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PARADICHLOROBENZENE

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Paradichlorobenzene is commonly used as an insecticidal fumigant (for domestic use against clothes moths), disinfectant, toilet and diaper pail deodorizer, and chemical intermediate. It should be differentiated from naphthalene, which is also used in these products, but is more toxic.

Specific Substances

    1) 1,4-Dichlorobenzene
    2) Paracide
    3) Paradi
    4) Paradichlorobenzol
    5) Paradon
    6) Paradow
    7) Paramoth
    8) Parazene
    9) PDCB
    10) PDB
    11) Santochlor
    12) CAS 106-46-7
    13) DICHLORICIDE
    14) PARA CRYSTALS
    15) PDB (PARADICHLOROBENZENE)
    16) PDCB (PARADICHLOROBENZENE)
    1.2.1) MOLECULAR FORMULA
    1) C6-H4-Cl2

Available Forms Sources

    A) FORMS
    1) p-Dichlorobenzene exists as volatile crystals with a characteristic penetrating odor: Monoclinic form (alpha modification); triclinic form (beta modification) (Budavari, 1996).
    B) USES
    1) It is used as an insecticidal fumigant (popular for domestic use against clothes moths), disinfectant, toilet and diaper pail deodorizer, and chemical intermediate (Budavari, 1996; Hathaway et al, 1991).

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: Paradichlorobenzene is used as a deodorizer, moth repellant, disinfectant, and fumigant. There are rare reports of chronic paradichlorobenzene abuse, either by inhalation or ingestion.
    B) TOXICOLOGY: Small amounts are converted to epoxide intermediates which are related to halobenzenes which can cause necrosis.
    C) EPIDEMIOLOGY: Common unintentional exposure in children usually does not cause toxicity. According to the American Association of Poison Control Centers, there were no deaths or serious toxicity reported during the 10 year observation period. Intentional misuse (by inhalation or ingestion) and addiction to paradichlorobenzene is rare but has been reported.
    D) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: Most inadvertent ingestions are asymptomatic. Inhalation can cause nausea, headache and vomiting. It can also cause irritation to the eyes and nose.
    2) SEVERE TOXICITY: Hepatotoxicity, hemolytic anemia, and methemoglobinemia have rarely been reported after large ingestions. CNS depression can occur after inhalation of very high concentrations. Chronic exposure can cause hepatotoxicity. In severe cases, cirrhosis, dizziness, headache, facial twitching, vomiting, and weight loss can occur. Chronic abuse has caused leukoencephalopathy characterized by ataxia, dysarthria, weakness, and impaired cognitive abilities.
    0.2.10) GENITOURINARY
    A) Glomerulonephritis was reported in conjunction with an allergic reaction. Tubular and glomerular degeneration were reported in chronic inhalation studies in animals.
    0.2.14) DERMATOLOGIC
    A) P-dichlorobenzene may produce irritation. Hypersensitivity reactions include purpura, hyperpigmentation, and keratotic dermatosis/plaques. Orthodichlorobenzene may produce blistering and hyperpigmentation with prolonged skin contact.
    0.2.20) REPRODUCTIVE
    A) Minimal data are available.
    B) Campbell reported a woman who ingested 1 to 2 air freshener blocks per week during her pregnancy. Her offspring developed no abnormalities.
    0.2.21) CARCINOGENICITY
    A) Carcinogenic in animals; unknown in humans.

Laboratory Monitoring

    A) Abdominal x-rays may be helpful as paradichlorobenzene is densely radiopaque.
    B) With large or symptomatic exposures, monitor a CBC, serum electrolytes, renal function, liver enzymes, bilirubin, methemoglobin concentration, urinalysis and urine output to evaluate for hemolysis or organ toxicity.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Most unintentional ingestions do not cause toxicity, and do not require treatment. GI decontamination is usually not indicated unless a massive ingestion occurs. If the exposure is inhalational, remove the victim from the exposure into fresh air and move to an open environment. Irrigate, if patient has had symptomatic dermal or ocular exposure.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Administer IV fluids and antiemetics for persistent vomiting. Treat symptomatic methemoglobinemia with methylene blue. Patients who develop severe hemolysis may require transfusion.
    C) DECONTAMINATION
    1) PREHOSPITAL: Most patients with unintentional ingestions do not require gastrointestinal decontamination. GI decontamination is not indicated unless large amounts are ingested.
    2) HOSPITAL: Less toxic p-dichlorobenzene has replaced naphthalene as the active ingredient in mothballs. If it is not possible to differentiate a naphthalene compound from p-dichlorobenzene, and the patient is symptomatic, then consider giving activated charcoal (or GI decontamination if a massive ingestion occurs).
    D) ANTIDOTE
    1) No antidote exists for paradichlorobenzene. Symptomatic and supportive care remains the mainstay of treatment.
    E) METHEMOGLOBINEMIA
    1) Initiate oxygen therapy. Treat with methylene blue if patient is symptomatic (usually at methemoglobin concentrations greater than 20% to 30% or at lower concentrations in patients with anemia, underlying pulmonary or cardiovascular disease). METHYLENE BLUE: INITIAL DOSE/ADULT OR CHILD: 1 mg/kg IV over 5 to 30 minutes; a repeat dose of up to 1 mg/kg may be given 1 hour after the first dose if methemoglobin levels remain greater than 30% or if signs and symptoms persist. NOTE: Methylene blue is available as follows: 50 mg/10 mL (5 mg/mL or 0.5% solution) single-dose ampules and 10 mg/1 mL (1% solution) vials. Additional doses may sometimes be required. Improvement is usually noted shortly after administration if diagnosis is correct. Consider other diagnoses or treatment options if no improvement has been observed after several doses. If intravenous access cannot be established, methylene blue may also be given by intraosseous infusion. Methylene blue should not be given by subcutaneous or intrathecal injection. NEONATES: DOSE: 0.3 to 1 mg/kg.
    F) ENHANCED ELIMINATION
    1) There is no experience with hemodialysis, hemoperfusion, or peritoneal dialysis.
    G) PATIENT DISPOSITION
    1) HOME CRITERIA: Patients with unintentional ingestions who are asymptomatic can remain at home.
    2) OBSERVATION CRITERIA: Patients with deliberate overdose, and those who are symptomatic should be referred to a healthcare facility.
    3) ADMISSION CRITERIA: Patients who are persistently symptomatic after large overdoses, despite supportive care may need to be admitted.
    4) CONSULT CRITERIA: If a patient is symptomatic and/or after a large ingestion, consult with a poison center or medical toxicologist.
    H) PITFALLS
    1) Failure to determine whether the ingestion was of naphthalene, paradichlorobenzene or camphor.
    I) PHARMACOKINETICS
    1) Absorbed orally and by inhalation. Typically distributed in adipose tissue. It primarily undergoes hepatic metabolism to sulfate and glucuronic conjugates, which are then excreted in the urine. Small amounts are eliminated by biliary excretion.
    J) DIFFERENTIAL DIAGNOSIS
    1) Camphor, naphthalene.
    0.4.3) INHALATION EXPOSURE
    A) INHALATION: Move patient to fresh air. Monitor for respiratory distress. If cough or difficulty breathing develops, evaluate for respiratory tract irritation, bronchitis, or pneumonitis. Administer oxygen and assist ventilation as required. Treat bronchospasm with an inhaled beta2-adrenergic agonist. Consider systemic corticosteroids in patients with significant bronchospasm.
    0.4.4) EYE EXPOSURE
    A) DECONTAMINATION: Remove contact lenses and irrigate exposed eyes with copious amounts of room temperature 0.9% saline or water for at least 15 minutes. If irritation, pain, swelling, lacrimation, or photophobia persist after 15 minutes of irrigation, the patient should be seen in a healthcare facility.
    0.4.5) DERMAL EXPOSURE
    A) OVERVIEW
    1) DECONTAMINATION: Remove contaminated clothing and jewelry and place them in plastic bags. Wash exposed areas with soap and water for 10 to 15 minutes with gentle sponging to avoid skin breakdown. A physician may need to examine the area if irritation or pain persists (Burgess et al, 1999).

