Extended one-generation reproductive toxicity study of food-grade titanium dioxide E171 with emphasis on reproductive and endocrine endpoints

• Published in: Reproductive toxicology (Elmsford, N.Y.) Vol. 130; p. 108687
• Main Authors: Battersby, Rodger V., Adam, Janine, Williams, Amy L., DeSesso, John M.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01-12-2024
• Subjects: E171; EOGRT; Extended one-generation reproductive toxicity study; Food-grade titanium dioxide; OECD 443; Reproduction; Food-grade titanium dioxide; Reproduction; E171; EOGRT; OECD 443; Extended one-generation reproductive toxicity study
• ISSN: 0890-6238; 1873-1708; 1873-1708
• DOI: 10.1016/j.reprotox.2024.108687

Food-grade titanium dioxide E171 was administered in feed to Sprague Dawley rats in an extended one-generation reproductive toxicity (EOGRT) study (OECD Test 443). The dosed diet (0, 100, 300, or 1000 mg/kg body weight/day) started 10 weeks before mating and continued throughout the study. After weaning, pups were allocated to Cohorts 1 A/1B (to assess reproductive toxicity), 2 A/2B (to assess developmental neurotoxicity), and 3 (to assess developmental immunotoxicity); in addition, Cohort 1B was mated to produce an F2 generation and satellite F0 animals were evaluated for colonic aberrant crypt foci (ACF). In F0 animals, there were no systemic toxicity or reproductive effects, no treatment-related histopathological changes, and no ACF in the colon. Serum estradiol or testosterone concentrations were not changed in F0 or F1 animals. No pre-/postnatal developmental changes related to treatment were noted in F1 animals, and the reproductive performance of F1 Cohort 1B animals was unaffected. F2 pups showed no abnormalities in pre- or postnatal development (postnatal days 4–8). No treatment-related developmental neurotoxicity was observed in Cohorts 2 A/2B. Although no treatment-related immunotoxicity was observed in Cohort 3, the positive control did not induce the expected response; this segment of the study will be repeated. Analyses of blood and urine showed negligible systemic absorption of E171 from the gastrointestinal tract upon dietary ingestion. The no observed adverse effect level (NOAEL) for parental systemic toxicity, reproductive toxicity, offspring toxicity, and developmental neurotoxicity was considered 1000 mg/kg body weight/day. For developmental immunotoxicity, a NOAEL was not determined owing to insufficient T-cell-dependent antibody response in the positive control. Our study provides robust data on the reproductive toxicity and preneoplastic potential of E171.
•Dietary E171 (titanium dioxide) doses ≥1000 mg/kg/day in male and female Sprague Dawley rats did not adversely affect reproduction.•F1 offspring were unaffected by parental treatment and successfully reproduced to form a healthy F2 generation.•Male reproductive organs exhibited no signs of gross or microscopic pathology.•No signs of developmental neurotoxicity were observed in the F2 generation.•No increase in aberrant crypt foci (ACF) was observed at any dose in satellite groups of F0 rats.