AERO 5100 PROMOTER

Endpoint summary

Description of key information

No studies are available. The molecular weight, physicochemical properties incl. water solubility and octanol-water partition coefficient of the substance suggest that oral, inhalative and dermal absorption occur. Widely distribution within the water compartment of the body after systemic absorption is because of lipophilicity of the test substance not expected. However, the distribution into cells particularly in fatty tissues is likely. Based on its log Pow the test substance is not considered to accumulate. The test substance might be metabolized after absorption. Excretion predominantly via the urine is expected.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Additional information

In accordance with Annex VIII, Column 1, Item 8.8 of Regulation (EC) 1907/2006 and with Guidance on information requirements and chemical safety assessment Chapter R.7c: Endpoint specific guidance (ECHA, 2017), assessment of the toxicokinetic behaviour of the test substance was conducted to the extent that can be derived from the relevant available information on physicochemical and toxicological characteristics. There are no studies available evaluating the toxicokinetic properties of the substance.

The test substance is a pale brown liquid with a molecular weight of 173.27 g/mol and a water solubility of 497 ± 33 mg/L at 20 °C. The substance has a low vapour pressure of 7.9 Pa at 25 °C and the log Pow is 2.84 at 23 °C.

Absorption

The major routes by which the test substance can enter the body are via the lung, the gastrointestinal tract, and the skin. To be absorbed, the test substances must transverse across biological membranes either by active transport mechanisms or - as being the case for most compounds - by passive diffusion. The latter is dependent on compound properties such as molecular weight, lipophilicity, or water solubility (ECHA, 2017).

Oral

In general, low molecular weight (MW≤500) and moderate lipophilicity (log Pow values of -1 to +4) are favourable for membrane penetration and thus absorption. The molecular weight of the test substance is relatively low with 173.27 g/mol, favouring oral absorption of the compound. This is supported by the determined log Pow value of 2.84, being advantageous for oral absorption. Moreover, water-soluble substances will readily dissolve in the gastrointestinal fluids which favour oral absorption. One other mechanism, by which small water-soluble molecules (molecular weight up to around 200) can be absorbed in the GI tract include the passage through aqueous pores or carriage of such molecules across membranes with the bulk passage of water (Renwick, 1994). Moreover, the observation of systemic toxicity following exposure by any route is an indication for substance absorption; however, this will not provide any quantitative information.

In an acute oral toxicity study conducted with the test substance in rats (McRae, 1998) signs of systemic toxicity were observed. Clinical signs were observed at 500 mL/kg bw in preliminary and main study. Reddening of the intestinal mucosa and the stomach lining was found in the moribund animals. Using Probit analysis, the LD50 for male and female rats was calculated to be 1.24 mL/kg bw (equivalent to 1265 mg/kg bw). Piloerection, increased salivation and ungroomed appearance were observed in all animals within 7 min of dosing. These signs persisted and were accompanied at later intervals on Day 1 or thereafter during the study with hunched posture, waddling/unsteady gait, lethargy, partially closed eyelids, pallid extremities, walking on toes, dull colouring to eyes in all rats and accompanied in a number of animals by abnormal respiration, increased lacrimation, increased sensitivity to touch, thin appearance, protruding eyes, discoloured bright/yellow urine, body tremors, prostration, blue/cold extremities and swollen abdomen. Recovery of surviving rats as judged by external appearance and behaviour was complete by Day 6. The body weight gain was not affected by the administration of the test substance and no abnormalities were observed at necropsy. Based on the results of this study, the oral LD50 value was determined to be > 500 - < 2000 mg/kg bw in rats.

In a supporting acute oral toxicity study (Kingery, 1982), mortality occurred 5 h after dosing at 5000 mg/kg bw (1/10), on Days 1 to 2 at 700 mg/kg bw (1/10), at 900 mg/kg bw (9/10) and at 5000 mg/kg bw (9/10). Signs of systemic toxicity were observed 30 min after dosing at all dose levels. Reactions ranged from lethargy, ataxia, inactivity, salivation, lacrimation to bodies cool to touch and slowed respiration. The severity of reactions appeared similar at all dose levels on the day of dosing but the incidence and length of time effected as well as mortality appeared directly related to amount of test substance ingested. Mean body changes appeared to be decreased for animals found dead. Positive gross pathologic findings (intestines mucoid with or without focal hemorrhage, focal hemorrhage or congestion on stomach and/or focal hemorrhage of lung) occurred at 700, 900 and 5000 mg/kg bw. Based on the results of this study, the oral LD50 value was calculated to be 773 mg/kg bw in rats.

Based on available data from the acute oral studies, oral toxicity was observed with the test substance and thus absorption of the test via the gastrointestinal tract has evidently occurred.