Range Of Toxicity

    A) TOXICITY: INGESTION: Generally up to 5 grams (one mothball) in children and 20 grams in adults are well tolerated. The threshold limit value time weighted average for an 8 hour work day (TLV-TWA) is 10 ppm, 150 ppm is considered immediately dangerous to life and health.

Clinical Effects

Summary Of Exposure

    A) USES: Paradichlorobenzene is used as a deodorizer, moth repellant, disinfectant, and fumigant. There are rare reports of chronic paradichlorobenzene abuse, either by inhalation or ingestion.
    B) TOXICOLOGY: Small amounts are converted to epoxide intermediates which are related to halobenzenes which can cause necrosis.
    C) EPIDEMIOLOGY: Common unintentional exposure in children usually does not cause toxicity. According to the American Association of Poison Control Centers, there were no deaths or serious toxicity reported during the 10 year observation period. Intentional misuse (by inhalation or ingestion) and addiction to paradichlorobenzene is rare but has been reported.
    D) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: Most inadvertent ingestions are asymptomatic. Inhalation can cause nausea, headache and vomiting. It can also cause irritation to the eyes and nose.
    2) SEVERE TOXICITY: Hepatotoxicity, hemolytic anemia, and methemoglobinemia have rarely been reported after large ingestions. CNS depression can occur after inhalation of very high concentrations. Chronic exposure can cause hepatotoxicity. In severe cases, cirrhosis, dizziness, headache, facial twitching, vomiting, and weight loss can occur. Chronic abuse has caused leukoencephalopathy characterized by ataxia, dysarthria, weakness, and impaired cognitive abilities.

Heent

    3.4.3) EYES
    A) SUMMARY: Eye irritation may occur. Cataract formation has been implicated with chronic vapor exposure, but not proven.
    B) IRRITATION: Painful irritation to the eyes may occur at 50 to 160 ppm (Grant & Schuman, 1993; Hollingsworth et al, 1956). Solid particles cause pain but no serious injury after direct contact with the eye (Grant & Schuman, 1993).
    C) CATARACT: Chronic vapor exposure has been implicated in cataract formation in two women, but naphthalene was likely in the material (Berliner, 1939). A follow-up study in 1956 disproved the notion (Hollingsworth et al, 1956a).
    1) LACK OF CONFIRMATION: This cataractogenic potential has not been confirmed by subsequent studies and it is suggested that impurities in the compound may have produced the cataract (Grant & Schuman, 1993). Another study states that no cataracts or any other lens changes in the eyes were attributable to exposure (Hollingsworth et al, 1956a).
    3.4.5) NOSE
    A) SUMMARY: May be irritating at concentrations above 50 to 80 ppm (Hollingsworth et al, 1956).

