Tris(oxiranylmethyl) benzene-1,2,4-tricarboxylate

Endpoint summary

Description of key information

A 28-day repeated dose oral toxicity study in rats conducted according to OECD test guideline 407 demonstrated a NOAEL of 150 mg/kg body weight/day for systemic toxicity of tris(oxiranylmethyl)benzene-1,2,4-tricarboxylate.  A repeated dose 90-day oral toxicity study is proposed by the lead registrant, subject to approval of the Test Plan by ECHA.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion

Dose descriptor:

NOAEL

150 mg/kg bw/day

Study duration:

subacute

Species:

rat

Additional information

In a 28-day repeated oral toxicity study no signs of toxicity were found at dose levels of 50 and 150 mg/kg bw/day. At a dose level of 500 mg/kg bw/day the following signs of toxicity were observed: slight clinical findings, slightly decreased body weight gain and food consumption intermittently during the treatment period in male animals. Increased spleen, kidney and adrenal weight and slightly decreased heart and prostate weight were without associated histopathological finding. Histopathological changes were seen in the testis and epididymis. Epididymal spermatic granuloma(s) were seen in all males of this group and were associated with inflammatory edema, increased incidence and degree of interstitial mononuclear cell infiltrates, condensed luminal content, bilateral oligospermia and/or bilateral intraluminal cellular debris in the epididymis and with tubular dilation of the testes in the same dose group.

Due to gender-specific signs of toxicity at the high dose level, separate NO(A)ELs can be placed for male and female animals of this study.

Male animals:

Signs of toxicity observed in male animals at the dose level of 500 mg/kg bw/day were: slightly decreased body weight, food consumption and the above-mentioned histopathological findings in reproductive organs. As no signs of toxicity were observed in male animals at the dose levels of the low and mid dose groups, the dose level of 150 mg/kg bw/day marks the NOAEL for male animals in this study.

Female animals:

No signs of toxicity were observed in female animals at dose levels of 50, 150 or 500 mg/kg bw/day. Thus, the dose level of 500 mg/kg bw/day marks the NOAEL for female animals in this study.

Minimal diffuse epithelial hyperkeratosis of the nonglandular part of the stomach was noted in a proportion of females treated at 500 mg/kg bw/day and considered to be possibly related to a local irritant effect of the test item formulation when administered repeatedly by oral gavage and therefore not to be relevant for humans.

Repeated dose toxicity: via oral route - systemic effects (target organ) urogenital: epididymides; urogenital: testes

Justification for classification or non-classification

Specific Target Organ Toxicity – Repeated Exposure: The notifiable substance did not exhibit significant toxic effects arising from a repeated exposure at a dose level of 500 mg/kg/day in female animals and at dose level of 150 mg/kg/day in male animals. As a result, the substance does not meet the criteria for classification according to Regulation (EC) No 1272/2008, Annex I section 3.9.