3-butoxypropylamine

Endpoint summary

Description of key information

No toxicokinetic data (animal or human studies) are available on the test substance. This evaluation based on physico-chemical parameters 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

BOPA (3-butoxypropan-1-amine; CAS 16499-88-0; EC 240-566-8), is a colorless liquid with an amine-like odour. It was determined to be a substance fully miscible in water (water solubility > 1000 g/L) with a moderate partition coefficient (log Kow = 1.05 at 20°C) and a vapour pressure of 129 Pa (at 20°C). It has a molecular weight of 131.216 g/mole. The substance is demonstrated to be corrosive to the skin (category 1A) based on the criteria of the CLP regulation (EC) No 1272/2008.

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. In addition, the test substance was found to be fully miscible in water. 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 moderate partition coefficient (-1 <log Kow <4) will favour absorption but only to a limited extent. 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.

In an acute oral toxicity study (OECD 425; Lemoncelli, 2014), the test substance was administered via oral gavage on a single occasion at dose levels of 55, 175 and 550 mg/kg to 2, 4 and 2 female rats respectively. The duration of observation period following administration was 14 days. Mortality/morbidity, clinical observations, body weights and necropsy of survivors were performed. At the dose of 550 mg/kg, the two out of two animals were found dead 30 mins post-dosing. For the dose of 175 mg/kg, 2 out of 4 females were found dead 30 min post-dosing and for the dose 55 mg/kg, no mortality was observed in any animals. At the 175 mg/kg dose, the surviving animals exhibited abnormal gait and stance, tremors, and decreased body tone, at 30 minutes post dose. At 4 hours post dose, only abnormal gait and stance as well as piloerection (for 1 animal) was noted. From Days 2-15, no clinical signs were observed except for 1 animal with only piloerection on day 2 which disappeared on day 3 onward. At the dose of 55 mg/kg the animal appeared normal from 30 minutes post dose through Day 15. No biologically significant effect was seen on body weight and terminal necropsy revealed no visible lesions in the any of the animals except the ones dosed at 550 mg/kg, found dead 30 minutes post dose on Day 1, whose necropsy revealed bright red intestines. Based on the results of this study, the estimated oral LD50 for the test substance in rats is 175 mg/kg and the test substance is therefore considered classified as GHS Category 3.

A combined repeated dose toxicity study with reproductive/developmental screening was performed via oral gavage of Wistar rats (12 males and 12 females per dose group) (OECD 422; Edwards, 2018). Once daily, for approx. 6 weeks for males and 8 weeks for females, the applied doses were 0, 30, 60, 120 (high dose from day 0 to 11), and 90 mg/kg bw/day (high dose from day 11 to the end of the study). Three females in the 120 mg/kg bw/day dose group, were killed in extremis due to adverse clinical signs including noisy, labored and gasping respiration, pilo-erection, lethargy, hunched posture and distended abdomen. Marked necrosis of the trachea was observed in 2/3 females, due to possible easophageal reflux. The remaining female showed no notable changes. A further female at 120/90 mg/kg bw/day died during the blood sampling procedure on Day 13 post partum (Day 51 of the study), without any notable changes at necropsy or histopathology. There were no further unscheduled deaths during the study. At 120/90 mg/kg bw/day animals of either sex exhibited increased salivation and noisy respiration on a number of occasions throughout the study. Similar observations were also seen at the lower dose levels of 60 and 30 mg/kg bw/day in both sexes; albeit at a lower frequency to animals dosed with 120/90 mg/kg bw/day.

There were no toxicologically significant effects detected in the behavioral assessments. There were no toxicologically significant changes detected in the functional performance parameters measured. There were no treatment-related changes in sensory reactivity. Males treated with 120 mg/kg bw/day initially showed a reduction in body weight gains during the first two weeks of treatment. Following the reduction of the dose level to 90 mg/kg bw/day body weight gains were generally similar to controls. No such effects were identified in females treated with 120/90 mg/kg bw/day or animals of either sex at 30 or 60 mg/kg bw/day. At 120/90 mg/kg bw/day food consumption for animals of either sex was slightly lower compared to controls during the first and/or second week of treatment. Food intake thereafter was comparable to controls. No such effects were detected in animals of either sex at 60 or 30 mg/kg bw/day or for females treated with 120/90 mg/kg bw/day during gestation and lactation phases. Similar trends were noted for food conversion efficiency. Daily visual assessment of water consumption did not reveal any significant intergroup differences.

