α,α,α-trifluoro-4-nitro-m-cresol

Endpoint summary

Description of key information

Based on its physicochemical properties systemic availability of the test substance is given. When taken up by the oral route, the substance is likely to be absorbed through the walls of the gastrointestinal tract by absorption and/or diffusion. The physicochemical and skin corrosive properties do favour transdermal absorption. Considering the liquid state of the test substance and its low vapour pressure, the risk of inhalation under normal use conditions is negligible. The substance is expected to be distributed and metabolized within the body if becoming systemically available. Based on the chemical characteristics renal and visceral excretion are assumed to be the major routes of excretion. According to the physiochemical properties and the fast excretion of the test substance, bioaccumulation is unlikely.

Key value for chemical safety assessment

Bioaccumulation potential:

low bioaccumulation potential

Additional information

Toxicokinetic analysis of 3-Trifluoromethyl-4-nitrophenol (TMF)

The test substance is a dark brown liquid at room temperature with a molecular weight (MW) of 207.1 g/mol. The water solubility is high (15.05 g/L, pH 6.1, 20 °C). A log Pow of 3.6 was determined. The pH of a 1 % aqueous solution is 7.7 (25 °C), undiluted solution pH 9.5 ± 1.

 

Absorption

After oral uptake, the chance of systemic absorption through the gastro-intestinal (GI) barrier depends on the physicochemical properties of the substance. For a conclusive judgment on the substance's potential to reach systemic circulation, important physiochemical factors such as molecular weight, water solubility and the log Pow value should be considered. The substance is moderately lipophilic (log Pow = 3.6) and is well soluble in water (15.05 g/L, pH 6.1, 20 °C). Due to the molecular structure of the test substance, at a physiological pH of ~7 and at a body temperature of ~37 °C a higher water solubility can be assumed. According to these properties and in combination with its moderate molecular weight (MW) of 207.1 g/mol, the substance will dissolve readily into the GI fluids. Absorption can occur either by transporter mediated uptake or by passive diffusion via aqueous pores. The possible gastrointestinal uptake is supported by acute and repeated dose oral toxicity studies in rats (Hazleton Laboratories, 1990; WARF Institute, 1971) and a bioaccumulation study in rainbow trout (Hubert, 1997). In a fish accumulation study conducted according to EPA subdivision N guidelines, rainbow trouts were exposed to non-radiolabeled plus uniformly phenyl ring-labeled [14C]TFM, at a nominal concentration of 62.0 µg/L, under flow-through aquarium conditions at a pH of 7.8 (Hubert, 1997). The radioactively labeled test substance was found in visceral tissue as well as in fillet of the trouts. Based on the observed toxicological effects in rats and the described test substance distribution in trout it is reasonable to conclude that oral and dermal (see below) absorption of the test substance takes place.

According to the liquid state of 3-Trifluoromethyl-4-nitrophenol and its moderate vapour pressure of 30 kPa at 20 °C exposure to the test substance as vapour is not negligible if handled at room temperature. Inhaled vapours may reach the alveolar region of the respiratory tract. If inhaled, the water soluble test substance will readily deposit at the mucus of the respiratory tract and will be absorbed. No data of inhalation studies were available. However, due to the determined skin corrosive and eye damaging potential (Hoechst AG, 1994, Hazleton Laboratories, 1990), also damages to lung epithelial tissue after inhalation can be assumed, favouring direct systemic absorption of the test substance.

Application of the test substance onto the skin of rabbits induced corrosion (Hoechst, 1994), which in turn could impair the natural barrier function of the skin against environmental influences and favour direct absorption into systemic circulation. The assumption that dermal absorption occurs is strengthened by results of an acute dermal study in rats showing an LD50 of 265.4 mg/kg bw (Hoechst, 1994). Furthermore, the physico-chemical properties of the test substance favour dermal uptake. The liquid test substance will wet the surface of the skin readily. Dermal uptake of substances <100 g/mol is favoured. The MW of the test substance of 207.1 g/mol hinders dermal absorption. According to the solubility (15.05 g/L) a moderate dermal uptake can be anticipated. However, due to the log Pow of 3.6, the lipophilicity will enhance penetration into the stratum corneum and hence dermal absorption.

