No signs of skin irritation were seen with MCCPs (C14-17, 45 wt% Cl), and only slight erythema on the shaved skin was reported in one rabbit at 24 hours exposed to MCCPs (C14-17, 40 wt% Cl) (Chater, 1978; cited in: ECB, 2008). A mild skin irritancy response was reported in one of nine unpublished skin irritation studies of MCCPs (C14-17, 51-60% Cl) in rats (Birtley et al., 1980; cited in: ECB, 2008). The material caused slight, transient eye irritation in rabbits (Birtley et al., 1980; Kuhnert et al., 1986; cited in: ECB, 2008).

No skin sensitization reactions were produced in guinea pig maximization tests conducted on MCCPs (C14-17, 40-45 wt% Cl) (Murmann, 1988; Chater, 1978; cited in: ECB, 2008).

Repeated-dose Toxicity
There are a number of repeated dose toxicity studies (up to 90-days duration) of MCCPs (C14-17 40 wt% Cl or 52 wt% Cl) in rats by oral exposure (CXR, 2005; Poon et al., 1995; IRDC, 1984; Birtley et al., 1980; and Wyatt et al., 1997; cited in: ECB, 2008). Though the quality and reliability of these studies differs, the liver, kidney, and thyroid were consistently established as the target organs. A summary of the results from these studies is provided in Table 1.

MCCPs caused an increase in liver weight in male rats at exposure levels of > 100 mg/kg-bw/day) and in female rats at exposure levels of > 32 mg/kg-bw/day. Liver enzyme induction was reported in male and female rats starting from 222 and 100 mg/kg-bw/day, respectively. Liver hypertrophy of trace to minimal severity was reported in male rats at dose levels of > 100 mg/kg-bw/day and higher. Collectively, these changes are likely to be related to an increase in metabolic demand as an adaptive response and to peroxisome proliferation, both of which are considered of no or limited toxicological significance to humans. Though Poon et al. (1995) reported various histopathological effects in the liver of male and female rats at dose levels > 36 mg/kg-bw/day, there are a number of deficiencies with this study, including the scoring and classification of histopathological findings and limited reporting of data, which preclude its utility in hazard evaluation. This conclusion is consistent with previous evaluations of this study (ECB, 2008). Further, despite the consistency of findings reported in the review article by Birtley et al. (1980) with other 90-day studies, these findings should be viewed cautiously because the original full study report is not available. Based on the available data, the studies by IRDC (1984) and CXR (2005) provide the most reliable data for identifying effect levels of MCCPs on the liver. For the purposes of this assessment, a NOAEL of 100 mg/kg-bw/day was chosen based on increases in absolute liver weight (i.e., 22-26 %), liver hypertrophy of trace severity, and enzyme induction (i.e., 30 % increase).

Kidney effects have been reported in a number of studies, with effect levels typically being observed at the limit doses. MCCPs (C14-17 52 wt% Cl) caused significant increases (9-13 %) in kidney weight at 222 mg/kg-bw/day (CXR, 2005; cited in: ECB, 2008), as well as "chronic nephritis" and tubular pigmentation in the kidney of female rats at 625 mg/kg-bw/day (IRDC, 1984, cited in: ECB, 2008). One study reported a dose-related increase in congestion starting at 32 mg/kg-bw/day; however, no information was provided on the incidence or severity of this effect (Birtley et al., 1980; cited in: ECB, 2008). An additional study reported minimal to mild hyaline-droplet like cytoplasmic inclusions, starting at > 0.4 mg/kg-bw/day in male rats. This effect is considered of limited relevance to humans. The authors also reported minimal dose-related increases with inner medullary tubular dilation at an incidence of 1/10, 4/10, and 8/10 female rats at 4, 42, and 420 mg/kg-bw/day, respectively (Poon et al., 1995; cited in: ECB, 2008). Though this effect is considered relevant to humans, the study suffers from a number of limitations, which preclude utilizing it for hazard evaluation. However, based on the incidence reported by the authors, the NOAEL of 42 mg/kg-bw/day for kidney effects is consistent with the NOAEL of 23 mg/kg-bw/day reported in the CXR (2005) study. Therefore, a NOAEL of 23 mg/kg-bw/day was chosen for the kidney, based on increases in organ weight at the next highest dose level.

MCCPs (C14-17 52 wt% Cl) have been reported to cause minimal to mild adaptive histopathological changes in the thyroid (i.e., follicular cell hypertrophy and hyperplasia) in two studies in rats starting at 50 ppm (4 mg/kg-bw/day) and above (Poon et al., 1995; IRDC, 1985). Decreased T4 levels and increased TSH levels in the plasma were also seen at similar dose levels. As noted previously, these results have been drawn into question based on the scoring and classification for histopathology, the limited reporting of data, and the inconsistent findings from other more robust studies (ECB, 2008). Therefore, these studies will not be considered further for hazard identification. IRDC (1985) reported mild to moderate hypertrophy and hyperplasia in male rats at dose levels of > 10 mg/kg-bw/day and higher, whereas changes in absolute organ weights of male and female rats were not observed except at the limit dose of 625 mg/kg-bw/day (IRDC, 1985; cited in: ECB, 2008). The remaining studies that evaluated thyroid hormone levels identified a decrease in plasma free T3 in male rats, but not total T3 or free/total T4, and an increase in TSH in female rats at dose levels of 24.6 or 242 mg/kg-bw/day, respectively (CXR, 2005; cited in: ECB, 2008), or fluctuations in thyroid hormones in male or female rats at doses of > 312 mg/kg-bw/day or higher (Wyatt et al., 1997; cited in: ECB, 2008). There is evidence that the thyroid effects observed are attributable to stimulation of this organ arising from a negative feedback effect arising from plasma T4 depletion following increased excretion of this hormone. This depletion of plasma T4 results from the induction of hepatic UDPG-transferase, increased glucuronidation, and ultimately excretion of T4 following exposure to MCCPs. The pituitary responds to the decreased levels of T4 by releasing more TSH, which in turn leads to increased production of T4 by the thyroid. The continuous stimulation of the thyroid in response to the increased excretion of plasma T4 is predicted to ultimately give rise to hypertrophy and hyperplasia in this organ. Humans, unlike rodents, possess T4-globulin binding protein and are therefore less susceptible to plasma T4 depletion and hence any resultant thyroid stimulation. The thyroid effects observed in rats are not considered to be of relevance to chronic human health at relevant levels of exposure, although these changes may be relevant for assessing potential adverse outcomes during reproduction and development, as discussed under Section C-1-7 in this Appendix.

Genotoxicity
MCCPs (C14-17 40-52 wt% Cl) are not mutagenic to bacteria. Three in vivo bone marrow studies also show that MCCPs are not clastogenic (cited in: ECB, 2008). Therefore, it may be concluded that MCCPs possess a low potential to cause genotoxic effects.

Carcinogenicity

There is no information on the carcinogenicity of MCCPs; however, carcinogenicity studies on a SCCP and a vLCCP are available. These studies, along with the genotoxicity data on MCCPs, may be used to inform the carcinogenic potential of MCCPs. When administered by gavage, a SCCP (C12, 60 wt% Cl) caused increased incidences of liver tumors in male and female rats, kidney tumors in male rats, and thyroid tumors in female rats (NTP, 1986a). However, based on mechanistic considerations, these tumors are considered to be of little or no relevance to humans.  This conclusion is consistent with previous carcinogenicity evaluations (ECB, 2008). An increased incidence of malignant lymphoma in male mice was reported at the highest dose of 5,000 mg/kg-bw/day in carcinogenicity studies of a vLCCP (C23, 43 wt% Cl) in male and female rats and mice (NTP, 1986b). Because it is unlikely that MCCPs are genotoxic, and the fact that cancer was only observed at the highest dose, the EU (UK 2009) assumed that there was a threshold for this effect in the mice. In addition, there was no increased incidence of malignant lymphoma observed in the carcinogenicity study on an SCCP discussed above. Further, MCCPs are non-genotoxic. Therefore, it may be concluded that MCCPs are unlikely to pose a carcinogenic hazard to humans.

Table Apx_C-1: Summary of Results from 90-day Studies in Rats Administered MCCPs.
                             Strain (sample size)
                        Test substance and dose levels
                                 Target organ
                                 Effect levels
F-344
(10 rats/sex/group)[1]
C14-17, 52 wt% Cl

Dietary intake for ♂: 0, 2.38, 9.34, 23.0, or 222 mg/kg-bw/day.

Dietary intake for ♀: 0, 2.51, 9.70, 24.6, or 242 mg/kg-bw/day.
Liver
♂ at 222 and ♀ at 242 mg/kg-bw/day, 13-31 % ↑ in organ weight

♂ at 222 mg/kg-bw/day, minimal centrilobular hypertrophy in 9/10 animals

♂ at 222 mg/kg-bw/day, 82 % ↑ in microsomal T4-UDPGA-glucuronyl transferase activity

♀ at 100, 300, and 300 mg/kg-bw/day, 30, 30, and 252 % ↑ in microsomal T4-UDPGA-glucuronyl transferase activity, respectively

Kidney
♂ at 222 and ♀ at 242 mg/kg-bw/day, 9-13 % ↓ in organ weight

♂ at > 222 and ♀ at 242 mg/kg-bw/day, no treatment-related histopathology

Thyroid
♂ at 222 mg/kg-bw/day, 17 % ↑ in plasma TSH

♂ at 23.0 and 222 mg/kg-bw/day, 26 % or 22 % ↓ in plasma free T3, respectively, but no effects on total T3 or on free/total T4 at any dose

♀ at > 242 mg/kg-bw/day, no effects on free/total T3 or T4

♀at 24.6 and 242 mg/kg-bw/day, 20 and 39 % ↑ in plasma TSH

♂at > 222 and ♀ at 242 mg/kg-bw/day, no treatment-related histopathology
Sprague-Dawley
(10 rats/sex/group)[2]
C14-17, 52 wt% Cl

Dietary intake for ♂: 0, 0.4, 4, 36, or 360 mg/kg-bw/day.

Dietary intake for ♀: 0, 0.4, 4, 42, or 420 mg/kg-bw/day.
Liver
♂ at 360 and ♀ at 420 mg/kg-bw/day, 28 and 48 % ↑ in absolute and relative weights, respectively

♂ and ♀ at < 4 mg/kg-bw/day, no treatment-related histopathology

♂at 36 and ♀ at 42 mg/kg-bw/day, minimal increase in anisokaryosis and vesiculation of the nuclei

♂ at 360 and ♀ at 420 mg/kg-bw/day, mild increase in anisokaryosis and vesiculation of the nuclei (7-10 animals)

♂ at 360 mg/kg-bw/day, ↑ in perivenous homogeneity

♀ at 42 and 420 mg/kg-bw/day, ↑ in perivenous homogeneity

♂ at 360 and ♀ at 420 mg/kg-bw/day, ↑ in single cell necrosis (incidence not reported)

Kidney
♂ at 360 and ♀ at 420 mg/kg-bw/day, 11 % ↑ in absolute and relative weights

♂ at > 0.4 mg/kg-bw/day, minimal to mild hyaline-droplet like cytoplasmic inclusions, with significant accumulation at the limit dose

♀ at > 4 mg/kg-bw/day, minimal dose-related inner medullary tubular dilation seen in 0/10, 0/10, 1/10, 4/10, and 8/10 animals

Thyroid
♂ at 36 and 360 mg/kg-bw/day, minimal to mild morphological changes affecting the architecture (i.e., reduced follicle sizes and collapsed angularity) and the epithelium (i.e., increased height, cytoplasmic vacuolation, and nuclear vesiculation)

♀ at > 4 mg/kg-bw/day, minimal to mild morphological changes affecting the architecture (i.e., reduced follicle sizes and collapsed angularity) and the epithelium (i.e., increased height, cytoplasmic vacuolation, and nuclear vesiculation)
F-344
(15 rats/sex/group)[3]
C14-17, 52 wt% Cl

Dietary intake for ♂ and ♀: 0, 10, 100, or 625 mg/kg-bw/day.

