2,2'-dimorpholinyldiethyl ether

Endpoint summary

Description of key information

For this substance, no study is available for the determination of toxicokinetics (absorption, distribution, metabolism and excretion). Therefore, a qualitative assessment is performed on the basis of the physico-chemical properties of the substance.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Absorption rate - oral (%):

50

Absorption rate - dermal (%):

50

Absorption rate - inhalation (%):

100

Additional information

The test substance is a liquid with a high water solubility (miscible), a moderate log Kow (0.5) and a low vapour pressure (66 Pa). Its pKa is 6.8. The substance is found not to be a skin irritant but a mild eye irritant. The substance is not a skin sensitiser.

No toxicokinetic data (animal or human studies) are available on this substance. The information present in this document is mostly based on physico-chemical parameters which allow a qualitative assessment of the toxicokinetic behaviour of the test substance rather than a quantitative assessment.

 

Absorption

Oral/GI absorption

Following its high water solubility, the substance will readily dissolve into the gastrointestinal fluids and subsequently pass through aqueous pores or be carried through the epithelial barrier by the bulk passage of water.

Based on the moderate log Kow, absorption by passive diffusion will be favoured. Although its molecular weight which is >200 (244 g/mol), passive diffusion is not considered to be significantly hindered. 

It is generally thought that ionised substances do not readily diffuse across biological membranes. The intestine is where absorption after oral administration normally takes place. The pKa of the test substance suggests that this substance will be partly in its ionised form and hence diffusion can be hampered in some extent.

In an acute oral toxicity study (Industrial Bio-Test Laboratories, 1978 owned by huntsman), the substance was tested in rats (OECD 401) at following doses: 118.5, 400, 1350, 2025, 3088 and 4556 mg/kg. No deaths were observed up to and including 1350 mg/kg. The LD50 was derived to be 2025 mg/kg. At 3038 mg/kg bw slightly pale spleen was observed in one male and at 4556 mg/kg bw moderate postmortem autolysis was observed in two females and advanced postmortem autolysis was observed in two males. These observations may indicate some absorption of the test substance.

In a 28-day oral rat study (Imatanaka, 1994, owned by Huntsman), animals were exposed to vehicle (olive oil), or 8, 40, 150 and 600 mg/kg bw/day of the substance. At 600 mg/kg bw/day, animals died or were killed in extremis before the end of the exposure period. This dose was clearly toxic. The main cause of death seems to be vacuolization in many organs and tissues,indicating significant absorption of the test substance.

In a combined repeated dose/reprotox/developmental screening study performed with the test substance according to OECD Guideline 422 (Martell, 2013, owned by Huntsman), the NOAEL was 300 mg/kg bw/day for F0 males and females. The NOAEL for embryo-fetal toxicity was 300 mg/kg bw/day. These results do not deviate from the oral absorption assumption as the substance, in this study, was tested up to 300 mg/kg bw/day, a lower dose than the one for which effects (and therefore absorption) were observed in the 28 -day study.

In the gastro-intestinal tract hardly any degradation of the substance is to be expected.

The oral absorption factor is set to 50%, based on the anticipated hampered diffusion of the test substance as an ionized substance. The results of the toxicity studies do not provide reasons to deviate from this proposed value. 

 

 

Respiratory absorption

Given the vapour pressure of 66 Pa, the test substance is a low volatile substance and the availability for inhalation as a vapour is limited.

Once in the respiratory tract, the very hydrophilic substance may be retained within the mucus, and subsequently absorption may occur. Absorption directly across the respiratory tract epithelium by passive diffusion is favoured in view of the moderate log Kow value.

Based on the above considerations, the inhalatory absorption factor for the substance is set to 100%, as a worst case assumption.

 

Dermal absorption

In view of its high water solubility and moderate log Kow, penetration into the lipid-rich stratum corneum and hence dermal absorption might be limited although its physical form (liquid) favours dermal absorption.

In an acute dermal toxicity study (Hunstman, 1978), New Zealand White male/female rabbits were acutely exposed to 1350, 2025, 3038 and 4556 mg/kg bw of DMDEE. No mortality was observed at 1350 or 2025 mg/kg bw/d. In the 3038 mg/kg bw 2 animals out of 4 died. All animals (4/4) died in the 4556 mg/kg bw dosing group. Therefore, after 14 days of observation, an LD50 value of 3038 mg/kg bw was reported. These observations may indicate some absorption of the test substance although the amounts dosed were higher than the upper dose used in acute dermal toxicity guidelines.

The substance is found not to be a skin irritant nor a skin sensitiser.

Generally default values of 10% and 100% are used for dermal absorption, based on molecular weight and log Kow value (ECHA guidance on IR&CSA, R.7c). The dermal absorption factor is therefore set to 100% (default), based on a molecular weight < 500 and a log Kow in the range of -1 to 4. However, it is also generally acknowledged that dermal absorption will not be higher compared to oral absorption; as a result, the dermal absorption factor for the substance is set to 50%. The results of the available toxicity studies using the dermal route do not provide reasons to deviate from this proposed value.

 

Distribution

The high water solubility, moderate log Kow and low molecular weight predict that the substance will distribute widely through the body. This is confirmed by the observations in a subacute oral toxicity study, in which vacuolization has been observed in many organs and tissues, indicating that the substance has distributed all through the animal’s body.

 

Accumulation

In view of the moderate log Kow and the high water solubility, the substance will not easily accumulate in the body (lung, adipose tissue, stratum corneum).

 

Metabolism

Once absorbed, the substance might undergo phase I biotransformation (including aliphatic and aromatic hydroxylation and cleavage of the ether group (O-dealkylation)) followed by conjugation reactions (phase II) including glucuronidation and sulfation.

 

Excretion

Given the high water solubility and low molecular weight (amplified by the expected cleavage of the ether bond), the substance and its metabolites will be mainly excreted via the urine.