Indirect precursors of long-chain perfluorocarboxylic acids (PFCAs): Human health tier II assessment
10 March 2017
- Chemicals in this assessment
- Grouping Rationale
- Import, Manufacture and Use
- Existing Worker Health and Safety Controls
- Health Hazard Information
- Risk Characterisation
- NICNAS Recommendation
Chemicals in this assessment
This assessment was carried out by staff of the National Industrial Chemicals Notification and Assessment Scheme (NICNAS) using the Inventory Multi-tiered Assessment and Prioritisation (IMAP) framework.
The IMAP framework addresses the human health and environmental impacts of previously unassessed industrial chemicals listed on the Australian Inventory of Chemical Substances (the Inventory).
The framework was developed with significant input from stakeholders and provides a more rapid, flexible and transparent approach for the assessment of chemicals listed on the Inventory.
Stage One of the implementation of this framework, which lasted four years from 1 July 2012, examined 3000 chemicals meeting characteristics identified by stakeholders as needing priority assessment. This included chemicals for which NICNAS already held exposure information, chemicals identified as a concern or for which regulatory action had been taken overseas, and chemicals detected in international studies analysing chemicals present in babies’ umbilical cord blood.
Stage Two of IMAP began in July 2016. We are continuing to assess chemicals on the Inventory, including chemicals identified as a concern for which action has been taken overseas and chemicals that can be rapidly identified and assessed by using Stage One information. We are also continuing to publish information for chemicals on the Inventory that pose a low risk to human health or the environment or both. This work provides efficiencies and enables us to identify higher risk chemicals requiring assessment.
The IMAP framework is a science and risk-based model designed to align the assessment effort with the human health and environmental impacts of chemicals. It has three tiers of assessment, with the assessment effort increasing with each tier. The Tier I assessment is a high throughput approach using tabulated electronic data. The Tier II assessment is an evaluation of risk on a substance-by-substance or chemical category-by-category basis. Tier III assessments are conducted to address specific concerns that could not be resolved during the Tier II assessment.
These assessments are carried out by staff employed by the Australian Government Department of Health and the Australian Government Department of the Environment and Energy. The human health and environment risk assessments are conducted and published separately, using information available at the time, and may be undertaken at different tiers.This chemical or group of chemicals are being assessed at Tier II because the Tier I assessment indicated that it needed further investigation.
For more detail on this program please visit:www.nicnas.gov.au
NICNAS has made every effort to assure the quality of information available in this report. However, before relying on it for a specific purpose, users should obtain advice relevant to their particular circumstances. This report has been prepared by NICNAS using a range of sources, including information from databases maintained by third parties, which include data supplied by industry. NICNAS has not verified and cannot guarantee the correctness of all information obtained from those databases. Reproduction or further distribution of this information may be subject to copyright protection. Use of this information without obtaining the permission from the owner(s) of the respective information might violate the rights of the owner. NICNAS does not take any responsibility whatsoever for any copyright or other infringements that may be caused by using this information.
The chemicals in this group include neutral and ionic organic substances of moderate to high molecular weight, and polymers with fluorinated side-chains. All of these substances are structurally related in that they contain a chain of perfluorinated carbons that are linked to another structural unit by at least one non-fluorinated carbon atom. Although some substances in this group are mixtures of discrete chemicals with a range of perfluorinated chain lengths, all potentially have at least one component chemical which has a chain of nine or more perfluorinated carbon atoms. Based on the ingredients in two chemicals (CAS Nos 254889-79-7 and 254889-72-0), the reactions are expected to create fluorotelomers of an unknown chain length. As a worst case scenario, the fluorotelomers are presumed to belong to a long-chain perfluorinated compounds.
NICNAS has developed an action plan to assess and manage chemicals which may degrade to perfluorocarboxylic acids (PFCAs), perfluoroalkane sulfonates (PFSAs) or similar chemicals. The primary assumption outlined in the action plan is that chemicals with a perfluorinated chain terminated with an alkyl or aryl group will degrade to form a mix of PFCAs with both the original chain length and one less perfluorinated carbon atom (for more information, see Appendix G of the NICNAS Handbook for Notifiers (NICNASa)). In this assessment, environmental degradation of the chemicals in this group is expected to primarily result in release of perfluorocarboxylic acids with one less perfluorinated carbon atom than the parent chemical.
On this basis, the chemicals in this group have the potential to degrade into a range of environmentally persistent long-chain PFCA anions including those containing eight or more perfluorinated carbon atoms. Whilst some members of this group can also degrade to shorter chain PFCAs, the toxicity profile will be dominated by the long-chain PFCAs. Therefore, the chemicals are considered to be indirect precursors of long-chain PFCAs. Indirect precursors for perfluorooctanoic acid (PFOA) with seven perfluorinated carbon atoms and short chain PFCAs which do not include long-chain components have been assessed separately (NICNASb and NICNASc).
These potential long-chain perfluorocarboxylic acid degradants are of concern because the immediate shorter chained homologue, PFOA, has been identified as a persistent, bioaccumulative and toxic (PBT) chemical according to domestic environmental hazard criteria. Chemicals with these hazard characteristics are of high concern to the environment and PFOA (and substances which may degrade to PFOA) are subject to increasingly stringent regulatory controls in other developed countries. Longer chain perfluorocarboxylic acids have received attention internationally for similar reasons. (see International restrictions).
The degradation of perfluorinated carboxylic acids is very slow compared with their rate of formation from degradation of the precursors and perfluorinated carboxylic acids will be the final degradants from multiple precursors. Therefore, the amount of perfluorinated carboxylic acids in the environment (general or local) is expected to be higher than that of any of the precursors. It will therefore be assumed for the purposes of this assessment that the primary risk posed by the chemicals in this group results from release of perfluorinated carboxylic acids to the environment. Therefore, this assessment will focus on long-term effects due to the chemicals degrading to long-chain PFCAs.
Import, Manufacture and Use
In July 2006, NICNAS collected information on manufacture, importation and uses of perfluorinated chemicals including PFCA-related substances and products/mixtures containing these substances for the calendar years 2004 and 2005.
Information obtained by NICNAS indicated that:
- Two PFCA precursors were imported into Australia in 2005. One was a perfluorinated furan compound (0.25 kg) used as an analytical reagent. The other substance was a polymer containing a perfluoroalkylethyl ester moiety imported at 150 kg in 2005, which was used to formulate coatings for wood boards of internal wall cladding.
- Eight products containing PFCA precursors were imported into Australia during 2004 and 2005. Five of these were water/oil repellent products used for textiles, carpets, and masonry/cement surfaces. The remaining three products were used for automotive painting, glass treatment and ink cartridges. These eight PFCA precursors included five perfluoroalkylethyl chemicals/polymers and three fluorinated acrylate polymers. The total volume of the eight products was up to 33,300 kgs per annum, with the majority of this being polymeric substances. The concentration of PFCA precursors in the products ranged from <0.1 % to 50 % (NICNAS, 2013).
The information collected for PFCA-related substances in July 2006 could be incomplete because the call for information did not specifically include the PFCAs group.
Fluorinated surfactants are reported to be imported into Australia. These surfactants can contain some of the fluorinated chemicals evaluated in this assessment and can be used as detergents, emulsifiers or dispersants in the above applications.
