1,2,3-trichloropropane

Endpoint summary

Description of key information

Short description of key information on bioaccumulation potential result: 
Bioaccumulation potential of 1,2,3-trichloropropane is regarded to be low.
It is easily absorbed via the oral route and very likely also via the inhalation and the dermal route.
Distribution is fast via the blood circulation and not hindered by blood tissue barriers.
Metabolisms is fast and extensive and is therefore mainly excreted as metabolites (about 50-60  % via urine, 20 - 25 % via feces and 20 - 25 % via exhalation in rodents).

Key value for chemical safety assessment

Bioaccumulation potential:

low bioaccumulation potential

Additional information

1,2,3 -trichloropropane is readily absorbed via the gastrointestinal tract resulting in a bioavailability for the oral route of up to 100 % (Mahmood, 1991). Given its lipophilic character and its log Pow of 2.2 - 2.6 a comparable bioavailability via the inhalative and the dermal route can be expected. This is further supported by the high LD50(dermal, rabbit) of390 mg/Kg bw as compared to an LD50(oral, rat) of 120 mg/Kg bw.
Distribution is swift via the blood circulation and not hindered by blood-tissue barriers. The substance is extensively metabolised bya combination of oxidative metabolism and glutathione coupling, leading to metabolites like 1,3-dichloro-2-propanol and 2,3-dichloropropanol (Weber 1991A) N-acetyl-S-(3-chloro-2-hydroxypropy1)-L-cysteine (ACPC), S-(3 -chloro-2 -hydroxypropy1)-L-cysteine (CPC) and 2 -(S-glutathionyl)malonic acid (GMA) Mahmood (1991).
The excretion of 1,2,3 -trichloropropane and its metabolites is fast in rodents (up to 90 % in rats and close to 100 % in mice within 60 h, Mahmood 1991) mainly via urine, but also significant amounts via exhalation and feces.
Bioaccumulation is expected to be low.

As absorption, distribution, metabolism and excretion are expected to be comparable for 1,2,3 -trichloropropane in rodents and humans (and other mammals) the above stated conclusions can be extended, at least qualitatively, also to humans (and other mammals)

Discussion on bioaccumulation potential result:

The key study of Mahmood (1991, single oral dose via gavage, 30 and 60 mg/Kg bw in rats and mice) and Volp (1984, single iv injection, 3.6 mg/Kg bw ) mainly agree in their finding regarding the toxicokinetic of 1,2,3 -trichloropropane. Mahmood (1991) did not find major species differences except for a faster overall metabolism in mice than in rats and a slightly different profile for the major metabolites.

Absorption:

In Volp (1984) rats were treated via iv injection while in Mahmood (1991) animals were administered via gavage. The excretion profiles of radioactivity for rats are essentially the same (Mahmood: 20 % via feces, 50 % via urine and 20 via exhalation; Volp: 18 % via feces, 40 % via urine, and 30 % via exhalation). Taken together this suggests that the bioavailability of 1,2,3 -trichloropropane via the oral route is up to 100 %. Given its lipophilic character and its log Pow of 2.2 - 2.6 a comparable bioavailability via the inhalation and the dermal route can be expected.

Distribution:

Both studies agree that the distribution is fast via the blood circulation that all tissues are reached (not hindered by blood tissue barriers) and that the liver and the kidneys are the main target tissues. High initial amounts in adipose tissue decrease within hours.

Metabolism:

Volp (1984) reports that in the first hour post dosing radioactivity is mainly excreted as unchanged 1,2,3 -trichloropropane via inhalation while later mainly labeled carbon dioxide is exhaled and labeled metabolite appear in urine bile and feces. This suggest a fast extensive metabolism as confirmed by Mahmood (1991) who isolated three major metabolites which are products of a combination of oxidative metabolism and glutathione coupling. These findings are supported by Weber (1991 A) where in invitro assays with human and rat microsomes 1,3-dichloro-2-propanol and 2,3-dichloropropanol were identified as main products of cytochrome P450 mediated oxidative metabolism of 1,2,3 -trichloropropane. Mahmood (1991) shows that 50 - 80 % of the radioactivity in liver and kidneys at 60 h post dosing are not extractable, indicating that the formed metabolites are reactive to some extent and able to bind to cellular macromolecules. In this study N-acetyl-S-(3-chloro-2-hydroxypropy1)-L-cysteine (ACPC, rat urine) S-(3 -chloro-2 -hydroxypropy1)-L-cysteine (CPC, mice urine) 2 -(S-glutathionyl)malonic acid (GMA, rat bile) were identified as metabolites, with ACPC and CPC probably stemming from an initial 1,3 -dichloroacetone formation .

Excretion:

The excretion of 1,2,3 -trichloropropane and its metabolites is fast in rodents (up to 90 % in rats and close to 100 % in mice within 60 h, Mahmood 1991) mainly via urine, but also significant amounts via exhalation and feces (Mahmood (1991, gavage): 20 % via feces, 50 % via urine and 20 via exhalation; Volp (1984, iv injection): 18 % via feces, 40 % via urine, and 30 % via exhalation). Findings of Volp (1984) comparing excretion via bile and feces indicate that metabolites are reabsorbed to some extent in the intestine (enterohepatic cycle). They also state an overall half-life of 44 h for 1,2,3 -trichloropropane derived radioactivity.

Bioaccumulation:

Mahmood (1991) a combined amount about 4 % of the radioactivity is found in liver, kidneys, skin, adipose tissue and muscles of rats and a total amount of about 2.5 % in male mice in these tissues 60 h after application. Therefore a low bioaccumulation potential is determined for 1,2,3 -trichloropropane. Volp (1984) reports that 1,2,3 -trichlorpropane is excreted up to 85 % within 24 h and 99% after 6 d in the rat.

Based on this data the potential for bioaccumulation is regarded as low.

Relevance for humans and other mammals:

As absorption and distribution of 1,2,3 -trichloropropane in rodents are mainly driven by its physico-chemical properties it is assumed that a comparable situation is found in humans and other mammals. As the metabolism comprises cytochrome P450 catalysed oxidation and glutathione coupling in rodent a comparable metabolism is expected for humans, though the turnover might be slower as rodent generally have a faster metabolism than humans.

Based on this findings the target organs and the route of excretion are also expected to be the same in humans and other mammals and therefore the bioaccumulation potential of 1,2,3-trichloropropane is regarded to be negligible for these species.

The identified target organs and the identified faster metabolism and thereby lower inner exposure in mice compared to rats are in very good agreement with the findings in repeated dose experiments in both species which further validates the findings of these toxicokinetic analysis.