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Description of key information

TOXICOKINETIC ASSESSMENT

Physico-chemical Properties

Boiling Point: Not determinable; decomposes at temperatures ≥100°C.

Water Solubility: <0.6 mg/L at 20°C

N-Octanol/Water Partition Coefficient: LogPow =  ≥5.6 at 35°C

Vapour Pressure: 8.5 Pa at 25°C

Surface Tension: Not surface active based on solubility

Toxicological Data

Acute toxicity in rat:  the substance is not well tolerated in rats following acute oral with two mortality observed within 4 hours post exposure. Clinical sings observed in deceased animals consisted of hunched posture, uncoordinated movement, respiratory abnormalities, hypothermia and/or ptosis at 2000 mg/kg bw/day. Recovery was observed in the only surviving animal from day 5 post treatment. Both weights were comparable with control groups and no abnormal macroscopic was observed. The reported LD50 of >300 - <2000 mg/kg bw/day (OECD 423; 2004). No overt toxicity, clinical signs death or abnormality at necropsy amongst animals following acute dermal exposure in rats. Therefore, the reported LD50 of 2000 mg/kg bw/day concluded under the condition of the study (OECD 402, 2004).

Local Toxicity:  The substance was not and irritant to the eye and skin in rabbits (OECD 405 and OECD 402; 2004). Furthermore, no sensitisation reactions were observed following an exposure via the local lymph node assay (OECD 429, 2004).  In both dermal exposures, there were no signs of systemic toxicity, no abnormal macroscopic observations or dermal reactions through the test period. Although, one mortality was observed in one animal treated with 100% test substance in the OECD 429 study.

There are several sub-acute studies conducted on the substance and the long-term systemic hazard assessment is based on a sub-acute toxicity study conducted on rats in accordance with OECD 407 under GLP (2012). Dose selection rationale was based on two 7-day screening studies in which the animals were dosed with 50, 250, and 1000 mg/kg bw/day (5 animals per sex and dose) or 1, 5, and 20 mg/kg bw/day (3 male animals per dose) test substance. Death and moribund animals (both sexes) were found in the 250 and 1000 mg/kg bw dose group. High AST and liver and kidney weights were observed in both sexes of the 50 mg/kg bw/day group. 1 male of this group showed discoloration of the heart, dark reddish macule of the lung, low values of body weight, food consumption and reticulocytes, and high values of platelets and monocytes. Effects on body weight and food consumption was also observed in 1 female of the 50 mg/kg bw dose group. Discoloration of the heart was also observed in dead animals of the 250 and 1000 mg/kg bw/day groups. No treatment-related changes were observed in the 1, 5, and 20 mg/kg bw/day groups. Thus 40 mg/kg bw/day was set as the high dose level in the main study (OECD 407) expecting that there would be no death or some toxicity change.

In the main study, the substance was administered to rats by oral gavage at dose levels of 2, 10 and 40 mg/kg bw/day with the inclusion of satellite and control groups. The substance was well-tolerated by the animals without premature deaths.  At 40 mg/kg bw/day, haematological changes consistent of high monocytes values in both sexes persisting throughout recovery. At this dose high values of platelets and low values of basophils and the ratio were noted (males, end of recovery period). Furthermore, high values of Aspartate transferase (AST) in both sexes, Alanine transferase (ALT) and inorganic phosphorus in males and low levels of glucose in males up to end of dosing were noted, all considered non-adverse and within historical control range.  In addition to the above, high values or tendencies of absolute and relative heart (both sexes) and kidney weights (females) persisted throughout recovery. Degeneration/necrosis of myocardial cell and inflammatory cellular infiltration in the myocardium in all animals after dosing period, fibrosis in the myocardium after the recovery period (1/5 males, 1/5 females) were noted in the heart. Further degeneration/necrosis (myocardial cell around the vein) and inflammatory cellular infiltration in the myocardium around the vein (2/5 males, 2/5 females) were noted in the lungs. At 10 mg/kg bw/day, haematological changes consisted of high platelets in male with reversal observed during recovery, prolongation of prothrombin time (PT), partial thromboplastin time (PTT) and high potassium values which were all within historical control values and as such considered non-treatment related. Mild and focal inflammatory cellular infiltration in the myocardium (2/5 males, 1/5 females) at the end of the dosing period and in 1/5 males after the recovery period, also observed in 3/5 control group throughout recovery. At 2 mg/kg bw/day, high eosinophil ratio males at the end of the dosing period (no dose-response correlation).  Based on the condition of the study, the no observed adverse effect level (NOAEL) was considered to be 10 mg/kg bw/day and based on the observed effects on the organs, the substance met the criteria for classification for specific target organ toxicity - repeated exposure (STOT-RE Category 2) in accordance with Regulation (EC) No 1272/2008 (CLP). 