Liver
♂ and ♀ at 100 and 625 mg/kg-bw/day, 22-26 % and 64-92 % ↑ in absolute weight values, respectively

♂ at 100 and 625 mg/kg-bw/day, hypertrophy of trace severity seen in 1/15 and 13/15 animals, respectively

♀ at 625 mg/kg-bw/day, hypertrophy of trace severity seen in 13/15 animals

Kidney
♂ and ♀ at 625 mg/kg-bw/day, 18 % ↑ in absolute weight values

♂ at > 10 mg/kg-bw/day, trace to mild nephritis seen in 1/15, 3/15, 4/15, and 10/15 animals

♀ at 625 mg/kg-bw/day, tubular pigmentation (9/14 animals)

Thyroid
♂ at 625 mg/kg-bw/day, 50 % ↑ in absolute weight values

♂ at > 10 mg/kg-bw/day, mild to moderate hypertrophy observed in controls with a dose-dependent trend towards ↑ severity in treated animals

♂ at > 10 mg/kg-bw/day, trace to mild hyperplasia with a dose-dependent trend towards ↑ severity

Adrenal
♂ and ♀ at 625 mg/kg-bw/day, 25 % ↑ in absolute weight values
Wistar-derived
(24 rats/sex/group)[4]
C14-17, 52 wt% Cl, containing epoxidized vegetable oil as a stabilizer

Dietary intake for ♂: 0, 33, 167, or 333 mg/kg-bw/day.

Dietary intake for ♀: 0, 32, 160, or 320 mg/kg-bw/day.

Liver
♂ at 167 and 333 mg/kg-bw/day, 15 and 22 % ↑ in relative weight values, respectively

♀ at 32, 160, and 320 mg/kg-bw/day, 11, 21, and 48 % ↑ in relative weight values, respectively

♂ at 333 and ♀ at 320 mg/kg-bw/day, no histopathological abnormalities

♂ at > 33 and ♀ at > 32 mg/kg-bw/day, dose-related ↑ in proliferation of smooth endoplasmic reticulum (electron microscopy)

Kidney
♂ and ♀ at limit dose, 15 % ↑ in relative weight

♂ and ♀, dose-related ↑ in congestion (incidence and severity not reported)

♂ and ♀ at > limit dose, no histopathological abnormalities
F-344
(10 rats/sex/group)[5]
C14-17, 40 wt% Cl

Oral gavage for ♂ and ♀: 0, 312, or 625 mg/kg-bw/day
Liver
♂ and ♀ at 312 and 625 mg/kg-bw/day, 37 and 72 % ↑ in relative weight, respectively, (absolute weight and bodyweight not presented)

♂ and ♀, dose-related ↑ in centrilobular hypertrophy (incidence and severity not reported)

♂ and ♀ at 312 and 625 mg/kg-bw/day, dose-related ↑ in β-oxidation from day 29 onwards (~2.7- and 3.3-fold ↑, respectively, at study termination)

♂ and ♀ at 312 and 625 mg/kg-bw/day, dose-related ↑ in UDPG-transferase activity from day 15 onwards (up to 100 % ↑, respectively)

Thyroid
♂ and ♀ at 312 and 625 mg/kg-bw/day, ↓ in levels of free and plasma T3, which reached statistical significance on days 15 and 57

♂ at 312 and 625 mg/kg-bw/day, ↑ TSH up to 2-fold on day 8 only

♀ at 312 and 625 mg/kg-bw/day, T3 significantly ↑ by day 91

♀ at 312 and 625 mg/kg-bw/day, total plasma T4 significantly ↓ by up to 25 % on day 57

♂ and ♀ at 312 and 625 mg/kg-bw/day, ↑ follicular cell hypertrophy throughout the study, and accompanied by follicular cell hyperplasia on days 55 and 91 (incidence and severity not reported)

♂ and ♀ at 312 and 625 mg/kg-bw/day, significantly ↑ replicative DNA synthesis on day 29, but not on day 91
[1] CXR (2005), cited in: ECB (2008).
[2] Poon et al. (1995), cited in: ECB (2008).
[3] IRDC (1984), cited in: ECB (2008).
[4] Birtley et al. (1980), cited in: ECB (2008); note, this study was only summarized in the review by Birtley et al. (1980). The underlying original study report was not available.
[5] Wyatt et al. (1997), cited in: ECB (2008).

Developmental Reproductive Toxicity Review
A series of range-finding and definitive prenatal developmental and reproductive toxicity studies were conducted in rats and rabbits with medium-chain chlorinated paraffins (MCCPs). These studies were conducted between 1981 and 1986. They appear to be valid toxicity studies, conducted according to the standard methodologies available at the time. More recently, additional studies with MCCPs have been conducted in an attempt to determine the cause of hemorrhaging in the pups observed in a one-generation reproductive toxicity range-finding study.

In several prenatal developmental toxicity studies with MCCPs conducted via gavage, no signs of maternal toxicity were seen at doses as high as 500 mg/kg-bw/day in rats and 100 mg/kg-bw/day in rabbits. Likewise, no signs of developmental toxicity were observed at doses as high as 5000 mg/kg-bw/day in rats and 100 mg/kg-bw/day in rabbits.

Two reproductive toxicity studies with MCCPs in rats have been conducted. A one-generation reproductive toxicity range-finding study showed that administration of approximately 100 and 400 mg/kg-bw/day MCCPs via the diet had no effect on fertility or other reproductive parameters; however, internal hemorrhaging and deaths in pups were observed beginning from 74 mg/kg-bw/day (1000 ppm) up to approximately 400 mg/kg-bw/day (6250 ppm). These effects in the pups were not seen in a more recent definitive one-generation reproductive toxicity study with exposure to MCCPs for 11-12 weeks to doses as high as 100 mg/kg-bw/day (1200 ppm). Internal hemorrhaging was not seen in the adult animals in either of these studies at doses as high as 400 mg/kg-bw/day (6250 ppm), or in another study in non-pregnant female rats repeatedly exposed to doses as high as 1000 mg/kg-bw/day. However, when dams were exposed to approximately 500 mg/kg-bw/day (6250 ppm) MCCPs during cohabitation, gestation, and lactation, signs of hemorrhaging were observed in dams that died at the time of parturition. Taken together, the results of these studies suggest that newborns during lactation and pregnant females at the time of parturition are a potentially sensitive subpopulation.

The UK Risk Assessment (February, 2008) did not use the LOAEL of 74 mg/kg-bw/day (1000 ppm) from the one-generation reproductive toxicity range-finder study as a point of departure because the pup deaths at that dose were not statistically significant. The study itself used a limited number of animals and was intended for dose range-finding purposes only and, more importantly, the pup deaths were not repeated in a more recently conducted definitive study. With respect to developmental/reproductive toxicity, the UK Risk Assessment identified two subpopulations at risk: offspring during lactation and pregnant dams at parturition. The NOAELs from the definitive one-generation reproductive toxicity study (a maternal NOAEL ~ 47 mg/kg-bw/day (600 ppm) for effects on the offspring mediated via lactation; and a maternal NOAEL ~ 100 mg/kg-bw/day (1200 ppm) for effects on the dam during the time of parturition) were used to calculate risk. Assuming a conservative value of 50 % oral absorption, the margin of safety (MOS) for effects on the offspring mediated via lactation and effects on the dam during the time of parturition were calculated for workers, consumers, and other scenarios. In all but one scenario (oil-based metal working fluids), the margins of safety were above 100 and in many cases, several fold above. In addition, margins of exposure were calculated for infants exposed via breast milk and via cow's milk, and in both instances, large MOEs (i.e., > 100) were calculated.

Additional studies with MCCPs have been conducted in an effort to clarify the possible causes of the hemorrhaging in the pups. One (single-dose; 6250 ppm or 538 mg/kg-bw/day) study showed maternal death during parturition due to low levels of vitamin K and related hemorrhaging, suggesting that the act of parturition places dams at higher risk. It was concluded in data from this study and a cross-fostering study that the fetus relies on clotting factors via mother's milk and severe deficiencies in vitamin K levels and related clotting factors in the pups results in hemorrhaging.

No definitive developmental neurotoxicity studies on MCCPs were located. It is not clear if any developmental neurotoxicity endpoints were actually measured in the available prenatal developmental/reproductive toxicity studies; none were explicitly stated. The only information available regarding behavior during development is from cage-side observations in pups through LD 21. In these cases, no dose-related differences were reported in F1 post-weaning appearance or cage-side behaviors.

In the prenatal developmental toxicity study in rats, the LOAEL for maternal toxicity was 2000 mg/kg-bw/day based on clinical signs. The NOAEL for maternal toxicity was 500 mg/kg/day. The NOAEL for developmental toxicity was 5000 mg/kg-bw/day, the highest dose tested.

In the prenatal developmental toxicity study in rabbits, no adverse, treatment-related effects were reported in the dams or the offspring. The NOAEL for both maternal and developmental toxicity was 100 mg/kg-bw/day, the highest dose tested.

In the reproduction range-finding study in rats (IRDC, 1981, cited in ECB,2008), the LOAEL for maternal toxicity was 6250 ppm (463 mg/kg-bw/day) based on reductions in body weight gains. The NOAEL for maternal toxicity was 1000 ppm (74 mg/kg-bw/day). The LOAEL for developmental toxicity was 1000 ppm (62/74 mg/kg/day) based on pup mortality associated with internal hemorrhages. The NOAEL for developmental toxicity was 100 ppm (6/8 mg/kg-bw/day). No effects on any reproductive parameters were reported. The NOAEL for reproductive toxicity was 6250 ppm (384/463 mg/kg-bw/day).

In the one-generation reproduction toxicity study in rats, the LOAEL for maternal toxicity was 1200 ppm (~100 mg/kg-bw/day) based on increases in liver weight; the NOAEL for maternal toxicity was 600 ppm (~ 47 mg/kg-bw/day). The NOAEL for developmental and reproductive toxicity was 1200 ppm (~ 84/99 mg/kg-bw/day), the highest dose tested.

Basis for Conclusions
In a range-finding prenatal developmental toxicity study in pregnant Charles River COBS CD rats administered MCCPs (C14-17, 52 wt% Cl) via gavage at dose levels of 0, 1000, 1500, and 2500 mg/kg-bw/day on gestation days (GD) 6-20, no effects were observed in the dams at doses up to 2500 mg/kg-bw/day (IRDC, 1983, 1984; cited in: ECB, 2008). As a result, doses greater than 2500 mg/kg-bw/day were selected for the definitive study.

