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: C

x Vapor Pressure: < 0.0000001 torr (est) Water Solubility: < 0.0000001 g/L (est)

Oil Absorpt ion: 333 ml/100 gm

From the distribution curve given in the submi ssion it is not possible to determine whether the particle size distribution was m easured using a weight distribu tion, a volume distribution or by particle count. However, the type of curve and data given in the distri bution curve is typically seen for a weight distribution curve. It is best therefore to assume that the particle size distribution given in the submissi on is a weight distribution curve and so does not represent the actual particle size distribution which most likely may be in th e 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 Stru cture/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 vi a all routes of exposure based on analogues. There are concerns for lung overload for poorly so luble particulates and for lung effects based on

submitted test data There are possible concer ns for immunotoxicity, oncogenicity and mutagenicity based on analogs (SAT Report)

General Toxicity (D. Lai) :

P10-246 is comprised of multiwalled carbon nano tubes (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 bul k of the PMN is in the micrometer range at a size of 10 μ m or larger, it would not be expect ed to be respirable into theStandard 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 appear ed 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/m 3 . The histopathological findings at lower concentration levels were similar to those observed at 2.5 mg/m 3 but of less severity. The No Lowest Observed Adverse Effect Concentration (L OAEC) from this study was 0.1 mg/m 3

.

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 part icles in order to increa se the possibility of detecting any inherent toxicity that such materials may possess.

is another MWCNT analogous to P10-246, w ith m ore detailed information regarding its dimensions. has an average diameter of and an average length of . exists as simple and comple x 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 a nd their dimensions range from a bout 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. On ce deposited in the alveolar region, simple agglomerates of may disassociate to indi vidual 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 nanoparticl es, including carbon nanotubes, may induce cardiovascular toxicity when inha led (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 an euploidy 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 penetrat e cells, testing of nanomaterials in genotoxicity assays is problematic, and negative responses wo uld not conclusively ru le out the potential mutagenicity hazard of nanotubule materials in hu mans. 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 cl earance of inhaled bacteria, inflammation, possible systemic immunosuppressi on, 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 na noparticles, 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/m 3 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 adjustme nts give a NCEL of

A brief explanation of potential lim itations of the 90-day inhalation study is appropriate for the sake of perspective. As is comm only done, the MWCNT’s used in the ratStandard 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 heal th effects in the animal study and could be expected to have provided a lowe r LOAEL than for unmicronized ma terial. 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 tr act can accommodate larger particles. If more realistic particle size s had been used in the rat stu dy, 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 rec ognized that the OSHA Permissible Exposure Limit (PEL) for nuisance particulate is 15 mg/m 3 and this value was used to estimate exposures for this risk assessment. This is a highl y conservative estimate of exposures intended to err on the side of protecting health in the abse nce of actual data.

Testing Recommendations

Based on the above information, it is recommen ded 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 recomm endations would depend on the portion of the PMN likely to be in the respirable range in the workplace.

Personal Protective Equipment and Indus trial 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 specie s tested in the laboratory at concentrations claimed to be above the expect ed water solubility limit. Reasons that might account for this apparent discre pancy include: 1) use of artific ial 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 perf ormance properties for a variety of applications. Some of these chemical moieties (e.g., hydroxylated derivatives, pr otein coats) may increas e water solubility of CNTs, accounting for reported effects at concentra tions higher than the theoretical solubility limit. With regard to exposure in the environment, grea ter than expected c oncentrations may be attained by CNTs in ambient waters due to the presence of organic part iculate matter such as humic acid or other forms of organic material s (i.e., total organic ca rbon 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 l ittle toxicity to aquatic orga nisms. Or observed toxicity might be due to physical effects rather than direct chemical toxicity, such as particles adhering to gills thereby interfering with oxyge n 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 c oncentration assigned by EETD/EAB (see exposure report) do not have any stated basis for use in th eir 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 expe cted to be low because of the extremely low solubility of these materials in water. No eco toxicity testing is recommended at this time.

References:

OPPTS/EETD/EAB (2009). Expos ure Assessment Branch of the Economics, Exposure and Technology Division, U.S. Envir onmental Protection Agency.

Hyung, H., Fortner, J.D., Hughes, J., Kim J.H., ( 2007). Natural Organic Matt er 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 Ma terial. Journal of Toxicol ogy and Environmental Health, Part A. 67(1):87-107.

OPPTS/EETD/EAB (2009). Expos ure Assessment Branch of the Economics, Exposure and Technology Division, U.S. Envir onmental Protection Agency.