Risk Characterization – Carbon Tetrachloride (CCl4)

Introduction/Problem Statement

Carbon tetrachloride ( CCl₄) is a man-made volatile organic compound that is extremely toxic to worlds and animate beings. It is a clear, colourless, non-flammable, heavy liquid with a pleasant characteristic smell and a molecular weight of 153.8g/mol.¹It besides exists as a gas in the ambiance. The Chemical Abstract Service Registry Number ( CASRN ) for CCl₄is 56-23-5.

Carbon tetrachloride has a broad scope of use in places, industrial, fabrication and agricultural procedures.²Carbon tetrachloride is a toxicant compound with carcinogenic and non-carcinogenic wellness effects. The U.S. Environmental Protection Agency has classified CCl₄as a Group B2, likely human carcinogen.³

Human exposure to carbon tetrachloride occurs through four primary paths ; H2O and other fluids, inspiration, consumption of groceries²and dermal. Lactational transportation has besides been suggested.

The aim of this reappraisal is to depict the hazard appraisal procedure for C tetrachloride exposures and to qualify the incremental life-time and single hazard attributable to atmospheric CCl₄exposures in Canadian population in 2014.

Hazard Identification

Surveies in worlds revealed that persons and workers with acute unwritten, inhalational and cuticular exposure to carbon tetrachloride exhibits toxicity to the compound.³These toxicities and diseases include ; hepatotoxicity, nephrotoxicity, GI toxicity, neurotoxicity, pneumonic hydrops ( secondary to nephritic inadequacy ) and birth defects. The weight of grounds for these associations lies on instance studies of human poisoning incidents, and epidemiological surveies.

One of such epidemiological surveies was a cross-sectional survey⁴of hepatic map in 135 CCl₄open workers in three chemical workss in northwest England and in a control group of 276 unexposed workers conducted between 1986 and 1987. Subjects were placed into one of three exposure classs ( low, medium, or high ) , harmonizing to their current occupations. This survey demonstrated an association between occupational exposure to carbon tetrachloride and hepatoxicity. The strengths of this survey include ; instances and controls were good matched and comparable, and the consistence of grounds in add-on to biological plausibleness of the findings. The restrictions on the other manus include ; the exposure appraisal was based on historical personal monitoring informations for assorted occupations at the three workss, some of the workers were classified into the exposure classs based on subjective qualitative standards, and it is ill-defined to what extent the ascertained alterations in serum enzyme degrees reflect clinically important alterations. In add-on, the deficiency of information pertaining to the dependability of the enzyme steps and trouble in set uping temporalty from the findings were ascertained restrictions.

Carbon tetrachloride is “ likely to be carcinogenic to worlds ” .³The weight of grounds are based on: ( 1 ) unequal grounds of carcinogenicity in worlds ( 2 ) sufficient grounds in animate beings by unwritten and inspiration exposure, i.e. , hepatic tumours in multiple species ( rat, mouse, and hamster ) and phaeochromocytoma ( adrenal secretory organ tumours ) in mice. Surveies of sub-chronic and chronic unwritten and inspiration exposure and malignant neoplastic disease bio-assaies in animate beings remain the best grounds of carcinogenicity of CCl₄.³

