TI: Steven Cragg RAD Disposition Meeting 

PM: Zofia Kosim February 11, 2011 

Risk Assessment for P10-246

This Report Contains CBI Information 

Background Information

P10-246, submitted by UBE America, Inc., is comprised of multi-walled nanotubes. The PMN 

is imported and expected to be used 

Physicochemical Properties (Chemistry Report)

Chemical properties affecting exposure and release

Physical Form: Amorphous solid 

Molecular Formula: Cx

Vapor Pressure: < 0.0000001 torr (est) 

Water Solubility: < 0.0000001 g/L (est) 

 

 

Oil Absorption: 333 ml/100 gm 

 

 

 

 

From the distribution curve given in the submission it is not possible to determine whether the 

particle size distribution was measured using a weight distribution, a volume distribution or by 

particle count. However, the type of curve and data given in the distribution curve is typically 

seen for a weight distribution curve. It is best therefore to assume that the particle size 

distribution given in the submission is a weight distribution curve and so does not represent the 

actual particle size distribution which most likely may be in the nano-range. A particle size 

distribution by count is needed to determine the amount of material in the nano-range. 
Standard Review Risk Assessment for P10-246 

January 24, 2011 Page 2 of 8 

TG/DTA: 499.3 C 

Impurities present: 

Cobalt 1.5% 

Amount of catalyst present as determined by XRF: Co: 0.83 wt% and Mg: 0.37 wt% 

Amount of catalyst present as determined by ICP: Co: 0.85 wt% and Mg: 0.28 wt% 

Manufacturing and Processing: 

The PMN material is imported and no process diagram is provided; however, a brief reaction 

scheme is given. 

Health Hazard Reports

Stated Concerns from the Structure/Activity Team (SAT) Report: 

There are possible concerns for immunotoxicity, oncogenicity and mutagenicity based on 

analogs (SAT Report) 

Absorption, Distribution, Metabolism, Excretion: 

The PMN is expected to be poorly absorbed via all routes of exposure based on analogues. 

There are concerns for lung overload for poorly soluble particulates and for lung effects based on 

submitted test data There are possible concerns for immunotoxicity, 

oncogenicity and mutagenicity based on analogs (SAT Report) 

General Toxicity (D. Lai): 

P10-246 is comprised of multiwalled carbon nanotubes (MWCNT) with the molecular weight, 

length, and diameter ranges stated above. MWCNTs are often highly agglomerated resulting in a 

size range which may be greater than that which is respirable. If the bulk of the PMN is in the 

micrometer range at a size of 10 μm or larger, it would not be expected to be respirable into the 
Standard Review Risk Assessment for P10-246 

January 24, 2011 Page 3 of 8 

deep lung or permeable to skin. The proportion of MWCNT’s and agglomerates in the respirable 

range (i.e. < 10 μm) is not known for PMN P10-246. 

A number of non-genetic in vitro and in vivo toxicity studies on the PMN substance were 

submitted for a prior case, which appeared to show low/no cytotoxicity and proinflammatory effects on HepG2 cells, and low/no dermal toxicity or sensitizing effects on in 

vitro reconstituted epidermis. However, in vitro assays have limited usefulness for hazard 

identification of nanoparticles due to a number of inherent issues; several studies have shown no 

correlations between in vitro and in vivo assays of some nanoparticles. 

A 5-day inhalation study in rats showed moderate increases in several biochemical parameters in 

the bronchoalveolar lavage fluid (BALF) analysis and mild multifocal granulomatous 

inflammation in the lungs. 

A 90-day inhalation study conducted by the submitter with revealed moderate 

granulomatous inflammation, severe alveolar histiocytosis, lipoproteinosis and minimal 

neutrophil infiltration at 2.5 mg/m3. The histopathological findings at lower concentration levels 

were similar to those observed at 2.5 mg/m3

 but of less severity. The No Lowest Observed 

Adverse Effect Concentration (LOAEC) from this study was 0.1 mg/m3. 

The aerosols of n these inhalation studies were produced by brush particle generators to 

reduce their size to ranges respirable by the deep lung (MMAD: 0.5-2.0 μm); as such the 

modified particles may not represent larger sizes of the PMN substance to which workers or the 

general public would more normally be exposed. This modification is performed intentionally 

and routinely in inhalation studies of solid particles in order to increase the possibility of 

detecting any inherent toxicity that such materials may possess. 

