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Table 3 In vivo data available to substantiate the oral grouping hypotheses, H-O-G1 and H-O-G2

From: Grouping of orally ingested silica nanomaterials via use of an integrated approach to testing and assessment to streamline risk assessment

NF

Model

Dose

Experimental design

Particles/Ions accumulation **

Effects

Reference

Local

Systemic

SiO2 (NM-203)

Rats

5, 10, or 20 mg/bw*

3-repeated exposure by oral gavage (sub-acute)

Not assessed

No histological changes of duodenum and colon;

weak genotoxic effects in the colon

No histological changes of tissue samples from spleen, liver and kidney

[37]

CuO (Plasma Chem, GmbH)

Rats

1, 2,

4, 8, 16, and 32 mg/kg bw

5-repeated exposure by oral gavage (sub-acute)

Copper ions detected in liver,

lung, kidneys, spleen, thymus, and mesenteric

lymph node tissue

Histological changes in stomach where inflammation was observed

Alterations

in the level of alkaline phosphatase (ALP) and aspartate aminotransferase (AST) liver enzymes;

Histological changes in liver and bone marrow;

Liver exhibited slight Kupffer cell hypertrophy/ hyperplasia and inflammation;

Bone marrow

changes included slight increased myeloid elements

and decreased erythroid elements

[38]

SiO2 (Levasil® 200; Levasil® 200 PEG treated;

Levasil® 200 phosphate treated; Levasil® 200 amino treated)

Rats

1000 mg/kg/bw

28-repeated exposure by oral gavage (sub-acute)

Not assessed

No adverse

effects for any of the tested silicas (histopathological examination)

No adverse

effects for any of the tested silicas (clinical pathology, clinical chemistry, acute phase proteins and metabolome analysis)

[39]

SiO2 (mesoporous silicas of two target sizes, 100 and 300 nm)

Mice

100 and 1000 mg/kg/bw

5-repeated exposure by oral gavage (sub-acute)

Silica particles detected in jejunum

No histological changes of small intestine;

No intestinal inflammation

No histological changes of liver

[40]

SiO2 (NM-203)

Rats

2, 5, 10, 20 and 50 mg/kg/bw*

90-repeated exposure by oral gavage (sub-chronic)

Silicon ions detected in liver and spleen

No histological changes of small intestine

No alteration in AST,

Alanine aminotransferase (ALT), blood urea nitrogen (BUN) and creatinine serum levels;

No histological changes of spleen, adrenals,

Kidneys and thyroid; Different alterations were reported in the liver (hepatocyte vacuolization/steatosis, intralobular lymphoid infiltration, enlarged sinusoids and congestion of sinusoids); Histomorphometrical alterations in spleen; Different alteration in the immunotoxicity markers in the blood

[36]

SiO2 (NM-200)

Mice

4.8 mg/kg/bw*

18 months via drinking water (chronic)

Silicon ions detected in liver and kidney

Not assessed

Histomorphological alterations were identified in kidneys (vacuolization of tubular epithelial cells);

Liver inflammation coupled to amyloidosis lesions

[41]

SiO2 (NM-203)

Rats

20 mg/kg/bw

1 and 5-repeated exposure by intravenous administration (acute and sub-acute)

Not assessed

Not assessed

Splenomegaly accompanied by

inflammatory granulomas; Granulomas in liver parenchyma

[42]

SiO2 (mesoporous silicas of 75 nm)

Mice

50-100-200 mg/kg/bw

14-repeated exposure by oral gavage (sub-acute)

Silica particles detected outside the intestinal tissue and in the cytoplasm;

Silicon ions detected in heart, liver, spleen, kidney, colon and intestine

Infiltration of inflammatory

cells in the intestines; Intestinal oxidative stress and colonic epithelial cell

apoptosis;

no sign of genotoxicity in intestine

Increase of ALP, ALT and AST

serum levels;

Infiltration of inflammatory

cells in the spleen

[43]

SiO2 (two colloidal silicas of 46 and 432 nm and mesoporous silicas of 466 nm)

Mice

100–300 mg/kg/bw (colloidal silicas); 100 mg/kg/bw (mesoporous silicas)

Single dose by intravenous administration (acute)

Not assessed

Not assessed

Tissue injury of heart, lungs, kidney, liver and spleen

[44]

SiO2 (NM-203)

Rats

2, 5, 10, 20 and 50 mg /kg/bw*

90-repeated exposure by oral gavage (sub-chronic)

Not assessed

Not assessed

Weak genotoxic effect in the spleen

[45]

SiO2 (NM-203)

Rats

2, 5, 10, 20 and 50 mg /kg/bw*

90-repeated exposure by oral gavage (sub-chronic)

Not assessed

Not assessed

No genotoxic effects in reproductive system (male and female)

[46]

  1. Acute studies involve a single exposure with endpoints assessed at 24 h, the sub-acute studies involve repeated exposures for between 24 h and 28 days, the sub-chronic exposures include repeated exposures for 90 days, while the chronic studies involved repeated exposures for 6–12 months
  2. *Silica dose relevant to daily intake [47]; **Ion accumulation refers to total ion content as measured in the relative organs by ICP-MS analyses