Ethylenediamine

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Description of key information

In a 2 -generation rat study there was no evidence of reproductive toxicity or developmental toxicity up to and including 227 mg EDA/kg bw/day.

Effect on fertility: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

227 mg/kg bw/day

Study duration:

subchronic

Species:

rat

Effect on fertility: via inhalation route

Endpoint conclusion:

no study available

Effect on fertility: via dermal route

Endpoint conclusion:

no study available

Additional information

In a two-generation reproduction study (Yang et al., 1984) there was no reproductive effect noted in any dose group as regards fertility, pup survival, number of pups born alive and number of pups weaned per litter; thus there was no evidence of reproductive toxicity at levels of 500 mg EDA.2HCl/kg/day in rats (recalculated as 227 mg/kg bw/day EDA base).

Effects on developmental toxicity

Description of key information

Growth retardation was observed in fetuses from rats receiving 1000 mg/kg bw/day, levels which resulted in maternal toxicity. However there was no evidence of a teratogenic effect. In rabbits, maternal toxicity and embryotoxicity/ teratogenicity was absent at the highest dose tested of 80 mg/kg bw/day. A higher dose could not be tested as 20% mortality or more was seen at dose levels of 100 mg/kg bw/day and higher.

Effect on developmental toxicity: via oral route

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEL

114 mg/kg bw/day

Study duration:

subacute

Species:

rat

Quality of whole database:

The results in the study were further investigated in two smaller studies which established that part of the findings were due to compound induced reduced food consumption. The three studies taken togther allow a scientifically valid interpretation of the study. In addition, a rabbit study is available.

Effect on developmental toxicity: via inhalation route

Endpoint conclusion:

no study available

Effect on developmental toxicity: via dermal route

Endpoint conclusion:

no study available

Additional information

There are both rat and rabbit pre-natal developmental toxicity (teratology)studies. The rabbit study consisted of New Zealand White rabbits, which were dosed by gavage with Ethylenediamine dihydrochoride (EDA*2HCL) on gestation days 6 -19. The dose levels were 0, 10, 40 and 80 mg/kg bw, calculated as Ethylenediamine base. The top dose of 80 mg/kg bw/day was selected due to 20% mortality in a dose ranging study at 100 mg/kg bw/day. In the main study, there were no adverse effects on the mothers and no indication of any developmental toxicity/teratogenicity in the foetuses.

 

In a rat teratology study Ethylenediamine dihydrochoride was administered in the diet at 0, 50, 250 and 1000 mg/kg bw/day on days 6 -15 of gestation. These doses were 0, 25, 114 and 454 mg/kg bw/day calculated as Ethylenediamine base. There was a significantly reduced body weight gain in the intermediate and high dose groups together with reduced food consumption. There were several findings in the offspring at the high dose, such as reduced ossification, increased resorptions, decreased foetal weight and length. The most important finding was an increased incidence of missing and shortened innominate artery. By missing the authors indicated that the right and left carotid branched off the brachiocephalic artery, rather than it becoming the innominate after the left carotid branches. So there is no innominate but this would not affect blood supply.  As a missing innominate artery had been observed in offspring of rats on diets deficient in folic acid, further studies were performed to determine if this effect was due to malnutrition due to decreased diet consumption. A first step was to establish if the reduced food consumption was due to palatability of the diet; 10 pregnant rats were dosed by gavage from days 6 -15 of gestation at 1000 mg/kg Ethylenediamine dihydrochloride (454 mg/kg bw/day calculated as Ethylenediamine base).These rats showed reduced bodyweight gain and food consumption, even though there was no ethylenediamine dihydrochoride in the diet. The foetuses were not examined internally, but there was a decrease in live foetuses/litter and an increase in resorptions.

This demonstrated that the reduced food consumption seen in the dietary study was not due to palatability of the diet. This study was followed by a paired feeding study where a group of pregnant females were fed the same amount of control diet as consumed by the rats who were receiving 1000 mg/kg EDA*2HCL (454 mg/kg Ethylenediamine base). The pair fed controls had the same incidence of missing innominate arteries as those fed Ethylenediamine; this was not seen in a second, ad libitum fed control group. This indicated that this effect was as suspected due to a folic acid deficiency caused by reduced food consumption. The ethylenediamine dosed rats, however, still showed shortened innominate arteries. The authors concluded that this shortening was not a teratogenic effect as it would not result in a functional deficit and, in addition, it may be reversible being a result of the growth retardation seen together with reduced foetal weights which only occurred in the presence of maternal toxicity.

Justification for classification or non-classification

The two generation study in rats showed there were no adverse effects on reproduction either on fertility or embryotoxicity from exposure to Ethylenediamine, administered in the diet up to 500 mg EDA*2HCL/kg bw/day (227 mg/kg bw/day calculated as Ethylenediamine base).

 

There were no indications of any developmental toxicity / teratogenicity seen in rabbits at a maximal dose of 80 mg/kg bw/day of Ethylenediamine by gavage.

 

In the rat teratogenicity study there were some findings interpreted as being due to malnutrition (low folic acid) which was the case for the missing innominate arteries, due to reduced maternal food consumption, caused by the ethylene diamine and not due to palatability of the diet. Other findings of shortened innominate arteries, delayed ossification etc. were considered to be due to the delayed fetal development linked to the reduced foetal weight at a maternally toxic dose level. The NOAEL for effects in the foetuses was 250 mg/kg EDA*2HCL (114 mg/kg bw/day calculated as Ethylenediamine base); the maternal NOAEL was 23 mg EDA/kg bw/day.

 

Based on these findings it is concluded that ethylene diamine would not require any classification under the EU CLP(GHS) criteria for adverse effects on reproduction or foetal development.