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) GRANULOMA
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: Pulmonary granulomatosis was seen in a case of p-dichlorobenzene inhalation abuse. A 53-year-old abused p-dichlorobenzene vapors at home for 3 years and developed pulmonary granulomatosis. Lung biopsy showed crystals similar to p-dichlorobenzene (Weller & Crellin, 1953).
    B) DYSPNEA
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: Dyspnea was seen in one case of hypersensitivity. A 69-year-old developed dyspnea after sitting in a p-dichlorobenzene treated chair (Nalbandian & Pearce, 1965).
    3.6.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) PULMONARY EDEMA
    a) Rabbits, rats, and guinea pigs exposed chronically to vapors developed pulmonary edema and hyperemia (Zupko & Edwards, 1949).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) DRUG WITHDRAWAL
    1) WITH POISONING/EXPOSURE
    a) Withdrawal of p-dichlorobenzene in a habituated adult caused tremulousness and sluggishness. Encephalopathy resulted in an adult upon withdrawal. Cerebellar ataxia has been seen after chronic exposure.
    1) CASE REPORT: A 19-year-old who ingested four to five p-dichlorobenzene moth-pellets daily for 2.5 years developed sluggishness and tremulousness upon discontinuation of the pellets (Frank & Cohen, 1961).
    b) CASE REPORT: A 42-year-old woman who had ingested mothballs and toilet-bowl fresheners for at least 2 years developed a mothball withdrawal encephalopathy. She presented with a 4 month history of increasing gait unsteadiness. During a 4 week hospital admission/period of abstinence, she manifested severe bradykinesia, moderate rigidity with prominent torticollis and dysphonic posturing of both hands, and mutism, but retained the intermittent ability to follow simple commands. A urinary organic acid assay revealed 2,5-dichlorophenol (DCP), a p-dichlorobenzene metabolite, more than 2 months after initial hospitalization. After 6 months of abstinence, she was alert, cooperative, and had normal language, naming, immediate recall, and attention, but she developed residual impaired calculation and abstract reasoning abilities (Cheong et al, 2006).
    B) ATAXIA
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: Reversible cerebellar ataxia and speech disturbance have been reported in a chronically exposed individual. A 25-year-old woman with an almost continuous six-year exposure to p-dichlorobenzene developed severe cerebellar ataxia, dysarthria, moderate weakness of all limbs, and hyporeflexia. All symptoms abated 8 months after removal from the source of exposure (Miyai et al, 1988).
    b) CASE REPORT: Reversible unsteady gait, signs of intracranial hypertension, an undefined "cerebellar syndrome" and mental sluggishness were reported in a chronically exposed individual. An 18-year-old woman who had inhaled p-dichlorobenzene mothball fumes daily for 10 minutes for 4 to 6 months and had chewed half a mothball daily for 2 months developed unsteady gait, urinary retention, signs of intracranial hypertension, a cerebellar syndrome, pyramidal signs in all limbs without weakness, mental sluggishness. She had a normal MRI, EEG, and CSF. Symptoms improved after 2 months of abstinence and completely resolved at 6 months. Her twin sister had sniffed mothballs 5 to 19 minutes daily for a few weeks and manifested unsteady gait (Feuillet et al, 2006).
    c) CASE REPORT: A 42-year-old woman who had ingested mothballs and toilet-bowl fresheners for at least 2 years developed a mothball withdrawal encephalopathy. She presented with a 4 month history of increasing gait unsteadiness. During a 4 week hospital admission/period of abstinence, she manifested severe bradykinesia, moderate rigidity with prominent torticollis and dysphonic posturing of both hands, and mutism, but retained the intermittent ability to follow simple commands. A urinary organic acid assay revealed 2,5-dichlorophenol (DCP), a p-dichlorobenzene metabolite, more than 2 months after initial hospitalization. After 6 months of abstinence, she was alert, cooperative, and had normal language, naming, immediate recall, and attention, but developed residual impaired calculation and abstract reasoning abilities (Cheong et al, 2006).
    C) LEUKOENCEPHALOPATHY
    1) WITH POISONING/EXPOSURE
    a) SUMMARY: There have been several case reports of toxic leukoencephalopathy following chronic ingestion of mothballs containing paradichlorobenzene (Weidman et al, 2015; Murray et al, 2010; Hernandez et al, 2010; Kumar et al, 2009; Avila et al, 2006) with one reported fatality (Friedman et al, 2012). In 2 cases, clinical improvement was noted, however, MRI findings were persistent with signs of diffuse leukoencephalopathy (Kumar et al, 2009; Avila et al, 2006).
    b) CASE REPORT: A 44-year-old man with a history of mild mental retardation presented with recent onset of bizarre behavior, weight loss and a flat affect as described by his family members. The patient appeared cachectic and was oriented to person and place only. Findings included hyperreflexia, cogwheel rigidity and an inability to stand without assistance. Multiple diagnostic studies were within normal limits or negative. A MRI showed a signal intensity on T2 and fluid-attenuated inversion recovery images in the subcortical white matter of the anterior temporal lobes. A repeat MRI 1 month later demonstrated confluent, symmetric and bilateral high signal in the periventricular white matter, sparing the subcortical U-fibers. His family reported that he had ingested mothballs for approximately 4 months prior to admission and would frequently "smoke" the mothballs by heating them and inhaling the vapor. The patient gradually made some improvements after 3 months, but was transferred to a skilled nursing facility for further care (Hernandez et al, 2010).
    c) CASE REPORT: A 32-year-old woman had recurrent hospital admissions for neurologic dysfunction which was later confirmed by the patient to be due to a repeated history of mothball sniffing (starting in childhood) that progressed to ingestion of 1 mothball daily for approximately 2 years. Symptoms included an acute onset of dysarthria, ataxia, cognitive decline (including catatonia during one admission). She improved during each hospitalization only to be readmitted with acute neurologic decline. During one admission, she showed evidence of dementia, limb spasticity and the inability to walk unassisted. A plasma PDB level by gas chromatography peaked at 34 mcg/mL. Following the discovery of PDB abuse, an MRI showed diffuse increased T2 signal involving the cerebral white matter (Kumar et al, 2009).
    d) CASE REPORT: A 21-year-old woman with a history of heroin use and severe postpartum depression began ingesting 1 to 2 mothballs (99.9% paradichlorobenzene) each day since the birth of her 7 month-old son. Once admitted she developed ataxia, nystagmus and her depression worsened. Her initial PDCB level was 0.5 mcg/mL and 1 month later was 0.39 mcg/mL (no further testing was done). On day 9, she developed stupor and repetitive jaw clenching, and EEG revealed status epilepticus with independent bilateral temporal lobe epileptiform discharges. MRI imaging done 1 week after admission showed diffuse leukoencephalopathy with predominance in the splenium and periatrial deep white matter. A repeat MRI 2 weeks later, showed an extension into the bilateral parieto-occipital region; the lesions remained 2 months later and were associated with an acute and subacute demyelinating process. Her clinical course was prolonged and she eventually required a gastrostomy tube and developed global disuse atrophy. She did have some mental status improvement with little change to her MRI findings (Avila et al, 2006).
    e) CASE REPORT: A 31-year-old woman was admitted with presumed severe depression presenting as almost complete withdrawal, becoming bed bound and incontinent and refusal to eat or drink. She had a flat affect, with severe limitations in judgment and attention. A trial of SSRIs did not improve her clinical condition. According to her family, she was noted to have started ingesting mothballs following a recent job loss. A MRI showed extensive periventricular white matter disease and an EEG was consistent with encephalopathy. She was eventually transferred to a skilled nursing facility unable to walk and minimally verbal. At 6 months, she was able to transfer from a wheelchair to a walker and was more verbal. At 9 months, the patient continued to struggle with residual impulsiveness and mood lability (Murray et al, 2010).
    f) CASE REPORT: A woman with a history of diabetes, kidney disease and chronic pruritus developed intense itching and ichtyosifom scaling over her extremities along with hyperpigmentation of her face, trunk and thighs. During her hospitalization, she was observed ingesting mothballs. She had a serum PDB level of 2.3 mcg/mL. On day 2, she developed hypotension and somnolence along with respiratory insufficiency requiring mechanical ventilation. A MRI showed increased signal intensity in the bilateral periventricular and deep white matter. She was transferred to hospice after she failed to regain consciousness and died of multi-organ failure (Friedman et al, 2012).
    g) CASE REPORT: A 19-year-old woman, 4 weeks postpartum, presented with a 2-week history of gradual mental status deterioration, lethargy, and general weakness. She was alert but unable to communicate or follow commands. Physical examination revealed a cachectic and tachycardic woman with an unusual body odor, large hyperkeratotic hyperpigmented plaques on her neck, trunk, axillae, and extremities, ataxia, hyporeflexia, cogwheel rigidity, and reduced muscle tone of all extremities. All laboratory results were normal, except for normocytic anemia (hemoglobin, 10.7 g/dL). An EEG revealed generalized slowness compatible with encephalopathy. T2 prolongation and restricted diffusion of posterior periventricular white matter and splenium of corpus callosum were observed on a brain magnetic resonance imaging scan, which suggested leukoencephalopathy. Biopsy of her skin showed papillomatosis with hyperkeratosis. All other causes, including postpartum depression, psychosis, and panhypopituitarism, were excluded. At this time, it was revealed that the patient had been chronically sniffing "toilet cake" (a toilet bowl deodorizer containing paradichlorobenzene). A urinalysis revealed a 2,5-dichlorophenol (a paradichlorobenene metabolite) concentration of 620 mg/L (3100 times higher than the average concentration with household exposure). Despite supportive care, her symptoms did not improve during the 30-day hospitalization. She was transferred to a long-term facility and a complete recovery of skin lesions and a partial recovery of aphasia, ataxia, and ambulatory function were observed on a 6-month follow-up (Zhang & Moreno, 2014).
    D) HEADACHE
    1) WITH POISONING/EXPOSURE
    a) Individuals exposed to p-dichlorobenzene have developed headache, weakness, and twitching of the facial muscles (ACGIH, 1991).
    E) NEUROPATHY
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: A 54-year-old woman had a history of mothball abuse (daily sniffing or ingestion) since her teens, as well as hemodialysis-dependent renal failure, insulin dependent diabetes mellitus, hypertension and congestive heart failure. She presented with a 3 week history of upper (3/5) and lower (2/5) extremity weakness that significantly improved after cessation of mothball exposure. It is likely that she was exposed chronically to both p-dichlorobenzene and naphthalene (Weintraub et al, 2000).
    F) NEUROLOGICAL FINDING
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: An 18-year-old girl developed an unsteady gait, urinary retention, evidence of intracranial hypertension, a cerebellar syndrome, pyramidal signs in all extremities without weakness and mental sluggishness after inhaling mothball fumes (also known as "bagging") 10 minutes daily over a 4- to 6-month period. She had also been chewing one-half of a mothball daily for 2 months. Cerebral and spinal MRI, an EEG and cerebrospinal fluid analysis were all normal. Laboratory analysis of her serum and urine revealed the presence of paradichlorobenzene (PDB) and 2,5-dichlorophenol (a metabolite of p-dichlorobenzene), respectively. The patient completely recovered within 6 months after cessation of mothball exposure (Feuillet et al, 2006).
    G) MULTIPLE SCLEROSIS
    1) WITH POISONING/EXPOSURE
    a) CHRONIC INGESTION: A woman in her late 30s developed relapsing-remitting multiple sclerosis after the chronic ingestion of toilet bowl deodorizing cakes (99.9% paradichlorobenzene) for more than 5 years of regular use. Her blood paradichlorobenzene concentrations were elevated on several hospital admissions. Despite long-term treatment with natalizumab, she continued to have neurological disability, cognitive decline, visual symptoms, left leg weakness, fatigue, gait instability, and an ichthyosiform skin rash. After the analysis of several MRI results, it was concluded that her symptoms were due to leukoencephalopathy as a result of long-term paradichlorobenzene exposure (Hession et al, 2014).
    3.7.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) TREMOR
    a) Mice given lethal doses developed tremors (Pielmeier, 1976).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) NAUSEA AND VOMITING
    1) WITH POISONING/EXPOSURE
    a) Nausea and vomiting may occur after ingestion.
    B) DIARRHEA
    1) WITH POISONING/EXPOSURE
    a) Diarrhea may occur after ingestion.

