Aluminum salts final content: appendix C

Species, sex, strain and number Al species (number of dose levels in addition to control)	Exposure Dose levels in study: Da (administered dose), or Dc (combined dose)	Critical neurotoxic effects in adults (>90-day exposure studies)	Lowest-observed-effect level (LOEL) or no observed effect level (NOEL) (mg Al/kg bw/d) Da = administered dose Dc = combined dose	References
Male Sprague-Dawley rats (five per group) Al sulphate	Drinking water, for various periods up to 12 months One dose level: Da: 165 mg Al/kg bw/d	Decrease in nitroxidergic neurons in the somatosensory cortex.	LOEL = 165 (Da)	Rodella et al. (2006)
Wistar rats (3 age groups: 3, 10, 24 months) (20 per dose per age group) Al chloride	Drinking water, for 90 days Three dose levels: Da: 11.1, 21.5 or 43.1 mg Al/kg bw/d	Impaired vestibulo-ocular reflex (results not influenced by age)	LOEL = 43.1 (Da) NOEL = 21.5 (Da)	Mameli et al. (2006)
Male Sprague-Dawley rats (six per group) Al maltolate	Drinking water, for 12 months One dose level: Da: 0.38 mg Al/kg bw/dFootnote a	Induced apoptosis in brain; Increased efficiency of monoamine oxidases; Increase in level of caspase 3 and 12 in brain.	LOEL = 1.0 (Dc)	Huh et al. (2005)
Male Wistar rats (seven per group) Al chloride	Gavage (101 mg Al/kg bw/d), for one month, drinking water (45 mg Al/kg bw/d) for additional four months One dose level: Da: 56 mg Al/kg bw/dFootnote a (weighted average dose)	Impaired performance in Morris water maze; Increased expression of amyloid precursor protein and caspase 3 in hippocampus.	LOEL = 56 (Da)	Gong et al. (2005)
Male Wistar rats (ten per group) Al chloride	Diet for four months One dose level: Da: 19 mg Al/kg bw/dFootnote b (assuming same weight gain as in 2002)	Decrease in Na+/K+-ATPase activity in brain cortex synaptosomes.	LOEL = 19 (Da)	Silva et al. (2005)
Sprague-Dawley rats (nine per group) Al chloride	Gavage, for three months One dose level: Da: 121 mg Al/kg bw/d	Impaired performance in Morris water maze; Decrease in long-term potentiation in hippocampal slices.	LOEL = 121 (Da)	Shi-Lei et al.(2005)
Male rats (strain not specified) (20-40 per group) Al species not specified (indicated to be water-soluble)	Gavage, for three months One dose level: Da: 500 mg Al/kg bw/d	Impaired performance in Morris water maze; Altered synapses in hippocampus and frontal cortex.	LOEL = 500 (Da)	Jing et al. (2004)
Male Wistar rats (ten per group) Al nitrate	Drinking water, for eight months One dose level: Da: 36 mg Al/kg bw/dFootnote a	Evidence of increased lipid peroxidation in brain.	LOEL = 36 (Da)	Flora et al. (2003)
Male Wistar rats (ten per group) Al chloride	Diet for four months One dose level: Da: 19 mg Al/kg bw/dFootnote b	Increase in synaptosomal membrane fluidity; Decrease in cholesterol/phospholipid ratio in synaptosomes.	LOEL = 19 (Da)	Silva et al. (2002)
Male Lister hooded rats (11-24 per group) Al sulphate	Drinking water, for up to seven months One dose level: Da: 140 mg Al/kg bw/dFootnote a</>	Progressive working memory in water maze.	NOEL= 140 (Da)	Von Linstow Roloff et al. (2002)
Male Sprague-Dawley rats (ten per group) Al nitrate with citrate (two dose levels)	Drinking water, for 6.5 months Two dose levels: Da: 50 or 100 mg Al/kg bw/d	No effects on open field activity or on shuttle box performance (passive avoidance).	NOEL = 100 (Da) No information on base diet (see Sanchez et al. 1997) where lab chow intake is estimated up to 13 mg/kg bw/d. Dc = 113.	Domingo et al. (1996)
Male Druckrey albino rats (40 per group) Al chloride	Drinking water, for 12 months One dose level: Da: 36 mg Al/kg bw/dFootnote b	Increase in lipid peroxidation in brain.	LOEL = 36 (Da)	Gupta and Shukla (1995)
Wistar rats (6-8 per group) Al citrate	Diet for six months One dose level: Da: 50 mg Al/kg bw/dFootnote a	Cytoplasmic vacuolation in astrocytes and neurons.	LOEL = 50 (Dc)	Florence et al. (1994)
Male Druckrey albino rats (90 per exposure group; 6 to 10 animals per test group) Al chloride	Drinking water, for six months One dose level: Da: 52 mg Al/kg bw/dFootnote b	Reduction in spontaneous motor activity; Impaired learning (shuttle box, maze); Increase in brain lipid peroxidation; Reduction in Mg2+- and Na+K+-ATPase activities.	LOEL = 52 (Da)	Lal et al. (1993)
Male Sprague-Dawley rats (4-6 per group) Al sulphate	Drinking water, for three months One dose level: Da: 420 mg Al/kg bw/dFootnote a	Decrease in levels of microtubule associated protein-2 and spectrin in hippocampus.	LOEL = 420 (Da)	Johnson et al. (1992)
Male Sprague-Dawley rats (8-14 per group) Al chloride	Diet for 11 months One dose level: Da: 50 mg Al/kg bw/dFootnote a	Reduction in motor activity; Impaired learning (shuttle box).	LOEL = 50 (Da)	Commissaris et al. (1982)

