Trimethylenediamine

Endpoint summary

Description of key information

Based on the results of the experimental investigations as well as on the molecular weight, the test item is considered to be bioavailable via oral and dermal route and potentially also via inhalation. Once systemic available, the substance might be widely distributed through the organism. 
Resorbed triethylenediamine is expected to be released quickly from blood plasma and excreted via urine, mainly as acetylated metabolite N-acetylpropylenediamine and to a minor extent as unchanged substance. Based on the low log Pow value, no bioaccumulation of the test substance is expected.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Additional information

The test item is a colourless liquid at 20°C and 1013 hPa with a boiling point of 139.3 °C. It has a molecular weight of 74.13 g/mol, a density of 0.89 g/cm3 (at 20 °C) and a log Pow value of -1.05 (20 °C). The vapour pressure is 4.1 hPa (20 °C) and the solubility in water is high (1000 g/L).

The dermal route is considered as the main exposure route at room temperature as the vapour pressure at 20 °C is quite low and inhalation exposure is therefore negligible.

In an acute oral toxicity study with the test item in rats (Smyth, 1962) the LD50 was determined to be 311 mg/kg bw for male rats. Details on clinical signs or toxic effects other than the lethal dose value were not reported.

In an acute inhalation toxicity study, six rats were exposed to a substantially saturated vapour for 8 hours (NTIS/OTS, 1991). No animal died after exposure time. Redness of extremities and a wet fur were observed within 3 hours after end of exposure.

In an acute dermal toxicity study with the test item in rabbits (Smyth, 1962; also reported by RTECS, 2011) mortality occurred and the LD50 was determined to be 178 mg/kg bw. Neither clinical signs nor any macroscopic pathologic abnormalities were reported in the publication. However, in an acute dermal irritation/corrosion study with rabbits (BASF, 1966) the application of the undiluted test material revealed full thickness necrosis after 1, 5 and 15 minutes of exposure which was not reversible within 8 days.

In an acute eye irritation test, corrosion of conjunctiva and the whole eyeball were noted after 10 minutes. All effects remained for days until eyelids were closed by scabs and eyeballs were most likely destroyed (BASF, 1966).

Administration of the read-across substance ethylenediamine (CAS 107-15-3) in a Magnusson-Kligman assay with guinea pigs revealed positive reactions in 45 % of the test animals. Therefore, the substance is considered to be sensitising.

In a 90-day study, equivalent to OECD guideline 408, conducted with the read-across substance ethylenediammonium dichloride (CAS 333-18-6) in rats, the test item was administered orally at concentrations of 50, 260 and 1040 mg/kg bw/day (Yang, 1983). There were no deaths and no abnormal clinical signs noted during the study. Body weight gains were significantly decreased in the high dose group which affected a number of absolute and relative organ weights in both males and females. Water consumption was comparable to control values at all dose levels in males but was decreased in a dose-response manner in female rats at all 3 dose levels. Slight reductions in serum glucose levels and an elevation of alkaline phosphatase, AST and ALT activities were observed in the high dose group. An elevation of ALT activity was also observed in the intermediate dose male rats. Urinary pH in the high dose group was decreased in both males and females. There were no dose-related gross lesions in any animal on the study. The most significant histopathological lesion, hepatocellular pleomorphism, was observed primarily in the high dose female and, to a lesser extent, male rats. A NOAEL of approximately 50 mg/kg bw/day was determined for the test item. Based on this a NOAEL of 27.9 mg/kg bw/day was calculated for trimethylenediamine.

In a chronic toxicity study (Hermansky, Yang, Garman, and Leung; 1999) also with the read-across substance ethylenediammonium dichloride (EDA) 100 rats per sex and dose were exposed to 20, 100 and 350 mg/kg bw/day for lifetime. No evidence for carcinogenic effects was observed up to the highest dose tested. Significant reduction in the absolute weights of liver, kidney, spleen (male) and increase of the relative weights of liver, kidney, heart, brain (females) in rats of the high dose group was seen. Further, no substance-related changes in hematologic data, clinical chemistry values and urinalysis except a decrease in erythrocyte count, hemoglobin concentration, hematocrit (male) and serum albumin concentration (female) in rats of the high dose group were examined. A significantly higher incidence of hepatocellular pleomorphism in female rats of the intermediate and the high dose group was observed. Rhinitis and tracheitis were seen with greater frequency in high dose males at 12, 18 and 24 months and in high dose females at 18 months; at 24 months. Rhinitis persisted at a significantly greater frequency in high dose females while tracheitis did not. A NOAEL of 20 mg/kg bw/day EDA, respectively 9 mg/kg bw/day trimethylenediamine was determined.

