Acetic acid, 2-oxo-, reaction products with ethylenediamine, iron chloride (FeCl3) and phenol, potassium salts

Endpoint summary

Key value for chemical safety assessment

Toxic effect type:

dose-dependent

Effects on fertility

Description of key information

See also read across document in section 13.

In a one-generation reproduction toxicity study (Reijnders, 1997), EDDHMA-Fe was administered to 28 Wistar rats/sex/dose level by single oral gavage at dose levels of 50, 200 or 750 mg/kg bw/day. A concurrent control group was treated with the vehicle only. Treatment commenced 10 weeks prior to mating for males and 2 weeks prior to mating for females and continued for both sexes until at least the end of the lactation period. Pregnant females were allowed to litter normally. On day 4 of lactation, each litter was adjusted to 4 males and 4 females or as near as possible. The surviving offspring was euthanised after weaning.

The primary effect on parental animals was poor physical condition, resulting in premature mortality, growth reduction and reduced food consumption in both sexes at 750 mg/kg bw/day. These signs were seen with reduced severity at 200 mg/kg bw/day in males only. Thus, the NOAEL for systemic toxcity in parental animals was 50 mg/kg bw/day under the conditions of this study.

Examination of the reproduction performance of males and females revealed a slight decrease of the fertility and conception indices in the 750 mglkg dose group. However, the fertility and conception indices in the control group were also low. Oral administration of EDDHMA-Fe to parental rats at dose levels up to 750 mglkg/day produced no histopathological evidence of toxicity to reproduction or infertility. As such the NOAEL for reproductive performance/fertility was established at at least 750 mg/kg bw/day.

In the offspring, increased post natal loss and reduced viability were noted during PND 0 -4 at 200 and 750 mg/kg bw/day, and with lower incidence at 50 mg/kg bw/day. With special regard to the low incidence and unusual distribution pattern of findings noted at 50 mg/kg bw/day, the NOAEL for developmental toxicity was 50 mg/kg bw/day under the conditions of this study. Effects at higher levels were considered to be closely related to (subclinical) maternal toxicity.

Effect on fertility: via oral route

Endpoint conclusion:

adverse effect observed

Effect on fertility: via inhalation route

Endpoint conclusion:

no study available

Effect on fertility: via dermal route

Endpoint conclusion:

no study available

Effects on developmental toxicity

Description of key information

In a developmental toxicity study (Reijnders, 1996) FeEDDHMA was administered once daily to groups of mated female rats by oral gavage at 0, 50, 200 or 1000 mg/kg bw/day from day 6 through day 16 of gestation. Control group females received the vehicle only. All dams were sacrificed on day 21 of the gestation period and foetuses removed for examination. In dams, there were no treatment-related clinical signs or incidences of mortality. The body weight gain and food intake was reduced at 1000 mg/kg bw/day. No adverse effects on pregnancy and no embryo-/foetotoxic effects were observed. There was no indication of teratogenic potential. On the basis of these results, the NOAEL was 200 mg/kg bw/day for maternal toxicity and at least 1000 mg/kg bw/day for develomental toxicity and teratogenicity. Although the duration of treatment was short, the results of this study are corroborated by the results of the one-generation study. The effects seen in fetuses in the one-generation study, consisting of mortality or reduced viability were related to the poor physical condition of the mothers that had been treated for a much longer period.

In a developmental toxicity study FeNaEDDHA was administered once daily to groups of 24 mated female Sprague-Dawley derived rats by oral gavage at 5, 100 or 500 mg/kg bw/day from day 6 through day 15 of gestation. Control group females received the vehicle only. All dams were sacrificed on day 21 of the gestation period and foetuses removed for examination. In dams, there were no treatment-related clinical signs or incidences of mortality. The body weight gain was reduced at 500 mg/kg bw/day for the period from days 6 -16 of gestation, and reduced food consumption was also noted at this dose level. No adverse effects on pregnancy and no embryo-/foetotoxic effects were observed. There was no indication of teratogenic potential. On the basis of these results, the NOEL was 100 mg/kg bw/day for maternal toxicity and at least 500 mg/kg bw/day for develomental toxicity and teratogenicity.

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no adverse effect observed

Effect on developmental toxicity: via inhalation route

Endpoint conclusion:

no study available

Effect on developmental toxicity: via dermal route

Endpoint conclusion:

no study available

Toxicity to reproduction: other studies

Additional information

Data waiving for EOGRTS or 2 -generation study:

The performance of a two-generation reproductive toxicity study is scientifically unjustified. Signs of reproduction and developmental toxicity were found in the one-generation study only at FeEDDHMA concentrations with parental toxicity. In the developmental toxicity studies with FeEDDHMA and FeNaEDDHA y no adverse effects on development were observed at all up to an exposure level of 1000 or 500 mg/kg bw/day. In several repeated dose toxicity studies with oral administration of FeEDDHMA and FeNaEDDHA, no adverse effects on the reproduction organs were seen (no organ weight changes and no adverse histopathological findings).

In summary, it is very unlikely that EDDHMA-Fe or FeNaEDDHA will cause adverse reproductive and/or developmental toxicity effects in concentrations without maternal systemic toxicity in an EOGRTS or two-generation reproductive toxicity study and conducting such a study is thus scientifically not justified. The available one-generation study and developmental toxicity studies are sufficient for hazard assessment and risk characterisation, also for FeKEDDHA (see section 13).

Justification for classification or non-classification

FeEDDHMA and FeNaEDDHA caused no developmental toxicity and no teratogenicity in the rat in a key developmental toxicity study according to test guideline OECD 414. Effects on reproductive performance/fertility were assessed for FeEDDHMA using a one generation toxicity study according to test guideline OECD 415. Only a slight decrease of the fertility and conception indices were seen in the high dose group of 750 mglkg bw. However, the fertility and conception indices in the control group were also low. In the absence of concomitant histopathological findings, this slight change in reproductive performance was considered to be secondary to the poor clinical condition of the animals at this dose level. Similarly, developmental effects were seen in this study at dose levels at pronounced maternal toxicity only. Accordingly, FeEDDHMA and FeNaEDDHA are not subject to classification for toxicity to reproduction according to CLP Regulation 1272/2008/EC. the same would apply to FeKEDDHA (see read across document in section 13).