Table C1 (Mice): Subset of experimental animal studies for consideration in the exposure-response analysis: neurotoxic effects in exposed adults

Species, sex, strain and number Al species (number of dose levels in addition to control)	Exposure Dose levels in study: Da (administered dose), or Dc (combined dose)	Critical neurotoxic effects in adults (>90-day exposure studies)	LOEL or NOEL (mg Al/kg bw/d) Da = administered dose Dc = combined dose	References
CD mice (10 per group) Al lactate	Gavage, for three months One dose level: Da: 333 mg Al/kg bw/dFootnote a	Increase in acetylcholinesterase activity.	LOEL = 333 (Da)	Zatta et al. (2002)
Swiss Webster mice (10-12 per group) Al lactate	Diet for 90 days One dose level: Dc: 160 mg Al/kg bw/dFootnote b	Decrease in motor activity, hindlimb grip strength, and auditory and air puff startle responsiveness.	LOEL = 160 (Dc)	Golub et al. (1992)

Table C1 (Dogs): Subset of experimental animal studies for consideration in the exposure-response analysis: neurotoxic effects in exposed adults

Species, sex, strain and number Al species (number of dose levels in addition to control)	Exposure Dose levels in study: Da (administered dose), or Dc (combined dose)	Critical neurotoxic effects in adults (>90-day exposure studies)	LOEL or NOEL (mg Al/kg bw/d) Da = administered dose Dc = combined dose	References
Beagle dogs (6M, 6F per dose) Acidic SALP	Diet for 6 months Three dose levels: Da: 9.5, 29.0 or 90.0 mg Al/kg bw/d	No difference in body weight; No ocular changes; No effect on haematological parameters; No change in organ weight.	NOEL = 90 (Da)	Katz et al. (1984)

Table C2 (Rats): Subset of experimental animal studies for consideration in the exposure-response analysis: developmental neurotoxicity or reproductive effects
(prenatal exposure and/or exposure during lactation)