The following uses were identified for products containing indirect precursors of PFCAs, sold in Australia:
- in sealants; and
- in cleaning products.
In addition, it is noted that the chemicals in this group may be present in the environment due to historic use, release from pre-treated articles imported into Australia, or as breakdown products resulting from using other indirect precursor chemicals covered in this assessment.
The following international uses for the chemicals in this group were identified through Galleria Chemica (Galleria), Organisation for Economic Development and Cooperation (OECD) Surveys (OECD 2005; OECD 2006; OECD, 2011), Danish EPA Surveys (Jensen et al, 2008; Danish EPA, 2013), European Chemicals Agency (ECHA) reports (ECHA, 2014), European Commission Health and Consumers website (CosIng), The Nordic Chemicals Group report (Posner, et al, 2013) and the Substances in Preparations in Nordic Countries (SPIN).
The neutral organic fluorotelomer derivatives in this group are used as industrial intermediates. Five of these chemicals (including 10:2 FTOH, 12:2 FTOH and 12:2 FTMAC) have recently been reported as in use in various Nordic countries. The two neutral organic UVCB substances (CAS Nos 68391-08-2 and 85631-54-5) are currently registered for use in the European Union. In the United States of America (USA), the UVCB fluorotelomer alcohol (CAS No. 68391-08-2) is also reported to have current or recent use (US EPA, 2015).
An additional 20 chemicals in this group have also recently been reported to be in use in various Nordic countries. A number of polymers have use in a range of applications, including use in coating products, fabric protectors, textile impregnation agents, fire-fighting foam and carpet protectors. Similarly, the alkyl ammonium and amine derivatives (CAS Nos 68187-47-3 and 70983-60-7) appear to have use in fire-fighting foam, while the thio ethyl carboxylic acid and its lithium salt (CAS Nos 65530-83-8 and 65530-69-0) are reported to be used in cleaning products, polishing agents and products for motor vehicle repair. Three of the four phosphate esters in this group (CAS Nos 65530-64-5, 65530-74-7 and 65530-63-4), and one of the polyethylene glycol compounds (CAS No. 65545-80-4), are reported to be used in paints, lacquers and varnishes.
Conversely, a number of chemicals in this group appear to have limited use internationally. Thirteen chemicals in this group (including ten polymers) were not identified as being listed on the chemical inventories of any other country.
Data for one neutral organic derivative (CAS No. 85631-54-5) indicate that it is being used at between 100 and 1000 tonnes per annum in the European Union. No further volume data were identified for the chemicals in this group. Nevertheless, it is noted that it has previously been estimated that approximately 1000 tonnes of PFOA-related substances for textile and leather treatment are introduced per annum in the European Union, with a further 1000 to 10 000 tonnes imported in textile articles (ECHA, 2014).
In 2007, a factsheet published by NICNAS recommended that industry seek alternatives to PFOA and chemicals that may degrade to PFOA, and ultimately aim to phase out use of these substances (NICNAS, 2013).
The Queensland Department of Environment and Heritage Protection, in conjunction with the Western Australian Department of Environmental Regulation, has developed a draft policy for the management of fire fighting foams, including those containing PFOA precursor compounds and their higher homologues (Queensland Government Department of Environment and Heritage Protection, 2014).
Substances with long-chain (C7-C20) perfluoroalkyl moiety in their structure are listed under Schedule 1 (the Toxic Substances List) of the Canadian Environmental Protection Act 1999 (CEPA 1999) (Government of Canada, 2013). In April 2015, amendments were proposed to regulations to prohibit long-chain PFCAs, their salts and their precursors and products containing them, unless present in manufactured items. Time-limited exemptions and ongoing uses are proposed for certain uses where the development of alternatives is underway or where there are currently no known alternatives (Government of Canada, 2015).
The US EPA published an action plan on long-chain perfluorinated chemicals, covering the chemicals in this group, in 2009 (US EPA, 2009).
US EPA proposed a Significant New Use Rule (SNUR) for long-chain PFCA chemicals, including CAS Nos 865-86-1, 39239-77-5, 68187-47-3, 68391-08-2, and 70969-47-0, in January 2015. Under the Rule, approval must be sought for new uses of these chemicals after December 2015. The existing uses of these chemicals are expected to be phased out by December 2015 under a voluntary stewardship programme (US EPA, 2015). For this SNUR, EPA is also proposing to make inapplicable the exemption for persons who import long-chain PFCA chemical substances as part of articles.
In 2013, PFOA, its ammonium salt, and C11-C14-PFCAs were included in the Candidate List of Substances of Very High Concern for Authorisation under the European Chemicals Regulation, REACH (ECHA, 2013). In October 2014, a proposal to restrict the manufacture, use and sale of PFOA, its salts, and substances that may degrade to PFOA, under the REACH legislation, was published (ECHA, 2014).
Existing Worker Health and Safety Controls
The chemicals in this group are not listed on the Hazardous Chemical Information System (HCIS) (Safe Work Australia).
No exposure standards exist for the chemicals in this group.
No exposure standards exist for the chemicals in this group.
Health Hazard Information
Very limited toxicity data were identified for the chemicals in this group. Based on the available Australian use data, non-polymeric substances are only introduced in small quantities. Polymers are generally of low bioavailability and have low toxicity. This is supported by the limited available data that suggest low acute and chronic toxicity as well as low reproductive/developmental toxicity (NICNAS, 1998; 1999; REACH; DuPont, 2001; DuPont, 2004). Some of the chemicals (especially the fluorosurfactants) can cause irritation to the eyes and skin (NICNAS, 1998; 1999; REACH) as well as irritation of the respiratory tract leading to acute lung injury if inhaled (Fischer, 2012). However, the primary health risk is expected to arise from secondary, long-term exposure to the degradation products, the long-chain PFCAs (see Grouping rationale). Therefore, the focus of this assessment is on the health effects of the degradation products and potential long-term effects following chronic low level exposure.
The long-chain PFCAs accumulate mainly in the liver (NICNASb; Vanden Heuvel et al 1991a; b) and this bioaccumulation is positively associated with carbon chain-length of the chemical (OECD, 2013). The estimated half-lives in men and older women were 4.3 years for perfluorononanoic acid (PFNA; CAS No 375-95-1), and 12 years for perfluorodecanoic acid (PFDA; CAS No 355-76-2) and perfluoroundecanoic acid (PFUA; CAS No 2058-94-8) (Zhang et al., 2013). The half-lives in young women were shorter for all PFCAs but followed the same pattern of being longer for longer carbon chain length.
In humans, urinary clearance decreased with increasing carbon chain length of the PFCAs, while biliary clearance increased. The chemicals PFNA and PFDA had the smallest total clearance among PFCAs with six to fourteen carbon atoms. The urinary clearances of PFCAs in humans were more than 200 times smaller than those in mice (Fujii et al., 2015).
Long-chain PFCAs were detected in maternal and umbilical cord blood (Monroy et al., 2008; Kim et al., 2011a; 2011b; Lien et al., 2011; Chen et al., 2012) and in maternal milk (Karrman et al., 2007; Tao et al., 2008; Fujii et al., 2012). They were also found to cross the placental barrier and accumulate in the developing foetus (Hinderliter et al., 2005; Das et al., 2014).
