Ethanol, 2,2'-oxybis-, reaction products with ammonia, morpholine derivs. residues

Endpoint summary

Description of key information

Based on the molecular weight (185 g/mol, <500 g/mol), the high water solubility (100 g/L) and the moderate partition coefficient (log Pow 0.565 and 0.3), it can be expected that oral absorption will be favoured. The oral absorption factor is therefore set to range from 50-100%. Respiratory absorption might be expected, considering the molecular weight (<200 g/mol) of the substance but also its moderate log Pow indicating a favourable absorption directly across the respiratory tract epithelium by passive diffusion. The respiratory absorption factor is therefore set to 100%.

The substance is only mildly irritant to the skin (no classification according to CLP). It is expected that the penetration of the test substance into the lipid rich environment of the stratum corneum will only occur to a limited extent as it is weakly lipophilic (log Pow of 0.565). Considering the high water-solubility, dermal uptake of the substance is expected to be moderate to high and dermal absorption factor is set to 50-100%.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Absorption rate - oral (%):

100

Absorption rate - dermal (%):

100

Absorption rate - inhalation (%):

100

Additional information

The test substance Ethanol, 2,2'-oxybis-, reaction products with ammonia, morpholine derivs. Residues (CAS 68909-77-3) is a dark brown liquid with a molecular weight of 185 g/mol. It has a high water solubility (with the bounded value of 100 g/L), a moderate partition coefficient (log Pow 0.565 at 20°C) and a low vapour pressure (0.55 Pa). The substance is only mildly irritating to the skin (no classification) and is considered as serious eye damage (category 1).

As the test item is a UVCB substance, not all physico/chemical properties are clearly defined but reflect the properties of a group of substances. 

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

 

Absorption

Oral/GI absorption:

Mechanisms by which substances can be absorbed in the gastro-intestinal (GI) tract include the passage of small water-soluble molecules (molecular weight up to around 200) through aqueous pores or carriage of such molecules across membranes with the bulk passage of water. As the test substance is miscible with water and has a mean molecular weight below 200, this passive diffusion will be the predominant mechanism for absorption in the GI tract. In addition, moderate octanol/water partition coefficient (log Pow) values (between -1 and 4) are favourable for absorption by passive diffusion; as log Pow values of 0.565 and <0.3 were obtained, uptake of several components in the test substance might be hampered. Ionized substances do not readily diffuse across biological membranes and the pKa is an important parameter to indicate ionization at a GI relevant pH. For UVCB substances, this parameter can however not easily be defined. Following pKa values of individual components in the test substance, it can be concluded that some ionization at the biologically relevant pH range might occur, thus hampering the uptake of these individual components. Following the above, it can be concluded that the test substance will show signs of systemic exposure after oral administration.

In an acute oral toxicity study (OECD 420, K1; Calvert Laboratories lnc, 2010), rats of both sexes were exposed to the test substance at 1000, 2000 or 5000 mg/kg bw. Five out of ten animals at the highest dose died. None of the animals died at 1000 mg/kg bw and 2000 mg/kg bw. The LD50 was established at 5000 mg/kg bw. Necropsy of the animals found dead on the study revealed distended and/or red to black fluid-filled stomachs. Terminal necropsy of the remaining animals revealed no visible lesions.

In a repeated dose toxicity study (OECD 407, K2; Walz, 2011), in Wistar rats of both sexes, the test substance was given daily for 28 days at the dose level of 100, 500 and 1000 mg/kg/day. The No Observed Adverse Effect Level (NOAEL) for systemic toxicity of the test item was considered to be 1000 mg/kg bw/day, as there the only statistically significant effects in absolute and relative female kidney weights could not be related to any macroscopic or microscopic findings or changes in clinical chemistry parameters.

In another repeated dose toxicity study (OECD 408, K1; Edwards, 2018), in Wistar rats of both sexes, the test substance was given daily for 90 days at the dose level of 10, 100, and 1000 mg/kg/day. The only observed changes in histopathology were an increased rarefaction in the liver at 1000 mg/kg bw/day which was non-adverse. Therefore, the NOAEL for either sex can be considered to be 1000 mg/kg bw/day.

In a reproductive/developmental toxicity screening in rats (OECD 421, K1; Calvert Laboratories, 2010), 1000 mg/kg/day of test item was given by daily gavage to 10 animals/sex (a minimum of 4 weeks for males and starting for a minimum of 15 days prior to cohabitation, during cohabitation and from presumed gestation days 0 through day 19 of gestation for females). One female animal was found dead. No treatment-related effects were observed in any of the parameters investigated. There was no treatment-related effect on reproductive performance or in reproductive parameters. The incidence of neonates born alive/found dead, stillborn or missing between lactation days 0 - 4 was comparable among study groups. A NOAEL of 1000 mg/kg bw/day was established.