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) TOXIC HEPATITIS
    1) WITH POISONING/EXPOSURE
    a) Five cases of presumed p-dichlorobenzene-induced hepatitis have been reported.
    1) CASE REPORT: A 31-year-old developed toxic hepatitis and esophageal varices after working for 2 years selling mothballs and insecticides containing p-dichlorobenzene (Summers et al, 1952).
    2) CASE REPORT: A 3-year-old developed jaundice after ingesting an unknown amount of p-dichlorobenzene crystals (Hallowell, 1959).
    3) CASE SERIES: Four cases of "acute yellow atrophy" in patients exposed to p-dichlorobenzene were reported by Cotter (1953).

Genitourinary

    3.10.1) SUMMARY
    A) Glomerulonephritis was reported in conjunction with an allergic reaction. Tubular and glomerular degeneration were reported in chronic inhalation studies in animals.
    3.10.2) CLINICAL EFFECTS
    A) GLOMERULONEPHRITIS
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: Glomerulonephritis was seen after a dermal exposure to p-dichlorobenzene. A 69-year-old developed an allergic reaction, after sitting in a p-dichlorobenzene treated chair. Allergic purpura occurred two days later, and was followed by glomerulonephritis (Nalbandian & Pearce, 1965).
    3.10.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) RENAL TUBULAR DISORDER
    a) Chronic inhalation in rabbits, rats, and guinea pigs showed tubular and glomerular degeneration (Zupko & Edward, 1949).

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) METHEMOGLOBINEMIA
    1) WITH POISONING/EXPOSURE
    a) Methemoglobinemia and hemolysis were seen in one pediatric case.
    1) CASE REPORT: A 3-year-old boy developed hemolysis and methemoglobinemia four days after ingestion of an unknown amount of p-dichlorobenzene crystals. P-dichlorobenzene metabolites were found in the urine. It was not specified if naphthalene metabolites were also screened (Hallowell, 1959).
    B) ANEMIA
    1) WITH POISONING/EXPOSURE
    a) SUMMARY
    1) Both aplastic anemia and hypochromic, microcytic anemia have been reported after chronic exposure. Naphthalene was also present in the case of aplastic anemia.
    b) ANEMIA APLASTIC
    1) CASE REPORT: For 39 years it was a 68-year-old woman's job was to mothproof all winter stock at the beginning of winter. The mothballs were p-dichlorobenzene contaminated with naphthalene. She developed aplastic anemia during one particularly warm summer, and it was suggested the mothballs may have been causative (Harden & Baetjer, 1978).
    c) ANEMIA HYPOCHROMIC
    1) CASE REPORT: A 21-year-old with pica consumed one to two toilet air freshener blocks per week during pregnancy and developed anemia unresponsive to iron. Her symptoms cleared upon withdrawal (Campbell & Davidson, 1970).
    2) CASE REPORT: Anemia and lymphoneutropenia were reported in an 18-year-old girl who had been inhaling mothball fumes (also known as "bagging") 10 minutes daily for a 4- to 6-month period. She had also been chewing one-half of a mothball daily for 2 months. Paradichlorobenzene and 2,5-dichlorophenol (a metabolite of paradichlorobenzene) were detected in the patient's serum and urine, respectively (Feuillet et al, 2006).
    C) HEMOLYTIC ANEMIA
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: A 19-month-old child with a history of sickle cell trait and asthma ingested an unknown amount of paradichlorobenzene mothballs and was initially asymptomatic. However, 3 days after exposure the child was icteric with a hemoglobin of 6.4 g/dL, a methemoglobin level of 2.5%, an elevated white count and a total bilirubin concentration of 12 mg/dL. Following a transfusion of 150 mL of packed red blood cells, the patient improved quickly with a hemoglobin of 8.4 mg/dL (Sillery et al, 2009).
    D) NEUTROPENIA
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: Anemia and lymphoneutropenia were reported in an 18-year-old girl who had been inhaling mothball fumes (also known as "bagging") 10 minutes daily for a 4- to 6-month period. She had also been chewing one-half of a mothball daily for 2 months. Paradichlorobenzene and 2,5-dichlorophenol (a metabolite of paradichlorobenzene) were detected in the patient's serum and urine, respectively (Feuillet et al, 2006).
    E) LACK OF EFFECT
    1) CASE SERIES: No hematologic effect was noted in 58 workers with inhalational exposure to 10 to 725 ppm for an average of 4.8 years (Hollingsworth et al, 1956).
    2) CASE SERIES: Following inhalation exposure of 58 workers to 10 to 725 ppm p-dichlorobenzene for an average of 4.8 years there were no abnormal hematologic effects observed (Hollingsworth, 1956).
    3.13.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) LEUKOPENIA
    a) Chronic vapor exposure in rats, rabbits, and guinea pigs produced reversible granulocytopenia (Zupko & Edwards, 1949).

