Diethylammonium chloride

Endpoint summary

Link to relevant study record(s)

Reference

Reference 1

Endpoint:

basic toxicokinetics in vivo

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

supporting study

Justification for type of information:

refer to analogue justification provided in IUCLID section 13

Reason / purpose for cross-reference:

read-across source

Executive summary:

Excerpt from NTP Report about ADME of diethylamine:

Very little information on the disposition and metabolism of diethylamine in experimental animals or humans was found in a review of the literature. The reaction of dietary amines with nitrite to produce nitrosamines, which are potential carcinogens, has been demonstrated both in vitro and in vivo (Sander, 1967; Sander et al., 1968; Mirvish, 1975). However, in Wistar rats administered 600 ppm diethylamine and sodium nitrite in the diet, diethylnitrosamine could not be detected (Galea et al., 1975). Diethylnitrosamine was not detected in blood or milk of goats fed kale containing 3% potassium nitrate followed by administration of a single oral dose of 200 mg/kg diethylamine hydrochloride (Juskiewicz and Kowalski, 1976). Monoamine oxidase is assumed to play an important role in the metabolism and detoxification of the aliphatic amines. Monoamine oxidase catalyzes the deamination of primary, secondary, and tertiary amines. Monoamine oxidase is widely distributed in tissues and is most concentrated in the liver, kidney, and intestinal mucosa (Beard and Noe, 1981). Traces of diethylamine (less than 0.5% of the dose) were detected in the urine of human volunteers following oral doses of triethylamine (Åkesson et al., 1989). Diethylamine was also found in the gastro-intestinal tract after oral doses of triethylamine-N-oxide, the oxidative metabolite of triethylamine, indicating that triethylamine-N-oxide is dealkylated in the gastro-intestinal tract to diethylamine. There was no evidence that diethylamine produced from triethylamine-N-oxide was subsequently metabolized to N-nitrosodiethylamine in the stomach.

References:

Åkesson, B., Vinge, E., and Skerfving, S. (1989). Pharmacokinetics of triethylamine and triethylamine-N-oxide in man. Toxicol. Appl. Pharmacol. 100, 529-538.

Beard, R.R., and Noe, J.T. (1981). Aliphatic and alicyclic amines. In Patty’s Industrial Hygiene and Toxicology, 3rd ed. (D.G. Clayton and F.E. Clayton, Eds.), Vol. 2B, pp. 3135-3173. Wiley-Interscience Publication, New York, NY.

Galea, V., Preda, N., and Simu, G. (1975). Experimental production of nitrosamines in vivo. IARC Sci. Publ. (N-Nitroso Compd. Environ. Proc. Work Conf.) 9, 121-122.

Juskiewicz, T., and Kowalski, B. (1976). An investigation of the possible presence or formation of nitrosamines in animal feeds. IARC Sci. Publ. (N-Nitroso Compd. Environ. Proc. Work Conf.) 14, 375-393.

Mirvish, S.S. (1975). Blocking the formation of N-nitroso compounds with ascorbic acid in vitro and in vivo. Ann. N. Y. Acad. Sci. 258, 175-180.

Sander, J. (1967). [A method for the demonstration of nitrosamines.] [article in German]. Hoppe Seylers Z. Physiol. Chem. 348, 852-854.

Sander, J., Schweinsberg, F., and Menz, H.P. (1968). [Studies on the origin of carcinogenic nitrosamines in the stomach.] [article in German]. Hoppe Seylers Z. Physiol. Chem. 349, 1691-1697.

Reference 2

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

supporting study

Study period:

2003

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Scientific publication that meets documentation requirements.

Justification for type of information:

refer to analogue justification provided in IUCLID section 13

Objective of study:

other: ADME

Qualifier:

no guideline followed

GLP compliance:

not specified

Radiolabelling:

no

Executive summary:

Excerpt from NTP Report about ADME of diethylamin:

