Effects of acute and sub-chronic administration of iron nitrilotriacetate in the rat

Preece, Nicholas E.; Hall, D.E.; Howarth, Julie A.; King, Laurence J.; Parke, Dennis V.

doi:10.1016/0300-483x(89)90155-8

Cited by 17 publications

(7 citation statements)

References 46 publications

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“…Increased kidney weight relative to body weight has been reported in rats following exposure to high doses of iron (Preece and others ), although the increase was in part due to the decreased body weight of the treated animals in this study. Iron associated kidney toxicity is often associated with marked evidence of iron deposition in the glomeruli and proximal and distal tubules, mesangial expansion, interstitial fibrosis, and tubular atrophy (Landing and others ; Pardo‐Mindan and others ; Zhou and others , ) and in some cases extensive renal tubule necrosis and renal failure (Preece and others ; Hard ; Kadkhodaee and Gol ). Induction of lipid peroxidation in the kidney as measured by the generation of thiobarbituric reactive substances has been shown to occur in kidney tissues in rats administered a diet supplemented with 2% iron(II)carbonyl for a period of 180 d (Kozlov and others ).…”

Section: Discussioncontrasting

confidence: 54%

Subchronic and Reproductive/Developmental (Screening Level) Toxicity of Complexation Products of Iron Trichloride and Sodium Tartrate (FemTA)

Lynch

Emmen²,

Otterdijk³

et al. 2013

Journal of Food Science

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A complexation/reaction product, termed FemTA, of sodium tartrate [D(-)- and L(+)-tartaric acid and mesotartaric acid], sodium hydroxide, and iron trichloride may have use as an anticaking agent in salt preparations. FemTA is composed of about 4% sodium tartrate, approximately 10% mesotartaric acid, approximately 7% chloride, approximately 4% iron, approximately 7% sodium, approximately 0.3% sodium oxalate, and approximately 65% water. FemTA was tested in a 90-d oral toxicity study, which included a screening level reproductive/developmental toxicity phase, in Harlan Wistar rats. FemTA was administered by oral gavage at 500, 1000, and 2000 mg/kg body weight/d prior to and during mating, or about 20, 40, or 80 mg of iron/kg body weight/d, such that males received 90/91 d of treatment and females 104 to 109 d. Treatment was associated with inflammatory lesions of the lower GI tract at the mid- and high-dose levels, increased liver and kidney weights, increased serum bile acids and blood urea nitrogen, decreased chloride, and changes to hematological parameters consistent with inflammation. The effects were considered the result of iron overload. There were no effects on reproductive/developmental toxicity parameters. The no-observed-adverse-effect level (NOAEL), based on gastrointestinal tract effects was 500 mg/kg body weight/d. The NOAEL for reproductive/developmental toxicity was 2000 mg/kg body weight/d, the highest dose tested.

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Section: Discussioncontrasting

confidence: 54%

Subchronic and Reproductive/Developmental (Screening Level) Toxicity of Complexation Products of Iron Trichloride and Sodium Tartrate (FemTA)

Lynch

Emmen²,

Otterdijk³

et al. 2013

Journal of Food Science

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“…We monitored forskolin‐treated animals for signs of toxicity throughout the three consecutive months of daily topical drug application, but found no overt worrisome signs or symptoms of toxicity, including lethargy, interference with feeding, loose stool, hunching, gait or neurologic imbalances, or coat changes. We reasoned weight changes would be an appropriate gauge for global toxicity in our animal model, and predicted failure to thrive might be an appropriate measure of chronic toxicity from the drug (Ellis et al., 1984; Pavan et al., 2003; Preece et al., 1989). We found both control‐ and forskolin‐treated groups exhibited weight gain over time, as would be expected in maturing young adult animals.…”

Section: Discussionmentioning

confidence: 99%

Prolonged treatment of fair‐skinned mice with topical forskolin causes persistent tanning and UV protection