Dermatologic

    3.14.1) SUMMARY
    A) P-dichlorobenzene may produce irritation. Hypersensitivity reactions include purpura, hyperpigmentation, and keratotic dermatosis/plaques. Orthodichlorobenzene may produce blistering and hyperpigmentation with prolonged skin contact.
    3.14.2) CLINICAL EFFECTS
    A) PURPURA
    1) WITH POISONING/EXPOSURE
    a) Purpura and increased pigmentation have been reported days after a dermal contact to p-dichlorobenzene.
    1) CASE REPORT: A 69-year-old developed purpura two days after dermal exposure to a chair that had been treated with p-dichlorobenzene (Nalbandian & Pearce, 1965).
    B) DISCOLORATION OF SKIN
    1) WITH POISONING/EXPOSURE
    a) Hyperpigmentation has been seen with both ortho and para-dichlorobenzene (Frank & Cohen, 1961).
    1) CASE REPORT: A 69-year-old developed increased pigmentation two days after dermal exposure to a chair that had been treated with p-dichlorobenzene (Nalbandian & Pearce, 1965).
    2) O-dichlorobenzene may produce hyperpigmentation if left on the skin (Hollingsworth et al, 1956).
    C) SKIN IRRITATION
    1) WITH POISONING/EXPOSURE
    a) P-dichlorobenzene may slightly irritate the skin with prolonged contact (Hathaway et al, 1991), o-dichlorobenzene may produce blistering if left on the skin (Hollingsworth et al, 1956).
    D) ERUPTION
    1) WITH POISONING/EXPOSURE
    a) CASE REPORTS: An ichthyosis-like dermatosis, involving the lower extremities, elbows, and hands bilaterally, was reported in 18-year-old twin girls, who had been inhaling mothball fumes (also known as "bagging") for 5 to 10 minutes daily over a period of several weeks to several months. One of the patients had also been chewing one-half of a mothball daily for 2 months. In that patient, paradichlorobenzene (PDB) and 2,5-dichlorophenol ( a metabolite of PDB) were detected in her serum and urine, respectively. Both patients completely recovered within 6 months after cessation of mothball exposure (Feuillet et al, 2006).
    b) CASE REPORT: A woman with a history of diabetes, kidney disease and chronic pruritus developed intense itching and ichtyosifom scaling over her extremities along with hyperpigmentation of her face, trunk and thighs. During her hospitalization, she was observed ingesting mothballs. She had a serum PDB level of 2.3 mcg/mL. On day 2, she developed hypotension and somnolence along with respiratory insufficiency requiring mechanical ventilation. A MRI showed increased signal intensity in the bilateral periventricular and deep white matter. She was transferred to hospice after she failed to regain consciousness and died of multi-organ failure (Friedman et al, 2012).
    E) PAPILLOMATOSIS
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: A 19-year-old woman who was chronically sniffing "toilet cake" (a toilet bowl deodorizer containing paradichlorobenzene) developed leukoencephalopathy. Physical examination revealed a large hyperkeratotic hyperpigmented plaques on her neck, trunk, axillae, and extremities. Biopsy of her skin showed papillomatosis with hyperkeratosis. Despite supportive care, her symptoms did not improve during the 30-day hospitalization. She was transferred to a long-term facility and a complete recovery of skin lesions and a partial recovery of her neurological symptoms were observed on a 6-month follow-up (Zhang & Moreno, 2014).

Musculoskeletal

    3.15.2) CLINICAL EFFECTS
    A) METHEMOGLOBINEMIA
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: A 19-month-old child ingested an unknown amount of paradichlorobenzene mothballs with a history of sickle cell trait and asthma and was initially asymptomatic. However, 3 days after exposure the child was icteric with a Hgb of 6.4 g/dL, a methemoglobin level of 2.5%, an elevated white count and a total bilirubin concentration of 12.0 mg/dL. Following a transfusion of 150 mL of packed red blood cells the patient improved quickly with a hemoglobin of 8.4 mg/dL (Sillery et al, 2009).

Reproductive

    3.20.1) SUMMARY
    A) Minimal data are available.
    B) Campbell reported a woman who ingested 1 to 2 air freshener blocks per week during her pregnancy. Her offspring developed no abnormalities.
    3.20.2) TERATOGENICITY
    A) LACK OF INFORMATION
    1) Little data are available for humans.
    B) ANIMAL STUDIES
    1) Studies in rats and rabbits show no evidence for teratogenic or embryotoxic potential following inhalation of up to 800 ppm (Hayes et al, 1985).
    3.20.3) EFFECTS IN PREGNANCY
    A) LACK OF EFFECT
    1) CASE REPORT - A woman ingested 1 to 2 air freshener blocks per week during her pregnancy. Her offspring developed no abnormalities (Campbell & Davidson, 1970).

Carcinogenicity

    3.21.1) IARC CATEGORY
    A) IARC Carcinogenicity Ratings for CAS106-46-7 (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004):
    1) IARC Classification
    a) Listed as: para-Dichlorobenzene
    b) Carcinogen Rating: 2B
    1) The agent (mixture) is possibly carcinogenic to humans. The exposure circumstance entails exposures that are possibly carcinogenic to humans. This category is used for agents, mixtures and exposure circumstances for which there is limited evidence of carcinogenicity in humans and less than sufficient evidence of carcinogenicity in experimental animals. It may also be used when there is inadequate evidence of carcinogenicity in humans but there is sufficient evidence of carcinogenicity in experimental animals. In some instances, an agent, mixture or exposure circumstance for which there is inadequate evidence of carcinogenicity in humans but limited evidence of carcinogenicity in experimental animals together with supporting evidence from other relevant data may be placed in this group.
    3.21.2) SUMMARY/HUMAN
    A) Carcinogenic in animals; unknown in humans.
    3.21.3) HUMAN STUDIES
    A) CARCINOMA
    1) Carcinogenic in animals; unknown in humans.
    2) P-dichlorobenzene is a ubiquitous contaminant of the general environment and may be carcinogenic (Yoshida et al, 2002).

Genotoxicity

    A) At the time of this review, no data were available to assess the mutagenic or genotoxic potential of this agent.

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Abdominal x-rays may be helpful as paradichlorobenzene is densely radiopaque.
    B) With large or symptomatic exposures, monitor a CBC, serum electrolytes, renal function, liver enzymes, bilirubin, methemoglobin concentration, urinalysis and urine output to evaluate for hemolysis or organ toxicity.
    4.1.2) SERUM/BLOOD
    A) HEMATOLOGIC
    1) For significant exposures, follow complete blood count for evidence of hemolysis, granulocytopenia, or anemia, although these are rare.
    B) CHEMISTRY
    1) Monitor liver enzymes in symptomatic patients.
    4.1.3) URINE
    A) URINARY LEVELS
    1) The metabolite 2,5-dichlorophenol has served as an index of exposure in PDB workers and not necessarily toxicity. P-dichlorobenzene is a ubiquitous contaminant in the general environment (Yoshida et al, 2002; Proctor & Hughes, 1978).