In the screening study OECD 421, the animals were exposed at up to 20 mg/kg bw/day of the substance without including recovery group.  Mortalities were observed at high dose groups, i.e. 2 dead females on day 1 and 2 of lactation with edema in the lung observed at necropsy.  At 20 mg/kg bw/day, moderate and and diffuse degeneration/necrosis in the myocardial cell and moderate and diffuse inflammatory cellular infiltration in the myocardium were noted in the dead dams. In addition, mild/moderate and diffuse fibrosis in the myocardium was noted in the dams.

There were no effects on reproductive performance, mating, estrous cycle, fertility with all gestation lengths, however, changes of an uncertain relationship to treatment were seen in the ovary of females at all dose groups. Low values of birth index were noted in 3 dams of the 20 mg/kg bw/day group (75%, 71.43%, and 72.73%) which were within historical control range and therefore not toxicologically related. No treatment related effects were observed in mid and low dose throughout the study.  It is concluded that the NOAEL was 20 mg/kg/day for reproductive performance and developmental toxicity and 4 mg/kg bw/day for systemic toxicity. Based on the observed effects on the organs, the substance met the criteria for classification for specific target organ toxicity - repeated exposure (STOT-RE Category 2) in accordance with Regulation (EC) No 1272/2008 (CLP). 

Bioaccumulation data: the bio-concentration factor (BCF) of component 1 in the substance at concentration of 0.15 mg/L and 1.5 mg/L on zebra fish (danio rerio) was determined using the semi-static bioaccumulation method lasting 28 days. The BCF of 0.648 and 3.611 for nominal concentrations 0.15 mg/L and 1.5 mg/L, respectively was reported. This is below the BCF cut off value of 2000 to be considered bioaccumulative and therefore the substance is considered non-bioaccumulative.

Absorption

The substance has a molecular weight of 452.59 g/mol, vapor pressure of 8.5 Pa at 25°C, Log P of  5.6 at 35°C with water solubility of the lowest component at 0.6 mg/l and it is not considered to be surface active.   These physicochemical properties are indicative of potential absorption by oral route only with uptake via intracellular pathway.  Intake from the intracellular pathway exits through the basolateral membrane into the portal blood would results into the liver. Theoretically, this route of uptake is expected to result into fast pass metabolism meaning that the concentration of the parent substance is reduced before reaching systemic circulation.  However, based on the structure and functional group of this compound, it is expected to enter intergalactic circulation upon uptake into the liver.  Enterohepatic circulation is associated with multiple peaks and longer apparent half-life in a plasma concentration-time profile. This will potentially amplify the effect of parent compound and metabolites, based on the effect it will have on apparent distribution and potential clearence.  Although similar absorption pattern is expected via inhalation, the substance is not volatile with reported vapor pressure of 8.5 Pa at 25°C means bioavailability via this route is limited. Based on the high Log P of  5.6, high molecular weight and not being surface active (surface tension 54.5 mN/m), means dermal absorption is limited since transfer of the substances between the stratum corneum and the epidermis is restricted. Therefore, overall uptake via this route is slightly reduced as demonstrated by the lack of toxicity observed following exposure via in vivo dermal route.