is another MWCNT analogous to P10-246, with more detailed information regarding its 

dimensions. has an average diameter of and an average length of 

. exists as simple and complex agglomerates of carbon nanotubes by weaving 

around each other and held together by van der Waals force. The carbon nanotube agglomerates 

are roughly spherical in shape and their dimensions range from about 10 to 100 μm. Some of the 

small agglomerates of (<10 μm) are respirable in humans. Furthermore, the 

agglomeration strength is not very high and they are considered loose with empty space between 

the individual carbon nanotube fibers. Once deposited in the alveolar region, simple 

agglomerates of may disassociate to individual carbon nanotubes when interacting with 

lung surfactant. Some research has suggested that carbon nanotubes may behave as asbestos 

fibers with similar consequences. Therefore, by analogy to asbestos fibers and based on data of 

some carbon nanaotubes (MWCNT and SWCNT), there is concern for pulmonary toxicity, 

fibrosis, lung cancer, and mesothelioma for these materials. Evidence in mice shows that carbon 

nanotubes can translocate from the respiratory tract to regional lymph nodes as well as penetrate 

to the pleural lining of the lung causing inflammation. In addition, there are data suggesting that 

pulmonary deposition of some nanoparticles, including carbon nanotubes, may induce 

cardiovascular toxicity when inhaled (see attachment # 1). 
Standard Review Risk Assessment for P10-246 

January 24, 2011 Page 4 of 8 

Mutagenicity (M. Cimino): 

No mutagenicity data were provided with PMN P10-246. Based upon reports on similar 

materials, P10-246 (1) may induce gene mutations in mammalian cells in culture but not in 

prokaryotes or lower eukaryotes; (2) may be a weak inducer of aneuploidy but not of structural 

chromosome aberrations in mammalian cells in culture; (3) may induce DNA effects in 

mammalian cells in culture, but not in lower eukaryotes in vivo, and; (4) may not induce cell 

transformation in mammalian cells in culture. 

 

Due to uncertainty about their ability to penetrate cells, testing of nanomaterials in genotoxicity 

assays is problematic, and negative responses would not conclusively rule out the potential 

mutagenicity hazard of nanotubule materials in humans. No testing of the PMN is recommended 

at this time. 

Immunotoxicity (R. Ward): 

Based on published scientific data for similar multi-walled carbon nanotubes, as the 

potential to cause immunotoxicity. Pulmonary exposure to this PMN may lead to reduced 

alveolar macrophage phagocytosis, impaired clearance of inhaled bacteria, inflammation, 

possible systemic immunosuppression, and promotion of allergy. 

 
Standard Review Risk Assessment for P10-246 

 February 11, 2011 Page 5 of 8 

Manufacturing: No exposures. PMN is imported. 

 

 

 

 

Uses: Same as Processing Scenarios with the same exposures. 

Risk Characterization for Health

As reviewed in the health hazard assessment above, the major health concerns for the PMN are 

for potential pulmonary toxicity, fibrosis and cancer to workers exposed via the inhalation route. 

There are also data suggesting that pulmonary deposition of some nanoparticles, including 

carbon nanotubes, may induce cardiovascular toxicity when inhaled. 

A NCEL may be derived from the 90-day rat inhalation study by dividing the 

LOAEL of 0.1 mg/m3

 by: 1) a factor of 1 to account for the uncertainty from using a subchronic 

study rather than a chronic study; 2) a factor of 1 to account for the uncertainty for extrapolating 

between species (rat to humans); 3) a factor of 3 to account for the uncertainty extrapolating 

from a LOAEL to a NOAEL; 

and, 5) a factor of 3 to account for the 

unc nty in the base. Together ese uncertainty adjustments give a NCEL of 

A brief explanation of potential limitations of the 90-day inhalation study is appropriate 

for the sake of perspective. As is commonly done, the MWCNT’s used in the rat 

 

 

 

 
Standard Review Risk Assessment for P10-246 

 February 11, 2011 Page 6 of 8 

inhalation study were “micronized” or made small enough to be deep-lung respirable in order to 

enhance the probability of detecting adverse health effects in the animal study and could be 

expected to have provided a lower LOAEL than for unmicronized material. Thus, the findings in 

the rat study reflect artificially enhanced exposure not found in the work environment. To offset 

this limitation somewhat, the human respiratory tract can accommodate larger particles. If more 

realistic particle sizes had been used in the rat study, the NCEL derived from it may have 

exceeded estimated exposures indicating a lack of an inhalation hazard under the conditions 

assumed in this risk assessment. 

 

 

 

It is not known if any CNTs are in the respirable range. Because of this it is assumed that they 

all are respirable. Further, it must be recognized that the OSHA Permissible Exposure Limit 

(PEL) for nuisance particulate is 15 mg/m3

 and this value was used to estimate exposures for this 

risk assessment. This is a highly conservative estimate of exposures intended to err on the side 

of protecting health in the absence of actual data. 

