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Description of key information

Based on the molecular weight (<500 g/mol), the high water solubility, the low partition coefficient (log Kow -2.67 (at 21.3°C), it can be expected that oral absorption will be favoured but only to a limited extent due to the hydrophilic character of the substance. The adverse effects of the oral repeated dose gavage toxicity study and the reproduction/developmental toxicity screening test confirm that the oral absorption is limited as only changes in the stomach of males and females treated with 500 mg/kg bw/day were observed and these findings were considered to be indicative of local irritation rather than demonstrating systemic toxicity. The oral absorption factor is therefore set at 50%. Respiratory absorption can be expected, considering the hydrophilic character of the substance and its molecular weight (<200 g/mol). However, the low log Kow indicates that absorption directly across the respiratory tract epithelium by passive diffusion is limited since the log Kow is only -2.67. The respiratory absorption factor is therefore set to 100%. The substance is corrosive to the skin (category 1A) and serious eye damage category 1 as its pH value is 13.9 (> 11.5). It is expected that the penetration of the test substance into the lipid rich environment of the stratum corneum will not be favoured due to its low lipophilic character (log Kow of -2.67) resulting in a low dermal absorption. The dermal absorption factor is set to 50%.

 

Key value for chemical safety assessment

Absorption rate - oral (%):
50
Absorption rate - dermal (%):
50
Absorption rate - inhalation (%):
100

Additional information

THEMAH (Tris(2-hydroxyethyl) methylammonium hydroxide; CAS 33667-48-0; EC 251-624-7), is translucent, homogenous liquid. It was determined to have a water solubility of 548 g/L at 20.0 ± 0.5°C. Its partition coefficient and vapour pressure are low at log Kow -2.67 (at 21.3 ± 0.5 °C) and 0.49 Pa (at 25°C) respectively. It has a molecular weight of 181.23 g/mole. The substance is classified as skin corrosive category 1B and serious eye damage category 1 as its pH value is 13.9 (> 11.5). Moreover, the substance is considered to be acute oral and dermal toxicant category 4.

No toxicokinetic data (animal or human studies) are available on this substance. The data present in this dossier are based on physico-chemical parameters and will allow a qualitative assessment of the toxicokinetic behaviour of the test substance.

Absorption

Oral/GI absorption

Generally, substances with a molecular weight below 500 g/mole are favourable for absorption; also the test substance was found to be a miscible in water (water solubility = 548 g/L). Water-soluble substances will readily dissolve into the gastrointestinal fluids. However, the absorption of very hydrophilic substances by passive diffusion may be limited by the rate at which the substance partitions out of the gastrointestinal fluid. The very low partition coefficient (log Kow <-1) will limit the absorption. It is generally assumed that the absorption along the gastrointestinal tract predominantly takes place in the small intestine since it has a very large surface area and the longest transit time.

A repeated dose toxicity study combined with the reproduction / developmental toxicity was performed via oral gavage of Wistar rats (12 males and 12 females per dose group) (OECD 422; Griffiths, 2018). Once daily, for approx. 6 weeks for males and 8 weeks for females, the applied doses were 0, 75, 250 and 500 mg/kg bw/day.