Distribution

Based on the physicochemical properties, the substance is expected to be distributed into lymphoid tissues or metabolic organs (Kidneys, liver and thyroid) and the GI track. Absorbed substance via the intracellular and active pathway would result into the liver which enter enterohepatic circulation into Hilary recycling and reabsorption into the small intestine. Unabsorbed components will most likely remain  in the GI track or bind to serum protein resulting into other tissue such as the heart and lungs. This is supported by observed effects such as increase liver and kidney weights, degeneration/necrosis as well as fibrosis observed in the heart and lungs following repeated exposure to substances. A higher concentration is expected in the liver compare to serum concentration as demonstrated by the increase AST and ALT.

Metabolism

The C-Cl and C-F bond is very strong and is expected to remain stable even the presence of acid, base, oxidant or reluctant. As such the uptake via intracellular pathway  result into breakdown of the substance. Although limited, potential for metabolic reaction via phase I and II metabolic enzymes in the gastrointestinal (GI) track and liver could ocure. Absorbed and unabsorbed substance is expected to undergo metabolism in the liver and gut respectively. This is through hydrolysis of the esters via esterase into chloropropenoic acid  and tridecafluorooctyl alcohol derivatives which will then get conjugated via glucuronosyl transferases (UGTs) and acyl-CoA enzymes into more soluble metabolites will be excreted via urine and bile. This is supported by the observed centrilobular hepatocyte hypertrophy the liver which was associated with hepatic enzyme induction and decrease in thyroid hormones following repeated exposure to the substance in rats.

Excretion

Based on the absorption, distribution and potential metabolic pathways highlighted coupled with available systemic data, the substance will most likely be excreted via bile, faces and to a small extend in urine. The intracellular pathways uptake would most likely be eliminated via bilary recreation and feces. Unabsorbed proption will most likely remain intestinal tract which would be excreted via both biliary excretion or feces.

Conclusion

Based on the physicochemical properties of this substance the potential for bioaccumulation of the substance is expected. However, accumulation was not observed at the primary site of exposure (the gut) as demonstrated in the long-term studies in OECD 420, 407 and OECD 421. Furthermore, the bioconcentration factor (BCF) in zebra fish was reported as 0.648 and 3.611, much lower than the cut of value of 2000 for substance considered bioaccumulative, although some specific target organ toxicity in the heart, lung, kidney and liver in sub-acute studies were reported. These consisted of degeneration/necrosis (myocardial cell around the vein) and inflammatory cellular infiltration in the myocardium around the vein (2/5 males, 2/5 females) were noted in the lungs. Discoloration of the heart, dark reddish macule of the lung, high values or tendencies of absolute and relative heart, liver and kidney weights  were observed. While the high liver weight could be considered an adaptive response since it was associated with hepatic enzyme induction i.e. high values of AST (both sexes), ALT (males), and inorganic phosphorus (males) and low levels of glucose (males). and decrease in thyroid hormones. Prolongation of prothrombin time (PT), partial thromboplastin time (PTT) and high potassium are usually associated with liver toxicity. It can be considered an indication of entrohepatic circulatory effects based on the recycling of the substance into the liver.  The result of this pathway would ensure longer half-life of the substance systemically and most likely account for the systemic toxicity observed following sub-acute exposure.  It can be concluded that the bioaccumulation of the substance if any, is very low however, based on the prolonged half-life as a result of enterohepatic circulation, it can be concluded that the toxicokinetic of the substance may pose some significant toxicological concern such as targeted organ toxicity in a long term exposure.

Key value for chemical safety assessment

Bioaccumulation potential:
low bioaccumulation potential
Absorption rate - oral (%):
100
Absorption rate - dermal (%):
100
Absorption rate - inhalation (%):
100

Additional information