Species, strain and number Al species (number of dose levels in addition to control)	Exposure GD = gestational day PND = postnatal day	Critical effects in pups (or dams where indicated)	LOEL or NOEL (mg Al/kg bw/d) Da = administered dose Dc = combined dose	References
Sprague-Dawley rats (12 per group) Al nitrate with citrate	Drinking water, during gestation and lactation Two maternal dose levels: Da: 50 or 100 mg Al/kg bw/d	Biphasic effect on learning: improved performance at Da= 50 mg/kg bw/d, but no difference compared to controls at Da= 100 mg/kg bw/d; No effect on motor activity.	NOEL= 103 (Dc)	Roig et al. (2006)
Wistar rats (eight per group) Al chloride	Gavage, during gestation and lactation One maternal dose level: Da: 70 mg Al/kg bw/d	Decrease in placental and fetal weight; Increase in number of resorptions; Increase in skeletal malformations; Increase in oxidative stress in brains of mothers/fetuses and sucklings.	LOEL = 70 (Da)	Sharma and Mishra (2006)
Sprague-Dawley rats (5-6 per group) Al chloride	Gavage, during lactation, pups also exposed 39 days after weaning via gavage One maternal dose level: Da: 100 mg Al/kg bw/d	Increased lipid peroxidation, decrease in superoxide dismutase and catalase activity in cerebrum and cerebellum.	LOEL = 100 (Da)	Nehru and Anand (2005)
Sprague-Dawley rats (10-14 per group) Al nitrate with citrate	Drinking water, during gestation and lactation Two maternal dose levels: Da: 50 or 100 mg Al/kg bw/d	Increase in number of days to sexual maturation.	LOEL = 53 (Dc) (females) LOEL = 103 (Dc) (males)	Colomina et al. (2005)
Sprague-Dawley rats (10-14 per group) Al nitrate with citrate	Drinking water, during gestation and lactation Two maternal dose levels: Da: 50 or 100 mg Al/kg bw/d	Improved performance in learning tests (passive avoidance, water maze).	LOEL = 103 (Dc)	Colomina et al. (2005)
Sprague-Dawley rats (10-14 per group) Al nitrate with citrate	Drinking water, during gestation and lactation Two maternal dose levels: Da: 50 or 100 mg Al/kg bw/d	Reduction in forelimb strength in males.	LOEL = 103 (Dc) NOEL = 53 (Dc)	Colomina et al. (2005)
Wistar rats (» seven pups per group) Al chloride	Drinking water, during lactation One maternal dose level: Da: 85 mg Al/kg bw/dFootnote a.1	Deficits in synaptic plasticity in dentate gyrus of hippocampus.	LOEL = 85 (Da)	Chen et al. (2002)
Wistar rats (4-10 per group) Al chloride	Drinking water, in three groups: gestation, lactation, and lactation and lifetime One maternal dose level: Da: 85 mg Al/kg bw/dFootnote a.1 (same dose for pups following lactation)	Reduced body weight; Deficits in synaptic plasticity in dentate gyrus of hippocampus. (greatest effect in rats exposed from parturition throughout life, while prenatal exposure was associated with the least effect)	LOEL = 85 (Da)	Wang et al. (2002a)
Wistar rats (number not specified) Al sulphate	Drinking water, during gestation One maternal dose level: Da: 63 mg Al/kg bw/dFootnote a.1	Decrease in pup body weight; Decreased number of cells in cerebellum; Disaggregation of microtubules and neuronal death in cerebellar neuron cultures.	LOEL = 663 (Da)	Llansola et al. (1999)
