Trientine

Endpoint summary

Description of key information

No reliable studies were available to derive a DNEL for TETA (base amine). However, a DNEL was derived for the salt of TETA (viz. TETA.2HCl; see below) 

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion

Dose descriptor:

LOAEL

50 mg/kg bw/day

Study duration:

subchronic

Species:

rat

Additional information

As indicated above, there were no reliable studies available for TETA (base amine); studies were available for TETA salt (TETA.2HCl).

In a 26 -week study (Yanagisawa, 1998) using dose levels of 50, 175 and 600 mg/kg bw/day, one male receiving 175 mg/kg bw/day and three males receiving 600 mg/kg/day died, showing lung changes. With regard to the lungs, histopathology revealed a dose-related incidence and severity of focal chronic interstitial pneumonitis accompanied by fibrosis of the alveolar walls in females receiving 175 mg/kg/day or more and all treated male groups. Apart from the histological changes found in the lung, all other changes were reversible. It was concluded that the NOAEL of TETA.2HCl in this 26 -week study was considered to be 50 mg/kg/day for females and less than 50 mg/kg/day for males; the latter, therefore, was considered a LOAEL.

It was suggested that TETA.2HCl, a kind of polyamine, could be taken into bronchiolar epithelium and/or alveolar epithelium by an endogenous polyamine uptake process and be accumulated in the specific tissue site of the lung. Polyamines are generally irritating agents for mucous membranes, upper respiratory tract and skin (Lenga 1988; Maisey et al., 1988). In 4 - or 8 -week study, the histopathological changes observed in the stomach (submucosal inflammation within the glandular region) indicated that TETA.2HCl was slightly irritant. Therefore, it is likely that chronic interstitial pneumonitis is caused by the cytotoxic effect of TETA.2HCl which was accumulated into the bronchiolar epithelial cells and the

alveolar pneumocytes.

In a 13 week study (Greenman, 1996), mice and rats received TETA.2HCl in the drinking water at concentrations of 0, 120, 600, or 3000 ppm for up to 92 days; they were fed diets containing nutritionally adequate levels of copper. An additional control group of rats and mice received a Cu-deficient diet. This low copper diet resulted in Cu-deficiency symptoms, such as anemia, liver periportal cytomegaly, pancreatic atrophy and multifocal necrosis, spleen hematopoietic cell proliferation, and increased heart weight, together with undetectable levels of plasma copper in rats but not in mice. TETA.2HCl lowered plasma copper levels somewhat (at 600 and 3000 ppm) in rats, but did not induce the usual signs of copper deficiency. TETA.2HCl caused an increased frequency of uterine dilatation at 3000 ppm in rats fed the adequate copper diet but was not noted in females fed the Cu-deficient diet. TETA.2HCl toxicity occurred only in mice in the highest dose group. Increased frequencies of inflammation of the lung interstitium and liver periportal fatty infiltration were seen in both sexes, and hematopoietic cell proliferation was seen in the spleen of males. Kidney and body weights were reduced in males as was the incidence of renal cytoplasmic vacuolization. There were no signs of copper deficiency in mice exposed to TETA.2HCl. Based on the effects in mice the NOAEL was 600 ppm or 92 mg/kg bw/day for males and 99 mg/kg bw/day for females.

In a 26 -week toxicity study (Maemura, 1998) Beagle dogs received TETA.2HCl orally at dosages of 50, 100 or 200 mg/kg bw/day for 26 weeks followed by a 13 -week reversibility phase. However, in view of the severe signs which resulted in the sacrifice for humane reasons of two males and one female receiving 200 mg/kg bw/day during week 9 of treatment, surviving dogs of this group were only treated for 10 weeks. Signs before killing included marked underactivity, body tremors, abnormal gait, limited use of limbs and prone posture. The ante mortem neurological

examination generally indicated depressed postural and flexor withdrawal reactions. The signs were rapidly reversible except in one female which was killed humanely on day 2 of the reversibility period. Abnormal "stiff legged" gait and underactivity were evident, from week 23 of treatment, in two males and one female receiving 100 mg/kg bw/day. In the absence of any macroscopic or histopathologic findings, even after the examination of additional samples of muscle and nerve, the exact nature of this condition could not be elucidated. In all treated groups low copper and zinc concentrations in the livers and high urinary copper and zinc concentrations were found. The NOAEL was considered to be 50 mg/kg bw/day.

Overall, the results from the 26 -week key study in rats (Yanagisawa, 1998) and another 13 -week study in mice (Greenman, 1996) showed lung toxicity. The 26 -week study in dogs (Maemura, 1998) did not show lung toxicity but showed neurological effects instead. The NOAELs in these studies were in the same order of magnitude, i.e. between 50 and 99 mg/kg bw/day, although for male rats the level of 50 mg/kg bw/day should be considered a LOAEL. The level of 50 mg TETA.2HCl per kg bw per day corresponds to (146.23/219.16) x 50 = 33 mg TETA per kg bw per day.

Repeated dose toxicity: via oral route - systemic effects (target organ) respiratory: lung

Justification for classification or non-classification

In the studies indicated above, the NOAELs were in the same order of magnitude, i.e. between 50 and 99 mg/kg bw/day, although for male rats the level of 50 mg/kg bw/day should be considered a LOAEL. The level of 50 mg TETA.2HCl per kg bw per day corresponds to (146.23/219.16) x 50 = 33 mg TETA per kg bw per day. However, the changes observed at this level were not considered to be sufficient for labeling with R48/20 (old classification), or STOT repeated Cat. 2.