Corrosion / Irritation
Repeated Dose Toxicity
The liver is the primary target organ of the long-chain PFCAs.
In four separate 14-day oral repeat dose studies in rats, PFNA caused increased liver and thymus weights and elevated triglycerides. Decreased spleen weights and increased lymphoid cell apoptosis noted in one of these studies indicated possible effects on the immune system. Alterations in pro- and anti-inflammatory cytokines were also observed in one study (Zhang et al., 2008; Feng et al., 2009; Fang et al., 2010; Fang et al., 2012).
Repeated dose (42-47 days) studies have been conducted with PFUA, perfluorododecanoic acid (PFDoA; CAS No 307-55-1), and perfluorooctadecanoic acid (PFOdA; CAS No 16517-11-6) in Sprague Dawley (SD) rats (Hirata-Koizumi et al., 2011; Kato et al., 2014; Takahashi et al., 2014). All studies were conducted according to OECD Test Guidelines.
In rats fed 0.1, 0.3 or 1.0 mg/kg PFUA, increased liver weights and hepatocellular hypertrophy were observed at 0.3 mg/kg bw/day in male and at 1.0 mg/kg bw/day in female rats. Body weight gain was inhibited at 1 mg/kg bw/day in both sexes. The no observed adverse effect level (NOAEL) for PFUA was concluded to be 0.1 mg/kg bw/day.
For PFDoA, male and female SD rats received daily doses of 0.1, 0.5 or 2.5 mg/kg bw/day of the substance. Doses at 0.5 mg/kg bw/day and higher caused liver hypertrophy, necrosis and inflammatory cholestasis in male and female rats. Significant decrease in body weight as well as reduced bone marrow haematopoiesis and atrophic changes in the spleen, thymus and adrenal glands were observed at 2.5 mg/kg bw/day. A NOAEL of 0.1 mg/kg bw/day was established for this study.
For the PFOdA study, male and female rats received daily doses of 40, 200 or 1000 mg/kg bw/day of the substance. Increased liver weights and hepatocellular hypertrophy were observed at 200 mg/kg bw/day in males and at 1000 mg/kg bw/day in female rats (Hirata-Koizumi et al., 2014). Body weight gain was inhibited at 1000 mg/kg bw/day in both sexes. The NOAEL for PFOdA was concluded to be 40 mg/kg bw/day.
No data are available.
No data are available.
Limited information on PFOA, PFNA, PFDA and PFDoA indicates that the chemicals in this group are not genotoxic (Eriksen et al., 2010; Butenhoff et al., 2014; NTP, 2015a; 2015b; NICNASb).
No data are available for long-chain PFCAs.
The seven fluorinated carbon PFCA (PFOA) has been classified as a Category 3 carcinogen (Carc. Cat 3 - Limited evidence of a carcinogenic effect) under the approved criteria for classifying hazardous substances; or Category 2 carcinogen (Carc. Cat. 2 - Suspected of causing cancer) under the globally harmonised system of classification (GHS). Two experimental carcinogenicity studies reported PFOA-induced liver adenomas, Leydig cell adenomas and pancreatic acinar cell tumours in rats. However, several epidemiological and medical surveillance studies of the workers at 3M plants (APFO manufacturing) in various cities of the US could not establish a link between PFOA exposure and cancer incidence.
Reproductive and Developmental Toxicity
Fertility parameters including survival and number of germ cells (male rats) as well as number of corpora lutea and implantations (female rats) were affected by some, but not all, long-chain PFCAs. Developmental effects, such as increased postnatal pup mortality, decreased pup body weight and delayed onset of puberty, were observed in mice and rats following exposure to most of the long-chain PFCAs evaluated. Developmental effects were also detected in the absence of marked maternal toxicity.
In three separate reproductive toxicity studies, conducted according to OECD guidelines, SD rats were exposed to PFUA (0.1, 0.3 or 1 mg/kg/day), PFDoA (0.1, 0.5 or 2.5 mg/kg bw/day), and PFOdA (40, 200 or 1000 mg/kg bw/day) for 14 days before mating, and during the pregnancy and lactation (Hirata-Koizumi et al., 2011; Kato et al., 2014; Takahashi et al., 2014).
PFUA had no effect on the reproductive parameters. PFDoA caused continuous dioestrus in all females only at the highest dose (2.5 mg/kg bw/day), at which histopathological changes including decreased spermatid and spermatozoa counts in males were also observed. Seven out of twelve females in the 2.5 mg/kg bw/day group died during pregnancy and four others did not deliver live pups. Daily exposure to 1000 mg PFOdA/kg bw/day (highest dose) decreased the number of corpora lutea, implantation and total number of pups born and this was associated with significantly reduced body weight. The NOAELs for reproductive effects for PFDoA and PFOdA were established as 0.5 and 200 mg/kg bw/day, respectively.
Rats exposed to PFNA (3 or 5 mg/kg bw/day) for 14 days showed increased cell death of spermatocytes and spermatogonia (Feng et al., 2009). However, S-111-S-WB, a product containing 74 % of PFNA, when administered daily via oral gavage (0.025, 0.125 and 0.6 mg/kg bw/day) to SD rats over two generations (70 days before mating, during pregnancy and lactation), did not affect reproductive performance, mean litter size, pup survival and pup weights (Stump et al., 2008).
In the studies described above, PFUA (0.1, 0.3 or 1 mg/kg/day), PFDoA (0.1, 0.5 or 2.5 mg/kg bw/day), and PFOdA did not have any effects on the development of pups.
In a developmental toxicity study, SD rats were exposed daily to 1, 3, or 5 mg/kg bw/day PFNA between gestation days 1 to 21 (GD1-21) by oral gavage. Maternal weight gain, number of implantations, foetal viability or foetal weight were not affected at any doses. The offspring exposed to 5 mg/kg bw/day PFNA in utero, had significantly lower birth weight than controls (by 16 %), and body weight remained lower than controls through early postnatal development (Das et al., 2012).
In another developmental toxicity study, not performed according to OECD guidelines, timed pregnant female CD-1 mice exposed were exposed to 1, 3, 5, or 10 mg/kg bw/day PFNA between gestation days 1 to 17. At 10 mg/kg bw/day, dams could not carry their pregnancy successfully. Daily exposure to 5 mg/kg bw/day significantly increased neonatal lethality, with 80% of neonates dying in the first 10 days of life (Das et al., 2014). At weaning, the body weight of the surviving offspring, when compared to controls, was reduced by 73% and 55% at doses of 3 and 5 mg/kg bw/day, respectively. The surviving neonates showed dose-dependent delays in eye opening and onset of puberty as well as increased liver weights that lasted to adulthood. Liver weight was increased in pregnant dams at 5 mg/kg bw/day, but no effects on the maternal body weight gain or number of implantations, foetal viability of foetal weights were reported. The NOAEL for developmental toxicity could not be determined, while the LOAEL was considered as 1 mg/kg bw/day based on the effects on developmental landmarks like eye opening and sexual maturation.
