Table 1: Overview of the pharmacokinetic studies conducted in response to the Alternative Tier 2 test program for MMT. The following forms of manganese (Mn) were used in these studies: Mn tetroxide, Mn sulfate, and Mn phosphate. Some studies also involved intravenous administration of radiolabeled Mn chloride (54MnCl2) to assess whole-body (WB) clearance.

Pharmacokinetic endpoint of interestRegulatory StatusAnimal SpeciesManganese species and exposure conditionsPrimary publication(s)

Particle solubility and dissolution kineticsVoluntaryRatPhosphate, sulfate, and tetraoxide—intratracheal instillation
0, 0.04, 0.08, or 0.16 μg Mn/g
Rats killed at 0, 1, 3, or 14 d
[42]
Exposure-response and WB clearanceVoluntaryRatPhosphate inhalation
6 h/d for either 5 d/wk or 7 d/wk at 0, 0.03, 0.3, or 3 mg Mn/m3 for up to 14 d
[43]
Particle solubility and WB clearanceVoluntaryRatSulfate and tetroxide inhalation
6 h/d for 7 d/wk at 0, 0.03, 0.3, or 3 mg Mn/m3 for 14 d
[44]
Diet-inhalation interaction and WB clearanceVoluntaryRatSulfate or tetroxide inhalation
6 h/d for 7 d/wk at 0, 0.03, or 0.3 mg Mn/m3 for 14 d
Low (2 ppm), sufficient (10 ppm), or high (100 ppm) Mn diets
[45, 46]
Olfactory transport of MnVoluntaryRatChloride and phosphate inhalation ~0.5 mg Mn/m3 for 90 min
Occluded nostril model
[47, 48]
Individual susceptibility WB clearance
Nasal pathology
RequiredRatInhalation
Exposed 6 h/d for 5 d/wk to sulfate at 0.01, 0.1, or 0.5 mg Mn/m3 or phosphate at 0.1 mg Mn/m3 for up to 90 d
Adult male, adult female, and senescent male
[49, 50]
Individual susceptibilityRequiredRatSulfate inhalation
Exposed 6 h/d for 7 d/wk at 0, 0.05, 0.5, or 1 mg Mn/m3 throughout the majority of pregnancy or lactation.
[41, 51]
Species differences
Brain imaging
Respiratory tract pathology and neurochemistry
RequiredRhesus monkeySulfate inhalation
Exposed 6 h/d for 5 d/wk at 0, 0.06, 0.3, or 1.5 mg Mn/m3 for up to 90 d.
[3438]