3-methoxypropylamine

Endpoint summary

Description of key information

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.

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

3-methoxypropylamine (CAS 5332-73-0), is a liquid with a high water solubility (miscible; 100 g/L as limit value), a moderate log Kow (-0.5) and a moderate vapour pressure (1.56 kPa). Its pKa is 10.4. It has a low molecular weight of 89.14 g/mole. The substance is demonstrated to be corrosive to the skin and sensitizing to the skin.

Its chemical structure is an aliphatic carbon chain containing an ether and a primary amine as functional groups. Because of the amine group, the substance have an alkaline character. The ether group is chemically inert and therefore most of the chemical reactions involve the primary amine group.

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 are favourable for absorption; also the test substance is found to be miscible in water (>100 g/L). Water-soluble substances 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. In addition, the moderate partition coefficient (-1 < log Kow < 4) also favours absorption (log Kow -0.5). 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. The substance is demonstrated to be corrosive to the skin (Kiecza, 1986; Mallory, 1990) and therefore it could enhance penetration by local necropsy of gastrointestinal tissue. However, based on its high pKa value (10.4), the substance is ionised at the pH values of the gastrointestinal tract and therefore, readily diffusion across biological membranes expected to be limited.

In an acute oral toxicity study, the oral LD50 in male/female Sprague-Dawley rats was determined to be 668.1 mg/kg bw in a study conducted similarly to OECD Guideline 401 (Mallory VT, 1991). Necropsy of the animals sacrificed during the study revealed distended and/or fluid filled stomachs and intestines, and pale livers and kidneys. Terminal necropsy of the remaining animals revealed distended fluid-filled intestines in just one female rat. These observations may indicate significant absorption of the test substance.

The hydrochloride salt of the test substance has been tested in a subacute oral toxicity study (Combined repeated oral toxicity study with the reproduction/developmental toxicity screening test; OECD 422). Clinical pathology examinations suggested a slightly impaired liver function of the high dose females (BASF, 2007). These data give an indication that absorption has occurred after oral intake.

The oral (gavage) administration of the test substance for up to ninety consecutive days, to Wistar rats of both sexes at dose levels of 10, 30 and 100 mg/kg bw/day resulted in unscheduled death of one male and two females treated with 100 mg/kg bw/day. These deaths were not associated with target organ histopathological changes which could point to systemic toxicity. The evidence of degenerative and inflammatory changes in the upper respiratory tract of these animals supports the conclusion that the deaths were associated with the process of gavage dose administration of an irritant material and the pathology was due to gastric reflux. The microscopic stomach changes identified in surviving animals of either sex at 100 mg/kg bw/day were also considered to be the result of gastric irritancy rather than attributable to true systemic toxicity. Therefore, the NOAEL for systemic toxicity was considered to be 100 mg/kg bw/day.

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

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

Respiratory absorption

Given the moderate vapour pressure of 1.56 kPa, the 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 the test substance, the high water solubility will favour the rate at which the particles dissolve into the mucus. Hydrophilic substances such as this one might be absorbed through aqueous pores. The test substance can also be retained in the mucus and transported out of the respiratory tract. However, the moderate log Kow would indicate a favourable absorption directly across the respiratory tract epithelium by passive diffusion.

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

Dermal absorption

The test substance is a liquid and therefore 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 be possible to a limited extent due to the limited lipophilic character (log Kow -0.5) of the substance resulting in a low dermal absorption. However, water solubility is sufficiently high to partition from the stratum corneum into the epidermis.

As the test substance is corrosive, absorption/penetration will be enhanced. The test substance has been demonstrated to be sensitising to the skin. It can be concluded that uptake must have been occurred although it may only have been a small fraction of the applied dose.

In an acute dermal toxicity study (Mallory VT, 1991), rabbits were exposed to 3000 mg/kg of the test substance for 24 hours. Terminal necropsy of the animals revealed mottled (9/10 animals), pale (1/10 animal), dark red (2/10 animals) or tan (3/10 animals) lungs and necrosis of underlying muscle tissue at the application site (10/10). Based on this data it could be concluded that absorption occurred in some extent after acute dermal exposure.

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 for the test substance is set to 50%.

Distribution

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

Based on the log Kow < 0, the substance will not likely distribute into cells and hence the intracellular concentration is not expected to be higher than the extracellular concentration.

Pale livers and kidneys where observed at necropsy (macroscopic observations) in a subacute oral toxicity study (BASF, 2007). This will not provide any information on the amount of the test substance that has distributed to any particular site but it can give evidence of distribution through the animal’s body.

Accumulation

Based on the liquid form of the test substance, no accumulation is expected within the lungs. As the substance is poorly lipophilic (low log Kow and high water solubility), the test substance is not expected to accumulate in the body (within the adipose tissue or the stratum corneum).

Metabolism

Once absorbed, the aliphatic carbons as well as the primary nitrogen will undergo extensive hydroxylation, followed by rapid sulfation or glucuronidation. Direct conjugation at the nitrogen in the parent compound is expected. Also extensive cleavage of the ether bound is anticipated.

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.

Given the high water solubility and low molecular weight, the test substance and its metabolites will be mainly excreted via the urine.