These findings are supported by another study in 129S1/SvlmJ mice, where exposure to 0.83, 1.1, 1.5, or 2 mg/kg bw/day PFNA on gestational days 1 to 18 had no effect on maternal body weight or fertility parameters such as number of implantations and total litter size (live and dead pups) (Wolf et al., 2010). However, the number of live pups at birth as well as survival of pups from birth to weaning was significantly reduced at 1.1 and 2.0 mg/kg bw/day. Eye opening was delayed and the offspring weight gain was reduced at 2 mg/kg bw/day. The developmental toxicity of PFNA appear to be mediated via peroxisome proliferator-activated receptor (PPAR)-alpha mediated mechanisms, as no developmental toxicity was detected in PPAR-alpha knockout mice (Wolf et al., 2012).
The developmental toxicity of PFDA was determined in C57BL/6N mice. The chemical PFDA was administered to pregnant mice between GD 10-13 or GD 6-15 with doses of 0, 0.25, 0.5, 1, 2, 4, 8, 16, or 32 mg/kg bw/day or 0, 0.03, 0.3, 1, 3, 6.4, or 12.8 mg/kg bw/day, respectively. Dams were euthanised on GD18 for maternal and foetal toxicity assessment (Harris and Birnbaum, 1989). Maternal body weight gain was significantly reduced at two highest doses of 6.4 and 12.8 mg/kg bw/day (GD 6-15) and 16 and of 32 mg/kg bw/day (GD10-13). Foetal viability was reduced only in litters of dams showing extensive maternal body weight loss (at 12.8 mg/kg bw/day for GD 6-15). However, foetal body weights were significantly reduced at 0.1 mg/kg bw/day (GD 6-15) and 0.5 mg/kg bw/day (GD 10-13). No malformations were observed in the offspring. The NOAEL for developmental effects of PFDA was 0.03 mg/kg bw/day (GD6-15) based on reduced foetal body weights.
Other Health Effects
Epidemiological findings in humans as well as experimental findings in vivo and in vitro indicate that long-chain PFCAs can affect the endocrine system (ECHA, 2014). There are several experimental studies that suggest that PFOA, PFNA, PFDA and PFDoA can alter production of hormones (Bookstaff et al., 1990; Biegel et al., 1995; Boujrad et al., 2000; Shi et al., 2007; 2009a, 2009b; Feng et al., 2009, 2010; Kraugerud et al., 2011; Zhao et al., 2012) or act indirectly, via testicular or ovarian effects (Feng et al., 2009; Dixon et al., 2012). The direct effect on testicular cells was further supported by the observation of reduced cell viability of isolated and cultured rat Sertoli cells treated with 100 µM PFNA for 14 days (Feng et al., 2010).
Critical Health Effects
The chemicals in this group with surfactant properties could induce slight to moderate irritation in eyes and skin as well as acute lung injury if inhaled (NICNAS, 1998; 1999; REACH). However, the main health risk for the chemicals in this group is expected to arise from secondary exposure to the long-chain PFCA degradation products.
The bioaccumulation potential of long-chain PFCAs varies with chain length, and the data indicate that the longer chain lengths are associated with increased bioaccumulation and increased toxicity. Long-term toxicity is reported for long-chain PFCAs that is similar to that of PFOA (see detailed information and relevant references in Human Health Tier II Assessment for Perfluorooctanoic Acid (PFOA) and its Direct Precursors (NICNASb)).
Liver is a target organ for long-chain PFCAs. Hepatocellular hypertrophy and degeneration as well as focal to multifocal necrosis were reported with increasing severity between oral doses of 0.3–15 mg/kg bw/day in rats and mice for C8-C12 PFCAs. Similar effects were observed for PFOdA at 200 mg/kg bw/day.
The immune system is also proposed to be a target for PFCA toxicity with PFNA affecting lymphoid organs including alterations in T-cells and immune cell homeostasis and in pro- and anti-inflammatory cytokines in mice and rats at 1-5 mg/kg bw/day for 14 days.
Fertility parameters such as the number of corpora lutea and implantations in female as well as spermatid and spermatozoa counts in male rats were reduced following exposure to PFNA, PFDoA or PFOdA. However, no major effects on number of pups born were detected for long-chain PFCAs. In several rat and mouse studies, increased postnatal pup mortality, decreased pup body weight and delayed sexual maturation were observed in the absence of marked maternal toxicity following daily exposure to C8-C18-PFCAs.
No carcinogenicity data are available for long-chain PFCAs. The evidence of PFOA carcinogenicity is regarded as limited. Two experimental carcinogenicity studies reported PFOA-induced liver adenomas, Leydig cell adenomas and pancreatic acinar cell tumours in rats. However, several epidemiological and medical surveillance studies of the workers at 3M plants (APFO manufacturing) in various cities of the US could not establish a link between PFOA exposure and cancer incidence.
Public Risk Characterisation
Use in consumer products
Whilst the public can be exposed to articles treated with the polymers in this group, these are not expected to present significant risks while in polymeric form. Significant direct exposure to the non-polymer substances is not expected. Therefore, public risk from these chemicals is not considered to be unreasonable.
Secondary exposure to long-chain PFCAs via the environment
The primary health risk for the public is expected to arise from secondary, long-term exposure to the long-chain PFCA degradation products from the chemicals in this group. While long-term studies in animals show adverse effects from exposure to long-chain PFCAs, epidemiological studies in the general public or in workers exposed to these chemicals do not provide clear evidence of effects in humans. Importantly, exposure of the general public is expected to be low. Blood monitoring data (international and national) suggested widespread exposure of the general population to low levels of PFOA (US EPA, 2005; Toms et al., 2014) and increasing trends for long-chain PFCAs (Karrman et al., 2007; Harada et al., 2011; Okada et al., 2013). In pooled human sera from the Australian population, PFNA and PFDA were detected in concentrations ranging from 0.1–1.6 ng/mL and <0.2–0.8 ng/mL, respectively compared with PFOA ranging from 0.8–9.1 ng/mL (Toms et al., 2014).
Nevertheless, long-chain PFCAs are persistent and bioaccumulative in the environment and, therefore, have the potential to become widely dispersed environmental contaminants (Environment Canada, 2012). Once in the environment, persistent chemicals that are also highly bioaccumulative pose an increased risk of accumulating in exposed organisms and chemical causing adverse effects. They can also biomagnify through the food chain, resulting in very high internal concentrations, especially in top predators.
Occupational Risk Characterisation
Based on the available use information, the non-polymeric substances are not likely to be used by workers in significant quantities in Australia. Polymers with low bioavailability generally do not present significant risks. Therefore the chemicals are not considered to pose an unreasonable risk to the health of workers. The irritant and acute effects of the chemicals with surfactant properties should be considered by a person conducting a business or undertaking (PCBU) at a workplace (such as an employer) in determining the appropriate controls.
Long term occupational exposure to low concentrations of long-chain PFCAs could occur while using these polymers or formulated products containing PFCAs as a contaminant.
Currently it is recommended that PFOA- and related PFCA-based chemicals be restricted to only essential uses for which no suitable or less hazardous alternatives were available.