Methods

    A) OTHER
    1) DIFFERENTIATING BETWEEN PARADICHLOROBENZE AND NAPHTHALENE
    a) SUMMARY: Differentiation is difficult because both are white crystalline solids at room temperature and have similar odors.
    b) PHYSICAL APPEARANCE: Naphthalene is dry while PDB looks wet and oily (Peterson WH & Liner MH, 1975).
    c) SOLUBILITY: PDB is more soluble in turpentine than naphthalene. A mothball of PDB will usually dissolve within 30 to 60 minutes whereas about 0.25 of the naphthalene mothball will be left (Winkler et al, 1985).
    d) HEAT: PDB reacts with copper wire in a Bunsen burner flame to produce a bright green flame; Naphthalene does not.
    e) MELTING POINT: PDB = 53 degrees C; NAPHTHALENE = 80 degrees C (Ambre et al, 1986). Placing a small piece of the mothball in a test tube heated to 60 degrees C in water bath may simplify the melting point test. PDB will liquefy within several minutes; naphthalene will remain intact (Reeves & Pendarus, 1986).
    f) CHEMICAL TEST: If chloroform and ammonium chloride anhydrous powder are added to PDB no color change occurs; naphthalene turns intensely blue.
    g) SPECIFIC GRAVITY: A method to distinguish camphor, naphthalene and PDB mothballs involves testing whether they float or sink in a saturated solution of salt water (4 ounces of tepid water to which 3 heaping tablespoons of table salt has been added and stirred vigorously until the salt will not dissolve any more) (Fukuda et al, 1991; Koyama et al, 1991).
    1) CAMPHOR mothballs: Float in both water and salt solution.
    a) NAPHTHALENE mothballs: Sink in water but float in saturated salt solution.
    b) PDB mothballs: Sink in both water and salt solution.
    c) STUDY: The above method successfully and rapidly distinguished 10 cases of naphthalene mothball ingestion from 638 cases of PDB mothball ingestion when callers (mostly housewives) were instructed on its performance over the phone by poison center personnel (Koyama et al, 1991).
    d) Composition of mothballs was later confirmed by gas chromatography.
    2) Paradichlorobenzene: Mean specific gravity: 1.433 +/- 0.034 (Fukuda et al, 1991)
    a) Range of specific gravity: 1.429 to 1.437 (p=0.99) (Fukuda et al, 1991).
    3) Naphthalene: Mean specific gravity: 1.097 +/- 0.012 (Fukuda et al, 1991)
    a) Range of specific gravity: 1.094 to 1.100 (p=0.99) (Fukuda et al, 1991)
    h) RADIOPACITY: Paradichlorobenzene is radiopaque under in vitro conditions. Naphthalene is radiolucent under in vitro conditions (Woolf et al, 1993).
    B) MRI
    1) LEUKOENCEPHALOPATHY
    a) CASE REPORT: A 44-year-old man with a history of mild mental retardation presented with recent onset of bizarre behavior, weight loss and a flat affect as described by his family members. The patient appeared cachectic and was oriented to person and place only. Findings included hyperreflexia, cogwheel rigidity and an inability to stand without assistance. Multiple diagnostic studies were within normal limits or negative. A MRI showed a signal intensity on T2 and fluid-attenuated inversion recovery images in the subcortical white matter of the anterior temporal lobes. A repeat MRI 1 month later demonstrated confluent, symmetric and bilateral high signal in the periventricular white matter, sparing the subcortical U-fibers. His family reported that he had ingested mothballs for approximately 4 months prior to admission and would frequently "smoke" the mothballs by heating them and inhaling the vapor. The patient gradually made some improvements after 3 months, but was transferred to a skilled nursing facility for further care (Hernandez et al, 2010).
    b) CASE REPORT: A 32-year-old woman had recurrent hospital admissions for neurologic dysfunction which was later confirmed by the patient to be due to a repeated history of mothball sniffing (starting in childhood) that progressed to ingestion of 1 mothball daily for approximately 2 years. Symptoms included an acute onset of dysarthria, ataxia, cognitive decline (including catatonia during one admission). She improved during each hospitalization only to be readmitted with acute neurologic decline. During one admission, she showed evidence of dementia, limb spasticity and the inability to walk unassisted. A plasma PDB level by gas chromatography peaked at 34 mcg/mL. Following the discovery of PDB abuse, an MRI showed diffuse increased T2 signal involving the cerebral white matter (Kumar et al, 2009).
    c) CASE REPORT: A 21-year-old woman with a history of heroin use and severe postpartum depression began ingesting 1 to 2 mothballs (99.9% paradichlorobenzene) each day since the birth of her 7 month-old son. Once admitted she developed ataxia, nystagmus and her depression worsened. Her initial PDCB level was 0.5 mcg/mL and 1 month later was 0.39 mcg/mL (no further testing was done). On day 9, she developed stupor and repetitive jaw clenching, and EEG revealed status epilepticus with independent bilateral temporal lobe epileptiform discharges. MRI imaging done 1 week after admission showed diffuse leukoencephalopathy with predominance in the splenium and periatrial deep white matter. A repeat MRI 2 weeks later, showed an extension into the bilateral parieto-occipital region; the lesions remained 2 months later and were associated with an acute and subacute demyelinating process. Her clinical course was prolonged and she eventually required a gastrostomy tube and developed global disuse atrophy. She did have some mental status improvement with little change to her MRI findings (Avila et al, 2006).
    d) CASE REPORT: MRI findings of a patient with rapidly progressive leukoencephalopathy, due to paradichlorobenzene mothball inhalation and ingestion, showed neuronal loss and inflammatory cell infiltration (Weidman et al, 2015).

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.1) DISPOSITION/ORAL EXPOSURE
    6.3.1.1) ADMISSION CRITERIA/ORAL
    A) Patients who are persistently symptomatic after large overdoses, despite supportive care may need to be admitted.
    6.3.1.2) HOME CRITERIA/ORAL
    A) Patients with unintentional ingestions who are asymptomatic can remain at home.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) If a patient is symptomatic and/or after a large ingestion, consult with a poison center or medical toxicologist.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) Patients with deliberate overdose, and those who are symptomatic should be referred to a healthcare facility.