Long Evans rats (number not specified) Al lactate	Drinking water, during gestation or prior to mating and then during gestation and lactation One maternal dose level: Da: 450 mg Al/kg bw/dFootnote a.1	Delayed expression of phosphorylated high molecular weight neurofilament protein in tracts in diencephalon; Maternal toxicity.	LOEL = 450 (Da)	Poulos et al. (1996)
THA rats (8-20 pups per group) Al chloride	Gavage, dams exposed one time (GD8) 2 maternal dose levels: Da: 183 or 366 mg Al/kg bw/d	Maternal toxicity; Decreased pup weight; Delay in pinna detachment and eye opening in females; Delayed development of auditory startle in males.	LOEL = 183 (Da)	Misawa and Shigeta (1993)
Sprague-Dawley rats (15-19 dams per group) Al hydroxide with and without citrate	Gavage, during gestation One maternal dose level: Da: 133 mg Al/kg bw/d	Fetal body weight reduced; Skeletal variations increased in Al hydroxide + citrate group.	LOEL = 133 (Da)	Gomez et al. (1991)
Wistar rats (6-9 dams per group) Al lactate	Diet during gestation One maternal dose level: Da: 400 mg Al/kg bw/d	Impaired negative geotaxis; Impaired performance in suspension and locomotor coordination tests.	LOEL = 400 (Da)	Muller et al. (1990)
Wistar rats (6-9 dams per group) Al lactate	Diet during gestation One maternal dose level: Da: 400 mg Al/kg bw/d	No effects in righting or grasping reflex.	NOEL = 400 (Da)	Muller et al. (1990)
Wistar rats (6-12 dams per group) Al chloride and Al lactate	Diet during gestation Three maternal dose levels Al chloride: 100, 300 and 400 mg Al/kg bw/d	Impaired grasping reflex and impaired righting reflex.	LOEL = 300 (Da) NOEL = 100(Da)	Bernuzzi et al. (1989b)
Wistar rats (6-12 dams per group) Al chloride and Al lactate	Diet during gestation Three maternal dose levels Al chloride: 100, 300 and 400 mg Al/kg bw/d	Negative geotaxis and locomotor coordination.	LOEL = 400 (Da) NOEL = 300 (Da)	Bernuzzi et al. (1989b)
Wistar rats (6-12 dams per group) Al chloride and Al lactate	Diet during gestation Three maternal dose levels Al lactate: 100, 200 and 400 mg Al/kg bw/d	Impaired grasping reflex.	LOEL = 100 (Da)	Bernuzzi et al. (1989b)
Wistar rats (6-12 dams per group) Al chloride and Al lactate	Diet during gestation Three maternal dose levels Al lactate: 100, 200 and 400 mg Al/kg bw/d	Impaired righting reflex.	LOEL = 200 (Da) NOEL = 100 (Da)	Bernuzzi et al. (1989b)
Wistar rats (6-12 dams per group) Al chloride and Al lactate	Diet during gestation Three maternal dose levels Al lactate: 100, 200 and 400 mg Al/kg bw/d	Negative geotaxis.	NOEL = 400 (Da)	Bernuzzi et al. (1989b)
Wistar rats (6-12 dams per group) Al chloride and Al lactate	Diet during gestation Three maternal dose levels Al lactate: 100, 200 and 400 mg Al/kg bw/d	Impaired locomotor coordination.	LOEL = 400 (Da) NOEL = 200 (Da)	Bernuzzi et al. (1989b)
Wistar rats (12 to 14 dams per groups) Al chloride	Diet, during gestationTwo maternal dose levels: Da: 160 or 200 mg Al/kg bw/d	Reduced body weight of pups; Impaired negative geotaxis.	LOEL = 160 (Da)	Bernuzzi et al. (1986)
Wistar rats (6-8 per group)Al chloride	Diet during gestation Two maternal dose levels: Dc: 25 or 50 mg Al/kg bw/dFootnote a.1	No differences in number of live fetuses and resorbed/dead fetuses, fetal body weight and length, or in skeletal anomalies.	NOEL = 50 (Da)	McCormack et al. (1979)