The chemicals in this group have been assessed as having the potential to cause adverse outcomes for the environment and public health. These chemicals are currently listed on the Australian Inventory of Chemical Substances (AICS), and are available to be introduced into Australia without any further assessment by NICNAS. Other chemicals with a reduced potential for adverse outcomes are becoming available but, given the properties of these chemicals, their assessment as new chemicals under the Industrial Chemicals (Notification and Assessment) Act 1989 (the ICNA Act) is still required to fully characterise the human health and environmental risks associated with their use.
It is recommended that NICNAS consult with industry and other stakeholders to consider strategies, including regulatory mechanisms available under the ICNA Act, to encourage the use of safer chemistry.
Advice for consumers
Products containing the chemicals should be used according to the instructions on the label.
Advice for industry
Control measures to minimise the risk from any exposure to the chemicals should be implemented in accordance with the hierarchy of controls. Approaches to minimise risk include substitution, isolation and engineering controls. Measures required to eliminate, or minimise risk arising from storing, handling and using a hazardous chemical depend on the physical form and the manner in which the chemicals are used. Examples of control measures which could minimise the risk include, but are not limited to:
· health monitoring for any worker who is at risk of exposure to the chemicals, if valid techniques are available to monitor the effect on the worker’s health;
· minimising manual processes and work tasks through automating processes;
· work procedures that minimise splashes and spills
· regularly cleaning equipment and work areas; and
· using protective equipment that is designed, constructed, and operated to ensure that the worker does not come into contact with the chemicals.
Guidance on managing risks from hazardous chemicals are provided in the Managing risks of hazardous chemicals in the workplace—Code of practice available on the Safe Work Australia website.
Personal protective equipment should not solely be relied upon to control risk and should only be used when all other reasonably practicable control measures do not eliminate or sufficiently minimise risk. Guidance in selecting personal protective equipment can be obtained from Australian, Australian/New Zealand or other approved standards.
Obligations under workplace health and safety legislation
Information in this report should be taken into account to help meet obligations under workplace health and safety legislation as adopted by the relevant state or territory. This includes, but is not limited to:
· ensuring that hazardous chemicals are correctly classified and labelled;
· ensuring that (material) safety data sheets ((M)SDS) containing accurate information about the hazards (relating to both health hazards and physicochemical (physical) hazards) of the chemicals are prepared; and
· managing risks arising from storing, handling and using a hazardous chemical.
Your work health and safety regulator should be contacted for information on the work health and safety laws in your jurisdiction.
Information on how to prepare an (M)SDS and how to label containers of hazardous chemicals are provided in relevant codes of practice such as the Preparation of safety data sheets for hazardous chemicals—Code of practice and Labelling of workplace hazardous chemicals—Code of practice, respectively. These codes of practice are available from the Safe Work Australia website.
A review of the physical hazards of these chemicals has not been undertaken as part of this assessment
Bacon IR, Keller WC, Andersen ME, Back KC, 1981. Teratologic Evaluation of a Model Perfluorinated Acid, NDFDA. Report AFAMRL-TR-81-14, Air Force Aerospace Medical Research Laboratory, Wright-Patterson Air Force Base, OH.
Biegel LB, Liu RC, Hurtt ME, Cook JC, 1995. Effects of ammonium perfluorooctanoate on Leydig cell function: in vitro, in vivo, and ex vivo studies. Toxicol Appl Pharmacol 134, 18-25.
Bookstaff RC, Moore RW, Ingall GB, Peterson RE, 1990. Androgenic deficiency in male rats treated with perfluorodecanoic acid. Toxicol Appl Pharmacol 104(2), 322-333.
Boujrad N, Vidic B, Gazouli M, Culty M and Papadopoulos V, 2000. The peroxisome proliferator perfluorodecanoic acid inhibits the peripheral-type benzodiazepine receptor (PBR) expression and hormone-stimulated mitochondrial cholesterol transport and steroid formation in Leydig cells. Endocrinology 141, 3137-3148
Butenhoff JL, Kennedy GL, Jung R, Chang S-C, 2014. Evaluation of perfluorooctanoate acid for genotoxicity. Toxicology Reports 1, pp. 252-270.
Chen MH, Ha EH, Wen TW, Su YN, Lien GW, Chen CY, Chen PC, Hsieh WS, 2012. Perfluorinated compounds in umbilical cord blood and adverse birth outcomes. Plos One 7(8), e42474
Christensen KY, Maisonet M, Rubin C, Holmes A, Calafat AM, Kato K, Flanders WD, Heron J, McGeehin MA and Marcus M, 2011. Exposure to polyfluoroalkyl chemicals during pregnancy is not associated with offspring age at menarche in a contemporary British cohort. Environment International 37, 129-135.
Cosmetics Directive (CosIng). Accessed April 2014 at http://ec.europa.eu/consumers/cosmetics/cosing/
Danish Environmental Protection Agency (Danish EPA), 2013. Survey of PFOS, PFOA and other perfluoroalkyl and Polyfluoroalkyl substances. Environmental Project No. 1475.
Das KB, Wood K, Zehr D, Tatum-Gibbs K, Grey B, Rosen M, Lau C, 2012. P46—Exposure to perfluorononanoic acid during pregnancy: Evaluations of rat and mouse models. Reproductive Toxicology 33 (4), 614–615.
Das KP, Grey BE, Rosen MB, Wood CR, Tatum-Gibbs KR, Zehr RD, Strynar MJ, Lindstrom AB, Lau C, 2014. Developmental toxicity of perfluorononanoic acid in mice. Reprod Toxicol. 25(51C), 133-144. doi: 10.1016/j.reprotox.2014.12.012.
Das KP, Grey BE, Rosen MB, Wood CR, Tatum-Gibbs KR, Zehr RD, Strynar MJ, Lindstrom AB, Lau C, 2014. Developmental toxicity of perfluorononanoic acid in mice. Reprod Toxicol. 25(51C), 133-144. doi: 10.1016/j.reprotox.2014.12.012.
Ding L, Hao F, Shi Z, Wang Y, Zhang H, Tang H, Dai J, 2009. Systems biological responses to chronic perfluorododecanoic acid exposure by integrated metabonomic and transcriptomic studies. J Proteome Res 8(6), 2882-2891. doi: 10.1021/pr9000256.
Dixon D, Reed CE, Moore AB, Gibbs-Flournoy EA, Hines EP, Wallace EA, Stanko JP, Lu Y, Jefferson WN, Newbold RR, Fenton SE, 2012. Histopathologic changes in the uterus, cervix and vagina of immature CD-1 mice exposed to low doses of perfluorooctanoic acid (PFOA) in a uterotrophic assay. Reprod Toxicol 33, 506-512.
