1: Toxicol Rev. 2005;24(3):161-6. Poisoning due to urea herbicides.
Watt BE, Proudfoot AT, Bradberry SM, Vale JA.
Urea herbicides, which act by inhibiting photosynthesis, were introduced in 1952 and are now used as pre- and post-emergence herbicides for general weed control in agricultural and non-agricultural practices. Urea herbicides are generally of low acute toxicity and severe poisoning is only likely following ingestion when nausea, vomiting, diarrhoea and abdominal pain may occur. As urea herbicides are metabolised to aniline derivatives, which are potent oxidants of haemoglobin, methaemoglobinaemia (18-80%) has been documented, as well as haemolysis. Treatment is supportive and symptomatic. Methylthioninium chloride (methylene blue) 1-2mg (the dose depending on the severity of features) should be administered intravenously over 5-10 minutes if there are symptoms consistent with methaemoglobinaemia and/or a methaemoglobin concentration >30%.
2: Ethn Dis. 2005 Autumn;15(4 Suppl 5):S5-81-7.
The hemotoxicity of para-substituted aniline analogs in dog and rat erythrocytes: a species comparison.
Purnell ET, Singh H.
INTRODUCTION: Hemolytic anemia, the early removal of erythrocytes from the circulation, has been recognized as a side effect of drugs and other environmental chemicals. Formation of methemoglobin (MetHb) following chemical

exposure is the first hemotoxic response in the induction of hemolytic anemia. The purpose of this study was to compare the species differences in the chemical induction of MetHb in dog and rat erythrocytes exposed to para-substituted halogenated aniline analogs (phenylhydroxylamine, p-bromo-, p-fluoro-, and p-iodo-phenyhydroxylamine).
METHODS: Whole blood was collected from a healthy, male Dalmatian dog that weighed 51 lbs and male Sprague-Dawley rats that weighed 100-125 g. Cells were washed (x3) with phosphate-buffered saline supplemented with glucose (pH 7.4). Methemoglobin (MetHb) induction was determined by treating aliquots with pre-specified micromoles of the test agents. Aliquots (75microL) were removed from each treatment group at specific time points and mixed with cold hemolysis buffer for MetHb determination. Methemoglobin (MetHb) was determined spectrophotometrically at 635 nm.
RESULTS: Methemoglobin (MetHb) levels in dog erythrocytes treated with the four analogs increased continuously over 180 minutes and showed no signs of declining. Methemoglobin (MetHb) levels in rat erythrocytes, however, immediately increased and continued to rise and fall before gradually approaching control levels.
CONCLUSIONS: Our data demonstrated the species differences in the MetHb-inducing ability of the analogs tested in both dog and rat erythrocytes. The differences in the patterns associated with MetHb induction in the animal models used may be attributed to variations in the MetHb reductase enzyme in both species.<
3: J Environ Pathol Toxicol Oncol. 2005;24(1):67-76.
Hemolytic potential of structurally related aniline halogenated hydroxylamines Singh H, Purnell ET
This study was undertaken to investigate the hemolytic potential of several structurally related aniline halogenated phenylhydroxylamines based on their decreasing electro negativity. The compounds compared are phenylhydroxylamine (PHA) and para-fluoro-, para-bromo-, and para-iodo-phenylhydroxylamines. Red blood cells of male Sprague-Dawley rats were labeled with radioactive chromium-51 and exposed to the test agent before being infused into the tail vein of isologous rats. The time course of blood radioactivity was monitored. The stability of some selected halogenated aniline analogs was also determined in blood. All four tested hydroxylamines produced dose-dependent reduction in the circulating labeled red blood cells indicating their destruction and loss. The most pronounced reduction was observed at doses from 175 to 250 microM. The dose of 100 microM appeared to be the threshold limit. The para-iodo-PHA was two times more toxic than para-fluoro-PHA in the destruction of red blood cells in rats

4: J Environ Pathol Toxicol Oncol. 2005;24(1):57-65.
Aniline derivative-induced methemoglobin in rats.< Singh H, Purnell ET.
Methemoglobinemia and hemolysis are the most prominent side-effects of exposure to a wide variety of arylamine drugs, including agricultural and industrial chemicals. Recent studies with aniline and dapsone have identified N-hydroxyl metabolites as the red blood cell (RBC) mediators. This study examines the time-course methemoglobinemic potential of several halogenated aniline phenylhydroxylamines. Symptoms of aniline poisoning include headache, fatigue, dizziness, respiratory and cardiac arrest, and possibly death. Initial studies indicated that the parent compounds are converted to their toxic metabolites (N-hydroxylamine), which enter the RBC and react with oxyhemoglobin. Our laboratory is investigating the role of redox cycling and an alternative hypothesis--that a \"hydroxylamine-centered\" radical formed during arylhydroxylamine-oxyhemoglobin reaction results in RBC injury.
The methemoglobinemic capacities of several structurally related N-hydroxy derivatives of aniline--phenylhydroxylamine (PHA), p-fluoro-, p-chloro-, p-bromo-, and p-iodo-PHA--were studied spectrophotometri-cally by treating washed rat RBC at concentrations ranging from 30 to 300 microM of the test compounds for up to 240 minutes. The results showed dose- and time-dependent changes in the induction of methemoglobin (MetHb) by aniline derivatives. The MetHb levels peaked to as high as 75% and remained elevated up to 240 minutes, depending on the electronegativity of halogenated phenylhydroxylamine aniline. This study supports the previous findings that there may be several aniline-derived metabolites other than PHA that are capable of inducing MetHb. The minimum dose required to induce this effect and duration of the MetHb may vary with the test agent

5: Toxicol Lett. 1999 Oct 29;110(1-2):57-66. Hemolytic drugs aniline and dapsone induce iron release in erythrocytes and increase the free iron pool in spleen and liver
Ciccoli L, Ferrali M, Rossi V, Signorini C, Alessandrini C, Comporti M
Incubation of rat erythrocytes with the hydroxylated metabolites of aniline and dapsone (4-4\'-diaminodiphenylsulfone), phenylhydroxylamine and dapsone hydroxylamine, respectively, induced marked release of iron and methemoglobin formation. On the contrary, no release of iron nor methemoglobin formation was seen when the erythrocytes were incubated with the parent compounds (aniline and