In an extended one-generation reproductive toxicity study in rats (OECD443, K1; Labcorp Early Development Laboratories Ltd, 2021), the doses of 150, 450 or 1000 mg/kg bw/day were given via oral gavage to 24 animals/sex/group in the F0 generation. In the F1 generation (divided in two cohorts 1A and 1B), 20 animals/sex/group/cohort received the same doses. The test item was given to F0 generation animals for 17-18 weeks. The F1 generation animals received it from weaning on Day 21 of age for approximately 10-11 weeks. There was no mortality and no clinical signs associated to the test item administration observed at any tested generation and dose groups. Reproductive parameters of the F0 and F1 generation were unaffected by treatment and macroscopic and microscopic evaluation did not show any organ target toxicity. Biochemical and urine analysis as well histopathological evaluation revealed no treatment related adverse effect. A NOAEL of 1000 mg/kg bw/day was established, confirming results in short term studies (see above).

In a prenatal development toxicity in rabbits (OECD 414, K1; Renaut, 2019), three groups of 22 females received the test substance at doses of 125, 250 or 500 mg/kg/day by oral gavage administration, from Day 6 to 28 after mating. Test item related changes included a low maternal body weight gain and food consumption at 500 mg/kg/day. Embryo-fetal survival, fetal and placental weight were unaffected by treatment and the fetal pathology findings at 500 mg/kg/day were minor skeletal variants that were not considered adverse. A NOEL of 250 mg/kg/day was concluded for both maternal toxicity and embryo-fetal development.

For risk assessment purposes, 50 to 100% oral absorption of the test substance is proposed. The results of the toxicity studies do not provide reasons to deviate from this proposed oral absorption factor.

 

Dermal absorption

The test substance is a water-soluble liquid and as such readily available for absorption through the skin. As the test substance is miscible with water and has a moderate log Pow (0.565 and <0.3) it may contain components which are too hydrophilic to cross the lipid rich environment of the stratum corneum. Dermal uptake might thus be slowed. With a molecular mass below 500 and log Pow in the range [-1, 4], the data meet the criteria for 100% dermal absorption as given in the ECHA Endpoint Specific Guidance 7.c for the implementation of REACH (R.7.12 “Guidance on Toxicokinetics”).

In an acute dermal toxicity study (OECD 402, K1; Calvert Laboratories lnc, 2010), 10 rats/sex were exposed to 2000 mg/kg bw of the test substance. No mortality occurred. Reversible effect of local erythema and edema were observed in males and in one female. In the 4 remaining females, necrosis and slouching appeared. The acute dermal LD50 was determined to be greater than 2000 mg/kg bw.

 

Based on the above, the dermal absorption factor is set to range from 50 to 100%.

 

Respiratory absorption

The test substance being a water soluble liquid will readily dissolve into the mucus lining the respiratory tract. Lipophilic substances (log P >0) would then have the potential to be absorbed directly across the respiratory tract epithelium. Hydrophilic substances might be absorbed through aqueous pores (for substances with molecular weights below around 200 as the test substance) or be retained in the mucus and transported out of the respiratory tract, subsequently swallowed and becoming available for oral absorption. In view of its low to moderate, but partly unbounded log Pow value (0.565 and <0.3) both processes will be relevant for its components. For risk assessment purposes the inhalation absorption of the test substance is set at 100%.

 

Distribution

In general, the smaller the molecule, the wider the distribution. Small water-soluble molecules, like the test substance, will diffuse through aqueous channels and pores. The high water solubility and low molecular weight predict that the substance will distribute widely through the body after absorption.

Based on the moderate log Kow and the high water solubility, the substance will not likely distribute into cells through the membrane and hence the intracellular concentration is not expected to be higher than the extracellular concentration.

 

Accumulation

In view of the moderate log Kow and the higher water solubility, the test substance is not expected to accumulate in the body (lung, adipose tissue, stratum corneum). Based on the liquid form of the test substance, no accumulation is expected within the lungs.

 

Metabolism

Once absorbed, extensive hydroxylation (aliphatic carbons) may occur to increase the solubility of the substance and oxidative deamination (tertiary amines), followed by rapid sulfation or glucuronidation is expected.

 

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.