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Key value for chemical safety assessment

Effects on fertility

Effect on fertility: via oral route
Dose descriptor:
NOAEL
30 mg/kg bw/day
Additional information

In a 90 day dietary study, Fischer 344 ratIn the were administered diethylene triamine (DETA) at 0, 1000, 7500, and 15000 ppm (70, 530, and 1060 mg/kg/day for males and 80, 620, and 1210 mg/kg/day for females). There were no treatment related differences in the organ weights, gross pathology or the histopathology of any of the gonads from both sexes.

In the reproduction/developmental screen, Wistar rats were exposed to 0, 30, 100, and 300 mg/kg/day. Body weights of both the males and females in the 300 mg/kg group decreased while food consumption in the high dose female showed a statistically significant decrease. There was no treatment related effect of DETA on precoital time, mating index, fertility index, and the number of live and dead pups. Duration of gestation in the 100 mg and 300 mg DETA groups was prolonged compared to the control group, and to the historical data. The number of implantation sites was similar in all groups. Mean litter size was somewhat reduced in the 100 mg and 300 mg DETA groups: in the 300 mg DETA group the difference with the control group reached the level of statistical significance. Post-implantation loss for the 100 mg and 300 mg DETA groups was increased 18.3 and 27.9%, respectively. For the 300 mg DETA group the increase was statistically significant.


Short description of key information:
A Reproductive/Developmental toxicity screen (OECD 421 Draft Guideline study) in rats via gavage and the histopathology on the sex organ of rats from a 90 day dietary study were available for review.

Effects on developmental toxicity

Description of key information
A Reproductive/Developmental toxicity screen (OECD 421 Draft Guideline study) in rats via gavage with gross examination of pups born to dam treated with up to 300 mg/kg/day DETA.
Effect on developmental toxicity: via oral route
Dose descriptor:
NOAEL
30 mg/kg bw/day
Additional information

In the reproductive/developmental study in rats, the animals were exposed to 0, 30, 100, and 300 mg/kg bw/day DETA. No treatment related terata were seen at any level. Post-implantation loss for the 100 mg and 300 mg/kg bw/day groups was increased 18.3 and 27.9%, respectively. For the 300 mg DETA group the increase was statistically significant. Therefore the NOAEL was 30 mg/kg bw/day for developmental effects.

Justification for classification or non-classification

The OECD 421 reproductive and developmental screen indicates a dose related increase in post implantation loss. The post-implantation loss was 5.4, 3.2, 18.3 and 27.9% for 0, 10, 100, and 300 mg /kg/day.  The post-implantation loss reached statistical significance only at the 300 mg/kg bw/day group. 

 

The post implantation loss may be considered a maternally mediated event. DETA is a copper chelator as are other higher ethylene amines. Keen et al. 1983, demonstrated that copper deficiency elicited by the chelating agent triethylenetriamine (TETA) caused terata in the offspring of laboratory animals and increased frequency of resorptions. In this study, rats were fed 0.17, 0.83 or 1.66% TETA in the diet corresponding to dose levels of 170, 830, and 1660 mg/kg/day. The copper concentrations of fetuses taken from the exposed dams were 43 and 15% in the medium and high dose groups. Corresponding increases in the number of resorptions were found in the mid and high dose groups, 5.8% and 18.8%, respectively. The frequency of malformations in the fetuses was 25.6 and 100% , respectively. 

 

In a similar experiment, Cohen et al. 1983, rats were fed 0.83 and 1.67% TETA in the diet. However, copper was supplemented at 5 ug of copper/gm or 50 ug/of copper/gm of feed.  Copper supplementation reduces the teratogenicity of TETA. The reduction was correlated with an increase in maternal and fetal tissue copper level suggesting that the teratogenicity of TETA was due to the copper deficiency. The frequency of resorptions was not statistically different in any copper supplemented group.

 

DETA could have similar potential for developmental effects as TETA, with potential to complex all dietary copper at 0.4 mg of copper/day in feed. The formation constant for Cu*DETA complex (log K=16) and Cu*TETA complex (log K=20.5) are somewhat similar (Sillen and Martell, 1964). Although DETA has slightly lower propensity to form a Cu complex, this is somewhat countered by its lower molecular weight. If a 1:1 molar ligand copper ratio is assumed, then there is a potential 40 to 100 fold excess of DETA to completely complex the 0.4 mg/kg/day dietary copper at the doses of 100 and 300 mg/kg/day. 

 

On a molar equivalency basis, 300 mg/kg/day dose would be expected to have the same effect as a 426 mg/kg/day dose of TETA if we assume equal ability to complex copper.  Furthermore, TETA is about 20% absorbed from the gut of rats while DETA is absorbed at approximately 80%.  Therefore, it is possible that DETA could reach concentrations in the maternal plasma that would decrease the availability of copper resulting in a nutritional deficiency and post implantation loss.

 

It is likely that the effect of DETA upon post-implantation loss may be mediated by effects on the dam rather than direct embryotoxicity. These effects may be due to chelation and the subsequent decrease of plasma copper levels in the dam. Investigations should be considered to investigate the role of maternally-mediated toxicity. 

Furthermore a test plan as previously proposed is being executed that will render additional information on the relevance of these finding to humans.  

DETA is not proposed to be classified DETA at this time so that the additional research can be considered. At this time 2 range finding studies in rats have been completed subsequest to a full developmental toxicity study as designated by our test plan. The full developmental study is scheduled with the report due by June 2016.

REFERENCES 

Cohen, N.L., Keen, C.L. Lonnerdal, B. and Hurley, L.S. (1983) The Effect of Copper Supplementation on the Teratogenic Effects of Triethylenetetramine in Rats. Drug-Nutrient Interactions 2:203-210.

 

Keen, C.L., Cohen, N.L., Lonnerdahl, B., and Hurley, L.S. (1983) Teratogenesis and Low Copper Status Resulting from Triethylenetetramine in Rats (41693). Proc. Soc. Exp. Biol. Med. 173:598-605.

 

Sillen, L. G. and Martell, A. E. (Eds.) 1964. Stability Constants of Metal-Ion Complexes. 2nd Ed. Special Publication No. 17,: The Chemical Society,House.

Additional information