2,4-dinitrophenol

Endpoint summary

Description of key information

2,4-dinitrophenol (2,4-DNP) as sodium salt can cause effects on human and its metabolism, manifesting by high fever, high temperature, high respiratory rate and death,  after acute, sub-acute and subchronic exposue. In  several clinical cases death occurred after ingestion and severe clinical signs were noted in all systems. In cases where the autopsy was done, also several lesions were found in all organs.

Toxicity on eye is the main reason 2,4-DNP was banned from use for weight control by the Food and Drug Administration.

In a specific study, a metabolite 2-amino-4-nitrophenol was detected by Derrien test.

In addition, also menstrual disorder and issue to reproductive female organs were noted.

Studies on occupational exposure in 1930 revealed toxicity by inhalation, dermal an oral route, with severe effects an deaths. Unfortunately, quantification of the exposure levels in industries haven't been done.

Additional information

A lot of observations on humans are available.

Clinical cases, poisoning incidents and exposure observations are the most important source of information below described.

In four different clinical cases reported, high fever, high temperature, high respiratory rate and death were observed. This increase in respiration is secondary to 2,4-DNP-induced uncoupling of oxidative phosphorylation, leading to elevation of basal metabolic rate and body temperature.

In the first study,Tainter et al., 1934 reported a case of fatal man poisoning of 2,4-dinitrophenol sodium salt. The dose was c.a 46 mg/kg (LOAEL) taken twice in 2 weeks.2,4-DNP appears to be readily absorbed from the respiratory and gastrointestinal tracts. The clinical signs and the autopsy and histological findings were considered by to be similar to those seen in heat stroke. Mild nephrotic changes and slight detachment of liver cells were seen during histopathological examination of tissues.

In the second case of death (Poole FE, Haining RB. 1934) a dose of 7 mg of 2,4-dinitrophenol sodium salt (LOAEL) has been taken for 5 days by a woman. It has been described a comatose condition and subsequently death. Nausea, vomiting, diarrhea, and heartburn were among the gastrointestinal effects. She had headache, backache, weakness, dizziness, shortness of breath, and excessive perspiration, high temperature and respiratory rate.

Symptoms of central nervous toxicity (headache, weakness, extreme fatigue, dizziness, euphoria, irrationality, confusion, stupor) musculoskeletal effects (probably secondary to uncoupling of oxidative phosphorylation or peripheral neuritis) were noted.

Upon autopsy and histological examination were found:

hyperemic and haemorrhagic lungs;

cloudy swelling, pyknosis in the renal tubules, edema in interstitial tissue, distention of capillary and arterial loops in the glomerulus, and haemorrhage: kidney is a target organ in fatal cases due to acute oral exposure;

disintegration of hepatocytes (granular cytoplasm and pyknotic nuclei);

segmentation and fragmentation of cardiac muscles;

hemorrhagic spleen;

edema and hemorrhage in the stomach and disintegration of the glandular mucosa;

histopathological lesions in the brain and spinal cord;

slight ganglion cell degeneration in the pons and medulla.

A report (Masserman JH, Goldsmith H. 1934) that summaries observations of a clinical study on human exposure a dose of 2.66 mg/kg/day of 2,4-DNP sodium salt for 14 day (LOAEL) to a woman psichiatric patient described a comatose condition.

She became became confused, torpid, stuporous, comatose, although there was a beneficial effect on depression. Symptoms of central nervous toxicity (headache, weakness, extreme fatigue, dizziness, euphoria, irrationality, confusion, stupor) have hence been experienced.

The basal metabolic rate increased by 38 %.

For the hepatic effects, a yellow discoloration of the skin and sclerae was observed in 5 patients, but the icteric index was normal in each case.

Because autopsy was delayed for 4 days, no conclusions regarding histopathological lesions could be made, though slight scarring of the tricuspid and mitral valves, hypertrophy of the right ventricle, and small scattered fatty deposits in the aorta (cardiovascular effect).

Ina 22-89 days study were observed different clinical signs in 159 patients at 3 mg/Kg/days of 2,4-DNP sodium salt (Simkins S. 1937a). Increased respiratory rate, bradycardia, decreased blood pressure in former hypertensive patients, diarrhea, vomiting, heartburn, albuminuria, cataract, loss of weight and increase of metabolic rate. In addition, menstrual disorders were noted (LOAEL of 3 mg/kg/day). Only for urticaria the effects were registered at dose of 2.3 mg/Kg/day (LOAEL).

Hemato and hepatic effect at the same dose were not observed (NOAEL of 3 mg/kg/day).

