Safety evaluation of certain food additives - ipcs inchem

CALCIUM LIGNOSULFONATE (40–65) 33
4. COMMENTS
4.1 Toxicological data
Studies with tritiated calcium lignosulfonate (40–65) in rats indicated that
only limited absorption occurs after oral exposure. Owing to the constant formation
of tritiated water from the product, most (98.5%) of the radioactivity in blood, tissues
and urine co-eluted with tritiated water, indicating that only about 1% was present
in higher molecular weight fractions of the purified material used for dosing.
The toxicity of calcium lignosulfonate (40–65) has been studied in 28-day
and 90-day studies of oral toxicity in which calcium lignosulfonate (40–65) was
incorporated into the diet. In the 28-day study of toxicity, groups of male and female
Wistar rats were given diets providing calcium lignosulfonate (40–65) at a target
daily dose of 0, 500, 1500 or 4000 mg/kg bw. The study was carried out in
accordance with OECD guidelines and involved complete pathological examination
of all major organs. With the exception of chronic inflammation of the rectum in
males at the highest dose, but not at the lowest or intermediate dose, no adverse
effects were observed. The NOAEL was equal to 1300 mg/kg bw per day for males
and 1350 mg/kg bw per day for females on the basis of the inflammatory response
in the rectum.
In a 90-day study that complied with GLP and with OECD guidelines, groups
of male and female Wistar rats were given diets providing calcium lignosulfonate
(40–65) at a target dose of 0, 500, 1000 or 2000 mg/kg bw per day. This study
involved complete pathological examination of all organs and tissues. No adverse
clinical or organ weight changes were reported. A functional observational battery
provided no evidence of adverse effects, and the results of a test for primary immune
response were normal. In this study, no histopathological changes were noted in
the rectum, but there was a dose-related increase in the incidence of histiocytosis
of the mesenteric lymph nodes in male and female rats. The magnitude of this effect
also increased with dose. The incidence and magnitude of this effect showed
minimal regression in a 28-day recovery study conducted in satellite groups of rats.
There was no evidence of histiocytosis in other lymphoreticular tissues. There was
also an increase in the incidence of tubular vacuolation of the kidney, but this was
not accompanied by a degenerative change and therefore was not considered to
be an adverse effect.
The finding of histiocytosis in the mesenteric lymph nodes of rats treated with
calcium lignosulfonate (40–65) has also been observed with other high molecular
weight, poorly absorbed materials, such as petroleum-derived mineral oils and
waxes and copovidone (a copolymer of vinylpyrrolidone and vinyl acetate) (Smith
et al., 1996; Mellert et al., 2004). Similar effects have also been observed with
polypentosan sulfate (National Toxicology Program, 2004). Histiocytosis appears
to be related to an attempt by the histiocytes of the mesenteric lymph nodes to
degrade the small amount of absorbed test article. Long-term studies in rats given
polypentosan sulfate and copovidone indicated that the histiocytosis does not
progress to any pathological lesion; thus, the Committee concluded that the
histiocytosis observed with calcium lignosulfonate (40–65) does not represent an
adverse effect. The NOEL in the 90-day study was therefore the target dose of
2000 mg/kg bw per day.