1,4-dihydroxy-2,2,6,6-tetramethyl piperidinium-2-hydroxy-1,2,3-propanetricarboxylate

Endpoint summary

Description of key information

The test item is considered to be bioavailable via oral, inhalation and dermal route. Once systemic available the substance might diffuse through aqueous channels and pores to cross cell membranes. Metabolic conversion of the main component into a secondary amine is expected as well as conjugation by Phase-II-enzymes. The minor component is a metabolic intermediate vital to the TCA respiration pathway. Therefore, excretion via exhalation is expected. However renal excretion of the substance and/or its metabolites might be the main excretion pathway. Based on the results of the repeated dose toxicity studies and the low log Pow value bioaccumulation of the test substance can be excluded.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Additional information

The test item consists of two components at a ratio of 3 to 1. It is a white solid at room temperature with a molecular weight of 365.38 g/mol, a density of 1.19 g/cm³and a log Pow value of -0.29. The substance has a vapour pressure of less than 0.6 Pa and is soluble in water (> 500 g/L at 20°C).

 

The main exposure route is dermal since the test item is used in cosmetics.

 

In an acute oral toxicity study with the test item in rats (SLI, 1999) the LD₅₀was determined to be 1757.8 mg/kg bw for male and female rats. The most notable clinical abnormalities observed during the study included decreased activity, convulsions, wobbly gait, breathing abnormalities, prostration, decreased defecation, soft stools, piloerection, apparent hypothennia, skin blue in colour, hunched posture, urine/fecal stain, partially closed eyelids, salivation, dilated pupil(s), ocular discharge and dark material around the facial area. The most notable gross internal findings were observed in the animals that died and included abnormal content in the digestive tract, stained mucosa in the stomach and dark red lungs. Exposition towards 5 mg/L of the test item in an acute inhalation study (PSL, 2003) revealed no mortality. No clinical signs and pathological alterations were noted. In an acute dermal toxicity study with the test item in rabbits (SLI, 1999) no mortality occurred and the LD₅₀was determined to be higher than an active dose level of 2000 mg/kg bw. The most notable clinical abnormalities observed during the study included soft/mucoid stools, fecal stain and dark material around the facial area. No significant gross internal findings were observed. Dermal irritation was noted at the site of test item application. However, in an acute dermal irritation/corrosion study with rabbits (SLI, 1999) the application of 0.5 g test item per animal revealed slight erythema which are reversible within 7 days. In a 28-day repeated dose toxicity study with rats, the test item was administered orally at concentrations of 0, 100, 500 and 1000 mg/kg bw/day. Main clinical signs of toxicity were observed in male and female animals at the mid and high dose level including salivation and apparent blood around the facial area, neck and forelimbs. Treatment-related effects in the mid and high dose group were decreased red blood cell counts, hemoglobin concentration and increased serum billirubin. A dose-dependent trend towards increased spleen weights was noted primarily in the 500 and 1000 mg/kg bw/day males. Repeated dose toxicity was further assessed after 90-day dermal administration of 0, 50, 150 and 500 mg/kg bw/day in male and female rats (CIT, 2010). The hematological signs were lower white blood cell counts correlated with lower lymphocyte counts in males and females. Clinical chemistry revealed low glucose and high urea concentrations in animals of the high dose group. Slightly higher ASAT and ALAT activities were noted in females at the high dose level. Increased splenic weights were noted in males and females from 150 and 500 mg/kg bw/day.

 

Absorption

After oral administration the substance will readily dissolve in the gastrointestinal fluids as indicated by the high water solubility. Since absorption of weak acidic compounds is favoured at low pH values uptake of the minor compound in the stomach is expected. Due to its high pKa value (~11) the main component is assumed to be ionic under the pH conditions of the stomach (pH ~1) and the intestine (pH 7-8). Therefore absorption via aqueous pores or carriage across membranes with the bulk passage of water might occur. The LD₅₀evaluated in an oral acute toxicity study and the clinical findings after repeated oral administration indicate that the compound becomes bioavailable after oral administration.

Due to the solid properties of the test substance inhalation of dust might occur. Since the aerodynamic diameter of the particles was shown to be approximately 5 µm (PSL, 2003), deposition in the deep lung might be possible. Generally, particles with aerodynamic diameters below 5 µm are most likely to settle in the tracheo-bronchial or pulmonary region of the lung. Due to the high water solubility the substance will dissolve into the mucus where it might be retained and transported out of the respiratory tract. Absorption through aqueous pores could not be excluded. However, no mortality or clinical signs were observed in an acute inhalation study up to 5 mg/L of the test substance.

Dermal absorption of the substance as such could be excluded since particles are unlikely to penetrate the skin. Dry particles will have to dissolve into the surface moisture of the skin or will be administered in a water-solution before uptake might occur.

Based on the physico-chemical properties penetration of the substance is not likely to occur as the high water solubility (> 500 g/L) as well as the low log Pow (< 0) limit uptake through the skin. However, single exposure of a high dose (2000 mg/kg bw) and repeated dermal administration of lower doses of the substance in a water-based solution revealed clinical signs and specific effects of systemic toxicity. These results indicate systemic availability after dermal application.

Taken together, physico-chemical properties and experimental data indicate bioavailability of the test substance via oral, dermal and inhalation route.

 

Distribution

Once systemic available the substance might diffuse through aqueous channels and pores to cross cell membranes. Based on the results of the repeated dose toxicity studies and the low log Pow value bioaccumulation of the test substance can be excluded.

 

Metabolism

The test item, in particular the main component, might be metabolised by formation of conjugates with glucuronic acid and/or sulfate to facilitate excretion. Potential reduction of the hydroxylamine could result in a secondary amine which was shown in anin vitrostudy with a keratinocyte cell line (Kroll et al. 1999). The minor component is a metabolic intermediate vital to the TCA respiration pathway.

 

There were indications of genotoxicity of the test item from the present clastogenic testin vitro(Covance, 1999). However, no formation of micronuclei was observed in anin vivomicronucleus assay in mice (Covance, 1999). Anin vitromutagenicity test revealed no increase of revertants in the absence and presence of metabolic activation (Covance, 1999). Thus, the test item and its metabolites are expected not to be genotoxic and metabolic activation is unlikely to occur.

 

Excretion

Due to the low molecular weight, the high water solubility (>500 g/L) and the presumed metabolism the test item and/or its metabolites are expected to be excreted via urine and via exhalation.

 

Conclusion

Based on the results of the experimental investigations as well as on the molecular weight and physico-chemical properties the test item is considered to be bioavailable via oral, inhalation and dermal route. Once systemic available the substance might diffuse through aqueous channels and pores to cross cell membranes. Metabolic conversion of the main component into a secondary amine is expected as well as conjugation by Phase-II-enzymes. The minor component is a metabolic intermediate vital to the TCA respiration pathway. Therefore, excretion via exhalation is expected. However renal excretion of the substance and/or its metabolites might be the main excretion pathway. Based on the results of the repeated dose toxicity studies and the low log Pow value bioaccumulation of the test substance can be excluded.