In the definitive study, four groups of 25 pregnant Charles River COBS CD rats were administered MCCPs (C14-17, 52 wt% Cl) via gavage at doses of 0, 500, 2000, and 5000 mg/kg-bw/day on GD 6-19 (IRDC, 1984; cited in: ECB, 2008). Unmated males and females were individually housed and acclimated for 21-days in an environmentally controlled room. At the end of the acclimation period, all animals were weighed and subjected to a detailed physical examination. One female and one male rat were placed together for mating. Confirmation of mating was based on evidence of a copulatory plug or by vaginal smear for sperm. The day mating was confirmed was designated as day 0 of gestation. Test article was administered to pregnant females orally by gavage as a single daily dose on GD 6-19. During treatment, pregnant females were observed daily for mortality and clinical signs of toxicity. Any females not surviving to scheduled sacrifice were necropsied. Body weights were recorded on GD 0, 6, 9, 12, 16, and 20. All females were sacrificed on GD 20 and the uterus and ovaries excised for examination. The number and location of viable and nonviable fetuses, early and late resorptions, and the number of total implantations and corpora lutea were recorded. The uterus was weighed. The abdominal and thoracic cavities underwent gross examination. Maternal tissues were preserved for future histopathological analysis. Fetuses were weighed, sexed, tagged, and examined for external malformations and variations, including the palate and the eyes. The fetuses underwent visceral and skeletal examinations for malformations and developmental variations.

The only effects reported in dams consisted of an increased incidence in wet matted and yellow stained haircoat in the anogenital area at 5000 mg/kg-bw/day, and soft stool at > 2000 mg/kg-bw/day. No treatment-related adverse effects were reported in offspring at doses up to 5000 mg/kg-bw/day. The LOAEL for maternal toxicity was 2000 mg/kg-bw/day based on clinical signs; the NOAEL for maternal toxicity was 500 mg/kg-bw/day. The NOAEL for developmental toxicity was 5000 mg/kg-bw/day, the highest dose tested.

In a range-finding prenatal developmental toxicity study in pregnant Dutch Belted rabbits administered MCCPs (C14-17, 52 wt% Cl) via gavage at dose levels of 0, 100, 300, 1000, 2000, and 3000 mg/kg/day on GD 6-27, an increase in the number of abortions was observed at > 1000 mg/kg/day (IRDC, 1985; cited in: ECB, 2008). Body weight reductions in the dams were reported at 100 and 300 mg/kg/day. As a result, another range-finding prenatal developmental toxicity study in rabbits was initiated. This second range-finding study showed decreases in maternal weight gain at 80 and 160 mg/kg-bw/day (IRDC, 1982b; cited in: ECB, 2008).

Based on the results of these range-finding studies, dose levels of 10, 30, and 100 mg/kg-bw/day were selected for the definitive prenatal oral gavage developmental toxicity study (IRDC, 1983; cited in: ECB, 2008). In the definitive study, four groups of 16 pregnant Dutch Belted rabbits were administered 0, 10, 30, and 100 mg/kg-bw/day MCCPs (C14-17, 52 wt% Cl) via gavage on GD 6-27. Unmated males and females were individually housed and acclimated for 50-days in an environmentally controlled room. As a result of a positive finding for parasites in stool samples collected during acclimation, all rabbits received sodium sulfamethazine in their drinking water for 16 days during the acclimation period. This treatment was terminated 4 weeks prior to study initiation and only rabbits testing negative for parasites were placed on study. At the end of the acclimation period, all animals were weighed and subjected to a detailed examination. Females were impregnated via artificial insemination. Three weeks prior to artificial insemination, females were given chorionic gonadotropin via an injection in a marginal ear vein in order to induce superovulation. Semen was collected from males of proven fertility and evaluated for motility. The day of artificial insemination was designated as day 0 of gestation. During treatment, pregnant females were observed for mortality and clinical signs of toxicity. Body weights were recorded on GD 0, 6, 12, 18, 24, and 28. Any females not surviving to scheduled sacrifice were necropsied. On GD 28, all surviving females were sacrificed and the uterus and ovaries excised for examination. The location and number of viable and nonviable fetuses, early and late resorptions, and the number of total implantations and corpora lutea were recorded. The uterus was weighed. The thoracic and abdominal cavities underwent gross examination. Pooled samples of abdominal adipose tissue from 3 dams were frozen for future analysis. Each fetus was sexed, weighed, and examined for external malformations and variations, including the palate and the eyes, as well as visceral and skeletal examinations for malformations and developmental variations, including examination of the brain and the heart.

No adverse, treatment-related effects were reported in the dams or the offspring at doses                  up to 100 mg/kg-bw/day. The NOAEL for both maternal and developmental toxicity was 100 mg/kg-bw/day, the highest dose tested.

In a one-generation reproductive toxicity range-finding study, four groups of 5 male and 10 female Charles River COBS SC rats were administered MCCP (C14-17, 52 wt% Cl) via the diet at 0, 100, 1000, and 6250 ppm (~ 0, 6, 62, and 384 mg/kg-bw/day, respectively, in males; and 0, 8, 74, or 463 mg/kg-bw/day, respectively, in females) (IRDC, 1985; cited in: ECB, 2008). F0 animals were exposed to test substance from 28 days prior to mating until sacrifice; F1 animals were treated from weaning until sacrifice, with additional potential exposures occurring in utero and during lactation. All F0 males were sacrificed after the mating period. Following the premating period, each male was cohabited with two females for 10 days. Females were examined for evidence of copulation by means of vaginal smears and/or the appearance of a vaginal plug. The day evidence of copulation was determined was designated as day 0 of gestation. Direct dosing began at 83 days of age for the F0 parents and at 21 days of age for the F1 weanlings. The F0 and F1 animals were observed for clinical signs of toxicity, changes in general appearance and behavior, and mortality. In the F0 adults, body weights and food consumption were measured weekly; in addition, body weights were measured in F0 females on GD 0, 7, 14, and 20; and on lactation days (LD) 0, 7, 14, and 21. Estrous cyclicity was determined in F0 females prior to mating, during mating, and prior to dosing. All F0 females were allowed to deliver. The day the entire litter was found and delivery was judged to be complete was designated as LD 0. Gestation duration was calculated. Following delivery, all pups were examined for external malformations and the numbers of live births and stillbirths (litter size) was recorded for each dam. Pups were weighed, sexed, and examined externally on LD 0, 7, 14, and 21. Litter size was determined on LD 0, 4, 10, and 21. The number of male and female pups was recorded on LD 4. Litters were examined daily for survival. F0 females were examined for behaviors in nesting and nursing. On LD 21, all dams were sacrificed and a gross necropsy performed, including examination of the uterine contents for implantation sites; and ten F1 weanlings/sex/dose were sacrificed and necropsied. Five F1 males and ten F1 females/dose group were retained after LD 21 and sacrificed at 70 days (10 weeks) of age and necropsied. Due to high mortality in high-dose F1 pups, the surviving F1 pups in the high-dose group and an equal number of control pups were sacrificed on LD 6 and 7 and necropsied. Blood was collected via heart puncture and complete blood counts performed. Bone marrow smears were collected from the femur, and the abdominal contents of the pups with milk in the stomach were collected and frozen for future analyses.

Effects in the adults consisted of isolated reductions food consumption and body weight in the dams at 6250 ppm. Effects in the offspring consisted of significant reductions in pup survival at the high dose (none of the F1 pups in the high-dose group survived until lactation day 21); and slight (11 %, not statistically significant) decreases in pup survival, and labored breathing, subcutaneous hematoma, pale discoloration, blood around the orifices, pale liver, kidney, and spleen, and blood in the cranial cavity and brain beginning at the mid-dose. No dose-response, treatment-related adverse effects were reported in the offspring in the low dose group. Reductions in body weight in F1 male and female pups occurred during LD 7, 14, and 21, but these reductions were not statistically significantly different from controls, and were seen only in the low- and mid-dose groups but not the high-dose group. There were no dose-related differences in F1 post-weaning appearance, behavior, food consumption, or clinical or anatomical pathology in the low- and mid-dose groups. Based on the results of this study, it was recommended that dosage levels in a two-generation reproduction toxicity study not exceed 1000 ppm. The LOAEL for maternal toxicity was 6250 ppm (~463 mg/kg-bw/day) based on reductions in body weight gains. The NOAEL for maternal toxicity was 1000 ppm (~74 mg/kg-bw/day). The LOAEL for developmental toxicity was 1000 ppm (~62/74 mg/kg-bw/day) based on pup mortality due to hemorrhaging. The NOAEL for developmental toxicity was 100 ppm (~6/8 mg/kg-bw/day). No effects on any of the reproductive parameters were reported. The NOAEL for reproductive toxicity was 6250 ppm (~384/463 mg/kg-bw/day).

In an effort to determine the cause of hemorrhaging in the pups at the high dose from the reproductive toxicity range-finding study, a screening level cross-fostering developmental toxicity study was conducted in Charles River COBS Wistar rats fed diets containing either 0 or 6250 ppm (~ 3125 mg/kg-bw/day) MCCPs (C14-17, 52 wt% Cl) for 4 weeks prior to mating and throughout pregnancy in a series of groups (Hart et al., 1985; cited in: ECB, 2008). Offspring from two of these groups (pups from control females reared from treated females, and pups reared from their treated mothers) showed high-pup mortality associated with internal hemorrhages. Hematological assays in the pups from these two groups showed decreases in factor X, resulting in a disruption of a vitamin K-dependent clotting system (lower plasma vitamin K levels). It was concluded that the pup mortalities were due to internal hemorrhages caused by a decrease in the vitamin K-dependent hemostatic mechanism (not examined in this study), induced during lactational exposures via the milk from mothers receiving MCCPs.

Additional studies have been conducted to investigate two hypotheses in an effort to clarify the possible causes of the hemorrhaging in the pups.

The first hypothesis proposes that MCCPs induce a catabolism of vitamin K in lactating rats leading to decreased plasma concentrations and ultimately low levels of vitamin K in the milk pups receive (vitamin K controls the formation of several clotting factors in the liver). In order to test this hypothesis, a preliminary study (CXR Biosciences Ltd., 2003; cited in: ECB, 2008) was conducted in which three groups of 6 female adult Sprague-Dawley were administered MCCPs (C14-17, 52 wt% Cl) via gavage at doses of 0, 500, or 1000 mg/kg-bw/day for 21 days while being fed a normal diet or a vitamin K-deficient diet. Following exposures to MCCPs, significant decreases in plasma concentrations of a clotting factor were seen in rats fed a normal diet; however, these decreases did not affect prothrombin clotting times. Reductions of a clotting factor in both treated and control groups were also seen in animals fed a vitamin-K deficient diet. Plasma vitamin K levels were not affected by treatment in the normal diets, but they were lower in high-dose animals fed vitamin K-deficient diets. The results from this study suggested that MCCPs did not adversely affect the blood clotting system in adult female rats treated for 3 weeks up to a dose of 1000 mg/kg-bw/day; and the hemorrhaging effects in pups are unlikely to be mediated by reduced vitamin K levels in breast milk.