Dermal

The dermal uptake of liquids and substances in solution is generally expected to be higher than that of dry particles. Molecular weights below 100 g/mol favour dermal uptake, while for those above 500 g/mol the molecule may be too large. Thus, for the molecular weight level of the test substance dermal uptake can be seen to be moderate. The log Pow value of the test substance is optimal for dermal absorption. For dermal uptake sufficient water solubility is needed for the partitioning from the stratum corneum into the epidermis. Therefore, if the water solubility is between 100 and 10000 mg/L the dermal absorption is anticipated to be moderate to high (ECHA, 2014).

The dermal permeability constant Kp of the substance was estimated to be 0.0129 cm/h using DermwinTM(v.2.01) and taking into account the molecular weight of 173.3 g/mol and the log Pow of 2.84. Thus taking also into account the water solubility of 497 mg/L, the absorption of the test substance is anticipated to be moderate to high. Data from an acute dermal toxicity limit test (McRae, 1998) revealed lethargy, partially closed eyelids and pallid extremities, notable between 4 and 6 h after dosing in one animal. No body weight gain was observed in one male and a slightly low weight gain was observed in two females on Day 8 only. No mortality occurred and thus the dermal LD50 value was greater than 2000 mg/kg bw. Against the background of the demonstrated toxic potency after oral exposure, the dermal toxicity seems to be of lower magnitude, presumably due to a lower dermal uptake in contrast to oral absorption.

Inhalation

Moderate log Pow values (between -1 and 4) are favourable for absorption directly across the respiratory tract epithelium by passive diffusion. However, the test substance has a low vapour pressure of 7.9 Pa at 20 °C. Therefore, under normal use and handling conditions, inhalation exposure and thus availability for respiratory absorption of the substance in the form of vapour can be considered negligible.

Distribution

Distribution of a compound within the body depends on the physicochemical properties of the substance especially the molecular weight, the lipophilic character and the water solubility. In general, the smaller the molecule, the wider is the distribution. If the molecule is lipophilic, it is likely to distribute into cells and the intracellular concentration may be higher than extracellular concentration particularly in fatty tissues (ECHA, 2017).

Since the test substance is lipophilic (log Pow 2.84) the distribution into cells is likely and the intracellular concentration may be higher than extracellular concentration particularly in fatty tissues, if the substance is absorbed systemically. Substances with log P values of 3 or less would be unlikely to accumulate in adipose tissues with the repeated intermittent exposure patterns normally encountered in the workplace but may accumulate if exposures are continuous. Once exposure to the substance stops, the substance will be gradually eliminated at a rate dependent on the half-life of the substance.

The acute oral toxicity study (McRae, 1998) provided evidence of systemic distribution of the substance or its metabolites with macroscopic findings in the subcutaneous tissue, brain, heart, liver, spleen, kidneys and the alimentary tract. In the subacute toxicity study (Chambers, 1998), changes in organ weights supported this assumption and hepatic microscopic changes identified the liver as the target organ.

 

Metabolism

No metabolism studies are available with the test substance itself. Prediction of compound metabolism based on physicochemical data is very difficult. Structure information gives some but no certain clue on reactions occurring in vivo. The potential metabolites following enzymatic metabolism were predicted using the QSAR OECD toolbox (v3.4, OECD, 2016). This QSAR tool predicts which metabolites may result from enzymatic activity in the liver and in the skin, and by intestinal bacteria in the gastrointestinal tract. 12 hepatic and 10 dermal metabolites were predicted for the test substance, respectively. Primarily, hydroxylation of the substance occurs in the liver. In general, the hydroxyl groups make the substances more water-soluble and susceptible to metabolism by phase II-enzymes. Up to 43 metabolites were predicted to result from all kinds of microbiological metabolism for the test substance. Most of the metabolites were found to be a consequence of the degradation of the molecule. There was evidence for differences in genotoxic potencies due to metabolic changes in elicited in vitro genotoxicity tests. Two studies performed on genotoxicity in bacteria (Ames test) were positive for strains TA 1535 and TA 100 tested with metabolic activation and negative without metabolic activation, and negative for remaining strains with and without metabolic activation (Finch, 1981; May, 1998). All other genotoxicity studies (HPRT and micronucleus test in vivo) were negative, with and without metabolic activation (Finch, 1981; Lloyd, 1998; Mason, 2000).

 

Excretion

Only limited conclusions on excretion of a compound can be drawn based on physicochemical data. Due to metabolic changes, the finally excreted compound may have few or none of the physicochemical properties of the parent compound. In addition, conjugation of the substance may lead to very different molecular weights of the final product. The molecular weight (< 300 g/mol) and the water solubility of the molecule are properties favouring excretion via urine. Additionally, discolouration of the urine in the acute oral toxicity study (McRae, 1998) provided evidence of renal excretion.

 

References

ECHA (2017): Guidance on information requirements and chemical safety assessment – Chapter 7c: Endpoint specific guidance. European Chemicals Agency, HelsinkiLiterature

Renwick, A.G. (1994) Toxicokinetics - pharmacokinetics in toxicology. In Hayes, A.W. (ed.) Principles and Methods of Toxicology. Raven Press, New York, p 103 as cited in ECHA 2014