4-nitrophenol

Endpoint summary

Description of key information

Short description of key information on bioaccumulation potential result: 
In the following, public literature on toxicokinetics and metabolism of 4-Nitrophenol is listed, which is summarized under "discussion" below:
 - ATSDR (Agency for Toxic Substances and Disease Registry) report on the toxicological profile of 2-Nitrophenol and 4-Nitrophenol, 1992;
 - National Toxicology Program (NTP) Technical Report on the Toxicology and Carcinogenesis Studies of p-Nitrophenol, 1993;
 - Beratungsgremium fuer umweltrelevante Altstoffe (BUA) report Vol. 75,  4-Nitrophenol, 1992
Short description of key information on absorption rate: 
In the following, public literature on toxicokinetics and metabolism of 4-Nitrophenol is listed, which is summarized under "discussion" below:
 - ATSDR (Agency for Toxic Substances and Disease Registry) report on the toxicological profile of 2-Nitrophenol and 4-Nitrophenol, 1992;
 - Beratungsgremium fuer umweltrelevante Altstoffe (BUA) report Vol. 75,  4-Nitrophenol, 1992

Additional information

According to regulation (EC) 1907/2006 of the European parliament and the council of 18 December 2006 (Article 18), information on toxicokinetics and metabolism has to be provided for transported isolated intermediates, where available, but no chemical safety assessment is necessary. Therefore, publicly available information on toxicokinetics and metabolism of 4 -Nitrophenol is summarized below, but no bioaccumulation potenial has been determined for 4 -Nitrophenol.

In the ATSDR (Agency for Toxic Substances and Disease Registry) report on the toxicological profile of 2-Nitrophenol and 4-Nitrophenol of 1992, data on the toxicokinetics of 4-Nitrophenol are reviewed which are summarized in the following.

The sulfate conjugate of 4-nitrophenol was detected in the urine of rabbits after gavage administration of single doses between 182 and 264 mg/kg (Williams 1938). A similar finding was reported by Robinson et al. (1951), who monitored the excretion of nitrocompounds and conjugates in the urine of rabbits after gavage doses of 4-nitrophenol (150-200 mg/kg). Based on excretion data, it was apparent that at least 80%-90% of the dose was rapidly absorbed. In a monkey, oral absorption of 4-nitrophenol was fast since peak blood concentrations of the compound were achieved within minutes after a gavage dose of 20 mg/kg (Lawford et al. 1954). The extent of absorption was not determined.

Application of 14C-labeled 4-nitrophenol to the skin of rabbits (0.12 mg/kg) and dogs (0.06 mg/kg) as well as intravenous injection of 14C-labeled 4-nitrophenol to rabbits (0.12 mg/kg) or dogs (0.06 mg/kg) resulted in no detectable radioactivity in specimens of all major tissues and organs 7 days later (Snodgrass 1983). No attempt was made to determine distribution at an earlier time following exposure. The study therefore suggests that following dermal or parenteral exposure, 4-nitrophenol does not bioaccumulate.

In the NTP Technical Report on the Toxicology and Carcinogenesis Studies of p-Nitrophenol the following information is provided regarding toxicokinetics and metabolism of the substance: p-Nitrophenol is metabolised, primarily in the liver, into conjugated glucuronide and sulfate ester forms, which are the forms of p-Nitrophenol excreted in urine by man or other animals (USEPA, 1980). Based o the rapid urinary elimination of mononitrophenols, the compounds may be restricted primarily to the blood and the urine following absorption in humans and animals. In rabbits, after oral administration of parathion (containing p-Nitrophenol), greater than 80% of the urinary p-Nitrophenol was excreted as glucuronide or sulfate ester conjugate within 6 hours (Pena-Egido et al, 1988). p-Nitrophenol can also be metabolized, but in smaller amounts, to p-aminophenol by nitro-reduction or to p-nitrocatechol by hydroxylation.

In the BUA report on 4 -Nitrophenol the following information on metabolism and toxicokinetics of 4 -nitrophenol is provided:

The greater part of absorbed 4 -Nitrophenol is excreted in conjugated form. Within 24 hours following administration of 4 -nitrophenol to rabbits by gavage, 65% of the dose was excreted in the animals urine as 4 -nitrophenol glucuronide and 16% as 4 -nitrophenyl sulphate, while less than 1% occur as free 4 -nitrophenol. Within 2 days, a mean total of 87.4% of the administered dose has been excreted as compounds with an unalterted nitro group, while 14.2% were excreted as amino compounds (Robinson et al, 1951).