Testing Recommendations

Based on the above information, it is recommended that the PMN be tested as follows: 

The particle size distribution of the MWCNT’s in the workplace should be characterized by 

particle count to determine the portion of PMN in the respirable range (< 10 μm). Any 

subchronic mammalian toxicity testing recommendations would depend on the portion of the 

PMN likely to be in the respirable range in the workplace. 

Personal Protective Equipment and Industrial Hygiene Control Recommendations

Until such time as particle size information is better characterized, PPE and IH controls should 

include: a NIOSH-approved, full-face air-purifying particulate respirator with N, P, or R-100 

filter, or power air purifying respirator with an assigned protection factor (APF) of at least 50; 

permeation resistant gloves; and impervious clothing. 
Standard Review Risk Assessment for P10-246 

 February 11, 2011 Page 7 of 8 

Ecological Risk Assessment for P10-246 

Ecological Hazard Assessment: This PMN and other carbon nanotubes (CNTs) have very low 

water solubility – estimated to be less than 1 μg/L (see chemistry report). As a result, one might 

expect that the concentrations of CNTs in the water column of surface water bodies or in 

groundwater would be negligible with little or no adverse effects to aquatic species. However, 

reports in the literature indicate adverse effects to aquatic species tested in the laboratory at 

concentrations claimed to be above the expected water solubility limit. Reasons that might 

account for this apparent discrepancy include: 1) use of artificial techniques to enhance the 

solubility of CNTs in the test media (e.g., with solvents), or 2) contamination of CNTs with 

heavy metals (e.g., oxides of aluminum, iron, cobalt) used during manufacture that may leach out 

during solubilization and be the actual cause of any observed toxicity at the CNT loading rates 

above anticipated solubility limits. Beyond this, CNTs may be derivatized with chemical 

moieties that confer desired performance properties for a variety of applications. Some of these 

chemical moieties (e.g., hydroxylated derivatives, protein coats) may increase water solubility of 

CNTs, accounting for reported effects at concentrations higher than the theoretical solubility 

limit. With regard to exposure in the environment, greater than expected concentrations may be 

attained by CNTs in ambient waters due to the presence of organic particulate matter such as 

humic acid or other forms of organic materials (i.e., total organic carbon or TOC) upon which 

CNTs may adsorb. CNTs adsorbed onto TOC in the water column or in sediments, if strongly 

bound, might be expected to show little toxicity to aquatic organisms. Or observed toxicity 

might be due to physical effects rather than direct chemical toxicity, such as particles adhering to 

gills thereby interfering with oxygen transfer, or blocking the gut of larval fish or copepods and 

causing immobilization or death from this effect. A brief review of the published literature 

follows. 

Hyung et al. (2007) reported enhanced solubilization of MWCNTs in the presence of “natural 

organic matter” that remained stable for over 1 month at measured concentrations as high as 500 

mg/L. A very recent study on the chronic toxicity of MWCNTs to Ceriodaphnia dubia in the 

presence of natural organic matter (NOM), indicate that the NOEC for reproduction is 

approximately 0.125 mg/L. 

Other issues such as the 1 ppb concerned concentration assigned by EETD/EAB (see exposure 

report) do not have any stated basis for use in their exposure report for this risk assessment; this 

value has not been evaluated by RAD and should not be used. RAD will continue to evaluate the 

relevant ecotoxicity literature including the recent Ceriodaphnia study for use in PMN risk 

evaluation. 
Standard Review Risk Assessment for P10-246 

 February 11, 2011 Page 8 of 8 

Ecological Risk Characterization: Consequently, the risk of such materials to aquatic organisms 

in the environment cannot be determined quantitatively by comparing predicted surface water 

concentrations with a concentration of concern. Qualitatively, risk to aquatic organisms from the 

chemical characteristics of CNTs might be expected to be low because of the extremely low 

solubility of these materials in water. No ecotoxicity testing is recommended at this time. 

References: 

OPPTS/EETD/EAB (2009). Exposure Assessment Branch of the Economics, Exposure and 

Technology Division, U.S. Environmental Protection Agency. 

Hyung, H., Fortner, J.D., Hughes, J., Kim J.H., (2007). Natural Organic Matter Stabilizes Carbon 

Nanotubes in the Aqueous Phase. Environ. Sci., Technol. 41:179-184. 

Maynard, A.D., Baron,P.A., Foley, M., Shvedova, A.A., Kisin, E.R., Castranova, V. (2004). 

Exposure to Carbon Nanobube Material: Aerosol release During the Handling of Unrefined 

Single-Walled Carbon Nanotube Material. Journal of Toxicology and Environmental Health, 

Part A. 67(1):87-107. 

OPPTS/EETD/EAB (2009). Exposure Assessment Branch of the Economics, Exposure and 

Technology Division, U.S. Environmental Protection Agency.