Assessment of hematology parameters did not indicate any obvious effect of treatment for either sex at 30, 60 or 120/90 mg/kg bw/day. Assessment of blood chemistry parameters did not indicate any obvious effect of treatment for either sex at 30, 60 or 120/90 mg/kg bw/day. There were no treatment-related abnormalities detected at necropsy.

Evaluation of Thyroxine (T4) in adult males and offspring at Day 13 of age did not identify any obvious effect of treatment or indication of endocrine disruption at 30, 60 or 120/90 mg/kg bw/day. There were no toxicologically significant changes detected in the organ weights measured.  

Histopathological examination did not reveal any findings considered to be related to treatment with the test item in animals surviving until the end of the treatment period.  

The three animals that died during the first week of treatment, 2/3 females showed marked necrosis in the trachea and the deterioration of health was considered to be related to this change, which possibly reflects esophageal reflux. With no notable changes apparent for Female 91 or Female 87 which died during the latter stage of the study.

The oral administration of the test substance to rats by gavage at dose levels of 30, 60 and 120 mg/kg bw/day resulted in the premature death of three females within the first week of treatment at 120 mg/kg bw/day. Microscopic examination revealed marked necrosis of the trachea due to possible esophageal reflux in two of these animals. This dose level was reduced to 90 mg/kg bw/day on Day 11 of study and there were no further treatment-related deaths.

 

The substance is classified as a Cat 1A skin corrosion and a Cat 1 serious eye damage (corrosion). Observations of this nature are common following the oral administration of a corrosive or irritant test item formulation and are considered not to represent an adverse systemic effect of treatment. Therefore, these effects do not, by themselves or together, indicate “significant” toxicity in relation to Specific Organ Toxicity – Repeated Exposure (STOT RE) classification in GHS, but a localized effect as a result of dosing. Since these observations in the substance study are considered not to support STOT RE classification, there is no need for this classification. Since no adverse effects have been identified at 90 mg/kg bw/day or below, this dose level for either sex, the NOAEL remain 90 mg/kg bw/day per study conclusion.

Based on the available data and on the physicochemical characteristics, the oral absorption factor is set to 50%.

Respiratory absorption

Given the vapour pressure of 129 Pa at 20°C, the test substance is not highly volatile 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 test substance, the high water solubility will favor 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 test substance can also be retained in the mucus and transported out of the respiratory tract. However, the low to moderate log Kow would indicate a favourable absorption directly across the respiratory tract epithelium by passive diffusion but to a limited extend since the log Kow is only 1.05 at 20°C.

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

Dermal absorption

The test substance is a liquid 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 BOPA into the lipid rich environment of the stratum corneum will be favoured to a small extent due to the limited lipophilic character (log Kow of 1.05) of the substance resulting in a low to moderate dermal absorption. Considering, its high-water solubility, dermal uptake of the substance is expected to be moderate to high. It is soluble enough in water to partition from the stratum corneum into the epidermis (water solubility >1000 g/L).

An in vivo skin irritation test on a New Zealand White rabbit (OECD 404; Lemoncelli, 2014) showed severe erythema and severe edema after 3 mins of exposure through the Day 14 period. Necrosis was also present through Day 14 as well as sloughing from Days 11-14 was. No mortality was observed. The test substance was classified as Category 1A according to GHS (Corrosive responses in at least one animal following exposure ≤ 3 min during an observation period ≤ 1 h).

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.

Since the substance is lipophilic (log Kow>1) it is likely to distribute into cells leading to a higher intracellular concentration in comparison to the extracellular concentration particularly in fatty tissue; but only to a limited extent considering the low to moderate Kow of the test substance.

Accumulation

Based on the liquid form of the test substance no accumulation is expected within the lungs. The substance is only low to moderately lipophilic it is not expected to accumulate within the adipose tissue or the stratum corneum.

Metabolism

Once absorbed, extensive hydroxylation may occur to increase the solubility of the substance and oxidative deamination, 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.