The Lowest published lethal dose LDLo on human is 36 mg/kg, with toxic effects noted as body temperature increasing, changing in cardiac rate and coma were described in another study (JAMAAP JAMA, 1933).

Ina study of Anderson, 1933 a woman patient who took 2.3 mg/kg/day 2,4-DNP for14 days had severe dermatological reactions: severe pruritus, edema, maculopapular eruptions covered the entire body, with the exception of the face and scalp (LOAEL for dermatological effects).

She did not exhibit dyspnea, changes in blood pressure or heart rate during the dosing period, nausea and diarrhea. No hematological effects were found (NOAEL).

The woman patient had a history of chronic hypertrophic arthritis of the cervical spine and knees. She developed pain in her fingers and all large joints after taking the dose (LOAEL of 2.3 mg/kg for neuritis).

Liver function, as assessed by the icteric index (a calorimetric estimation of bilirubin in the serum by comparison with the absorbance of a standard solution of potassium dichromate which is no longer used clinically) (Lichtman 1953) and Van den Bergh test, was not affected. Similarly, the blood non protein nitrogen level was normal. For all these effects, a NOAEL of 2.3 mg/kg/day was set.

Goldman A, Haber M. 1936 observed that a young woman died after had taken a dose of 1.03 mg/Kg/day for 46 days. Elevated respiratory rates, dyspnea, cyanosis, vascular congestion in the lungs and have been reported at 1.03 mg/kg/day (LOAEL). Elevated pulse rate, tachycardia, hyigh body temperature and excessive perspiration were also noted.

At the same dose, necrosis and ulceration of small intestine, severe neutropenia, agranulocytosis, servere fatty changes, hemorrhagic nephritis, extensive vascularization of spleen and pituary, goiter an thyroid were serious symptoms revealed at 1.03 mg/kg/day (LOAEL).

In a metabolic study (Davidson EN, Shapiro M. 1934) the presence of 2-amino-4-nitrophenol (Derrien test) and 2,4-DNP (“indicator test” not further described) was in the urine of a woman who ingested sodium 2,4-DNPat 3.5 mg/kg/day 2,4-DNP for 20 days tested positive (LOAEL) Impaired liver function as measured by a bromsulphalein test was observed and the authors concluded it may be a factor in susceptibility to the hematological effects granulocytosis.

Hitch JM, Schwartz WF reported symptoms of a woman who took a dose of 1.86 mg/kg/day 2,4-DNP.

Slight anemia was found upon hematological analysis at the same dose (LOAEL).

Severe skin lesions were developed, with exfoliating dermatitis over 100% of body surface, redness, edema, oozing of serum, scaling, and crusting were also reported. Furthermore, cataracts developed in patients who were at an age when senile cataracts do not occur. She developed blurred vision which was attributed to bilateral cataracts.

Generally, cataracts developed in a small percentage of patients who took 2,4-DNP or sodium 2,4-DNP as a weight reduction aid for acute, intermediate, and chronic durations. This is the main reason 2,4-DNP was banned from use for weight control by the Food and Drug Administration. The EPA identified a LOAEL for cataracts of 2 mg/kg/day based on a compilation of a case reports of Horner, 1942. As cataracts develop in some humans exposed to 2,4-DNP and can lead to blindness, the appearance of lens opacities can serve as an early warning that more serious cataracts could eventually develop. The author indicated that the progression of cataracts in birds fed 2,4-DNP was “remarkably similar” to that reported in humans exposed to 2,4-DNP (Robbins 1944; Horner 1942).

In humans, however, the cataracts did not regress. Agranulocytosis (a syndrome characterized by marked decrease in the number of granulocytes, lesions of the throat and other mucous membranes, and fever (also called granulocytopenia, malignant neutropenia, agranulocytic angina) was reported in 8 patients treated orally with 2,4-DNP or its sodium salt in capsule. These effects occurred in acute, intermediate, and chronic durations of treatment.

Tainter et al. 1935, described in his study different clinical signs based on different doses at intermediate exposure duration.

Generally, there were no deaths in the number of clinical and experimental studies in which obese or normal subjects were given 2,4-DNP or its sodium salt at oral dosages of 1.2-4.3 mg/kg/day 2,4-DNP for ≤ 14 days.

The MRL for acute-duration oral exposure of 0.01 mg/kg/day was derived from the lowest observed adverse effect level (LOAEL) of 1.2 mg/kg/day identified in 37 humans who took 2,4-DNP for weight reduction for an average of 14 days (U.S Department of health and human services, 1995).