Dose-Response Analysis

The Reference Dose (Rural free delivery)for C tetrachloride is 0.004 mg/kg/d. This is based on informations set from the sub-chronic unwritten rat survey by Bruckner et Al.⁵in 1986. An analytical-grade C tetrachloride was administered to groups of 15-16 grownup male Sprague-Dawley rats at doses of 0, 1, 10, or 33 mg/kg by unwritten forced feeding in maize oil 5 days/week for 12 hebdomads ( time-weighted norm doses of 0, 0.71, 7.1, or 23.6 mg/kg-day ) . Elevated serum sorbitol dehydrogenase ( SDH ) was identified as a particular and sensitive biomarker of liver toxicity ( critical consequence ) . The dose-response mold was done utilizing the benchmark dosage ( BMD ) methods. The power theoretical account provided the best tantrum of the 10-week SDH information ( based on goodness-of-fitP-value ?0.1 and the lowest Akaike ‘s Information Criterion [ AIC ] value ) and was hence selected as the footing for the POD. This theoretical account estimated a BMD_2Xof 7.32 mg/kg-day and a BMDL_2Xof 5.46 mg/kg-day. To obtain a value stand foring an mean day-to-day dosage, the BMDL_2Xof 5.46 mg/kg-day was multiplied by 5/7, to give an adjusted BMDL_2Xof 3.9 mg/kg-day. The doses were extrapolated from animate beings to worlds by using an uncertainness factor ( UF ) of 1,000 ( three factors of 10 to account for interspecies and inter-human variableness and extrapolation from sub-chronic to chronic exposure ) to the BMDL_2X-ADJof 3.9 mg/kg-day.

Thechronic inspirationMentionConcentration(RfC)for C tetrachloride is 0.1 mg/m³. This is based on informations set from the chronic inspiration toxicity survey in rats by Nagano et Al.⁶in 1998. In the survey, groups of F344/DuCrj rats ( 50/sex/group ) were exposed ( whole-body ) to 0, 5, 25, or 125 ppm ( 0, 31.5, 157, or 786 mg/m³) of C tetrachloride ( 99.8 % pure ) vapour for 6 hours/day, 5 days/week for 104 hebdomads. Fatty alteration in the liver of rats was selected as the specific end point for dose-response analysis ( critical consequence ) . BMD patterning methodological analysis ( U.S. EPA, 2000 ) was used to analyse the information. A human PBPK theoretical account was used to gauge uninterrupted human tantamount concentrations ( HECs, in mg/m³) that would ensue in values for the internal dosage metric ( MRAMKL ) equal to the BMDL₁₀values for fatty alterations of the liver. The HEC calculated from male rat informations ( 14.3 mg/m³) was used as the POD for RfC derivation. The doses were extrapolated from animate beings to worlds by using an uncertainness factor ( UF ) of 100 ( two factors of 10 to account for interspecies and inter-human variableness ) to the BMCL_{10 [ HEC ]}: 14.3 mg/m³.

Theauthority or unwritten incline factorfor C tetrachloride is 7 ? 10^-2per mg/kg-day. This is based on informations set from the chronic inspiration toxicity survey in female BDF1 mouse by Nagano et Al.⁶in 1998. The unwritten incline factor was derived from the LED₁₀. The imbibing H2O unit hazard is 2 ? 10^-6per µg/L. The extrapolation method used was the multi-stage theoretical account with additive extrapolation from the POD ( LED₁₀) while the route-to-route extrapolation was performed utilizing PBPK mold.

Exposure appraisal

The open population is the Canadian population with a jutting population of 35,540,400 in the twelvemonth 2014 a life anticipation at birth of 82.5 old ages and a malignant neoplastic disease decease rate of 211 per 100,000 per twelvemonth.⁷Exposure to CCl₄was assessed through a Canadian-wide study⁸of about 7000 ambient air samples collected across 17 rural and 40 urban sites in 2009. The mean concentration of CCl₄was 0.60µg/m³( 6 x 10^-4mg/m³) . The concentration varies from 0.34 – 1.02µg/m³. The variableness may be driven by differential emanation of the compound into the environment in different metropoliss.

Hazard word picture

Using the information above, the jeopardy quotient for non-carcinogenic effects of CCl₄and the malignant neoplastic disease decease per twelvemonth attributable to CCl₄in Canada were estimated. The Hazard quotient was 1.714 ten 10^-3( Average daily dose during exposure period in mg/kg-day ? RfD ) presuming breathed air per twenty-four hours is 20m³/day and Average adult male weight is 70kg. Therefore the jeopardy quotient is less than 1.0 proposing that CCl₄concentration in the ambiance is safe.

