PEER REVIEWED**
  • A NUMBER OR SUBSTITUTED ANILINES, PARTICULARLY WHERE THE SUBSTITUTION IS BY AN ORTHO-METHYL GROUP, ARE WEAKLY CARCINOGENIC. LIKE ANILINE, THEY INDUCE SPLENIC SARCOMAS AND, IN ADDITION ... ORTHO-ANISIDINE AND PARA-CRESIDINE ALSO INDUCED CANCER IN THE URINARY BLADDER /OF ANIMALS/, THOUGH AT HIGH DOSE LEVELS. ... SIGNIFICANCE OF CARCINOGENIC EFFECTS OF SINGLE RING AROMATIC AMINES IN RELATION TO POSSIBLE HUMAN EXPOSURE TO THESE RELATIVELY WEAK CARCINOGENS REQUIRES FURTHER EVALUATION. [Doull, J., C.D.Klassen, and M.D. Amdur (eds.). Casarett and Doull's Toxicology. 3rd ed., New York: Macmillan Co., Inc., 1986., p. 110]**PEER REVIEWED**

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Human Toxicity Values

  • None found

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Non-Human Toxicity Values

  • LD50 Rat oral 2000 mg/kg [IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work)., p. V27 74 (1982)]**PEER REVIEWED**
  • LD50 Mouse oral 1400 mg/kg [IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work)., p. V27 74 (1982)]**PEER REVIEWED**
  • LD50 Rabbit oral 870 mg/kg [IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work)., p. V27 74 (1982)]**PEER REVIEWED**
  • LD50 Wild bird oral 422 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. 240]**PEER REVIEWED**

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Absorption, Distribution and Excretion

  • ... ABSORBED THROUGH SKIN. [ITII. Toxic and Hazardous Industrial Chemicals Safety Manual. Tokyo, Japan: The International Technical Information Institute, 1988., p. 45]**PEER REVIEWED**

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Metabolism/Metabolites

  • Horseradish peroxidase oxidized ortho-anisidine via a nitrogen-centered cation radical to the diimine, quinone imine and an azo dimer in vitro. The metabolism led to covalent binding to calf thymus DNA. Metabolites of ortho-anisidine were consistently more reactive with protein and glutathione than metabolites of para-anisidine. [IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work)., p. V73 51 (1999)]**PEER REVIEWED**
  • Experiments in vitro with microsomes from rat liver showed that the ortho isomer is dealkylated more readily than the para derivative; the capacity of microsomes to dealkylate para-anisidine was increased by 3-methylcholanthrene. [IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work)., p. V27 75 (1982)]**PEER REVIEWED**

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TSCA Test Submissions

  • o-Anisidine (CAS # 90-04-0) was evaluated for subacute oral toxicity in male rats (5/dose group, breed unspecified) fed 1-12 gavage doses of 0, 10, 100, 500, or 1000 mg/kg over 1-16 days. A first dose of 1000 mg/kg (1 dose) resulted in unanimous prostration, with rapid breathing and heart rate within 1 hour. At 24 hours, 1 rat had recovered, 2 were moribund with persisting acute symptoms, and 3 rats had died. Urine was brown with no evidence of blood on dipstick. All surviving high-dose rats were necropsied with the lethalities 24 hours after a single dose. In the remaining groups clinical signs included prostration (500 mg/kg), rapid and shallow respiration (500 mg/kg), accelerated heart rate (500 mg/kg), mortality (1/5, 500 mg/kg), dark urine (500, 100 mg/kg), slight anorexic weight loss (500 mg/kg), and depression (100 mg/kg). Clinical chemistries revealed slight elevation of GPT only in the 500 mg/kg group. This group also demonstrated moderate elevation of white blood cell count, anomalies of red cell indices and cellular morphology. Increased corpuscular volume and mean hemoglobin with normal hemoglobin concentration indicated normochromic macrocytosis; the blood smear showed polychromasia, anisocytosis, macrocytosis, and Howell-Jolly bodies. Upon necropsy, relative liver weights were increased slightly in 500 mg/kg rats, while absolute and relative spleen weight elevations were marked in 100 mg/kg rats and moderate in 50 and 10 mg/kg rats. Necropsy also revealed urethral obstruction (1/5, 1000 mg/kg), pale and swollen kidneys (2/5 1000 mg/kg), blood in small intestine with brown urine-filled distended urinary bladders (4/5, 1000 mg/kg; 1/5, 500 mg/kg), enlarged spleen (5/5, 500 mg/kg), and darkened spleen (4/5, 500 mg/kg). A repeat-dose oral LOAEL was 10 mg/kg. Histologic changes in the 500 mg/kg group included splenic congestion (1/5), hypertrophy of hepatic nuclei (1/5), and mild granular hepatic cytoplasm (3/5). The authors concluded that erythrocytes, spleen, and possibly liver appear to be targets of o-anisidine toxicity. In addition, portal of entry effects were observed from local high dose in the gastrointestinal tract.[Eastman Kodak Co; The Basic Toxicity of o-Anisidine; 02/11/80; EPA Doc No. 88-920008931; Fiche No. OTS0546352]**UNREVIEWED**
  • o- Anisidine (CAS # 90-04-0) was evaluated for mutagenicity in vitro in the TA1535, TA1537, and TA1538 strains of Salmonella typhimurium, both in the presence and absence of Aroclor-induced rat liver S-9 metabolic activation. Following range-finding toxicity assay, bacterial cultures with and without metabolic activation were supplemented with 0 (ethanol solvent control) 0.1, 0.250, 0.5, 0.75, 1.0 and 1.5 mg/plate. Relative to negative controls, the exposures did not increase frequency of base-pair or frame-shift histidine revertants in tested strains, regardless of the presence or absence of metabolic activation.[E I DuPont de NeMours & Co; In Vitro Microbial Mutagenicity Studies of Ortho-Anisidine; 00/00/00; EPA Doc No. 86940000734S; Fiche No. OTS0557144]**UNREVIEWED**
  • o-Anisidine (CAS # 90-04-0, purity unspecified) was evaluated for mutagenicity in cultured TA1535, TA1537, TA1538, TA98, and TA100 strains of Salmonella typhimurium, both in the presence and absence of Aroclor-induced rat liver S-9 metabolic activation. Following range-finding toxicity testing, in two independent assays, bacterial cultures in triplicate with and without metabolic activation were exposed to 0 (DMSO solvent control), 0.025, 0.25, 2.5, 5.0, and 10.0 mg/plate for 36-72 hours. Relative to historical controls (N), exposures did not increase mean frequency of base-pair or frame-shift histidine revertants (E) in any strain regardless of metabolic activation, except in TA-100. In TA-100 cultures, a slight and equivocal dose-related response (E >/= N +/- 3.5SN, but E < 2N and response slope < 0.010 revertants/nM) with apparent toxicity at 5.0 mg/plate prompted repeat study: Metabolically-activated TA-100 cultures exposed to doses of 0, 0.25, 0.50, 1.0, 2.0, and 4.0 mg/plate again failed to meet protocol requirements establishing significant dose-related mutagenicity response. In conclusion, the authors reported a negative result in the Salmonella/Microsome mutagenicity assay as tested.[Eastman Kodak Co; Evaluation of Ortho-Anisidine in the Salmonella Microsome Mutagenicity Assay; 02/28/85; EPA Doc No. 86940000283; Fiche No. OTS0572386]**UNREVIEWED**

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Footnotes

1 Source: the National Library of Medicine's Hazardous Substance Database, 10/28/2007.

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Web page last updated on May 14, 2008