The second hypothesis proposes that MCCPs transferred to the pups through breast milk causes disruption of the pup clotting system. In order to test this hypothesis, a study (CXR Biosciences Ltd., 2004; cited in: ECB, 2008) was conducted in two groups of 16 male and 32 female Sprague-Dawley rats administered 0 or 6250 ppm (~ 0 and 513 and 538 mg/kg-bw/day in males and females, respectively) MCCPs (C14-17, 52 wt% Cl) for 4 weeks prior to mating, during cohabitation, gestation, and lactation until study termination (at about 2 weeks after the first litters were born, due to high rate of pup mortality). Milk, blood, and liver samples from lactating dams, and blood and liver samples from lactating pups were assessed for plasma vitamin K levels. Five dams died or were killed at the time of parturition (16 % mortality). These deaths were considered to be treatment-related as there was no indication of obstruction or hindrance to delivery. The clinical necropsy of these dams showed effects suggestive of hemorrhaging in 3 out of the 5 dams and one male who died. Slight reductions in food consumption and body weight gains were observed during gestation and lactation. There were no effects on mating performance or duration of gestation. Concentrations of plasma vitamin K levels in adult females having gone through lactation and pregnancy was markedly decreased by treatment with MCCPs, which in turn produced a decrease in activity of the plasma clotting factors in treated dams. Prothrombin clotting times were not affected in the dams, suggesting that the functional reserve in these adult animals was sufficient. Pup plasma volumes were reportedly insufficient to measure vitamin K directly, but clotting factor activities were possible to analyze. No effects on litter size at birth or on pup mortality from birth to LD 4 were reported; however, after pup mortality increased significantly after LD 4. The majority of these pups showed internal hemorrhages at necropsy. It was concluded that data from this study and the cross-fostering study performed by Hart et al. (1985) suggest that the fetus receives sufficient vitamin K via the placenta, but after birth becomes severely deficient in vitamin K and related clotting factors and relies on these factors via mother's milk. In addition, the pups also receive considerable levels of MCCPs via lactation (through mother's milk) which may also contribute to further reducing the vitamin K levels. These severe deficiencies in vitamin K levels and related clotting factors in the pups results in hemorrhaging. It was also concluded that the act of parturition places dams at higher risk.

More recently, a definitive one-generation reproductive toxicity study was conducted to refine the NOAEL for effects in the offspring and to further explore the mechanisms of hemorrhaging (CXR, 2006; cited in: ECB, 2008). This study was reportedly conducted in compliance with OECD TG 421 and Good Laboratory Practice standards. Four groups of 12-17 male and female Sprague-Dawley rats were administered 0, 300, 600, and 1200 ppm (~ 0 and 21, 44, and 84 mg/kg-bw/day in males; and 0, 23, 47, and 99 mg/kg-bw/day in females) MCCPs (C14-17, 52 wt% Cl) for 4 weeks prior to mating, during cohabitation, gestation, and lactation until study termination (for a total treatment of 11-12 weeks). Males were terminated on LD 4 (9 weeks of treatment) and females were allowed to litter and rear their offspring until PND 21. Females were sacrificed on LD 21. Adult males were assessed for signs of clinical toxicity, body weight, food consumption, and macropathology. Adult females were assessed for signs of clinical toxicity, body weight, food consumption, gestation length, parturition, liver weights, and macropathology. Mating performance and fertility were also evaluated. Offspring evaluations included clinical signs of toxicity, litter size, survival, sex ratio, body weight, and pathological examinations at necropsy. Milk, blood, and liver samples were obtained from selected offspring at specific time points between birth of litters and PND 21. In addition, blood, liver, and milk samples from a satellite group of five females and their litters from the control and high-dose group (1200 ppm) were collected for future analysis. Analysis of these samples was still pending at the time of the UK assessment.

No adverse effects were reported in the adult animals for clinical condition, body weight, body weight gain, food consumption, estrous cycling, mating performance, pre-coital interval, fertility, number of implantations, gestation lengths, or parturition. The only effect reported was for higher absolute and relative liver weights in high-dose females (1200 ppm; 99 mg/kg-bw/day). Likewise, no adverse effects were in the offspring at any dose level for litter size, sex ratio, offspring survival, body weights, body weight gains, macropathology and liver weights. No adverse effects were reported on pre- and post-natal survival and growth up to sacrifice (weaning). Though no histopathology was performed, the body cavity and cranial cavity were opened and examined for any signs of hemorrhaging. None was reported. Based on the results of this study, the LOAEL for maternal toxicity was 1200 ppm (~100 mg/kg-bw/day) based on increases in liver weight; the NOAEL for maternal toxicity was 600 ppm (~ 47 mg/kg-bw/day). The NOAEL for developmental and reproductive toxicity was 1200 ppm (~ 84/99 mg/kg-bw/day), the highest dose tested.

LCCP Health Data Review

P-12-0284 is a C18 LCCP. Much of the information presented here is based on data with vLCCPs (i.e., carbon chain lengths of >C20).

The National Research Council (NRC, 2000) reviewed the toxicological risks of selected flame retardant, including a LCCP containing C24 with 70 wt% Cl. Based on the NOAEL of 900 mg/kg-bw/day (liver toxicity), the NRC derived an RfD of 0.3 mg/kg-bw/day. Using this RfD and the worst case average daily exposure to be 0.16 mg/kg/day, NRC concluded: "LCCP do not pose a noncancer risk when incorporated into residential furniture at the estimated application levels." Further, it was concluded that: "LCCP are not likely to be a human carcinogen and derivation of a cancer potency factor is unnecessary."

Metabolism
There is no information on inhalation absorption of LCCPs in humans or in animals. Based on their low vapor pressure and low water solubility, absorption following inhalation or dermal exposure is expected to be limited.
Oral (gavage) studies (IRDC, 1981; cited in: UK, 2009) showed that approximately 82-95 % of a single dose of [8-[14]C]-labeled C22-26 chlorinated paraffin (43 % Cl) was recovered in the feces in rats during the seven-day collection period. Only 0.1-0.8 % of the radiolabel was excreted in the urine. For C22-26 chlorinated paraffin (70 wt% Cl), it was found that 61-88 % of the administrated radioactivity was recovered in the feces in rats during the seven-day collection period. Less than 0.1-1 % was excreted in the urine.

Acute Toxicity
Acute toxicity studies have been conducted in rats, mice or dogs on five LCCPs: C20-30 , 41-50 wt% Cl; C22-26, 42 wt% Cl, C23, 43 wt% Cl; C20-30, 61-70 wt% Cl; C24, 70 % Cl. The maximum dose levels used in these studies ranged from 4-50 g/kg-bw. No deaths were reported in any of the studies (IUCLID, 2003; cited in: UK, 2009).

Irritation and Sensitization
Skin irritation testing has been conducted on four LCCPs: C19 ,44 wt% Cl; C22-26, 42 wt% Cl; C20-30, 41-50 wt% Cl; C20-30, 70 wt% Cl. No evidence of irritation was seen in three of the four LCCPs. For the C22-26, 42 wt% Cl product, erythema was observed in two of six animals tested; the severity threshold was below the classification of the EU system (IUCLID, 2003; cited in: UK, 2009).

Evidence of slight eye irritation was seen in a test of a C22-26, 42 wt% Cl product. However, the criteria for classification as an eye irritant were not met (IUCLID, 2003; cited in: UK, 2009).

In a maximization test and a Buehler test using guinea pig, a C22-26, 42 wt% Cl product was negative (IUCLID, 2003; Bailey and Sheldon, 1998; cited in: UK, 2009). A C18-27, 40 wt% Cl product was reported to elicit a positive response in the guinea pig maximization test (IUCLID, 2000; cited in: UK, 2009). However, no information is available on the quality of this study.

Repeated-dose Toxicity
LCCPs with C20-30, 43 wt% Cl were dissolved in corn oil and given by gavage at 100, 900 or 3,750 mg/kg-bw/day to groups of 15 male and female Fisher 344 rats in a 14- and a 90-day studies (IRDC1981, 1984; cited in: Serront et al., 1987). There was a treatment-related effect on the liver of female rats at all dose levels, but no liver effects were seen in the males. Female liver weights were increased and a multifocal granulomatous hepatitis characterized by inflammatory changes and necrosis. Nephrosis was observed in the kidney of male rats and mineralization in the kidneys of female rats at 3,750 mg/kg-bw/day. Similar liver effects were observed in the high-dose (3,750 mg/kg-bw/day) rats of both sexes in a 90-day study on LCCPs with C22-26, 70 wt% Cl (IRDC1981; cited in: Serront et al., 1987) and in a 90-day study as well as a 2-year bioassay on a LCCP with an average of C23, 43 wt% Cl at 100 mg/kg-bw/day (NTP, 1986). Based on the liver toxicity, a LOAEL of 100 mg/kg-	bw/day is established for the LCCPs with 43 wt% Cl and a NOAEL of 900 mg/kg-bw/day is identified for the LCCPs with 70 wt% Cl.

Genotoxicity
Both LCCPs of C22-26, 43 wt% Cl and C23, 43 wt% Cl were negative in several Salmonella strains of the Ames test with or without metabolic activation (IUCLID, 2003; NTP, 1986; cited in: UK, 2009). LCCPs with C20-30 with 43 wt% Cl or C22-26 with 70 wt% Cl did not induce significant increases of chromosomal or chromatid aberrations in bone marrow cells of rats (IRDC1983; cited in: Serrone et al., 1987).

Carcinogenicity
The carcinogenicity of a vLCCP (C23, 43 wt% Cl) was studied by administering the chemical in corn oil by gavage to groups of 50 F344/N rats and 50 B6C3F1 mice of each sex, 5 days per week for 103 weeks (NTP, 1986). Male rats received doses of 0, 1,875 or 3,750 mg/kg-bw/day; female rats and mice received 0, 2,500 or 5,000 mg/kg-bw/day. An increased incidence of malignant lymphomas was reported for male mice given the LCCP; the incidences for the controls, low- and high dosed groups are 6/50, 12/50, and 16/50, respectively. vLCCPs are not genotoxic (see review in Appendix C, Section C-2-6), and the fact that cancer was only observed at the highest dose, the EU (UK 2009) assumed that there was a threshold for this effect in the mice. In addition, there was no increased incidence of malignant lymphoma observed in the carcinogenicity study on an SCCP (also discussed above in the MCCP section). It has been concluded that LCCPs are unlikely to pose a carcinogenic hazard to humans (NRC, 2000; Serrone et al., 1987).
Developmental Reproductive Toxicity Review
In a prenatal developmental toxicity study in rats, no treatment-related effects were reported. The NOAEL for both maternal and developmental toxicity was 5000 mg/kg-bw/day, the highest dose tested.

In a prenatal developmental toxicity study in rabbits, the LOAEL for maternal toxicity was 500 mg/kg-bw/day (the lowest dose tested) based on increased incidence of clinical signs. The NOAEL for developmental toxicity was > 2000 mg/kg-bw/day, the highest dose tested.

In a prenatal developmental toxicity study in rabbits, the NOAEL for both maternal and developmental toxicity was 1000 mg/kg-bw/day, the highest dose tested.