In a two-generation study conducted with the read-across substance EDA, rats were exposed to 50, 150 and 500 mg/kg bw/day (Yang, 1984). Significant reduction of parental body weight gain in the high dose groups of male and female rats of both F0 and F1 generation were seen. No macroscopic or histopathological findings except a significant higher incidence of hepatocellular pleomorphism in both sexes of the high dose group of the F1 generation (6/10 male, 10/10 female; control: 0/20 each) and a significant decreased prevalence of kidney tubular mineralization in female rats of the high dose group of the F1 generation (0/10 female; control: 10/20) were seen. But there was no evidence of fertility impairment or embryotoxic effect at dose levels that show maternal or paternal toxicity.

These findings are further supported by two developmental toxicity studies conducted in rats and rabbits (DePass, 1987; Price, 1993) with ethylenediammonium dichloride. Rats were exposed to 50, 250 and 1000 mg/kg bw/day. Rabbits received concentrations of 10, 40 and 80 mg/kg bw/day. Both studies did not show any teratogenic effects on the pups of both species up to the highest concentrations tested.

Absorption

After oral administration the substance is assumed to dissolve in the gastrointestinal fluids and absorption via aqueous pores or carriage across membranes with the bulk passage of water might occur as indicated by the high water solubility. In addition, absorption of the substance via passive diffusion might be favoured due to the log Pow value of -1.05. The LD50 evaluated in an oral acute toxicity study and the pathological and histopathological findings after repeated oral administration indicate that the compound becomes bioavailable after oral administration.

The test items volatility is considered to be low as the vapour pressure is less than 0.5 kPa at 20 °C. Therefore, inhalation of vapour is unlikely. However, if the test item becomes available for inhalation as under the conditions of an acute inhalation toxicity study, it might cross the respiratory tract epithelium by passive diffusion or active transport via aqueous pores as indicated by the small molecular weight and the physic-chemical properties of the substance. This assumption is supported by the results of the acute inhalation toxicity study in which signs of systemic toxicity were observed.

Dermal absorption of trimethylenediamine is suspected to be low as uptake into the stratum corneum is limited by very high water solubility and a log Pow value below 0. But mortality was observed in the available acute dermal toxicity study. This may be ascribed to the highly corrosive potential of the substance as damage to the skin surface enhances the penetration of the substance. Further, the test substance was identified as a skin sensitiser supporting the assumption of a dermal uptake of the substance.

Taken together, experimental data indicate bioavailability of the test substance via oral, dermal and possibly also via inhalation route.

Distribution

A wide distribution of the test substance in the organism is expected due to its low molecular weight and high water solubility. In the available chronic and sub-chronic studies on reproduction toxicity, the liver was identified as a target organ. Based on the low log Pow value, no bioaccumulation of the test substance is expected.

Metabolism:

A metabolism similar to ethylenediamine can be assumed. Resorbed ethylenediamine is quickly released from blood plasma and excreted via urine, mainly as acetylated metabolite N-acetylethylenediamine and to a minor extent as unchanged substance. This information is supported by respective animal studies.
Thus, N-acetylpropylenediamine is expected as the main metabolite of trimethylenediamine.

There are no indications of genotoxicity of the test item and its metabolites from the present mutation assays (Zeiger, 1987; BASF, 2012) conducted in bacteria and mammalian cells. Thus, trimethylenediamine and its metabolite are expected not to be genotoxic and metabolic activation is unlikely to occur.
This assumption is further supported by a carcinogenicity study in rats. No evidence of carcinogenic effects was exhibited.

Excretion

Due to the low molecular weight (74.13 g/mol), the high water solubility (>500 g/L) and the presumed metabolism, trimethylenediamine and/or its metabolite is/are expected to be excreted via urine (similar to ethylenediamine).