Dong GH, Tung KY, Tsai CH, Liu MM, Wang D, Liu W, Jin YH, Hsieh WS, Lee YL and Chen PC, 2013. Serum Polyfluoroalkyl Concentrations, Asthma Outcomes, and Immunological Markers in a Case-Control Study of Taiwanese Children. Environ Health Perspect 121(4), 507-13. doi:10.1289/ehp.120535
DuPont, 2001. 8EHQ-01-14880; TSCATS Low Detail Report for Alcohols, C8-14, .gamma.-.omega.-perfluoro (CAS No 68391-08-2). DuPont Haskell Laboratory. Accessed May 2015 at http://www.epa.gov/oppt/tsca8e/pubs/8ehq/2001/sep01/8ehq_0901_14880b.pdf
DuPont, 2004. 8EHQ-01-14915; TSCATS Low Detail Report for Poly(oxy-1,2-ethanediyl), .alpha.-hydro-.omega.-hydroxy-, ether with .alpha.-fluoro-.omega.-(2-hydroxyethyl)poly(difluoromethylene) (1:1) (CAS No 65545-80-4). DuPont Haskell Laboratory. Accessed May 2015 at http://yosemite.epa.gov/oppts/epatscat8.nsf/ReportSearchView/993BCFDCD6C39D8E852578D8006148C0
Eriksen KT, Raaschou-Nielsen O, Sørensen M, Roursgaard M, Loft S and Møller P, 2010. Genotoxic potential of the perfluorinated chemicals PFOA, PFOS, PFBS, PFNA and PFHxA in human HepG2 cells. Mutation Research-Genetic Toxicology and Environmental Mutagenesis 700, 39-43.
European Chemicals Agency (ECHA), 2013. Candidate list of substances of very high concern for authorisation. Accessed April 2014 at http://echa.europa.eu/candidate-list-table
European Chemicals Agency (ECHA), 2014. Annex XV Restriction Report for Perfluorooctanoic Acid (PFOA), PFOA salts and PFOA related substances. Accessed April 2015 at http://echa.europa.eu/documents/10162/e9cddee6-3164-473d-b590-8fcf9caa50e7
Fang X, Feng Y, Shi Z and Dai J, 2009. Alterations of cytokines and MAPK signaling pathways are related to the immunotoxic effect of perfluorononanoic acid. Toxicological Sciences, 108, 367-376.
Fang X, Feng Y, Wang J, Dai J, 2010. Perfluorononanoic acid-induced apoptosis in rat spleen involves oxidative stress and the activation of caspase-independent death pathway. Toxicology 267, 54-59.
Fang X, Gao G, Xue H, Zhang X and Wang H, 2012. In vitro and in vivo studies of the toxic effects of perfluorononanoic acid on rat hepatocytes and Kupffer cells. Environmental Toxicology and Pharmacology, 34, 484-494.
Feng Y, Fang X, Shi Z, Xu M, Dai J, 2010. Effects of PFNA exposure on expression of junction-associated molecules and secretory function in rat Sertoli cells. Reproductive Toxicology 30, 429-437.
Feng Y, Shi Z, Fang X, Xu M, Dai J, 2009. Perfluorononanoic acid induces apoptosis involving the Fas death receptor signaling pathway in rat testis. Toxicol Lett 190(2), 224-230. doi: 10.1016/j.toxlet.2009.07.020.
Fischer M, Koch W, Windt H and Dasenbrock C, 2012. A Pilot Study on the Refinement of Acute Inhalation Toxicity Studies: the Isolated Perfused Rat Lung as a Screening Tool for Surface-active Substances. ATLA, 40:199-209.
Fujii Y, Niisoe T, Harada KH, Uemoto S, Ogura Y, Takenaka K, Koizumi A (2015). Toxicokinetics of perfluoroalkyl carboxylic acids with different carbon chain lengths in mice and humans. J Occup Health 57(1), 1-12. doi: 10.1539/joh.14-0136-OA.
Fujii Y, Yan J, Harada KH, Hitomi T, Yang H, Wang P, Koizumi A, 2012. Levels and profiles of long-chain perfluorinated carboxylic acids in human breast milk and infant formulas in East Asia. Chemosphere 86(3), 315-21. doi: 10.1016/j.chemosphere.2011.10.035.
Galleria Chemica. Accessed February 2015 at http://jr.chemwatch.net/galeria/
Government of Canada, 2013. Order Adding Toxic Substances to Schedule 1 to the Canadian Environmental Protection Act, 1999. Canada Gazette Part II, 147(23), pp 2441.
Government of Canada, 2015. Regulations Amending the Prohibition of Certain Toxic Substances Regulations, 2012. Canada Gazette Volume 149. April 2015. Accessed June 2015 at http://www.gazette.gc.ca/rp-pr/p1/2015/2015-04-04/html/reg2-eng.php
Harada KH, Hitomi T, Niisoe T, Takanaka K, Kamiyama S, Watanabe T, MoonCS, Yang HR, Hung NN, Koizumi A, 2011. Odd-numbered per?uorocarboxylates predominate over per?uorooctanoic acid in serum samples from Japan, Korea and Vietnam. Environ Int 37, 1183–1189.
Harris MW and Birnbaum LS, 1989. Developmental toxicity of perfluorodecanoic acid in C57Bl/6N mice. Fundamental and Applied Toxicology 12, 442-448.
Hinderliter PM, Mylchreest E, Gannon SA, Butenhoff JL, Kennedy GL, Jr, 2005. Perfluorooctanoate: placental and lactational transport pharmacokinetics in rats. Toxicology 211, 139-148.
Hirata-Koizumi M, Fujii S, Furukawa M, Ono A, Hirose A, 2012. Repeated dose and reproductive/developmental toxicity of perfluorooctadecanoic acid in rats. J Toxicol Sci 37(1), 63-79.
Hubbard HF, Guo Z, Krebs KA (2012). Removal of Perfluorocarboxylic Acids (PFCAs) from Carpets Treated with Stain-protection Products by Using Carpet Cleaning Machines. United States Environmental Protection Agency (US EPA) - EPA/600/R-12/703. Accessed May 2015 at http://nepis.epa.gov/Adobe/PDF/P100FBQ9.pdf.
Jensen AA, Poulsen PB and Bossi R, 2008. Survey and environmental/health assessment of fluorinated substances in impregnated consumer products and impregnating agents. Survey of Chemical Substances in Consumer, Products, No. 99. Danish Environmental Protection Agency (EPA), Denmark.
Joensen UN, Bossi R, Leffers H, Jensen AA, Skakkebaek NE and Jorgensen N, 2009. Do perfluoroalkyl compounds impair human semen quality? Environ Health Perspect 117, 923-927.
Johansson N, Fredriksson A and Eriksson P, 2008. Neonatal exposure to perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA) causes neurobehavioural defects in adult mice. NeuroToxicology 29, 160-169.
Karrman A, Ericson I, van Bavel B, Darnerud PO, Aune M, Glynn A, Lignell S, Lindström G, 2007. Exposure of Per?uorinated Chemicals through Lactation: Levels of Matched Human Milk and Serum and a Temporal Trend, 1996–2004, in Sweden. Environ Health Perspect 115, 226-230
Kato H, Fujii S, Takahashi M, Matsumoto M, Hirata-Koizumi M, Ono A, Hirose A, 2014. Repeated dose and reproductive/developmental toxicity of perfluorododecanoic acid in rats.Environ Toxicol. 2014 Apr 22. doi: 10.1002/tox.2199
Kim S, Choi K, Ji K, Seo J, Kho Y, Park J, Kim S, Park S, Hwang I, Jeon J, Yang H and Giesy JP, 2011a. Trans-placental transfer of thirteen perfluorinated compounds and relations with fetal thyroid hormones. Environmental science& technology, 45, 7465-7472.