Very little information on the disposition and metabolism of diethylamine in experimental animals or humans was found in a review of the literature. The reaction of dietary amines with nitrite to produce nitrosamines, which are potential carcinogens, has been demonstrated both in vitro and in vivo (Sander, 1967; Sander et al., 1968; Mirvish, 1975). However, in Wistar rats administered 600 ppm diethylamine and sodium nitrite in the diet, diethylnitrosamine could not be detected (Galea et al., 1975). Diethylnitrosamine was not detected in blood or milk of goats fed kale containing 3% potassium nitrate followed by administration of a single oral dose of 200 mg/kg diethylamine hydrochloride (Juskiewicz and Kowalski, 1976). Monoamine oxidase is assumed to play an important role in the metabolism and detoxification of the aliphatic amines. Monoamine oxidase catalyzes the deamination of primary, secondary, and tertiary amines. Monoamine oxidase is widely distributed in tissues and is most concentrated in the liver, kidney, and intestinal mucosa (Beard and Noe, 1981). Traces of diethylamine (less than 0.5% of the dose) were detected in the urine of human volunteers following oral doses of triethylamine (Åkesson et al., 1989). Diethylamine was also found in the gastro-intestinal tract after oral doses of triethylamine-N-oxide, the oxidative metabolite of triethylamine, indicating that triethylamine-N-oxide is dealkylated in the gastro-intestinal tract to diethylamine. There was no evidence that diethylamine produced from triethylamine-N-oxide was subsequently metabolized to N-nitrosodiethylamine in the stomach.

References:

Åkesson, B., Vinge, E., and Skerfving, S. (1989). Pharmacokinetics of triethylamine and triethylamine-N-oxide in man. Toxicol. Appl. Pharmacol. 100, 529-538.

Beard, R.R., and Noe, J.T. (1981). Aliphatic and alicyclic amines. In Patty’s Industrial Hygiene and Toxicology, 3rd ed. (D.G. Clayton and F.E. Clayton, Eds.), Vol. 2B, pp. 3135-3173. Wiley-Interscience Publication, New York, NY.

Galea, V., Preda, N., and Simu, G. (1975). Experimental production of nitrosamines in vivo. IARC Sci. Publ. (N-Nitroso Compd. Environ. Proc. Work Conf.) 9, 121-122.

Juskiewicz, T., and Kowalski, B. (1976). An investigation of the possible presence or formation of nitrosamines in animal feeds. IARC Sci. Publ. (N-Nitroso Compd. Environ. Proc. Work Conf.) 14, 375-393.

Mirvish, S.S. (1975). Blocking the formation of N-nitroso compounds with ascorbic acid in vitro and in vivo. Ann. N. Y. Acad. Sci. 258, 175-180.

Sander, J. (1967). [A method for the demonstration of nitrosamines.] [article in German]. Hoppe Seylers Z. Physiol. Chem. 348, 852-854.

Sander, J., Schweinsberg, F., and Menz, H.P. (1968). [Studies on the origin of carcinogenic nitrosamines in the stomach.] [article in German]. Hoppe Seylers Z. Physiol. Chem. 349, 1691-1697.

Description of key information

There are no experimental studies available in which the toxicokinetic behavior of diethylammonium chloride (CAS 660-68-44) has been assessed. Supporting data on basic toxicokinetics of the source substance diethylamine (CAS 109-89-7) were taken into account.

Oral and dermal absorption is likely for diethylammonium chloride (CAS 660-68-44). Inhalation absorption is assumed to be low. Diethylammonium chloride will be distributed in the body and excretion is expected via urine.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Additional information

There are no studies available in which the toxicokinetic behaviour of diethylammonium chloride (CAS 660-68-4) has been investigated. Also for the structurally related substance diethylamine very little information on the disposition and metabolism in experimental animals or humans was found in a review of the literature (NTP, 2011).

In accordance with Annex VIII, Column 1, Section 8.8.1, of Regulation (EC) No 1907/2006 and with Guidance on information requirements and chemical safety assessment Chapter R.7c: Endpoint specific guidance (ECHA, 2017), assessment of the toxicokinetic behaviour of diethylammonium chloride (CAS 660-68-4) is conducted to the extent that can be derived from the relevant available information. This comprises a qualitative assessment of the available substance specific data on physico-chemical and toxicological properties according to Guidance on information requirements and chemical safety assessment Chapter R.7c: Endpoint specific guidance (ECHA, 2017) and taking into account further available information on structural analogue substances.

The substance diethylammonium chloride (CAS 660-68-4) is an organic solid at 20°C with a molecular weight of 109.598 g/mol. The measured water solubility and log Pow values are 510 g/L at 20 °C and -1.3, respectively.The vapour pressure for diethylammonium chloride was determined to be 4.6E-06 hPa at 20 °C.

