2-nitrophenol

Endpoint summary

Description of key information

Short description of key information on bioaccumulation potential result: 
A study in rabbits show that o-nitrophenol mainly undergoes phase II conjugation at the hydroxy group. Metabolites are eliminated via the kidneys within 24 hours. The substance penetrates the skin.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Additional information

The test substance is a yellowish solid in the form of needles or prismas with a phenolic odour and a molecular weight of 139.11 g/mol. The vapour pressure was found to be 0.0069 KPa, the log P o/w value is 1.77 - 1.79 and the solubility in water is < 2.1 g/l (20°C).

 

Gastrointestinal absorption, metabolism and excretion

The physico-chemical parameters (molecular weight, log P o/w value, solubility in water) lead to the assumption of a favourable gastrointestinal absorption of the test substance (ECHA R7c). This is supported by a study conducted by Robinson et al. (1951) to determine the renal excretion of test substance originated metabolites after oral gavage of aqueous suspension to rabbits. For the determination of the excreted free or conjugated test substance, 3 animals were administered a dose of 200 mg/kg bw and 1 animal a dose of 450 mg/kg bw, respectively. Another 3 animals were administered a dose of 330 mg/kg bw for the determination of the excreted amino derivates of the test substance, and further 3 animals received a dose of 200 mg/kg bw for the determination of the excreted glucuronic acid and ethereal sulphate conjugations of the test substance. At least 80 – 90 % of the test substance was excreted within 24 hours (most of it in the form of metabolites and only a small ratio unchanged), indicating a rapid gastrointestinal absorption and a fast elimination via the renal pathway. The main metabolites found were analysed as glucoronyl (app. 70 %) and sulfate conjugates (app. 10 %). Only traces of the test material were detected to be reduced at the nitro group (app. 6 %) and less than 1 % was found to be oxidised to 2-Nitroquinone. The findings suggest that the test substance is absorbed in the gastrointestinal tract and metabolised in Phase II biotransformation forming water-soluble conjugates, which can easily be filtered out by the kidneys (ECHA R7c). Further data from acute toxicity studies (BASF XIX/429, 1970) support this conclusion, as necropsy of a cat, which died after gavage of the test substance at a dose of 250 mg/kg bw, revealed a tightly filled urinary bladder with yellow-green-brownish urine, which was described as the colour of the test substance. Another study, reported by the International Programme on Chemical Safety (IPCS), revealed darkly coloured urine and yellow staining of the nose -, mouth -, and anogenital haircoat in orally treated rats. The systemic availability of the test substance was also proved in a study after oral administration to rats (Kolodub & Vasilenko, cited in: ECB-IUCLID, 2000). Treated animals showed increased liver NADH (35 %), decreased ATP (38 %), inhibited cytochrome oxidase activity, and uncoupled oxidative phosphorylation. A further report of the same source describes slight liver discolouration and acute gastrointestinal inflammation in rats after oral intake of the test compound.

The low acute oral toxicity of the test substance, which is described in its high LD50 (> 2000 mg/kg bw: BASF XIX/429, 1970; Vernot et al., 1977; ECB-IUCLID, 2000; and Commission of the European Communities DG XI, 1993), can be explained by its fast renal excretion, revealing a fast detoxification. However, it is likely that a notably amount of the test substance remains in the organism as yellow staining of haircoat at > 250 mg/kg body weight was observed (International Research and Developmental Corporation IR-83-100, cited in: International Programme on Chemical Safety (IPCS)).

 

Dermal absorption

The physico-chemical parameters indicate a dermal uptake of the test substance, since the log P o/w value, water solubility, and the molecular weight suggest possible skin absorption (ECHA R7c). In vitro studies, conducted to determine the skin permeation ability of the test substance, support this consideration: Huq et al. (1986) conducted a two-chamber system with abdominal skin from adult SKH/HR1 mice for this purpose. The system was placed in a waterbath at 37 °C and both donor and receiver chamber were filled with normal saline. The test substance was added to the donor chamber and sampling was carried out from the receiver compartment. The samples were analysed using UV spectrophotometry and revealed an apparent permeability coefficient of the test substance of 101 (± 6.9) x 10³ cm/h (at pH 3.46 in the donor compartment and pH 6.2 in the receiver compartment). Ohkura et al. (1990) analysed the permeation of the test substance through newborn rat abdominal epidermis and a cultured skin cell monolayer in vitro. 0.28 µmol/cm² of the test substance permeated through the cultured skin cell monolayer in 2.5 h, which is 49.1 % of the initial test substance content. The permeation process obeys a first-order reaction kinetic (k = 0.245/h) and did not show saturation at least up to a donor concentration of 1.5 mM. Furthermore, the permeation was found to be insensitive to changes in temperature and independent from biological energy. The authors concluded that the permeation process of the test substance through cultured skin cell monolayer is based on simple diffusion. Additionally, the test substance was found to permeate through newborn rat abdominal epidermis less than through cultured skin cell monolayer. However, the test substance does not show acute dermal toxicity as the LD50 was found to be very high in rabbits (> 7940 mg/kg bw: ECB-IUCLID, 2000) and rats (> 2000 mg/kg bw: Commission of the European Communities DG XI, 1993; and > 5000 mg/kg bw: International Programme on Chemical Safety (IPCS)). No in vivo data is given concerning the systemic availability of the test substance after dermal application.

 

Respiratory absorption

As the test substance was observed to be absorbed through the gastrointestinal tract, the uptake via the respiratory system is very likely (ECHA R7c). The log P o/w value and the water solubility support this estimation. In contrast, the vapour pressure of the test substance contradicts the respiratory absorption. No data is given concerning the particle size of the test material and its aerodynamic diameter. Systemic availability of the test substance can be expected due to met-Hb formation after repeated inhalation ( Hazleton Lab. 82-254, 1984, cited in: International Programme on Chemical Safety (IPCS)).However, an acute inhalation study (BASF XIX/429, 1970) did not reveal acute toxic effects of the test substance in rats after exposure to an atmosphere saturated with vapors of the volatile components of a test substance at 20°C (temperature chosen for vapor generation). No mortalities occurred, no clinical signs were observed, and gross pathology did not reveal any abnormalities.