 

Distribution

The estimated distribution of the test substance is based on findings of a bioaccumulation study in rainbow trouts (Hubert, 1997). Based on the total radioactivity, the max. bioconcentration factors were 50.3x for viscera, 1.3x for fillet, and 8.4x for whole body tissues. The max. mean conc. of [14C] residues were 3.0 ± 0.9 - 1.7 ppm for the viscera tissue, 0.08 ± 0.03 ppm for the fillet tissue and 0.5 ± 0.1-0.2 ppm for the whole fish tissue. The test substance was present at 1.4 ± 0.05 ppm in the viscera, and 0.006 ± 0.006 ppm in the fillet tissues. Provided, that a similar visceral uptake in fish and higher vertebrates takes place, a similar distribution of the test substance in higher vertebrates can be assumed. Based on the molecular weight of 207.1 g/mol and the high water solubility (15 g/L), a wide distribution of the test substance via the blood stream can be assumed. The log Pow of 3.6 indicates, that a cellular uptake of the test substance in different tissues is likely. However, the bioaccumulation potential of the test substance is low, indicated by the results of the bioaccumulation study in rainbow trouts (Hubert, 1997). The depuration of the test substance in rainbow trout was fast, >98.7 % of total accumulated [14C] residues was eliminated by day 4 (viscera), day 15 (fillet), and day 11 (whole body).

 

Metabolism

In the above mentioned accumulation study in rainbow trout (Hubert, 1997), the test substance glucuronide was determined as main metabolite. Given the molecular structure of the test substance, it is very likely, that hepatic glucuronidation will also be the main route of metabolisation in higher vertebrates. This assumption is strengthened by the results of a chromosome aberration study (Hazleton Laboratories, 1988). The number of induced chromosome aberrations was reduced in treated cells with S9 mix compared to the treated cells without S9 mix, indicating possible processes which involve hepatic detoxification systems. Regarding the molecular structure of the test substance (hydroxy group at the benzyl ring), a metabolic activation requiring phase I enzymes (e.g. P450) seems not necessary. A direct phase II-metabolisation in form of the above mentioned glucuronidation can be assumed.

 

Excretion

According to the physicochemical properties of the test substance, molecular weight and water solubility, a possible route of excretion would be renal secretion. Furthermore, based on the metabolism of the test substance, only a part of the test substance will be excreted unchanged. Following the presumed glucuronidation of the test substance, a part of the absorbed test substance will be excreted as the corresponding glucuronide. Therefore, renal excretion could be complemented by visceral excretion (via feces).

 

Summary

Based on its physicochemical properties systemic availability of 3-Trifluoromethyl-4-nitrophenol is given. When taken up by the oral route, the substance is likely to be absorbed through the walls of the gastrointestinal tract by absorption and/or diffusion. The physicochemical and skin corrosive properties do favour transdermal absorption. Considering the liquid state of the test substance and its moderate vapour pressure, the risk of inhalation under normal use conditions is not negligible. The substance is expected to be distributed and metabolized within the body if becoming systemically available. Based on the chemical characteristics renal and visceral excretion are assumed to be the major routes. According to the physiochemical properties and the fast excretion of the test substance, bioaccumulation is unlikely.

 

References

Hubert, T., Uptake and Elimination of Lamprecide TFM by Rainbow Trout: Lab Project Number: CAP-97-00079-01: CAP-97-0079-01-FFS00. Unpublished study prepared by Upper Mississippi Science Center. 677 p., 1997

Hazleton Laboratories, Acute Oral Toxicity Study of a,a,a-trifluoro-nitro-m-cresol (TFM), Technical Grade, in Rats (EPA Guidelines), report No. HLA00504436, unpublished report, 1990

Hazleton Laboratories, Primary Eye Irritation Study of a,a,a-trifluoro-nitr-m-cresol (TFM), Technical Grade in Rabbits (EPA Guidelines), report No. HLA00504439, unpublished report, 1990

Hoechst AG, 4-Nitro-3-trifluormethylphenol Test for Primary Dermal Irritation in the Rabbit, report No. 94.0280, unpublished report, 1994

Hoechst AG, 4-Nitro-3-trifluormethylphenol Testing for Acute Dermal Toxicity in the Male and Female Wistar Rat, Report No. 94.0255, unpublished report, 1994