Basis for Conclusions
In a range-finding study (Study # 438-033, October 27, 1981; Chlorinated Paraffin Consortium), in pregnant Charles River COBS rats administered LCCP (22-26 carbons, 43 wt% Cl) via gavage at dose levels of 0, 3000, and 5000 mg/kg-bw/day on GD 6-19, the only effects reported occurred in dams and consisted of a slight increased incidence in anogenital matting during the latter portion of the treatment period at 5000 mg/kg-bw/day. No adverse treatment-related effects were reported in offspring at doses up to 5000 mg/kg-bw/day.

Based on the findings of the range-finding study, four groups of 25 pregnant Charles River COBS CD rats were administered LCCP (22-30 carbons, 70 wt% Cl) via gavage at doses of 0, 500, 2000, and 5000 mg/kg-bw/day on GD 6-19 (Study # 438-045, April 11, 1984; Chlorinated Paraffin Consortium). Unmated males and females were individually housed and acclimated for 15-days in an environmentally controlled room. At the end of the acclimation period, all animals were weighed and subjected to a detailed physical examination. One female and one male rat were placed together for mating. Confirmation of mating was based on evidence of a copulatory plug. The day mating was confirmed was designated as day 0 of gestation. Test article was administered to pregnant females orally by gavage as a single daily dose on GD 6-19. During treatment, pregnant females were observed daily for mortality and clinical signs of toxicity. Any females not surviving to scheduled sacrifice were necropsied. Body weights were recorded on GD 0, 6, 9, 12, 16, and 20. All females were sacrificed on GD 20 and the uterus and ovaries excised for examination. The number and location of viable and nonviable fetuses, early and late resorptions, and the number of total implantations and corpora lutea were recorded. The uterus was weighed. The abdominal and thoracic cavities underwent gross examination. Maternal tissues were preserved for future histopathological analysis. Fetuses were weighed, sexed, tagged and examined for external malformations and variations, including the palate and the eyes. The fetuses underwent visceral and skeletal examinations for malformations and developmental variations.

No adverse treatment-related effects were reported in the dams or offspring at doses up to 5000 mg/kg-bw/day. The NOAEL for both maternal and developmental toxicity was 5000 mg/kg-bw/day, the highest dose tested.

In a range-finding study (Study # 438-018, October 27, 1981; Chlorinated Paraffin Consortium) in pregnant Dutch Belted rabbits administered LCCP (22-26 carbons, 43 wt% Cl) via gavage at doses of 0, 500, 1000, 2000, 3000, and 5000 mg/kg-bw/day on GD 6-27, a slight decrease in the amount of feces and a slight increase in matting and/or staining of the haircoat was reported in the dams at > 3000 mg/kg-bw/day. No other effects were reported. Observations of offspring did not appear to be included.

Based on the results of the range-finding study, four groups of 16 Dutch Belted pregnant rabbits were administered LCCP (22-26 carbons, 43 wt% Cl) via gavage at doses of 0, 500, 2000, and 5000 mg/kg-bw/day on GD 6-27 (Study # 438-030, August 26, 1982; Chlorinated Paraffin Consortium). Unmated males and females were individually housed and acclimated for 9-weeks in an environmentally controlled room. As a result of a positive finding for parasites in stool samples collected during acclimation, all rabbits received sodium sulfamethazine in their drinking water for 19 days during the acclimation period. This treatment was terminated 5 weeks prior to study initiation and only rabbits testing negative for parasites were placed on study. At the end of the acclimation period, all animals were weighed and subjected to a detailed examination. Females were impregnated via artificial insemination. Immediately after insemination, ovulation was induced via an injection of chorionic gonadotropin in a marginal ear vein. Semen was collected from males of proven fertility and evaluated for motility. The day of artificial insemination was designated as day 0 of gestation. During treatment, pregnant females were observed for mortality and clinical signs of toxicity. Body weights were recorded on GD 0, 6, 12, 18, 24, and 28. Any females not surviving to scheduled sacrifice were necropsied. On GD 28, all surviving females were sacrificed and the uterus and ovaries excised for examination. The location and number of viable and nonviable fetuses, early and late resorptions, and the number of total implantations and corpora lutea were recorded. The uterus was weighed. The thoracic and abdominal cavities underwent gross examination. Pooled samples of abdominal adipose tissue from 3 dams were frozen for future analysis. Each fetus was sexed, weighed, and examined for external malformations and variations, including the palate and the eyes, as well as visceral and skeletal examinations for malformations and developmental variations, including examination of the brain and the heart.

A dose-related trend in an increased incidence in soft stool and/or anogenital matting or staining was observed in the dams beginning at the low-dose group. Three dams aborted and were sacrificed during treatment; one in the mid-dose group, and two in the high-dose group. Increases in postimplantation loss and corresponding decreases in viable fetuses, and increases in late resorptions were reported at the high-dose group, however, these effects were not reported as being statistically significant.  No signs of treatment-related developmental toxicity were reported in the offspring at < 5000 mg/kg-bw/day, although the sample size in the high-dose group was limited, precluding any definitive conclusions. Therefore, the LOAEL for maternal toxicity was 500 mg/kg-bw/day (the lowest dose tested), based on increased incidence of clinical signs. The NOAEL for developmental toxicity was > 2000 mg/kg-bw/day.

 In a range-finding study (Study # 438-038, November 1, 1982; Chlorinated Paraffin Consortium) in pregnant Dutch Belted rabbits administered LCCP (22-30 carbons, 70 wt% Cl) via gavage at doses of 0, 2000, 3750, and 5000 mg/kg-bw/day on GD 6-27, increases in abortions, reductions in maternal body weight, and increases in post-implantation losses were reported at > 2000 mg/kg-bw/day. Therefore, a second range-finding study was conducted at dose levels of 0, 50, 200, and 1000 mg/kg-bw/day (Study # 438-040, November 4, 1982; Chlorinated Paraffin Consortium). A slight decrease in viable fetuses and a slight increase in postimplantation loss were reported at 1000 mg/kg-bw/day. No other effects were reported.

Based on the results of the range-finding studies, four groups of 16 Dutch Belted pregnant rabbits were administered LCCP (22-30 carbons, 70 wt% Cl) via gavage at doses of 0, 100, 300, and 1000 mg/kg-bw/day on GD 6-27 (Study # 438-039, July 18, 1983; Chlorinated Paraffin Consortium). Unmated males and females were individually housed and acclimated for 40-days in an environmentally controlled room. At the end of the acclimation period, all animals were weighed and subjected to a detailed examination. Females were impregnated via artificial insemination. Immediately after insemination, ovulation was induced via an injection of chorionic gonadotropin in a marginal ear vein. Semen was collected from males of proven fertility and evaluated for motility. The day of artificial insemination was designated as day 0 of gestation. During treatment, pregnant females were observed for mortality and clinical signs of toxicity. Body weights were recorded on GD 0, 6, 12, 18, 24, and 28. Any females not surviving to scheduled sacrifice were necropsied. On GD 28, all surviving females were sacrificed and the uterus and ovaries excised for examination. The location and number of viable and nonviable fetuses, early and late resorptions, and the number of total implantations and corpora lutea were recorded. The uterus was weighed. The thoracic and abdominal cavities underwent gross examination. Pooled samples of abdominal adipose tissue from 3 dams were frozen for future analysis. Each fetus was sexed, weighed, and examined for external malformations and variations, including the palate and the eyes, as well as visceral and skeletal examinations for malformations and developmental variations, including examination of the brain and the heart.

No treatment-related adverse effects were observed in the dams or the offspring at any dose level. The increases in postimplantation losses noted in the two previous range-finding studies reported above were not reproduced in the definitive study. Therefore, the NOAEL for both maternal and developmental toxicity was 1000 mg/kg-bw/day, the highest dose tested.

ENVIRONMENTAL MONITORING DATA

MCCP MONITORING DATA
Surface Water
It is known that over time, based on their molecular weight and physicochemical properties, MCCPs in surface water will partition to suspended particulates, sediment, sludge, or soil. Reported MCCP concentrations in surface water range from < 2.50 x 10[-10] mg/L to 1.49 x 10[-3] (Table D-1). Very little information is available on the specific sampling locations for many of the surface water measurements reported in Table D-1. Limited documentation is available on two of the studies (Petersen et al., 2006 and Muir, 2003). Two sources provide a review of the literature with very little details (IPCS, 1996 and EC, 2008b). Two studies do provide detailed information on the sampling approach, including location (Houde et al., 2008 and USEPA, 1988). The Petersen et al. (2006) study, which had the highest published concentration, reported results for water samples collected from different Norwegian locations. EPA/OPPT assumes that these samples were collected in non-marine waters. Three studies found were not used in this assessment (BUA, 1992; Hoechst, 1987; and Willis, 1994). However, all of the studies used in the assessment use modern analytical techniques, reference the specific CPs of interest, and provide, at a minimum, general information on the sampling location. Given the paucity of surface water data available, EPA/OPPT used measurements from the selected studies and used the minimum and maximum values in this assessment.

Measurements of dissolved (filtered) concentrations were generally ND with few exceptions. Concentrations measured in surface water were largely from studies that measured total water concentrations which included MCCPs sorbed to particulates. More recent monitoring studies (Table D-1) have focused on measuring MCCPs in suspended solids, sediment pore water, and sediment.

Early analytical methods using thin layer chromatography (TLC) were used to measure CPs in surface water. However, this method has poor sensitivity and reproducibility, and provide false negative results. Current methods of quantification using gas or liquid chromatography coupled with a range of detectors (i.e., mass spectrometry; MS) are more reliable. Nearly all of the water concentrations were measurements taken at a single point in time (i.e., the samples were not time series samples). Absent more extensive monitoring data, EPA/OPPT assumed that the available data could be extrapolated to longer time periods for determination of a chronic exposure concentration.

MCCP concentrations in surface water, reported in Table D-1, rely on test methods that filtered or pre-filtered samples before they were analyzed, which can underestimate environmental concentrations. Where appropriate, reported values were converted to a common unit, as presented in the table. For the purposes of this assessment, in the studies considered acceptable, EPA/OPPT used the lowest and highest reported concentrations (< 2.50 x 10[-10] mg/L to 1.49 x 10[-3]) to evaluate risks of potential concern to aquatic organisms.