Monitoring

    A) Abdominal x-rays may be helpful as paradichlorobenzene is densely radiopaque.
    B) With large or symptomatic exposures, monitor a CBC, serum electrolytes, renal function, liver enzymes, bilirubin, methemoglobin concentration, urinalysis and urine output to evaluate for hemolysis or organ toxicity.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) SUMMARY
    1) Most patients with unintentional ingestions do not require gastrointestinal decontamination. GI decontamination is not indicated unless large amounts are ingested.
    2) Adults have tolerated ingestions of up to 20 grams without serious sequelae. In one case report, a child ingested 5 grams and did well.
    3) Ingestion of p-dichlorobenzene causes nausea and vomiting which may result in self-decontamination. In addition, unintentional exposures do not cause life-threatening toxicity.
    4) Less toxic p-dichlorobenzene has replaced naphthalene as the active ingredient in mothballs. If one is unable to differentiate a naphthalene compound from p-dichlorobenzene, and if the patient is symptomatic, then consider giving activated charcoal.
    B) ACTIVATED CHARCOAL
    1) Activated charcoal, although not studied for PCDB, may be reasonable for large, intentional ingestions.
    2) PREHOSPITAL ACTIVATED CHARCOAL ADMINISTRATION
    a) Consider prehospital administration of activated charcoal as an aqueous slurry in patients with a potentially toxic ingestion who are awake and able to protect their airway. Activated charcoal is most effective when administered within one hour of ingestion. Administration in the prehospital setting has the potential to significantly decrease the time from toxin ingestion to activated charcoal administration, although it has not been shown to affect outcome (Alaspaa et al, 2005; Thakore & Murphy, 2002; Spiller & Rogers, 2002).
    1) In patients who are at risk for the abrupt onset of seizures or mental status depression, activated charcoal should not be administered in the prehospital setting, due to the risk of aspiration in the event of spontaneous emesis.
    2) The addition of flavoring agents (cola drinks, chocolate milk, cherry syrup) to activated charcoal improves the palatability for children and may facilitate successful administration (Guenther Skokan et al, 2001; Dagnone et al, 2002).
    3) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.2) PREVENTION OF ABSORPTION
    A) SUMMARY
    1) Most patients with unintentional ingestions do not require gastrointestinal decontamination. GI decontamination is not indicated unless large amounts are ingested.
    B) ACTIVATED CHARCOAL
    1) Activated charcoal, although not studied for PCDB, may be reasonable for large, intentional ingestions.
    2) CHARCOAL ADMINISTRATION
    a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.
    3) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.3) TREATMENT
    A) SUPPORT
    1) There is no antidote. Treatment is symptomatic and supportive.
    2) Fatty foods, oils, and milk should be withheld for at least for two hours post ingestion to minimize absorption. It has been shown in dogs that milk or fatty meat administered after oral p-dichlorobenzene greatly enhances toxic effect (Pielmeier, 1976).
    B) MONITORING OF PATIENT
    1) Abdominal x-ray may be helpful, as paradichlorobenzene is densely radiopaque.
    2) With large or symptomatic exposures, monitor CBC, serum electrolytes, renal function, liver enzymes, bilirubin, methemoglobin concentration, urinalysis and urine output to evaluate for hemolysis or organ toxicity.
    C) METHEMOGLOBINEMIA
    1) SUMMARY
    a) Determine the methemoglobin concentration and evaluate the patient for clinical effects of methemoglobinemia (ie, dyspnea, headache, fatigue, CNS depression, tachycardia, metabolic acidosis). Treat patients with symptomatic methemoglobinemia with methylene blue (this usually occurs at methemoglobin concentrations above 20% to 30%, but may occur at lower methemoglobin concentrations in patients with anemia, or underlying pulmonary or cardiovascular disorders). Administer oxygen while preparing for methylene blue therapy.
    2) METHYLENE BLUE
    a) INITIAL DOSE/ADULT OR CHILD: 1 mg/kg IV over 5 to 30 minutes; a repeat dose of up to 1 mg/kg may be given 1 hour after the first dose if methemoglobin levels remain greater than 30% or if signs and symptoms persist. NOTE: Methylene blue is available as follows: 50 mg/10 mL (5 mg/mL or 0.5% solution) single-dose ampules (Prod Info PROVAYBLUE(TM) intravenous injection, 2016) and 10 mg/1 mL (1% solution) vials (Prod Info methylene blue 1% intravenous injection, 2011). REPEAT DOSES: Additional doses may be required, especially for substances with prolonged absorption, slow elimination, or those that form metabolites that produce methemoglobin. NOTE: Large doses of methylene blue may cause methemoglobinemia or hemolysis (Howland, 2006). Improvement is usually noted shortly after administration if diagnosis is correct. Consider other diagnoses or treatment options if no improvement has been observed after several doses. If intravenous access cannot be established, methylene blue may also be given by intraosseous infusion. Methylene blue should not be given by subcutaneous or intrathecal injection (Prod Info methylene blue 1% intravenous injection, 2011; Herman et al, 1999). NEONATES: DOSE: 0.3 to 1 mg/kg (Hjelt et al, 1995).
    b) CONTRAINDICATIONS: G-6-PD deficiency (methylene blue may cause hemolysis), known hypersensitivity to methylene blue, methemoglobin reductase deficiency (Shepherd & Keyes, 2004)
    c) FAILURE: Failure of methylene blue therapy suggests: inadequate dose of methylene blue, inadequate decontamination, NADPH dependent methemoglobin reductase deficiency, hemoglobin M disease, sulfhemoglobinemia, or G-6-PD deficiency. Methylene blue is reduced by methemoglobin reductase and nicotinamide adenosine dinucleotide phosphate (NADPH) to leukomethylene blue. This in turn reduces methemoglobin. Red blood cells of patients with G-6-PD deficiency do not produce enough NADPH to convert methylene blue to leukomethylene blue (do Nascimento et al, 2008).
    d) DRUG INTERACTION: Concomitant use of methylene blue with serotonergic drugs, including serotonin reuptake inhibitors (SRIs), selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), norepinephrine-dopamine reuptake inhibitors (NDRIs), triptans, and ergot alkaloids may increase the risk of potentially fatal serotonin syndrome (U.S. Food and Drug Administration, 2011; Stanford et al, 2010; Prod Info methylene blue 1% IV injection, 2011).
    3) TOLUIDINE BLUE OR TOLONIUM CHLORIDE (GERMANY)
    a) DOSE: 2 to 4 mg/kg intravenously over 5 minutes. Dose may be repeated in 30 minutes (Nemec, 2011; Lindenmann et al, 2006; Kiese et al, 1972).
    b) SIDE EFFECTS: Hypotension with rapid intravenous administration. Vomiting, diarrhea, excessive sweating, hypotension, dysrhythmias, hemolysis, agranulocytosis and acute renal insufficiency after overdose (Dunipace et al, 1992; Hix & Wilson, 1987; Winek et al, 1969; Teunis et al, 1970; Marquez & Todd, 1959).
    c) CONTRAINDICATIONS: G-6-PD deficiency; may cause hemolysis.

Inhalation Exposure

    6.7.1) DECONTAMINATION
    A) Move patient from the toxic environment to fresh air. Monitor for respiratory distress. If cough or difficulty in breathing develops, evaluate for hypoxia, respiratory tract irritation, bronchitis, or pneumonitis.
    B) OBSERVATION: Carefully observe patients with inhalation exposure for the development of any systemic signs or symptoms and administer symptomatic treatment as necessary.
    C) INITIAL TREATMENT: Administer 100% humidified supplemental oxygen, perform endotracheal intubation and provide assisted ventilation as required. Administer inhaled beta-2 adrenergic agonists, if bronchospasm develops. Consider systemic corticosteroids in patients with significant bronchospasm (National Heart,Lung,and Blood Institute, 2007). Exposed skin and eyes should be flushed with copious amounts of water.

Eye Exposure

    6.8.1) DECONTAMINATION
    A) EYE IRRIGATION, ROUTINE: Remove contact lenses and irrigate exposed eyes with copious amounts of room temperature 0.9% saline or water for at least 15 minutes. If irritation, pain, swelling, lacrimation, or photophobia persist after 15 minutes of irrigation, an ophthalmologic examination should be performed (Peate, 2007; Naradzay & Barish, 2006).

Dermal Exposure

    6.9.1) DECONTAMINATION
    A) DERMAL DECONTAMINATION
    1) DECONTAMINATION: Remove contaminated clothing and wash exposed area thoroughly with soap and water for 10 to 15 minutes. A physician may need to examine the area if irritation or pain persists (Burgess et al, 1999).

Enhanced Elimination

    A) SUMMARY
    1) There is no experience with hemodialysis, hemoperfusion, or peritoneal dialysis.

Abstracts

Case Reports

    A) PEDIATRIC
    1) METHEMOGLOBINEMIA: In the only case report of acute oral toxicity, a 3-year-old boy after playing with an unknown amount of p-dichlorobenzene crystals developed jaundice, methemoglobinemia, and hemolysis 4 days later. Presumptive evidence included the finding of p-dichlorobenzene metabolites in the urine. It was not specified if naphthalene metabolites were screened for as well (Hallowell, 1959).

Range Of Toxicity

Summary

    A) TOXICITY: INGESTION: Generally up to 5 grams (one mothball) in children and 20 grams in adults are well tolerated. The threshold limit value time weighted average for an 8 hour work day (TLV-TWA) is 10 ppm, 150 ppm is considered immediately dangerous to life and health.

Maximum Tolerated Exposure

    A) Inhalation of 50 ppm or greater may cause irritation to eyes, throat, and skin.
    B) Toxic oral dose is unknown. Unintentional ingestions of up to 5 grams (or one mothball) in children and up to 20 grams in adults are generally well tolerated (Galbo, 2007).
    C) ANIMAL DATA
    1) NON-TOXIC EFFECT: Dogs given 1.5 grams/kilogram of PDB did not develop toxic effects (Sollman, 1919).

