Calcium lignosulphonate: Re-evaluation of relevant endpoints to re-confirm validity and NOAEL of a 90-day feeding study in rats

• Published in: Regulatory toxicology and pharmacology Vol. 66; no. 3; pp. 286 - 299
• Main Authors: Thiel, Anette, Braun, William, Cary, Maurice G., Engelhardt, Jeffery A., Goodman, Dawn G., Hall, William C., Romeike, Annette, Ward, Jerrold M.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Inc 01-08-2013
• Subjects: Animals; Dose-Response Relationship, Drug; Endpoint Determination; Female; Guidelines as Topic; Histiocytosis; Histiocytosis - chemically induced; Histiocytosis - pathology; Lignin - analogs & derivatives; Lignin - toxicity; Ligninsulphonate; Lignosulphonate; Male; No-Observed-Adverse-Effect Level; Product Surveillance, Postmarketing; PWG; Rats; Rats, Wistar; Reproducibility of Results; Toxicity Tests, Subchronic - methods; Toxicity Tests, Subchronic - standards; PWG; H&E; SRBC; TDAR; Ligninsulphonate; Lignosulphonate; NTP; Histiocytosis; STP; EFSA; NOAEL; BALT; NALT
• ISSN: 0273-2300; 1096-0295
• DOI: 10.1016/j.yrtph.2013.04.007

•Determination of normal immunological tissue response.•Use of adequate process for evaluation of animal health status.•Undigestible material produce adaptive foamy histiocytosis in mesenteric lymph node.
A 90-day feeding study in Han/Wistar rats with calcium lignosulphonate was evaluated by the EFSA. The study was considered to be inadequate due to potentially impaired health status of the animals based upon a high incidence of minimal lymphoid hyperplasia in mesenteric/mandibular lymph nodes and Peyer’s patches, and minimal lymphoid cell infiltration in the liver in all animals. The EFSA Panel further disagreed with the conclusion that the treatment-related observation of foamy histiocytosis in mesenteric lymph nodes was non-adverse and asked whether this observation would progress to something more adverse over time. A PWG was convened to assess the sections of lymph nodes, Peyer’s patches and liver. In addition, all lymphoid tissues were re-examined. The clinical pathology and animal colony health screening data were re-evaluated. The question whether the foamy histiocytosis could progress to an adverse finding with increasing exposure duration was addressed by read-across. In conclusion, the animals on the 90-day feeding study were in good health, the study was adequate for safety evaluation, and the foamy histiocytes in the mesenteric lymph nodes were not considered adverse, but rather an adaptive response that was considered unlikely to progress to an adverse condition with time. The NOAEL was re-affirmed to be 2000mg/kgbw/d.