TableApx_D-1-1: Surface Water Concentrations of MCCPs, Sorted by Country.
                                     Media
                                    Country
                                   Location
                            City, State or Province
                                   Comments
                            Converted Concentration
                                 Common Units
                               Analytical Method
                                  References
                                 Surface water
                                    Canada

                                 Lake Ontario

                                    Maximum

                                 2.60x10[-9]

                                     mg/L

                                      NR

                                  EC (2008b)

                                     <
                                 2.50x10[-10]
                                     mg/L
                                  GC-HRMS-MAB
                              Houde et al. (2008)

                                     <
                                 1.00x10[-8]
                                     mg/L
                                  GC-ECNI-MS
                              Muir et al. (2003)

                                    Maximum
                                 4.70x10[-8]
                                     mg/L
                                  GC-HRMS-MAB
                              Houde et al. (2008)

                                     Mean
                                 9.00x10[-10]
                                     mg/L
                                  GC-HRMS-MAB
                              Houde et al. (2008)

                                    Germany
                            River Lech at Langsweid
                                      ---
                                 1.90x10[-4]
                                     mg/L
                                      NR
                                  IPCS (1996)

                              River Lech at Rain
                                      ---
                                 1.70x10[-4]
                                     mg/L
                                      NR
                                  IPCS (1996)

                           River Lech at Gersthofen
                                      ---
                                 9.00x10[-5]
                                     mg/L
                                      NR
                                  IPCS (1996)

                            River Lech at Augsburg
                                     <
                                 2.50x10[-5]
                                     mg/L
                                      NR
                                  IPCS (1996)

                           River Danube at Marxheim
                                      ---
                                 7.00x10[-5]
                                     mg/L
                                      NR
                                  IPCS (1996)

                                     <
                                 3.00x10[-5]
                                     mg/L
                                      NR
                                  IPCS (1996)

                                    Norway
                                      NR
                                      ---
                                 1.49x10[-3]
                                     mg/L
                                  GC-ECNI-MS
                            Petersen et al. (2006)

                                United Kingdom
                              Multiple locations
                                     <
                                   1x10[-4]
                                     mg/L
                                   GC-ECNI-MS
                            Nicholls et al. (2001)

                                 United States
                               Sugar Creek, Ohio
                                     <
                                 7.50x10[-5]
                                     mg/L
                                  GC-ECNI-MS
                                 USEPA (1988)

                           Central European Country
                                      NR
                                     <
                                 5.00x10[-5]
                                     mg/L
                                  GC-ECNI-MS
                                Coelhan (2010)
NR: Not recorded. Location description was not provided in the study.
--: Single sample value reported above the detection limit; therefore, no data qualifier required.
GC-HRMS-MAB: Gas chromatography-high resolution mass spectrometry with metastable atom bombardment ionization
GC-ECNI-MS: Gas chromatography in combination with electron capture negative ion mass spectrometry
Notes:
1.    All values provided in the table above represent total MCCP and not individual MCCP isomers
2.    In some cases, the minimum values in the table are preceded by "<". This indicates that the value reported in article was reported as a non-detect. In such cases, one half of the lowest reported detection limit was compiled as the `minimum' reported monitoring data
3.   All concentrations measured from impoundment lagoons and drainage ditches from the USEPA (1988) study have not been included as they are not considered as surface water concentrations
4.    All concentrations measured from suspended solid matter fraction from influents from the Coelhan (2010) study have not been included as they are not considered as surface water concentrations
Sediment
MCCP sediment concentrations from marine and non-marine environments ranged from 5.00 x 10[-3] to 1.64 x 10[1] mg/kg dw and from 2.00 x 10[-3] to 6.51 x 10[1] mg/kg dw, respectively.

For the purposes of this assessment, in the studies considered acceptable, EPA/OPPT used the lowest and highest reported marine and non-marine sediment concentrations (5.00 x 10[-3] to 1.64 x 10[1] mg/kg dw and 2.00 x 10[-3] to 6.51 x 10[1], respectively) to evaluate risks of potential concern to sediment organisms (Table D-2). Where appropriate, reported values were converted to a common unit, as presented in the table.
Table Apx_D-1-2: Sediment Concentrations of MCCPs, Sorted by Country.
                                     Media
                                    Country
                                   Location
                                   Comments
                            Converted Concentration
                                 Common Units
                                  References

                            City, State or Province

                                   Sediment
                                   (Marine)
                                   Australia
                                      NR
                                      ---
                                     1.11
                                   mg/kg dw
                            Kemmlein et al. (2002)

                                      ---
                                     1.17
                                   mg/kg dw
                            Kemmlein et al. (2002)

                                      ---
                                     3.11
                                   mg/kg dw
                            Kemmlein et al. (2002)

                                      ---
                                  1.64x10[1]
                                   mg/kg dw
                            Kemmlein et al. (2002)

                                    Canada
                      Hamilton Harbour (Windemere basin)
                                      ---
                                 2.90x10[-1]
                                    mg/kg*
                              Muir et al. (2000)

                                    Germany
                            German Bight, North Sea
                                      ---
                                 5.00x10[-3]
                                   mg/kg dw
                             Hüttig et al. (2004)

                                      ---
                                 9.00x10[-3]
                                   mg/kg dw
                             Hüttig et al. (2004)

                                      ---
                                 9.00x10[-3]
                                   mg/kg dw
                             Hüttig et al. (2004)

                                      ---
                                 1.30x10[-2]
                                   mg/kg dw
                             Hüttig et al. (2004)

                                      ---
                                 2.80x10[-2]
                                   mg/kg dw
                             Hüttig et al. (2004)

                                      ---
                                 1.46x10[-1]
                                   mg/kg dw
                             Hüttig et al. (2004)

                                  Baltic Sea
                                      ---
                                 9.30x10[-2]
                                   mg/kg dw
                             Hüttig et al. (2004)

                                      ---
                                 1.15x10[-1]
                                   mg/kg dw
                             Hüttig et al. (2004)

                                      ---
                                 1.22x10[-1]
                                   mg/kg dw
                             Hüttig et al. (2004)

                                      ---
                                 2.11x10[-1]
                                   mg/kg dw
                             Hüttig et al. (2004)

                                      ---
                                 4.99x10[-1]
                                   mg/kg dw
                             Hüttig et al. (2004)

                             North and Baltic Sea
                                      ---
                                 2.20x10[-2]
                                   mg/kg dw
                           Hüttig and Oehme (2006)

                                      ---
                                 2.30x10[-2]
                                   mg/kg dw
                           Hüttig and Oehme (2006)

                                      ---
                                 3.30x10[-2]
                                   mg/kg dw
                           Hüttig and Oehme (2006)

                                      ---
                                 3.40x10[-2]
                                   mg/kg dw
                           Hüttig and Oehme (2006)

                                      ---
                                 3.70x10[-2]
                                   mg/kg dw
                           Hüttig and Oehme (2006)

                                      ---
                                 3.90x10[-2]
                                   mg/kg dw
                           Hüttig and Oehme (2006)

                                      ---
                                 4.30x10[-2]
                                   mg/kg dw
                           Hüttig and Oehme (2006)

                                      ---
                                 4.30x10[-2]
                                   mg/kg dw
                           Hüttig and Oehme (2006)

                                      ---
                                 4.80x10[-2]
                                   mg/kg dw
                           Hüttig and Oehme (2006)

                                      ---
                                 5.40x10[-2]
                                   mg/kg dw
                           Hüttig and Oehme (2006)

                                      ---
                                 5.80x10[-2]
                                   mg/kg dw
                           Hüttig and Oehme (2006)

                                      ---
                                 6.10x10[-2]
                                   mg/kg dw
                           Hüttig and Oehme (2006)

                                      ---
                                 7.20x10[-2]
                                   mg/kg dw
                           Hüttig and Oehme (2006)

                                      ---
                                 7.60x10[-2]
                                   mg/kg dw
                           Hüttig and Oehme (2006)

                                      ---
                                 7.70x10[-2]
                                   mg/kg dw
                           Hüttig and Oehme (2006)

                                      ---
                                 8.10x10[-2]
                                   mg/kg dw
                           Hüttig and Oehme (2006)

                                      ---
                                 8.50x10[-2]
                                   mg/kg dw
                           Hüttig and Oehme (2006)

                                      ---
                                 8.70x10[-2]
                                   mg/kg dw
                           Hüttig and Oehme (2006)

                                      ---
                                 1.49x10[-1]
                                   mg/kg dw
                           Hüttig and Oehme (2006)

                                      ---
                                 1.49x10[-1]
                                   mg/kg dw
                           Hüttig and Oehme (2006)

                                      ---
                                 1.49x10[-1]
                                   mg/kg dw
                           Hüttig and Oehme (2006)

                                      ---
                                 2.75x10[-1]
                                   mg/kg dw
                           Hüttig and Oehme (2006)

                                      ---
                                 9.10x10[-2]
                                   mg/kg dw
                           Hüttig and Oehme (2005)

                                      ---
                                 4.80x10[-2]
                                   mg/kg dw
                           Hüttig and Oehme (2005)

                                      ---
                                 1.98x10[-1]
                                   mg/kg dw
                           Hüttig and Oehme (2005)

                                      ---
                                 1.31x10[-1]
                                   mg/kg dw
                           Hüttig and Oehme (2005)

                                      ---
                                 1.32x10[-1]
                                   mg/kg dw
                           Hüttig and Oehme (2005)

                                      ---
                                 3.03x10[-1]
                                   mg/kg dw
                           Hüttig and Oehme (2005)

                                      ---
                                 1.53x10[-1]
                                   mg/kg dw
                           Hüttig and Oehme (2005)

                                      ---
                                 1.14x10[-1]
                                   mg/kg dw
                           Hüttig and Oehme (2005)

                                      ---
                                 4.00x10[-2]
                                   mg/kg dw
                           Hüttig and Oehme (2005)

                                      ---
                                 2.70x10[-2]
                                   mg/kg dw
                           Hüttig and Oehme (2005)

                                      ---
                                 1.80x10[-2]
                                   mg/kg dw
                           Hüttig and Oehme (2005)

                                      ---
                                 1.90x10[-2]
                                   mg/kg dw
                           Hüttig and Oehme (2005)

                                      ---
                                 3.00x10[-2]
                                   mg/kg dw
                           Hüttig and Oehme (2005)

                                      ---
                                 3.20x10[-2]
                                   mg/kg dw
                           Hüttig and Oehme (2005)

                                      ---
                                 1.80x10[-2]
                                   mg/kg dw
                           Hüttig and Oehme (2005)

                                      ---
                                 2.40x10[-2]
                                   mg/kg dw
                           Hüttig and Oehme (2005)
                                   Sediment
                                 (Non-marine)
                                    Canada
                                   Lake Erie
                                      ---
                                 6.80x10[-2]
                                   mg/kg dw
                             Tomy and Stern (1999)

                                Lake St Francis
                                    Minimum
                                 7.50x10[-1]
                                   mg/kg dw
                                  EC (2008b)

                                    Maximum
                                      1.2
                                   mg/kg dw
                                  EC (2008b)

                                Czech Republic
                                      NR
                                    Minimum
                                 2.00x10[-3]
                                    mg/kg*
                            Pribylova et al. (2006)

                                     Labe
                                      Sum
                                 1.80x10[-2]
                                   mg/kg dw
                            Pribylova et al. (2006)

                                      Sum
                                 7.30x10[-2]
                                   mg/kg dw
                            Pribylova et al. (2006)

                                  Libis-Labe
                                      Sum
                                      1.6
                                   mg/kg dw
                            Pribylova et al. (2006)

                                    Bilina
                                      Sum
                                 3.10x10[-2]
                                   mg/kg dw
                            Pribylova et al. (2006)

                                  Mala Becva
                                      Sum
                                 1.13x10[-1]
                                   mg/kg dw
                            Pribylova et al. (2006)

                                     Becva
                                      Sum
                                 1.20x10[-1]
                                   mg/kg dw
                            Pribylova et al. (2006)

                                    Morava
                                      Sum
                                 1.93x10[-1]
                                   mg/kg dw
                            Pribylova et al. (2006)

                                     Ohre
                                      Sum
                                 3.08x10[-1]
                                   mg/kg dw
                            Pribylova et al. (2006)