One female animal died during blood sampling procedure, unrelated to treatment with the test item. There were no further unscheduled deaths during the study. Isolated occurrences of clinical signs like increased salivation and noisy respiration were observed in the high dose group. Significant reductions in body weight gain were observed but considered not related to test item treatment. There were no effects detected in food consumption, hematology and clinical biochemistry as well as in behavioral, functional performance, and sensory reactivity parameters. An increase in epididymis and prostate weights in males in the high and mid dose group and a decrease in heart weight in female animals in the mid dose group were considered to be incidental and unrelated to treatment with the test item. Gross pathology findings included isolated incidences of small and flaccid testis, fluid filled colon, masses on the epididymis, kidney, prostate and urinary bladder as well as pale pituitary or an increased pelvic space in the kidney, without histopathological correlated. Histopathological findings included changes in the glandular region including ulceration, erosion and inflammatory cell infiltration, diffuse or focal hyperplasia of the non-glandular region, occasionally accompanied by inflammatory cell infiltration. The stomach findings were considered likely to be indicative of local irritation rather than demonstrating systemic toxicity, however is considered to be adverse in the animals affected. No effects on estrous cycle, mating, fertility and gestation length, spermatogenesis were observed. There were no test item related microscopic findings in the reproductive tracts or the evaluation of the uterus or of follicles and corpora lutea in the ovaries. One female animal which was treated with 75 mg/kg bw/day exhibited a total litter loss. The on the study were typical for the age observed. No adverse effect of treatment with the test item was indicated by necropsy findings and clinical signs of surviving offspring, offspring body weight or body weight gain and litter weights or evaluation of thyroid hormones.

As a result, the default oral absorption factor is set to 50%.

Respiratory absorption

Given the vapour pressure of 0.49 Pa, the test substance is not a highly volatile substance and the availability for inhalation as a vapour is limited.

Generally, liquids readily diffuse/dissolve into the mucus lining of the respiratory tract. In the case of this substance, the high-water solubility will favour the rate at which the particles dissolve into the mucus. Very hydrophilic substances such as this one might be absorbed through aqueous pores especially with its molecular weight is <200 g/mol. The substance can also be retained in the mucus and transported out of the respiratory tract. However, the low log Kow indicates that absorption directly across the respiratory tract epithelium by passive diffusion is limited since the log Kow is only -2.67.

Based on the physicochemical properties, the respiratory absorption factor is set to 100%.

Dermal absorption

The substance is a liquid substance and therefore it is more easily taken up by the skin in comparison to solid products. In order to cross the skin, a compound must first penetrate into the stratum corneum (non-viable layer of corneocytes forming a complex lipid membrane) and may subsequently reach the viable epidermis, the dermis and the vascular network. It is expected that the penetration of the test substance into the lipid rich environment of the stratum corneum will not be favoured due to its low lipophilic character (log Kow of -2.67) resulting in a low dermal absorption. The high-water solubility of the substance suggest that it is soluble enough in water to partition from the stratum corneum into the epidermis (water solubility >10000 mg/l) but as mentioned above, this substance is not lipophilic enough to penetrate the into the first lipid membrane (stratum corneum).

Also, the substance is a strong acid classified as skin corrosive category 1B and serious eye damage category 1 as its pH value is 13.9 (> 11.5).

As a result, the default dermal absorption factor is set to 50%.

Distribution

The high-water solubility and moderate molecular weight predict that the substance will distribute widely through the body.

The log Kow value was experimentally determined to be -2.67, thus the substance is not likely to distribute into cells and the intracellular concentration is not expected to be higher than the extracellular concentration.

Accumulation

Based on the solubility of the test item, no deposition or accumulation is expected within the alveolar region of the lungs. The substance is not considered lipophilic and thus it is not expected to accumulate within the adipose tissue or the stratum corneum

Metabolism

Once absorbed, hydroxylation may occur to increase the solubility of the substance as well as oxidative deamination, followed by rapid sulfation or glucuronidation. Metabolism mainly takes place in the liver, causing route specific pre-systemic (or first pass) effects, especially after oral intake. Other metabolic changes may take place in the gastrointestinal (GI) flora or within the GI tract epithelia (mainly in the small intestine), respiratory tract epithelia (in the nasal cavity, trachea-bronchial mucosa and alveoli and skin), etc.

Excretion

The water soluble conjugated metabolites from Phase II biotransformation will be excreted from the systemic circulation through the urine. Most of them will have been filtered out from the blood by the kidneys, though a small amount can enter the urine directly by passive diffusion. There is also the potential for re-absorption into the systemic circulation across the tubular epithelium.

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