 

Absorption

Absorption is a function of the potential for a substance to diffuse across biological membranes. The most useful parameters providing information on this potential are the molecular weight, the octanol/water partition coefficient (log Pow) value and the water solubility. The log Pow value provides information on the relative solubility of the substance in water and lipids (ECHA, 2017).

Oral

In general, molecular weights below 500 and log Pow values between -1 and 4 are favourable for absorption via the gastrointestinal (GI) tract, provided that the substance is sufficiently water soluble (> 1 mg/L). Diethylammonium chloride has a very high water solubility of 510 g/L, a molecular weight of 109.598 g/mol and the log Pow is close to -1.Therefore, good absorption of the molecule in the gastrointestinal tract can be expected.

An acute oral toxicity study was performed with the structurally similar analogue substance diethylamine (CAS 109-89-7) indicating signs of systemic toxicity and resulting in an acute oral LD50 value of 540 mg/kg bw (7.2.1-1).

Overall, taking into account the physical-chemical properties of diethylammonium chloride (CAS 660-68-4) and the available toxicological data with the appropriate analogue substance, the oral absorption potential of the substance is anticipated to be high.

Dermal

A substance must be sufficiently soluble in water to partition from the stratum corneum into the epidermis (ECHA, 2017). As the water solubility of diethylammonium chloride (CAS 660-68-4) is very high (540 g/L) partition from the stratum corneum into the epidermis is expected to be high. However, due to the low log Pow of -1.3 the substance may be too hydrophilic to cross the lipid rich environment of the stratum corneum.

The smaller the molecule, the more easily it may be taken up. In general, a molecular weight below 100 g/mol favors dermal absorption, above 500 g/mol the molecule may be too large (ECHA, 2017). As the molecular weight of diethylammonium chloride is 109.598 g/mol, dermal absorption of the molecule is likely. However, as the test substance is a solid, hindered dermal absorption has to be considered as dry particulates first have to dissolve into the surface moisture of the skin before uptake via the skin is possible (ECHA, 2017).

The dermal permeability coefficient (Kp) can be calculated from log Pow and molecular weight (MW) applying the following equation described in US EPA (2014):

log Kp (cm/h) = -2.80 + 0.66 log Pow – 0.0056 MW

The calculated Kp for diethylammonium chloride (CAS 660-68-4) is 1.14 x 10E-5.QSAR calculations confirmed this assumption, as a dermal flux rate of 0.0158 mg/cm2 per h was calculated indicating high dermal absorption potential for diethylammonium chloride (CAS 660-68-4) (please refer to Table 1).

Table 1: Dermal absorption value for diethylammonium chloride (CAS 660-68-4) (calculated with Dermwin v 2.02, Epi Suite 4.1)

Component	Structural formula	Flux (mg/cm2/h)
diethylammonium chloride	C4 H11 N1 ∙ HCl	0.0158

 

If the substance is a skin irritant or corrosive, damage to the skin surface may enhance penetration (ECHA, 2017). In vivo skin irritation studies with the analogue substance diethylamine (CAS 109-89-7) revealed skin corrosive properties, thus damage to the skin surface is likely leading to an enhanced penetration (7.3.1-1 and 7.3.1-2).

Moreover, an acute dermal toxicity study performed with the analogue substance diethylamine (CAS 109-89-7) has demonstrated signs of systemic toxicity and resulted in an acute dermal LD50 value of 582 mg/kg bw (7.2.3-1).

Overall, based on the physico-chemical and the available toxicological data, dermal uptake of diethylammonium chloride is considered to be high.

Inhalation

In humans, particles with aerodynamic diameters below 100 μm have the potential to be inhaled. Particles with aerodynamic diameters below 50μm may reach the thoracic region and those below 15μm the alveolar region of the respiratory tract (ECHA, 2017). Based on the granulometry data (D10: 83.1 µm; D50: 309.0 µm; D90: 623.4 µm), inhalation potential of diethylammonium chloride (CAS 660-68-4) is low. In addition, the vapour pressure of diethylammonium chloride (CAS 660-68-4) was determined to be 4.6E-06 hPa at 20 °C, thus being of low volatility (ECHA, 2017). Since it is expected that diethylammonium chloride dissociates indiethylamine and hydrochloric acid in the presence of water or in surface moisture, the high volatile source substance diethylamine (CAS 109-89-7) was taken into account as worst case for inhalation potential.

An acute inhalation toxicity study was evaluated with the structurally similar analogue substance diethylamine (CAS 109-89-7) which was indicating local effects (respiratory tract irritation) and resulting in an acute inhalation LC50 value of 25922 mg/m³ (calculated) (7.2.2-1).