                                      Sum
                                 6.00x10[-1]
                                   mg/kg dw
                            Pribylova et al. (2006)

                                      Sum
                                     5.58
                                   mg/kg dw
                            Pribylova et al. (2006)

                                    Morava
                                      Sum
                                 4.16x10[-1]
                                   mg/kg dw
                            Pribylova et al. (2006)

                                     Dyje
                                      Sum
                                 7.57x10[-1]
                                   mg/kg dw
                            Pribylova et al. (2006)

                                   Drevnice
                                      Sum
                                 8.93x10[-1]
                                   mg/kg dw
                            Pribylova et al. (2006)

                                    Germany
                               Bodensee (middle)
                                     <
                                 5.00x10[-3]
                                   mg/kg dw
                                  IPCS (1996)

                                      ---
                                 7.00x10[-2]
                                   mg/kg dw
                                  IPCS (1996)

                                  River Lech
                                     <
                                 5.00x10[-3]
                                   mg/kg dw
                                  IPCS (1996)

                                      ---
                                 3.25x10[-1]
                                   mg/kg dw
                                  IPCS (1996)

                                    Maximum
                                 7.00x10[-1]
                                    mg/kg*
                              Tomy et al. (1998)

                                  River Rhine
                                      ---
                                 6.00x10[-2]
                                   mg/kg dw
                                  IPCS (1996)

                                      ---
                                 8.50x10[-2]
                                   mg/kg dw
                                  IPCS (1996)

                                      ---
                                 1.40x10[-1]
                                   mg/kg dw
                                  IPCS (1996)

                                    Minimum
                                 1.45x10[-1]
                                   mg/kg dw
                                  IPCS (1996)

                                    Maximum
                                 2.05x10[-1]
                                   mg/kg dw
                                  IPCS (1996)

                             River Elbe at Hamburg
                                    Minimum
                                 1.30x10[-1]
                                   mg/kg dw
                                  IPCS (1996)

                                    Maximum
                                 2.30x10[-1]
                                   mg/kg dw
                                  IPCS (1996)

                                  River Main
                                    Minimum
                                 1.60x10[-1]
                                   mg/kg dw
                                  IPCS (1996)

                                    Maximum
                                 2.60x10[-1]
                                   mg/kg dw
                                  IPCS (1996)

                             Outer Alster, Hamburg
                                      ---
                                 3.70x10[-1]
                                   mg/kg dw
                                  IPCS (1996)

                                    Norway
                                      NR
                                    minimum
                                 5.00x10[-2]
                                   mg/kg dw
                            Petersen et al. (2006)

                                    maximum
                                     3.24
                                   mg/kg dw
                            Petersen et al. (2006)

                                      ---
                                      2.7
                                   mg/kg ww
                             Borgen et al. (2003)

                                      ---
                                  1.14x10[1]
                                   mg/kg ww
                             Borgen et al. (2003)

                                  South China
                               Pearl River Delta
                                    Minimum
                                 8.80x10[-1]
                                   mg/kg dw
                              Chen et al. (2011)

                                    Minimum
                                      1.1
                                   mg/kg dw
                              Chen et al. (2011)

                                    Minimum
                                      1.4
                                   mg/kg dw
                              Chen et al. (2011)

                                    Maximum
                                      1.4
                                   mg/kg dw
                              Chen et al. (2011)

                                    Maximum
                                      3.8
                                   mg/kg dw
                              Chen et al. (2011)

                                     Mean
                                      3.9
                                   mg/kg dw
                              Chen et al. (2011)

                                     Mean
                                  2.10x10[1]
                                   mg/kg dw
                              Chen et al. (2011)

                                    Maximum
                                  3.80x10[1]
                                   mg/kg dw
                              Chen et al. (2011)

                                  Switzerland
                                   Lake Thun
                                    Minimum
                                 5.00x10[-3]
                                   mg/kg dw
                              Iozza et al. (2008)

                                    Maximum
                                 2.60x10[-2]
                                   mg/kg dw
                              Iozza et al. (2008)

                                  Lake Zurich
                                    Maximum
                                 5.00x10[-3]
                                    mg/kg*
                              Tomy et al. (1998)

                                United Kingdom
                                      NR
                                     <
                                 1.00x10[-1]
                                   mg/kg dw
                            Nicholls et al. (2001)

                     South West Region: Grand Union Canal
                                      ---
                                 3.00x10[-1]
                                   mg/kg dw
                            Nicholls et al. (2001)

                                      ---
                                      2.7
                                   mg/kg dw
                            Nicholls et al. (2001)

                                      ---
                                      2.8
                                   mg/kg dw
                            Nicholls et al. (2001)

                     South West Region; Bristol Avon River
                                      ---
                                 5.00x10[-1]
                                   mg/kg dw
                            Nicholls et al. (2001)

                                      ---
                                 6.00x10[-1]
                                   mg/kg dw
                            Nicholls et al. (2001)

                                      ---
                                 8.00x10[-1]
                                   mg/kg dw
                            Nicholls et al. (2001)

                         North East Region: Hull River
                                      ---
                                      1.0
                                   mg/kg dw
                            Nicholls et al. (2001)

                                      ---
                                  1.35x10[1]
                                   mg/kg dw
                            Nicholls et al. (2001)

                                      ---
                                      1.1
                                   mg/kg dw
                            Nicholls et al. (2001)

                        South West Region: Colne River
                                      ---
                                      1.4
                                   mg/kg dw
                            Nicholls et al. (2001)

                                      ---
                                      2.0
                                   mg/kg dw
                            Nicholls et al. (2001)

                       West Midlands Region: Trent River
                                      ---
                                      3.8
                                   mg/kg dw
                            Nicholls et al. (2001)

                                      ---
                                  6.02x10[1]
                                   mg/kg dw
                            Nicholls et al. (2001)

                                      ---
                                  6.51x10[1]
                                   mg/kg dw
                            Nicholls et al. (2001)

                      North West Region: Hornsmill brook
                                      ---
                                      5.6
                                   mg/kg dw
                            Nicholls et al. (2001)

                                      ---
                                  1.25x10[1]
                                   mg/kg dw
                            Nicholls et al. (2001)

                                      ---
                                  1.83x10[1]
                                   mg/kg dw
                            Nicholls et al. (2001)

                         North East Region: Hull River
                                      ---
                                      1.0
                                   mg/kg dw
                            Nicholls et al. (2001)

                                      ---
                                      1.1
                                   mg/kg dw
                            Nicholls et al. (2001)

                                      ---
                                  1.35x10[1]
                                   mg/kg dw
                            Nicholls et al. (2001)

                       East Midlands Region: Idle River
                                      ---
                                  1.62x10[1]
                                   mg/kg dw
                            Nicholls et al. (2001)

                                      ---
                                  4.39x10[1]
                                   mg/kg dw
                            Nicholls et al. (2001)

                      Northumberland Region: Skerne River
                                      ---
                                  1.80x10[1]
                                   mg/kg dw
                            Nicholls et al. (2001)

                                      ---
                                  2.56x10[1]
                                   mg/kg dw
                            Nicholls et al. (2001)

                                      ---
                                  5.84x10[1]
                                   mg/kg dw
                            Nicholls et al. (2001)

                        East Anglia Region: Lark River
                                      ---
                                  3.22x10[1]
                                   mg/kg dw
                            Nicholls et al. (2001)

                                      ---
                                  4.50x10[1]
                                   mg/kg dw
                            Nicholls et al. (2001)

                                      ---
                                  6.04x10[1]
                                   mg/kg dw
                            Nicholls et al. (2001)

                                 United States
                                 Detroit River
                                      ---
                                 6.80x10[-2]
                                   mg/kg dw
                              Tomy et al. (1999)

                               Sugar Creek, Ohio
            Reported as trace with range of 1.5-5; used the average
                                 3.25x10[-3]
                                   mg/kg dw
                                 USEPA (1988)

            Reported as trace with range of 1.5-5; used the average
                                 3.25x10[-3]
                                   mg/kg dw
                                 USEPA (1988)

                                      ---
                                 6.80x10[-3]
                                   mg/kg dw
                                 USEPA (1988)

                                      ---
                                 8.20x10[-3]
                                   mg/kg dw
                                 USEPA (1988)

                                      ---
                                 7.60x10[-1]
                                   mg/kg dw
                                 USEPA (1988)

                                      ---
                                  2.10x10[1]
                                   mg/kg dw
                                 USEPA (1988)

                                      ---
                                  3.40x10[1]
                                   mg/kg dw
                                 USEPA (1988)

                                      ---
                                  5.00x10[1]
                                   mg/kg dw
                                 USEPA (1988)
Note:
NR: Not recorded. Location description was not provided in the study.
--: Single sample value reported above the detection limit; therefore, no data qualifier required.
1.    All values provided in the table above represent total MCCP and not individual MCCP isomers
2.    In some cases, the minimum values in the table are preceded by "<". This indicates that the value reported in article was reported as a non-detect. In such cases, one half of the lowest reported detection limit was compiled as the `minimum' reported monitoring data
3.    dw.  -  dry weight and ww.  -  wet weight

Biosolids and Soil
CPs are detected more frequently and at higher concentrations in treated sewage sludge (i.e., biosolids) than in soil. MCCP concentrations ranged from 5.00 x 10[-5] to 9.70 x 10[3] mg/kg dw in sludge and from 1.5 x 10[-2] to 8.5 x 10[-2] mg/kg dw in soil. It is unclear if the difference in MCCP concentrations in sludge and soil is related to the smaller sample sizes for these media compared to the typically larger data sets available for water and sediment. To determine the most reliable studies for its consideration, EPA used the following criteria: designation of specific MCCP chain length and the appropriate analytical methodology. Thus, EPA/OPPT did not use information from other published studies reporting measured CPs in sludge and soil because they did not distinguish the CPs measured (e.g., Nicholls et al., 2001); although they reported total CP concentrations at much lower levels ranging from 3.00 x 10[-5] to 2.3 mg/kg dw. .

Stevens et al. (2003) measured MCCP concentrations in sludge samples obtained from 14 WWTPs in the UK. MCCP concentrations ranged from 3.00 x 10[1] to 9.70 x 10[3] mg/kg dw. The authors concluded that these very high concentrations were likely the result of releases from numerous and ongoing diffuse sources.

Although risk to terrestrial species was not calculated, EPA/OPPT notes that the lowest and highest reported biosolid and soil concentrations (5.00 x 10[-5] to 9.70 x 10[3] mg/kg dw and 1.5 x 10[-2] to 8.5 x 10[-2] mg/kg dw, respectively) represents a very large range (up to eight orders of magnitude (Table D-3).