Kim SK, Lee KT, Kang CS, Tao L, Kannan K, Kim KR, Kim CK, Lee JS, Park PS, Yoo YW, Ha JY, Shin YS and Lee JH, 2011b. Distribution of perfluorochemicals between sera and milk from the same mothers and implications for prenatal and postnatal exposures. Environmental Pollution, 159, 169-174.
Kleszczynski K, Gardzielewski P, Mulkiewicz E, Stepnowski P, Skladanowski AC, 2007. Analysis of structure–cytotoxicity in vitro relationship (SAR) for perfluorinated carboxylic acids. Toxicol. In Vitro 21, 1206–1211.
Kraugerud M, Zimmer KE, Ropstad E and Verhaegen S, 2011. Perfluorinated compoundsdifferentially affect steroidogenesis and viability in the human adrenocortical carcinoma (H295R) in vitro cell assay. Toxicology Letters 205, 62-68.
Kristensen SL, Ramlau-Hansen CH, Ernst E, Olsen SF, Bonde JP, Vested A, Halldorsson TI, Becher G, Haug LS, Toft G, 2013. Long-term effects of prenatal exposure to perfluoroalkyl substances on female reproduction. Hum Reprod 28(12):3337-48. doi: 10.1093/humrep/det382.
Kudo N, Bandai N, Suzuki E, Katakura M, Kawashima Y, 2000. Induction by perfluorinated fatty acids with different carbon chain length of peroxisomal beta-oxidation in the liver of rats. Chemico-Biological Interactions 124, 119-132.
Kudo N, Suzuki E, Katakura M, Ohmori K, Noshiro R, Kawashima Y, 2001. Comparison of the elimination between perfluorinated fatty acids with different carbon chain lengths in rats. Chemico-Biological Interactions 134, 203-216.
Lien GW, Wen TW, Hsieh WS, Wu KY, Chen CY, Chen PC, 2011. Analysis of per?uorinated chemicals in umbilical cord blood by ultra-highperformance liquid chromatography/tandem mass spectrometry. J Chromatogr B Analyt Technol Biomed Life Sci (879(9-10), 641-646.
Louis GM1, Peterson CM, Chen Z, Hediger ML, Croughan MS, Sundaram R, Stanford JB, Fujimoto VY, Varner MW, Giudice LC, Kennedy A, Sun L, Wu Q, Kannan K, 2012. Perfluorochemicals and endometriosis: the ENDO study. Epidemiology 23(6), 799-805. doi: 10.1097/EDE.0b013e31826cc0cf.
Monroy R, Morrison K, Teo K, Atkinson S, Kubwabo C, Stewart B, Foster WG, 2008. Serum levels of perfluoroalkyl compounds in human maternal and umbilical cord blood samples. Environmental Research 108, 56-62.
National Industrial Chemical Notification and Assessment Scheme (NICNASa). Data requirements for notification of new chemical substances containing a perfluorinated carbon chain. Available at https://www.nicnas.gov.au/notify-your-chemical/data-requirements-for-new-chemical-notifications/data-requirements-for-notification-of-new-chemicals-containing-a-perfluorinated-carbon-chain
National Industrial Chemicals Notification and Assessment Scheme (NICNAS), 1998. Public Report for Lodyne 106A. Accessed May 2015 at http://www.nicnas.gov.au
National Industrial Chemicals Notification and Assessment Scheme (NICNAS), 1999. Public Report for Polymer in Foraperle 225. Accessed May 2015 at http://www.nicnas.gov.au
National Industrial Chemicals Notification and Assessment Scheme (NICNAS). PFC derivatives and chemicals on which they are based. Available at https://www.nicnas.gov.au/chemical-information/Topics-of-interest/subjects/per-and-poly-fluorinated-chemicals-pfcs/pfc-derivatives-and-chemicals-on-which-they-are-based
National Industrial Chemicals Notification and Assessment Scheme (NICNASb). Human Health Tier II Assessment for Indirect Precursors to Perfluorooctanoic Acid (PFOA). Accessed May 2015 at http://www.nicnas.gov.au
National Industrial Chemicals Notification and Assessment Scheme (NICNASc). Human Health Tier II Assessment for Short-Chain Perfluorocarboxylic Acids (PFCA) and Their Direct Precursors. Accessed at http://www.nicnas.gov.au
National Toxicology Program (NTP), 2015a. Testing status for Perfluorodecanoic acid (PFDA). Accessed April 2015 at http://ntp.niehs.nih.gov/testing/status/agents/ts-m920006.html
National Toxicology Program (NTP), 2015b. Testing status for Perfluorododecanoic acid (PFDOA). Accessed April 2015 at http://ntp.niehs.nih.gov/testing/status/agents/ts-m040050.html
National Toxicology Program (NTP), 2015c. Testing status for Perfluorononanoic acid (PFNA). Accessed April 2015 at http://ntp.niehs.nih.gov/testing/status/agents/ts-m040049.html
Okada E, Kashino I, Matsuura H, Sasaki S, Miyashita C, Yamamoto J, Ikeno T, Ito YM, Matsumura T, Tamakoshi A, Kishi R, 2013. Temporal trends of perfluoroalkyl acids in plasma samples of pregnant women in Hokkaido, Japan, 2003-2011. Environ Int 60,89-96. doi: 10.1016/j.envint.2013.07.013.
Organisation for Economic Cooperation and Development (OECD), 2005. Results of survey on production and use of PFOS, PFAS, and PFOA, related substances and products/mixtures containing these substances. Accessed May 2015 at http://www.oecd.org/officialdocuments/publicdisplaydocumentpdf/?cote=env/jm/mono%282005%291&doclanguage=en
Organisation for Economic Cooperation and Development (OECD), 2006. Results of the 2006 survey on production and use of PFOS, PFOA, PFCA, their related substances and products/mixtures containing these substances. Accessed February 2015 at http://www.oecd.org/officialdocuments/publicdisplaydocumentpdf/?doclanguage=en&cote=env/jm/mono%282006%293
Organisation for Economic Cooperation and Development (OECD), 2007. OECD Environment, Health and Safety Publications, Series on Risk Management, No. 21. Lists of PFOS, PFAS, PFOA, PFCA, Related Compounds and Chemicals that may degrade to PFCA. Accessed February 2015 at http://www.oecd.org/officialdocuments/publicdisplaydocumentpdf/?doclanguage=en&cote=env/jm/mono%282006%2915
Organisation for Economic Cooperation and Development (OECD), 2011. OECD series on Risk Management, No. 24. PFCs:Outcome of the 2009 survey on the production, use and release of PFOS, PFAS, PFOA, PFCA, their related substances and products/mixtures containing these substances. Accessed May 2015 at http://www.oecd.org/officialdocuments/publicdisplaydocumentpdf/?cote=env/jm/mono%282011%291&doclanguage=en
Organisation for Economic Cooperation and Development (OECD), 2013. OECD/UNEP Global PFC Group, Synthesis Paper on Per- and Polyfluorinated Chemicals (PFCs). Environment, Health and Safety, Environment Directorate Organisation for Economic Cooperation and Development (OECD). Accessed February 2015 at http://www.oecd.org/env/ehs/risk-management/PFC_FINAL-Web.pdf
Posner S, Roos S, Brunn Poulsen P, Jörundsdottir HO, Gunnlaugsdóttir H, Trier X, Jensen AA, Katsogiannis AA, Herzke D, Bonefeld-Jörgensen EC, Jönsson C, Alsing Pedersen G, Ghisari M, 2013. Per- and polyfluorinated susbtances in the Nordic Countries - use,occurence and toxicology, TemaNord 2013:542. Accessed April 2015 at http://www.norden.org/en/publications/publikationer/2013-542
Queensland Department of Environment and Heritage Protection (2014) Draft Policy. Management of firefighting foam. Accessed June 2015 at http://ebooks.hgluk.com/~production/ebooks/ifj/Fire_Fight_Foams_Policy/
Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH) Dossier. Alcohols, C8-14, ?-?-perfluoro (CAS No. 68391-08-2). Accessed October 2014 at http://echa.europa.eu/web/guest/information-on-chemicals/registered-substances
Safe Work Australia (SWA). Hazardous Chemicals Information System (HCIS). Accessed March 2017 at http://hcis.safeworkaustralia.gov.au/.