Moreover, several subchronic (90-day) repeated dose toxicity studies are available with the analogue substance diethylamine (CAS 109-89-7). Primarily, local effects were observed indicating severe irritation of the respiratory tract. Based on the results of the study, the subchronic NOAEC for local and systemic effects was considered to be 16 ppm corresponding to 49 mg/m³ in mice and rats, respectively.

In conclusion, systemic bioavailability of diethylammonium chloride (CAS 660-68-4) cannot be excluded, however the systemic effects can be regarded as secondary effects due to the corrosiveness of the substance leading to severe local effects.

Distribution and Accumulation

Distribution of a compound within the body depends on the rates of the absorption and the physico-chemical properties of the substance; especially the molecular weight, the lipophilic character and the water solubility. In general, the smaller the molecule, the wider is the distribution. Small water-soluble molecules and ions will diffuse through aqueous channels and pores. The rate at which very hydrophilic molecules diffuse across membranes could limit their distribution (ECHA, 2017).

Diethylammonium chloride (CAS 660-68-4) has a low molecular weight and high water solubility. Based on the physico-chemical properties and the absorption potential, distribution within the body can be considered as very likely. After absorption, diethylammonium chloride (CAS 660-68-4) will enter the blood circulating system through which it will be distributed within the body. This assumption is based on the systemic toxicity findings observed in the acute oral toxicity study.

Highly lipophilic substances in general tend to concentrate in adipose tissue, and depending on the conditions of exposure may accumulate. Although there is no direct correlation between the lipophilicity of a substance and its biological half-life, it is generally the case that substances with high log Pow values have long biological half-lives.The very low log Pow of -1 implies that diethylammonium chloride (CAS 660-68-4) may have no potential to accumulate in adipose tissue (ECHA, 2017).

Metabolism

No data are available regarding metabolism of diethylammonium chloride. Prediction of compound metabolism based on physicochemical data is very difficult. Structure information gives some but no certain clue on reactions occurring in vivo. The potential metabolites following enzymatic metabolism were predicted using the QSAR OECD toolbox (v4.0, OECD, 2017). This QSAR tool predicts which metabolites may result from enzymatic activity in the liver and in the skin, and by intestinal bacteria in the gastrointestinal tract. No hepatic and 1 dermal metabolite was predicted for the test substance, respectively. Oxidation of one of the ethyl side chains occurs in the skin. In general, hydroxyl groups increase water-solubility and make substances more susceptible to metabolism by phase II-enzymes. Up to 5 metabolites were predicted to result from all kinds of microbial metabolism for the test substance. Most of these metabolites were found to be a consequence of the degradation of the molecule by microbial metabolism.

Available genotoxicity data with the structurally similar source substance diethylamine (CAS 660-68-4) do not show any genotoxic properties of the test substance. An Ames-test, an in vitro HPRT test and an in vivo micronucleus test with diethylamine (CAS 660-68-4) were consistently negative. Thus, there was no indication that the test substance may cause genotoxic reactivity.

Excretion

The major routes of excretion for substances from the systemic circulation are the urine and/or the faeces (via bile and directly from the GI mucosa). Only limited conclusions on excretion of a compound can be drawn based on physicochemical data. Low molecular weight (below 300 g/mol in rat), good water solubility, and ionization of the molecule at the pH of urine are characteristics favourable for urinary excretion. Based on the high water solubility and low molecular weight, distribution within the body in the blood circulating system followed by excretion via urine is expected.

 

References

ECHA (2017) Guidance on information requirements and chemical safety assessment, Chapter R.7c: Endpoint specific guidance.

NTP (2011): NTP Technical Report on the Toxicology and Carcinogenesis Studies of Diethylamine (CAS 109-89-7) in F344/NN Rats and B6C3F1 Mice (Inhalation Studies), NTP TR 556, October 2011.

OECD (2017). OECD QSAR Toolbox v4.0, April 2017, Laboratory of Mathematical Chemistry Oasis. Downloaded from https://qsartoolbox.org/ Prediction performed on 21 September 2017.

US EPA. (2012). Estimation Programs Interface Suite™ for Microsoft® Windows, v 4.1.; Prediction of dermal flux rate: DERMWIN v.2.02 (September 2012); United States Environmental Protection Agency, Washington, DC, USA; Prediction performed on 05 May 2017.