Registration Dossier

Administrative data

Description of key information

In a 90-Day gavage study (OECD guideline 408; 0, 50, 150, 500 mg/kg bw/day), EUF induced local effects in the stomach at dose levels of 150 and 500 mg/kg bw (NOAELlocal 50 mg/kg bw, NOAELsystemic 500 mg/kg bw).
In a 28-Day dermal toxicity study, the NO(A)EL was at 160 mg/kg bw.
The subacute toxicity was investigated in rats in a 28-day repeated dose dermal toxicity study ( according to OECD guideline 411. Groups of 5 male and 5 female rats received dosages of 0, 40, 80 or 160 mg/kg bw. The No-Observed-Adverse-Effect-Level (NO(A)EL) for systemic effects was above 160 mg/kg b.w./day after a daily dermal administration to rats over 28 days

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Dose descriptor:
NOAEL
500 mg/kg bw/day
Study duration:
subchronic
Species:
rat

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion
Dose descriptor:
NOAEL
160 mg/kg bw/day
Study duration:
subacute
Species:
rat

Additional information

A 28-Day preliminary subacute dose-range-finding study in rats by daily gavage with EUF (without laboratory and histopathological examinations) resulted in no test item-related findings at 50 or 150 mg/kg bw/day. At the high dose (500 mg/kg bw/day) salivation was observed in all animals at termination. Body weights and weight gains were reduced in males. No macroscopic changes were noted.

In the subsequent subchronic 90-Day gavage study (OECD guideline 408;0, 50, 150, 500 mg/kg bw/day), EUF induced local effects in the stomach. Histopathological changes were confined to changes of the forestomach (subepithelial mixed cell infiltrations) and epithelial hyperplasia at 150 and 500 mg/kg. In addition at 500 mg/kg, the fundus region showed mucosal erosions with neutrophilic granulocytes on the surface of the damaged mucosa. Other effects at the mid and high dose level (haematology) are considered to be a consequence of the gastric changes.

As far as the hydrolysis products are concerned, the results of the 90-Day oral toxicity study with EUF closely correspond with chronic drinking water studies with formaldehyde. This substance also induced local effects, i.e. changes of the gastric mucose membrane. The long-term NOAELlocal was reported to be at 15 mg/kg bw/day.

No ethylene glycol induced systemic nephrotoxicity (NOAEL 71 mg/kg bw/day) was observed in the 90-Day oral toxicity study with EUF and also no toxic effects could be derived from urea with a systemic long-term NO(A)EL of 2250 mg/kg bw/day.

 

In a 28 -Day dermal toxicity study, treatment with EUF caused very slight and transient erythemas to the treated skin sites in individual animals, but no such findings were seen at treatment termination.Therefore, EUF had no consistent effect on the skin as the findings were neither time- nor dose-related and occurred only sporadically.

No test item-related histopathological changes were noted for any of the examined organs including the treated skin sites.The systemic NOAEL was > 160 mg/kg bw.

In summary, in gavage studies in rats with EUF, local effects in the stomach were detected, which are most likely due to formaldehyde release. Ethylene glycol-induced nephrotoxicity was not detected, i.e. the threshold is above the 500 mg/kg bw systemic NOAEL of the 90-Day oral toxicity study with EUF. After dermal administration over 28 days, the NO(A)EL was at 160 mg/kg bw/day, i.e. at the highest dose. No systemic efects were noted.


Repeated dose toxicity: via oral route - systemic effects (target organ) digestive: stomach

Repeated dose toxicity: dermal - systemic effects (target organ) other: skin

Justification for classification or non-classification