Table C2 (Mice): Subset of experimental animal studies for consideration in the exposure-response analysis: developmental neurotoxicity or reproductive effects
(prenatal exposure and/or exposure during lactation)

Species, strain and number Al species (number of dose levels in addition to control)	Exposure GD = gestational day PND = postnatal day	Critical effects in pups (or dams where indicated)	LOEL or NOEL (mg Al/kg bw/d) Da = administered dose Dc = combined dose	References
Swiss Webster mice (15-17 pups per dose group per sex) Al lactate Less than optimal diet--trace element reduction in lab chow based on deficiencies measured in U.S. women.	Diet during gestation and lactation, continued exposure of pups via diet for 14 days. Three maternal dose levels: Dc: 10, 50 and 100 mg Al/kg bw/d	Decreased weight gain in pups; Impaired learning of maze with respect to cue utilization (females).	LOEL = 50 (Dc) NOEL = 10 (Dc)	Golub and Germann (2001b)
Swiss Webster mice (15-17 pups per dose group per sex) Al lactate Less than optimal diet--trace element reduction in lab chow based on deficiencies measured in U.S. women.	Diet during gestation and lactation, continued exposure of pups via diet for 14 days. Three maternal dose levels: Dc: 10, 50 and 100 mg Al/kg bw/d	Impaired performance in rotarod test (males).	LOEL = 100 (Dc) NOEL = 50 (Dc)	Golub and Germann (2001b)
Swiss Webster mice (15-19 pups per dose group) Al lactate	Diet during gestation and lactation, continued exposure of pups via diet to PND 35 One maternal dose level: Dc: 100 mg Al/kg bw/d	Reduced forelimb and hindlimb grip strength; Decreased thermal sensitivity.	LOEL = 100 (Dc)	Golub et al. (2000)
Swiss Webster mice (six pups per dose group) Al lactate	Diet during gestation and lactation, continued from PND 21-45. One maternal dose level: Dc: 100 mg Al/kg bw/d	Decrease in myelin sheath width.	LOEL = 100 (Dc)	Golub and Tarara (1999)
Charles River CD1 mice (10-32 dams per group) Al nitrate	Gavage, dams exposed during gestation One maternal dose level: Dc: 29 mg Al/kg bw/d	Increased mortality of dams; Reduced fetal body weight.	LOEL = 29 (Da)	Belles et al. (1999)
NIH mice (seven dams per group) Al lactate	Diet, dams exposed during gestation and lactation, pups then exposed PND 21-40 One maternal dose level: Da: 100 mg Al/kg bw/d	Increased phospholipid and galactolipid contents in brain myelin; Increased lipid peroxidation.	LOEL = 130 (Dc)	Verstraeten et al. (1998)
Swiss Webster mice and Sprague-Dawley rats (8-12 per group) Al lactate	Diet, dams exposed during gestation and lactation One maternal dose level: Dc: 100 mg Al/kg bw/d	Lower retention of both Mn and Fe following gavage of solutions with these elements.	LOEL = 100 (Dc)	Golub et al. (1996)
Swiss mice (number not specified) Al hydroxyde (with and without ascorbic acid)	Gavage, during gestation One dose level: Da: 103.8 mg Al/kg bw/d	No differences found in body weight of dams; No malformations or developmental variations observed.	NOEL = 103.8 (Da)	Colomina et al. (1994)
Swiss Webster mice (12 pups per group) Al lactate	Diet, dams exposed during gestation and lactation, continued exposure of one group via diet during lifespan One maternal dose level: Da: 100 mg Al/kg bw/d	Reduced auditory startle response.	LOEL = 130 (Dc)	Golub et al. (1994)
Swiss Webster mice (6-8 pups per group) Al lactate	Diet, dams exposed during gestation and lactation, continued exposure of one group via diet during lifespan One maternal dose level: Dc: 130 mg Al/kg bw/d	Effects on manganese metabolism.	LOEL = 130 (Dc)	Golub et al. (1993)
Swiss mice (10-13 dams per group) Al hydroxide or Al lactate	Gavage, dams exposed during gestation One maternal dose level: Da: 57.5 mg Al/kg bw/d	Maternal toxicity; Fetal body weight reduced in Al lactate group; Increased incidence of morphological effects (cleft palate, delayed ossification of parietals) in Al lactate group.	LOEL = 57.5 (Da)	Colomina et al. (1992)