This considered study tested 37 patients. The MRL study were part of a larger clinical trial of sodium 2,4-DNP involving 170 patients who ingested an average of 4.0 mg/kg/day 2,4-DNP for an average of 88 days. These 37 obese patients took sodium 2,4-DNP at 1.2 mg/kg/day 2,4-DNP for an average of 14 days having an average weight loss of 0.43 kg/week. They had not been losing weight at the time treatment began and had been given instructions to continue the same food intake as before treatment. No dermal effects were seen. No symptoms of peripheral neuritis were reported. The threshold for elevation of basal metabolic rate from ingested 2,4-DNP has not been established for humans, but increases appear to start at ≈1-1.2 mg/kg/day, the level at which related effects, such as weight loss, also become apparent.

The overall study involved also a duration of 88 days and dose of 4.0 -4.3 mg/kg/day 2,4-DNP for obese patient. Change in metabolic rate, catarat and skin reaction were observed.

 

Three case reports and a clinical study of women taking 2,4-DNP orally for weight reduction suggest that 2,4-DNP may affect the female reproductive system (Beinhauer 1934; Epstein and Rosenblum 1935; Goldman and Haber 1936; Simkins 1937a, 1937b), but this limited information is inconclusive.

Menstrual disorders in 15-18 women of an unspecified number of women treated with 2,4-dinitrophenol sodium salt (dose not specified) were described in the study of Simkins S. 1937a, 1937b (LOAEL 3 mg/kg/day).

Beinhauer LG. 1934 observed fibroid degeneration of the uterus and cystic left ovary in a woman that took a dose of 2.32 mg/Kg/day for 37 days by capsules(whether or not these were pre-existing conditions is not known)

In a study described (Epstein E, Rosenblum H. 1935) a woman patient took a dose of 3.3 mg/Kg/day of sodiumsalt for143 days. After 98 days from observations the authors concluded the 2,4-DNP caused a premature separation of the placenta, resulting in miscarriage.

In the last study of Goldman A, Haber M. 1936. Data obtained from an observation on human poisoning of 2,4-dinitrophenol revealed that a young woman died after had taken a dose of 1.03 mg/Kg/day for 46 day sand a small and infantile uterus and numerous follicular cysts in the ovary have been found.

 

Exposure in industrial condition some evidences can be summarized.

Von Oettinger in 1949 stated that there had been 27 reported cases of fatal occupational dinitrophenol poisoning in the United States between 1914 and 1916.

2,4-dinitrophenol is considered a solid irritant that causes smarting of skin (CHRIS U.S, Lewis, R.J. Sax's, 1996).

Von Oettingen, W.F., ed. 1949 indicated that the dinitrophenol isomers are readily absorbed from the gastrointestinal tract and through the skin and lungs. It has been stated that there had been 27 reported cases of fatal occupational dinitrophenol poisoning in the United States between 1914 and 1916.

Two studies study on occupational exposure to 2,4-dinitrophenol were reported. Perkins RG. 1919 observed workers exposed to airborne vapour, dust and direct dermal contact, Gisclard JB, Woodward MM. 1946 reported of a poisoning of two workers after occupational exposure to 2,4-dinitrophenol dust in a manufacture in a U.S. chemical plan as intermediate of picric acid. Deaths occurred after occupational exposure in both situations.

In the first study fatal cases were noted especially among alcoholics or workers with renal or hepatic disease. The deaths were preceded by sudden onset of extreme fatigue, elevation of the body temperature to ≥40 °C, and other clinical signs of 2,4-DNP poisoning, such as profuse sweating, thirst, and laboured respiration. No characteristic lesions were found at autopsy. In addition, examination of the blood, unspecified organs, and urine of was done. The method included the detection of the metabolite by the Derrien test in the urine. The compounds found were 2,4-DNP, 2-amino-4-nitrophenol, 4-amino-2-nitrophenol, 2,4-diaminophenol, and other unidentified nitrogen compounds, which may have been glucuronide conjugation products (NRC 1982). Absorption from inhalation exposure was the main route, but dermal absorption was also important. After the distribution to tissues and organs, the excretion occurred by sweat and urine.

The second study revealed signs of metabolic toxicity (fever, profuse sweating, restlessness); following treatment and rest, before collapsing and death. 2-amino-4-nitrophenol was detected in the urine of one worker.

Workroom air levels, determined after the deaths occurred, were “normally” at least 40 mg/m3, but this value may underestimate breathing zone levels. In addition, significant dermal exposure and even oral absorption may have contributed to the total dose.

The warmer weather during the both exposure was thought to be a contributing factor because of the greater skin exposure and potential for increased dermal absorption, and may have exacerbated the effects.