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Description of key information

Based on its physico-chemical characteristics, diisopropanol-p-toluidin is considered to be bioavailable after oral absorption. Once inhaled, diisopropanol-p-toluidin will be absorbed quantitatively. However, absorption after inhalation is negligible due to the lack of a quantative aerosol formation. Dermal absorption of diisopropanol-p-toluidin in toxicologically relevant amounts is unlikely. Following uptake the compound can be distributed through the body thereby a pronounced metabolism is not anticipated. It is expected that diisopropanol-p-toluidin will be rapidly excreted via the urine. 

Key value for chemical safety assessment

Bioaccumulation potential:
low bioaccumulation potential
Absorption rate - oral (%):
50
Absorption rate - dermal (%):
50
Absorption rate - inhalation (%):
100

Additional information

Discussion

In line with chapter R.7 c (ECHA, 2012) the main toxicokinetic properties of diisopropanol-p-toluidine are assessed on the basis of its physico-chemical properties and with special regard to the results of the standard toxicity studies performed with this substance. Specific toxicokinetics or dermal absorption studies are not available for the substance.

 

1. Relevant physico-chemical properties of diisopropanol-p-toluidine

Molecular weight: 223.3 g/mol

Physical state: solid

Log Pow: 2.1 (24°C, pH 7.5)

Water solubility: 7.0 ± 0.2 g/L (20°C ± 0.5°C)

Vapour pressure: 0.0000024 hPa at 20°C

 

2. Absorption

 

Oral absorption

In general, small molecules with a molecular weight below 500 g/mol are favorable for absorption. Based on its molecular weight of 223.3 g/mol diisopropanol-p-toluidine is expected to be absorbed in the GI tract. The fact that severe signs of systemic toxicity, i.e. mortality, convulsion and pronation, were noted in the key acute oral toxicity study (RTC, 2001) at dose levels of 200 and 2000 mg/kg bw and in the key repeated dose toxicity study at dose levels of 80 mg/kg bw (BASF, 2018) pointed out that the test item was able to pass the intestinal wall.

 

In the key repeated dose toxicity study at dose levels of 80 mg/kg bw (BASF, 2018) poor general condition was noted in 3/10 male rats between 2 and 5 hours after administration. These animals recovered overnight or the same day, which indicates that the substances will be readily dissolved without accumulation. The log Pow value of approximately 2 and the water solubility (approximately 7 g/L) underlines the conclusion that the substance will be readily dissolved into the gastrointestinal fluids and absorbed via passive diffusion which generally requires a moderate log Pow value (between -1 and 4) and good water solubility. In addition, due to the molecular weight of around 200 absorption of diisopropanol-p-toluidine in the GI tract through aqueous pores or carriage across membranes with the bulk passage of water may be a further relevant absorption mechanism.

 

Absorption after inhalation

In view of the above considerations for the oral route of exposure, diisopropanol-p-toluidine will be quantitatively absorbed if it is inhaled. Due to the low vapour pressure of diisopropanol-p-toluidine (0.0000024 hPa at 20°C), a vapour concentration of 0.0000076 mg/ml and the resulting low volatility, an inhalation exposure to the compounds vapour phase is rather unlikely. Furthermore an inhalation risk test showed no mortality and no abnormal findings after incubation for 8 hours at a saturated atmosphere (BASF, 1987). The substance is marketed or used in a non-solid or granular form, and aerosol formation of diisopropanol-p-toluidine is considered negligible. Thus, absorption of quantitative amounts of the substance in its aerosol or dust form is not expected.

 

Dermal absorption

For dermal absorption a substance must be sufficiently lipophilic to cross the stratum corneum. Furthermore, the substance must be adequately soluble in water to partition from the stratum corneum into the viable epidermis. Since diisopropanol-p-toluidine shows a log Pow between 1 and 4 and a good water solubility, dermal absorption is likely. However, in an acute dermal toxicity study (Bioassay, 2012) performed on rats no mortality and no systemic toxic effects were observed for the highest dose and the respective LD50 was determined to be greater than 2000 mg/kg bw. Based on the results of this study diisopropanol-p-toluidine can be considered as not bioavailable in toxicologically relevant amounts.

 

3. Distribution/Metabolism

In the key acute toxicity study (RTC, 2001) and the key repeated dose toxicity study (BASF, 2018) severe signs of systemic toxicity were observed when the test item was administered orally to rats. Mortality, pronation and convulsion were noted for animals treated with 200 or 2000 mg/kg bw respectively 80 mg/kg bw. In view of these results a distribution of diisopropanol-p-toluidine in the body is most likely. Since diisopropanol-p-toluidine exhibits a lipophilic character (log Pow > 0) distribution into cells as well as a higher intracellular than extracellular concentrations may be expected. 

Generally, metabolism will render a xenobiotic molecule more polar and harmless, leading to fast and quantitative excretion which is considered to be the case for diisopropanol-p-toluidine. For diisopropanol-p-toluidine, no conversion into a metabolite that was more cytotoxic or more genotoxic than the parent substance was noted when comparing in vitro test results with metabolic activation to in vitro test results without metabolic activation system (genetic toxicity tests). Furthermore, in the key repeated dose toxicity study at dose levels of 80 mg/kg bw (BASF, 2018) poor general condition recovered overnight or the same day, which indicates that the substances will be readily dissolved without accumulation. Thus, the formation of reactive metabolites in vivo is unlikely.

 

4. Excretion

Substances with log Pow value of 3 or less are unlikely to accumulate with the repeated intermittent exposure pattern normally encountered in the workplace but may accumulate if exposures are continuous. In the key repeated dose toxicity study at dose levels of 80 mg/kg bw (BASF, 2018) poor general condition recovered overnight or the same day, which indicates that the substances will be readily dissolved without accumulation. Based on this result and considering the log Pow of 2, the low molecular weight (below 300) and the good water solubility quantitative and rapid urinary excretion is most likely without accumulation.

 

5. Generic absorption rates

Based on the above information and due to the fact that there are no specific toxicokinetic data available, the generic values of 50% for oral as well as dermal absorption and 100% for inhalation absorption of respirable particles/vapour are applied.

 

Reference

ECHA (2012). Guidance on information requirements and chemical safety assessment, chapter R.7c: Endpoint specific guidance.