Shi Z, Ding L, Zhang H, Feng Y, Xu M, Dai J, 2009a. Chronic exposure to perfluorododecanoic acid disrupts testicular steroidogenesis and the expression of related genes in male rats. Toxicol Lett. 188(3), 192-200. doi: 10.1016/j.toxlet.2009.04.014.
Shi Z, Zhang H, Ding L, Feng Y, Xu M, Dai J, 2009b. The effect of perfluorododecanonic acid on endocrine status, sex hormones and expression of steroidogenic genes in pubertal female rats. Reprod Toxicol 27(3-4), 352-359. doi: 10.1016/j.reprotox.2009.02.008
Shi Z, Zhang H, Liu Y, Xu M, Dai J, 2007. Alterations in gene expression and testosterone synthesis in the testes of male rats exposed to perfluorododecanoic acid. Toxicol Sci 98(1), 206-215.
Specht IO, Hougaard KS, Spano M, Bizzaro D, Manicardi GC, Lindh CH, Toft G, Jonsson BAG, Giwercman A and Bonde JPE, 2012. Sperm DNA integrity in relation to exposure to environmental perfluoroalkyl substances - A study of spouses of pregnant women in three geographical regions. Reproductive Toxicology 33, 577-583.
Stump DG, Holson JF, Murphy SR, Farr GH, Schmit B, Shinohara M, 2008. An oral two-generation reproductive toxicity of S-111-S-WB in rats. Reproductive Toxicology 25, 7-20.
Substances in Preparations in Nordic Countries (SPIN). Accessed April 2015 at http://spin2000.net/
Takahashi M, Ishida S, Hirata-Koizumi M, Ono A, Hirose A, 2014. Repeated dose and reproductive/developmental toxicity of perfluoroundecanoic acid in rats. J Toxicol Sci 39(1), 97-108.
Tao L, Kannan K, Wong CM, Arcaro KF, Butenhoff JL, 2008. Perfluorinated compounds in human milk from Massachusetts, U.S.A. Environ. Sci. Technol 42, 3096–3101.
Toft G, Jonsson BAG, Lindh CH, Giwercman A, Spano M, Heederik D, Lenters V, Vermeulen R, Rylander L, Pedersen HS, Ludwicki JK, Zviezdai V, Bonde JP, 2012. Exposure to per?uorinated compounds and human semen quality in arctic and European populations. Human Reproduction 27(8), 2532-2540.
Toms LM, Thompson J, Rotander A, Hobson P, Calafat AM, Kato K, Ye X, Broomhall S, Harden F, Mueller JF, 2014. Decline in perfluorooctane sulfonate and perfluorooctanoate serum concentrations in an Australian population from 2002 to 2011. Environ Int 71:74-80.
United States Environmental Protection Agency (US EPA), 2005. Draft risk assessment of the potential human health effects associated with exposure to perfluorooctanoic acid and its salts. U.S. Environmental Protection Agency. Office of Pollution Prevention and Toxic Risk Assessment Division, January 4, 2005
United States Environmental Protection Agency (US EPA), 2009. Long-Chain Perfluorinated Chemicals (PFCs) Action Plan. Accessed 10 December 2014 at https://www.epa.gov/assessing-and-managing-chemicals-under-tsca/long-chain-perfluorinated-chemicals-pfcs-action-plan
United States Environmental Protection Agency (US EPA), 2014. TSCA Chemical Substance Inventory. Accessed 26 February 2015 at http://www.epa.gov/oppt/existingchemicals/pubs/tscainventory/howto.html
United States Environmental Protection Agency (US EPA), 2015. Significant New Use Rules: Long-Chain Perfluoroalkyl Carboxylate and Perfluoroalkyl Sulfonate Chemical Substances. Accessed 25 February 2015 at http://www.regulations.gov/#!documentDetail;D=EPA-HQ-OPPT-2013-0225-0001
Vanden Heuvel JP, Kuslikis BI, Van Rafelghem MJ, Peterson RE, 1991a. Disposition of perfluorodecanoic acid in male and female rats. Toxicol Appl Pharmacol 107(3), 450-459.
Vanden Heuvel JP, Kuslikis BI, Van Rafelghem MJ, Peterson RE, 1991b. Tissue distribution, metabolism, and elimination of perfluorooctanoic acid in male and female rats. J Biochem Toxicol 6(2), 83-92.
Vestergaard S, Nielsen F, Andersson AM, Hjollund NH, Grandjean P, Andersen HR and Jensen TK, 2012. Association between perfluorinated compounds and time to pregnancy in a prospective cohort of Danish couples attempting to conceive. Hum Reprod 27, 873-880.
Wang IJ, Hsieh W-S, Chen C-Y, Fletcher T, Lien G-W, Chiang H-L, Chiang C-F, Wu T-N and Chen P-C, 2011. The effect of prenatal perfluorinated chemicals exposures on pediatric atopy. Environmental research, 111, 785-791.
Wolf CJ, Zehr RD, Schmid JE, Lau C, Abbott BD, 2010. Developmental effects of per?uorononanoic acid in the mouse are dependent on peroxisome proliferator-activated receptor-alpha. PPAR Research, 11 pages
Wolf CJ, Zehr RD, Schmid JE, Lau C, Abbott BD, 2012. P48—Developmental toxicity of perfluorononanoic acid in the wild-type and PPAR-alpha knockout mouse after gestational exposure. Reproductive Toxicology 33, 18.
Zhang H, Shi Z, Liu Y, Wei Y and Dai J, 2008. Lipid homeostasis and oxidative stress in the liver of male rats exposed to perfluorododecanoic acid. Toxicology and Applied Pharmacology 227, 16-25.
Zhang Y, Beesoon S, Zhu L, Martin JW, 2013. Biomonitoring of Perfluoroalkyl Acids in Human Urine and Estimates of Biological Half-Life. Environmental Science&Technology 47, 10619-10627.
Zhao Y, Tan YS, Strynar MJ, Perez G, Haslam SZ, Yang C, 2012. Perfluorooctanoic acid effects on ovaries mediate its inhibition of peripubertal mammary gland development in Balb/c and C57Bl/6 mice. Reprod Toxicol 33, 563-576.