Following intraperitoneal administration of 50 mg 4 -nitrophenol/kg bw to male mice, 24 -50% of the administered dose was excreted in metabolised form in the animals urine during the first 5 hours. Glucuronic acid and sulphate ester accounted for 95% of the excreted metabolites. A small portion of 1 -2% of the metabolites were identified as 4 -nitrophenyl glucoside (Gessner & Hamada, 1970). These results were confirmed by Minck et al (1973) in male rats.

Meerman et al (1987) injected 60 µmol 4 -nitrophenol/kg bw in physiological saline into the tail vein of male and female rats. During the 24 hour observation period, 35% of the administered dose were excreted as glucuronide and 40% as sulphate in the animals urine. No sex-speciic differences were noted.

Tremaine et al (1984) continously infused 4 -nitro[2,6 -14C]phenol over 90 minutes into the jugular vein of rats. After 75 -180 minutes, a steady state had been reached. More than 98% of the infused 4 -nitrophenol was found in the animals urine as sulphate and glucuronide conjugates.

Hekman et al (1985) reported an investigation on the excretion of 4 -nitrophenol in dogs from which it could be concluded that failing binding to blood proteins, glomerular infiltration is the only mechanism of renal excretion for glucuronides of 4 -nitrophenol in dogs.

Extrahepatic conjugation has also been observed in chickens (Diamond & Quebbeman, 1981). After intravenous administration, about 93 -94% of the administered dose was found in the birds urine, 98% of which was 4 -nitrophenol sulphate, 1.9% as 4 -nitrophenol glucuronide and 1.7% as unaltered 4 -nitrophenol.

Besides the conjugates, small amounts of free 4 -nitrophenol are also excreted, thus indicating enterohepatic circulation.

For the excretion of unaltered 4 -nitrophenol following intraperitoneal administration of 0.05 and 7 µg/kg bw in rats sex-specific differences were found: in the first 24 hours, male rats excreted 41% and females 15% of the unlatered form (Rush et al, 1983).

In experiments with isolated, perfused livers, dose dependency was observed: At high concentrations of 4 -nitrophenol in the perfusion solution, the formation of glucuronide conjugates and sulphate conjugates was roughly equal, while at low concentrations formation of the sulphate conjugate dominated (Sultatos and Minor, 1985).

Discussion on absorption rate:

According to regulation (EC) 1907/2006 of the European parliament and the council of 18 December 2006 (Article 18), information on dermal absorption has to be provided for transported isolated intermediates, where available, but no chemical safety assessment is necessary. Therefore, publicly available information on dermal penetration/absorption of 4 -Nitrophenol is summarized below, but no key value for chemical safety assessment has been determined.

In the ATSDR (Agency for Toxic Substances and Disease Registry) report on the toxicological profile of 2-Nitrophenol and 4-Nitrophenol, data on the dermal absorption of 4-Nitrophenol are reviewed which are summarized in the following.

In animals, absorption efficiency appeared to be species-specific. In rabbits and beagle dogs, 35% and 11%, respectively, of a dose of 14C-labeled 4-nitrophenol dissolved in ethanol and applied to the skin under a patch, was recovered in the urine over 7 days, indicating absorption through the skin (Snodgrass 1983). In the rabbits, the absorption rate was approximately 16% of the dose/day for 2 days, whereas in the dogs the absorption rate was 3% of the dose/day for 2 days. Thus, absorption was more extensive and more rapid in rabbits than in dogs. Unabsorbed 4-nitrophenol accounted for 53% and 86% of the applied dose in rabbits and dogs, respectively (Snodgrass 1983).

In the BUA report on 4 -Nitrophenol the following information on the dermal absorption of 4 -Nitrophenol is provided: Investigations by Snodgrass (1983) show that 4 -Nitrophenol is absorbed via the skin in vivo, as investigated in both rabbits and dogs. The animals were exposed over a period of 7 days towards 375 µg of 4 -Nitrophenol, covered by non-occlusive dressing which was renewed every 24 hours. Of the applied dosage, 35% and 11% were absorbed in rabbits and dogs, respectively.

From an in vitro study by Huq et al (1986) using isolated skin of hairless mice in a 2 -chamber diffusion cell it was concluded that permeability for 4 -Nitrophenol is largely dependent on the dead layer of skin.