Table Apx_D-1-3: Biosolid and Soil Concentrations of MCCPs
Location
                                     Media
                                 Concentration
                                     Units
                                  References

                                    Minimum
                                    Maximum

Switzerland
                                     Soil
                                1.5 x 10[-2]
                                 8.5 x 10[-2]
                                   mg/kg dw
                                 Iozza (2010)
China
                                     Soil
                                 2.1 x 10[-6]
                                1.53 x 10[-3]
                                   mg/kg dw
                              Wang et al. (2013)
Czech Republic
                                 Sewage Sludge
                                7.36 x 10[-1]
                                     2.30
                                   mg/kg dw
                            Pribylova et al. (2006)
United Kingdom
                                 Sewage Sludge
                                 3.00 x 10[1]
                                 9.70 x 10[3]
                                   mg/kg dw
                             Stevens et al. (2003)
United States
                                 Sewage Sludge
                                5.00 x 10[-5]
                                5.00 x 10[-5]
                                   mg/kg dw
                            Pribylova et al. (2006)

Biota
EPA/OPPT reviewed available published literature and summarized MCCP concentrations in tissues of aquatic and terrestrial biota (Table D-4). Measured tissue concentrations for aquatic biota ranged from ND to 2.63 mg/kg ww (i.e., beluga whales, seals, rainbow trout, carp, mackerel, arctic char, mussels, crustaceans, and plankton) and ranged from 5.00 x 10[-3] to 3.70 x 10[-1] mg/kg ww in terrestrial biota. The concentrations measured in the terrestrial studies did not designate the specific CP congener groups measured.

As a result of EPA/OPPT's evaluation, MCCPs were found in organisms across many different trophic levels indicating widespread environmental contamination (Table D-4). The data were insufficient for EPA/OPPT to draw conclusions about trends based on region, species, time, or other factors.

While EPA/OPPT determined the concentrations of MCCPs in aquatic and terrestrial biota range from ND to 2.63 mg/kg ww and from 5.00 x 10[-3] to 3.70 x 10[-1] mg/kg ww, respectively, in this assessment, EPA/OPPT did not use tissue concentrations to determine risks of potential concern for biota. Rather, it used the risk quotient (RQ) method and the conventional PMN approach as described in Section 6

Table_Apx D-1-4: MCCP Biota Concentrations of MCCPs
 Location
                               Media Description
                                    Minimum
                                     Units
                                 Min Reference
                                    Maximum
                                     Units
                                 Max Reference

                                 Aquatic Biota
 Australia
                                 Invertebrates
                                  2.32x10[-5]
                                    mg/kg lw
                             Kemmlein et al. (2002)
                                  3.05x10[-5]
                                    mg/kg lw
                             Kemmlein et al. (2002)
 Canada
                                    Mammals
                                  5.45x10[-7]
                                    mg/kg ww
                              Bennie et al. (2000)
                                  8.00x10[-5]
                                    mg/kg ww
                              Bennie et al. (2000)

                                      Fish
                                  2.57x10[-7]
                                    mg/kg ww
                              Bennie et al. (2000)
                                      2.63
                                    mg/kg ww
                               Muir et al. (2000)

                                 Invertebrates
                                     ND[1]
                                    mg/kg ww
                                   EC (1993)
                                     ND[1]
                                    mg/kg ww
                                   EC (1993)

                                     Total
                                     ND[1]
                                    mg/kg ww
                                   EC (1993)
                                      2.63
                                    mg/kg ww
                               Muir et al. (2000)
 Europe
                                      Fish
                                  7.00x10[-3]
                                    mg/kg ww
                               Reth et al. (2006)
                                  4.70x10[-2]
                                    mg/kg ww
                               Reth et al. (2006)
 North Sea/Baltic Sea Region[2]
                                      Fish
                                     ND[3]
                                    mg/kg ww
                                   IVL (2009)
                                  2.6x10[-1]
                                    mg/kg ww
                               Reth et al. (2005)
 United States
                                      Fish
                                  2.90x10[-3]
                                    mg/kg ww
                             Tomy and Stern (1999)
                                  9.04x10[-1]
                                    mg/kg ww
                             Tomy and Stern (1999)

                                 Invertebrates
                                  3.50x10[-3]
                                    mg/kg ww
                                  USEPA (1988)
                                  1.70x10[-1]
                                    mg/kg ww
                                  USEPA (1988)

                                     Total
                                  2.90x10[-3]
                                    mg/kg ww
                             Tomy and Stern (1999)
                                  9.04x10[-1]
                                    mg/kg ww
                             Tomy and Stern (1999)
 United States / Canada
- Great Lakes
                                      Fish
                                  1.80x10[-3]
                                    mg/kg ww
                               Muir et al. (2003)
                                  1.10x10[-1]
                                    mg/kg ww
                               Muir et al. (2003)

                                 Invertebrates
                                  2.40x10[-3]
                                    mg/kg ww
                                   EC (2008a)
                                  1.60x10[-2]
                                    mg/kg ww
                               Muir et al. (2003)

                                     Total
                                  1.80x10[-3]
                                    mg/kg ww
                               Muir et al. (2003)
                                  1.10x10[-1]
                                   mg/kg ww.
                               Muir et al. (2003)
 Terrestrial Biota
 Europe
                                     Birds
                                  5.00x10[-3]
                                    mg/kg ww
                               Reth et al. (2006)
                                  3.70x10[-1]
                                    mg/kg ww
                               Reth et al. (2006)
 Notes:
 Summary values represent total MCCP and not individual MCCP isomers.
 [1] MCCPs were not detected in Invertebrates from Canada. Detection limit = 4.0 x 10[-7] mg/kg; (1/2) DL = 2.0 x 10[-7] (EC, 1993).
 [2] North Sea/Baltic Sea Region includes the following countries: Estonia, Latvia, Lithuania, Norway, Poland, and Sweden.
[3] The minimum MCCP concentration value for fish from the North Sea/Baltic

             LCCP MONITORING DATA
Kemmlein et al. (2002) optimized and tested the carbon skeleton reaction gas chromatography analytical method to analyze environmental samples for CPs. The optimized method was used for marine sediments, mussels and crabs taken from an area influenced by a CP manufacturer in Yarraville, Australia. LCCP (C18-20) concentrations in marine sediment ranged from 1.02 x 10[-1] to 4.31 x 10[-1] mg/kg dw (Table_Apx D-2), those in mussels ranged from 4 x 10[-1] to 1.9 mg/kg lw, and those in crab ranged from 3 x 10[-2] to 4.4 mg/kg lw. The results presented in this paper show that bioaccumulation is evident. The mussel samples contained approximately two times and crab tissue around six times the concentration of CPs found in the most contaminated sediment sample. No other adequate studies were found to characterize LCCP concentrations in surface water, fresh water sediment or soil.

Table_Apx D-2-1: Marine Sediment Concentrations of LCCPs
                                     Media
                                    Country
                                   Location
                                   Comments
                                 Concentration
                                     Units
                                  References

                            City, State or Province

                                   Sediment
                                   (Marine)
                                   Australia
                                      NR
                                      Sum
                                 1.02x10[-1]
                                   mg/kg dw
                            Kemmlein et al. (2002)

                                      Sum
                                 1.28x10[-1]
                                   mg/kg dw
                            Kemmlein et al. (2002)

                                      Sum
                                 3.04x10[-1]
                                   mg/kg dw
                            Kemmlein et al. (2002)

                                      Sum
                                 4.31x10[-1]
                                   mg/kg dw
                            Kemmlein et al. (2002)
Notes:
    Values provided in the table above represent total LCCP (C18-20) and not individual isomers.
    dw  -  dry weight

Table_Apx D-2-2: LCCP Biota Concentrations of LCCPs
                                     Media
                                    Country
                                   Location
                                    Minimum
                                    Maximum
                                     Units
                                  References

                            City, State or Province

                                 Aquatic Biota
                                   Australia
                                      NR
                                 2.89x10[-6]
                                 6.90x10[-6]
                                   mg/kg lw
                            Kemmlein et al. (2002)
Notes:
    Minimum and Maximum concentrations provided in the table above represent total LCCP (C18-20) and not individual isomers.
    lw  -  lipid weight

ENGINEERING (ChemSTEER) REPORTS ON P-12-0282, P-12-0283 and P-12-0284
 (Used for both identifying potential releases to the environment and for estimated occupational exposures.)

INITIAL REVIEW ENGINERING REPORT

P-12-0282
Post Focus Review Draft 10/20/2016

This section provides details on EPA's original engineering assessment of occupational exposure and environmental releases from 2012 as well as the Expanded EPA assessment from 2016.

ENGINEER: Macek/Choudhary
PV (kg/yr): 11,749,910

Revision Notes/Assessment Overview: 07/26/2016 Update: This IRER was revised to utilize the methodologies from 2 CP assessments in 2015. Industry comments were also used in this assessment. Changes include: providing several release scenarios for all uses (using WWT removal efficiencies of 50, 70 and 99% as well as assuming monthly and quarterly release of container residuals per industry practices). Occupational assessments remained the same as in the previous version of this IRER. However dermal assessments increase as a result of a larger hand surface are used as default in dermal exposure calculations. Note: This is the CEB Review version of the Standard Review Draft. On February 7, 2012, the U.S. Environmental Protection Agency (EPA_ and the U.S. Department of Justice announced a settlement agreement with Dover Chemical Corporation resulting from an unauthorized manufacture of chemical substances at facilities in Dover, Ohio and Hammond, Indiana. As a result of the settlement, EPA has received several premanufacture notices (PMN) from Dover Chemical Corporation for various existing medium-chain and long-chain chlorinated paraffins (MCCP and LCCP) products. The review of these PMNs is complimented by EPA's current initiatives to conduct a review of the environmental and health impacts of MCCPs and LCCPs as part of EPA's Work Plan Chemicals Initiative. /// For each substance, Dover Chemical has provided detailed information for the manufacturing and downstream processing and use as part of the PMN submissions. Prior to receiving the submissions, EPA conducted a literature review on release and exposure data for the manufacture and downstream processing and use of chlorinated paraffins as a means to supplement information provided by Dover Chemical and/or fill any data gaps that may exist. Literature sources that have been reviewed include: 1) previous EPA asessments on chlorinated paraffins; 2) foreign risk assessments on MCCPs and LCCPs (e.g., EU risk assessments); 3) EPA/OPPT Generic Scenarios; 4) OECD Emission Scenario Documents; and 5) Toxics Release inventory data. Data provided by Dover Chemical, data identified in the literature review, and EPA/OPPT standard models were reviewed and the best available data were used to assess environmental releases and occupational exposures.

SUBMITTER: Dover Chemical

USE: Generic uses MCCP: 1) Forty-three percent of the notification substances are used as a flame retardant/plasticizer in polymers. Typical concentration in the plastic is 12-30%. 2) Thirty percent of the notification substance is used as a lubricant in metal working fluids (MWFs). The notification substance is blended into the MWFs at 5-10%. 3) Two percent of the notification substances is used as lubricants in automotive. The notification substances is blended into the lubricant at 4%. [20% consumer uses]. 4) Twenty-four percent of the notification substance is used as a flame retardant/plasticizer in rubber. Typical total concentration of flame retardant/plasticizer in the rubber is 1-10%, with a media value of 5.5%. 5) One-half of one percent of the notification substances are used as plasticizer in solvent based paints, adhesives and sealants. The paints are specialty paints for applications where weather resistant coatings are needed, such as steel construction, industrial flooring, road marking, and swimming pools. The notification substance is blended into the paints at 5-15%. [0.1% consumer uses as sealants in windows] and 6) One-half of one percent of the notification substances are applied as a flame retardant/waterproofers to textiles. The notification substance products are added at 5% of the textile coating finishing solution.