The incremental life-time malignant neoplastic disease hazard ( Chronic daily dose ten authority ) was 12 ten 10^-6cases/lifetime. So, over 82.5 old ages ( specific for Canada ) life-time period, the upper-bound chance that a individual will acquire malignant neoplastic disease in Canada from take a breathing air is 12 per million which is higher than the acceptable degree of 10^-6. If there are 12 malignant neoplastic diseases per million people over 82.5 old ages period, so in any given twelvemonth in Canada with a population of 35,540,400 the figure of malignant neoplastic diseases by CCl₄would be 5.2cancers/year ( computations are shown in Analytica ) .

However, the entire figure of all malignant neoplastic disease decease that would be expected in Canada was ( 35,540,400 x [ 211 cancers/year ? 10⁵people ] ) 74.99 malignant neoplastic disease decease / twelvemonth

Decision

It would look that an extra 5 new malignant neoplastic diseases per twelvemonth from CCl₄would add to the malignant neoplastic disease mortality. Besides, it was observed that CCl₄was manner below the RfD but was above the desired hazard end. This is common when jeopardy index is computed for carcinogens. Therefore, hazard direction schemes have to be employed to assist do grounds based determinations towards decrease of CCl₄degrees in the Canadian ambiance.

The strengths of the scientific support for my estimations include ; ( 1 ) the concentration of CCl₄used in the appraisal was from a nation-wide study which can be judged to be representative of the population exposure. ( 2 ) estimations were based on Canada specific values such as life anticipation at birth and malignant neoplastic disease decease rates.

Possible restrictions include ; ( 1 ) utilizing 2009 concentration estimations of CCl₄for 2014 hazards assessment. The emanation rate may hold changed. ( 2 ) population used were jutting Numberss. All these may hold introduced uncertainnesss in the appraisals.

The estimations will be more believable if current atmospheric concentration degrees of CCl₄are used every bit good as current Canadian particular estimations.

Mention

1. U.S. Environmental Protection Agency.Carbon tetrachloride Health Advisory. Office of Drinking Water, Washington, DC. 1987. hypertext transfer protocol: //www.nature.nps.gov/hazardssafety/toxic/carbtet.pdf ( accessed 7/3/2015 ; 16:20 hours )
2. U.S. Environmental Protection Agency. Integrated Risk Information System ( IRIS ) on Carbon tetrachloride. National Center for Environmental Assessment, Office of Research and Development, Washington, DC. 1999.
3. U.S. Environmental Protection Agency ( 2010 ) . Toxicological reappraisal of C tetrachloride. In support of drumhead information on the Integrated Risk Information System. EPA/635/R-08/005F.
4. Tomenson, JA ; Baron, CE ; O’Sullivan, JJ ; et Al. ( 1995 ) Hepatic map in workers occupationally exposed to carbon tetrachloride. Occup Environ Med 52:508–514
5. Bruckner, JV ; MacKenzie, WF ; Muralidhara, S ; et Al. ( 1986 ) Oral toxicity of C tetrachloride: ague, subacute and subchronic surveies in rats. Fundam Appl Toxicol 6:16–34
6. Nagano, K. ( 2005 ) . Email dated October 15, 2005. Capable: Carbon tetrachloride 1998 inhalati on survey. From Kasuke Nagano, JBRC, to Mary Manibusan, U.S. EPA.
7. Statisticss Canada from ; hypertext transfer protocol: //www.statcan.gc.ca/tables-tableaux/sum-som/l01/cst01/health26-eng.htm ( accessed 8/03/2015 )
8. Health Canada ( 2009 ) . Carbon tetrachloride in imbibing H2O papers for public wellness remark. From ; hypertext transfer protocol: //www.carexcanada.ca/en/carbon_tetrachloride/ ( accessed 07/03/2015 )