Spry

Vanover

Scott

et al. 2009

Pigment Cell Melanoma Res

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We previously reported that topical application of forskolin to the skin of fair-skinned MC1R-defective mice with epidermal melanocytes resulted in accumulation of eumelanin in the epidermis and was highly protective against UV-mediated cutaneous injury. In this report, we describe the long-term effects of chronic topical forskolin treatment in this animal model. Forskolin-induced eumelanin production persisted through 3 months of daily applications, and forskolin-induced eumelanin remained protective against UV damage as assessed by minimal erythematous dose (MED). No obvious toxic changes were noted in the skin or overall health of animals exposed to prolonged forskolin therapy. Body weights were maintained throughout the course of topical forskolin application. Topical application of forskolin was associated with an increase in the number of melanocytes in the epidermis and thickening of the epidermis due, at least in part, to an accumulation of nucleated keratinocytes. Together, these data suggest in this animal model, short-term topical regular application of forskolin promotes eumelanin induction and that over time, topical forskolin treatment is associated with persistent melanization, epidermal cell accumulation, and skin thickening.

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“…The thermodynamic complex formation constants (logK), as they are mostly reported in the literature, 3,31 seem to suggest that Fe(III) is much stronger-bound to NTA than many other metal ions including Zn: the binding constant of Fe(III) to NTA is about 10 15 and exceeds those of other metal ligands including Zn and also Fe(II) (Table 2a). This normally implies very low pH values and does not hold true for realistic conditions: at neutral pH and in aqueous media, competing reactions such as the formation and precipitation of Fe(OH) 3 Ð a sequel of the extremely low solubility of Fe(OH) 3 at neutral pH ± are favoured against the formation (or persistence) of FeNTA.…”

Section: Discussionmentioning

confidence: 66%

“…Earlier investigators had not found lipid peroxidation with NTA alone at similar dose levels over 13 days. 15 Andersson et al did not find an altered Fe content in kidney homogenates after a five-week feeding with high-dose levels, suggesting that renal clearance of NTA does not lead to renal Fe accumulation as does FeNTA after intraperitoneal administration. 3,13 Andersson et al also observed that 1% FeNTA in the diet did not show clinical or morphological effects in rats, concluding that ingested FeNTA is less nephrotoxic than a comparable dose of ingested NTA.…”

Section: Discussionmentioning

confidence: 94%

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NTA and Fe(III)NTA: differential patterns of renal toxicity in subchronic studies

Leibold¹,

Deckardt²,

Mellert³

et al. 2002

Hum Exp Toxicol

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Differential patterns in terms of nephropathology and 8-hydroxyguanine formation in the course of oral 28-day studies were observed with nitrilotriacetic acid (NTA) and FeNTA. FeNTA, but not NTA, caused enhanced 8-hydroxyguanine formation in kidney DNA after oral and intraperitoneal administration. Enhanced lipid peroxidation in the kidney homogenate was observed with FeNTA as well as with NTA. For NTA, the low dose (9 mg/kg per day) was without adverse effect. The kidney toxicity of oral FeNTA (50, 200, and 1000 mg/ kg per day) was only mild, 50 mg/ kg per day; however, it still led to an increased 8-hydroxyguanine content. The relevance of Iron(III) (Fe(III)) or Fe(III)NTA formation as a relevant mediator of NTA-related toxicity was excluded on the basis of these data. Also, a thermodynamic consideration presented here, supports the view that zinc (Zn), and not Fe, is likely to mediate the tubular cell cytotoxicity of NTA.

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Effects of acute and sub-chronic administration of iron nitrilotriacetate in the rat

Cited by 17 publications

References 46 publications

Subchronic and Reproductive/Developmental (Screening Level) Toxicity of Complexation Products of Iron Trichloride and Sodium Tartrate (FemTA)

Subchronic and Reproductive/Developmental (Screening Level) Toxicity of Complexation Products of Iron Trichloride and Sodium Tartrate (FemTA)

Prolonged treatment of fair‐skinned mice with topical forskolin causes persistent tanning and UV protection

NTA and Fe(III)NTA: differential patterns of renal toxicity in subchronic studies

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