Workplace Standards

    A) ACGIH TLV Values for CAS106-46-7 (American Conference of Governmental Industrial Hygienists, 2010):
    1) Editor's Note: The listed values are recommendations or guidelines developed by ACGIH(R) to assist in the control of health hazards. They should only be used, interpreted and applied by individuals trained in industrial hygiene. Before applying these values, it is imperative to read the introduction to each section in the current TLVs(R) and BEI(R) Book and become familiar with the constraints and limitations to their use. Always consult the Documentation of the TLVs(R) and BEIs(R) before applying these recommendations and guidelines.
    a) Adopted Value
    1) p-Dichlorobenzene
    a) TLV:
    1) TLV-TWA: 10 ppm
    2) TLV-STEL:
    3) TLV-Ceiling:
    b) Notations and Endnotes:
    1) Carcinogenicity Category: A3
    2) Codes: Not Listed
    3) Definitions:
    a) A3: Confirmed Animal Carcinogen with Unknown Relevance to Humans: The agent is carcinogenic in experimental animals at a relatively high dose, by route(s) of administration, at site(s), of histologic type(s), or by mechanism(s) that may not be relevant to worker exposure. Available epidemiologic studies do not confirm an increased risk of cancer in exposed humans. Available evidence does not suggest that the agent is likely to cause cancer in humans except under uncommon or unlikely routes or levels of exposure.
    c) TLV Basis - Critical Effect(s): Eye irr; kidney dam
    d) Molecular Weight: 147.01
    1) For gases and vapors, to convert the TLV from ppm to mg/m(3):
    a) [(TLV in ppm)(gram molecular weight of substance)]/24.45
    2) For gases and vapors, to convert the TLV from mg/m(3) to ppm:
    a) [(TLV in mg/m(3))(24.45)]/gram molecular weight of substance
    e) Additional information:

    B) NIOSH REL and IDLH Values for CAS106-46-7 (National Institute for Occupational Safety and Health, 2007):
    1) Listed as: p-Dichlorobenzene
    2) REL:
    a) TWA:
    b) STEL:
    c) Ceiling:
    d) Carcinogen Listing: (Ca) NIOSH considers this substance to be a potential occupational carcinogen (See Appendix A in the NIOSH Pocket Guide to Chemical Hazards).
    e) Skin Designation: Not Listed
    f) Note(s): See Appendix A
    3) IDLH:
    a) IDLH: 150 ppm
    b) Note(s): Ca
    1) Ca: NIOSH considers this substance to be a potential occupational carcinogen (See Appendix A).

    C) Carcinogenicity Ratings for CAS106-46-7 :
    1) ACGIH (American Conference of Governmental Industrial Hygienists, 2010): A3 ; Listed as: p-Dichlorobenzene
    a) A3 :Confirmed Animal Carcinogen with Unknown Relevance to Humans: The agent is carcinogenic in experimental animals at a relatively high dose, by route(s) of administration, at site(s), of histologic type(s), or by mechanism(s) that may not be relevant to worker exposure. Available epidemiologic studies do not confirm an increased risk of cancer in exposed humans. Available evidence does not suggest that the agent is likely to cause cancer in humans except under uncommon or unlikely routes or levels of exposure.
    2) EPA (U.S. Environmental Protection Agency, 2011): Not Assessed under the IRIS program. ; Listed as: 1,4-Dichlorobenzene
    3) IARC (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004): 2B ; Listed as: para-Dichlorobenzene
    a) 2B : The agent (mixture) is possibly carcinogenic to humans. The exposure circumstance entails exposures that are possibly carcinogenic to humans. This category is used for agents, mixtures and exposure circumstances for which there is limited evidence of carcinogenicity in humans and less than sufficient evidence of carcinogenicity in experimental animals. It may also be used when there is inadequate evidence of carcinogenicity in humans but there is sufficient evidence of carcinogenicity in experimental animals. In some instances, an agent, mixture or exposure circumstance for which there is inadequate evidence of carcinogenicity in humans but limited evidence of carcinogenicity in experimental animals together with supporting evidence from other relevant data may be placed in this group.
    4) NIOSH (National Institute for Occupational Safety and Health, 2007): Ca ; Listed as: p-Dichlorobenzene
    a) Ca : NIOSH considers this substance to be a potential occupational carcinogen (See Appendix A in the NIOSH Pocket Guide to Chemical Hazards).
    5) MAK (DFG, 2002): Category 2 ; Listed as: 1,4 Dichlorobenzene
    a) Category 2 : Substances that are considered to be carcinogenic for man because sufficient data from long-term animal studies or limited evidence from animal studies substantiated by evidence from epidemiological studies indicate that they can make a significant contribution to cancer risk. Limited data from animal studies can be supported by evidence that the substance causes cancer by a mode of action that is relevant to man and by results of in vitro tests and short-term animal studies.
    6) NTP (U.S. Department of Health and Human Services, Public Health Service, National Toxicology Project ): R ; Listed as: 1,4-Dichlorobenzene (p-Dichlorobenzene)
    a) R : RAHC = Reasonably anticipated to be a human carcinogen

    D) OSHA PEL Values for CAS106-46-7 (U.S. Occupational Safety, and Health Administration (OSHA), 2010):
    1) Listed as: p-Dichlorobenzene
    2) Table Z-1 for p-Dichlorobenzene:
    a) 8-hour TWA:
    1) ppm: 75
    a) Parts of vapor or gas per million parts of contaminated air by volume at 25 degrees C and 760 torr.
    2) mg/m3: 450
    a) Milligrams of substances per cubic meter of air. When entry is in this column only, the value is exact; when listed with a ppm entry, it is approximate.
    3) Ceiling Value:
    4) Skin Designation: No
    5) Notation(s): Not Listed

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) References: Lewis, 1992 RTECS, 1993
    1) LD50- (INTRAPERITONEAL)MOUSE:
    a) >2 g/kg
    2) LD50- (ORAL)MOUSE:
    a) 2950 mg/kg
    3) LD50- (SUBCUTANEOUS)MOUSE:
    a) 5145 mg/kg
    4) LD50- (INTRAPERITONEAL)RAT:
    a) 2562 mg/kg
    5) LD50- (ORAL)RAT:
    a) 500 mg/kg
    6) LD50- (SKIN)RAT:
    a) >6 g/kg

Pharmacology Toxicology

Toxicologic Mechanism

    A) Toxicity may be low because only relatively small amounts are converted to epoxide intermediates. Epoxide intermediates of related halobenzenes cause necrosis after microsomal conversion and binding to tissue proteins (Pielmeier, 1976).

Physicochemical

Physical Characteristics

    A) ODOR:
    1) Characteristic, penetrating (Budavari, 1996)
    2) Penetrating, camphoraceous (ACGIH, 1991)
    B) COLOR:
    1) Colorless or white crystals or solid (HSDB, 2005; Hathaway et al, 1991; Clayton & Clayton, 1981)
    2) White (Lewis, 1992)
    C) p-Dichlorobenzene exists as volatile crystals with a characteristic penetrating odor: Monoclinic form (alpha modification); triclinic form (beta modification) (Budavari, 1996).

Ph

    1) No information found at the time of this review.

Molecular Weight

    A) 147.00

Other

    A) ODOR THRESHOLD
    1) 15-30 ppm (CHRIS, 2005)

Animal Toxicology

Clinical Effects

    11.1.13) OTHER
    A) OTHER
    1) Acute poisonings were characterized by hyperemia of the mucous membranes, salivation, lacrimation, initial excitation followed by sleepiness and respiratory paralysis.
    2) Autopsy revealed hypertrophy and necrosis of the liver, submucosal hemorrhages of the stomach, and slight brain edema. Histological exams showed vascular and kidney disorders (Pielmeier, 1976).

References

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