Registration Dossier

Administrative data

Description of key information

Oral: 3.6 mg a.i./ kg bw/day, LOAEL for male rats (liver necrosis). OECD Guideline GLP study in rats with Zonyl surrogate administered for 90-days. NOAEL for liver effects 21.4 mg a.i./kg BW/day for female rats, LOAEL for male rats 3.6 mg a.i./kg BW/day. Classification for specific target organ toxicity is proposed.  Reliability = 2.
Dermal: 357 mg a. i. /kg bw/day, a NOAEL for liver enzyme elevation was determined based on the observance of necrosis in the oral study, OECD Guideline 410, GLP study in male rats with surrogate administered for 28-days. NOAEL for liver enzyme elevation observed at administered dose of 1000 mg aqueous dispersion /kg BW/day. Reliability = 2.
Inhalation: 1.2 mg/m³ (total solids), NOAEL. OECD 412, GLP 2-week study in male and female rats. Minimal inflammation and minimal to mild mineralization of the U-shaped cartilage in rats exposed to 5.2 mg/m³ (total solids). Reliability = 2.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Dose descriptor:
LOAEL
3.6 mg/kg bw/day
Study duration:
subchronic
Species:
rat

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Dose descriptor:
NOAEC
1.2 mg/m³
Study duration:
subacute
Species:
rat

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion
Dose descriptor:
NOAEL
357 mg/kg bw/day
Study duration:
subchronic
Species:
rat

Additional information

Studies conducted on Zonyl were used as a read across for The Notified Substance (TNS). Zonyl is representative of the composition of TNS. It is a comparable mixture of mono, bis, pyro/poly and trifluoroalkyl phosphates as ammonium salts but which varies in carbon chain length and percentage composition. The carbon chain length varies from 4-12+ i. e. the repeating unit F(CF2) m where m = 4,6,8,10,12+ though m=6 and m=8 dominate the composition on a per weight percentage. As such it is expected that certain properties can be read-across. In this case, the Zonyl surrogate (~35.5% solids, ~ 20% isopropanol, and ~40-45% water) was the test substance administered. A 90-day oral rat study was performed at doses of 10, 60, or 300 mg/kg/day. Based on hepatocellular necrosis observed after a 90-day oral exposure in the 10 and 60 mg/kg/day groups as well as after one and three months of recovery in male rats of all dose levels, a NOEL was not determined for male rats. The NOEL for female rats was 60 mg/kg/day, based on elevated liver enzymes and thyroid gland hypertrophy observed in female rats administered 300 mg/kg/day. Since the Zonyl test material was ~35.5% solids, the adjusted NOEL is 36 mg a.i./kg bw/day for female rats and a NOEL was not determined for male rats. The LOEL was determined to be 3.6 mg a.i./kg bw/day for male rats based on mild hepatocellular necrosis observed among males treated with 3.6 or 36 mg a.i./kg bw/day at the end of the 90-day dosing period. The repeated dose toxicity potential of the TNS itself was assessed by administering 0, 5, 25, and 125 mg a.i. /kg bw/day via gavage to SD rats for 28 days. Main study animals (10 rats/sex/group) were sacrificed at the end of the dosing period.There were no test substance-related adverse effects on in-life parameters, clinical pathology, gross observations, organ weights, and microscopic findings. The increase in liver (males and females) and kidney (males) weights at 125 mg/kg/day as compared to controls noted at the end of exposure period was not considered adverse as there were no correlative microscopic findings. There were no organ weight changes following the recovery period. The NOAEL was 125 mg/kg/day. This study only provides supporting evidence that the effects of TNS are mild due to the congruent target organ effect on the liver. 28-days was not a sufficient dosing period to achieve the mild liver necrosis observed in the 90-day study with the analog material.

The NOAEC for repeated inhalation exposure (two-week inhalation study in rats) was 1.2 mg/m3, respirable particulate, based on histopathological findings in the respiratory tract. In a 28-day dermal study in rats, the NOEL was 100 mg/kg/day, based on the presence of mildly increased liver enzymes at 1000 mg/kg/day. Since the Zonyl material was 35.5% solids the adjusted LOEL is 357 mg a.i./kg bw/day and the NOEL is 35.7 mg a.i./kg bw/day.

An additional study was performed on a metabolite of TNS (sodium perfluoroheptanoate). In a GLP compliant 90-day study with reproductive and developmental toxicity screening, mice were exposed to the test substance via gavage at doses of 0, 0.5, 10, or 50 mg/kg/day. Adverse effects in the liver (hepatocellular hypertrophy with hepatocellular necrosis) were observed starting from the lowest dose level of 0.5 mg/kg bw/day. Associated changes in clinical chemistry included higher ALP, ALAT, and triglyceride values in high-dose males and higher ALP and triglyceride values in high-dose non-mated females, and higher relative liver weights at 10 and 50 mg/kg bw/day in both sexes. These changes were considered to be adverse. Therefore, the lowest dose level of 0.5 mg/kg bw/day was considered to be the LOAEL for systemic toxicity in the parental generation.


Repeated dose toxicity: via oral route - systemic effects (target organ) digestive: liver

Repeated dose toxicity: inhalation - systemic effects (target organ) respiratory: larynx

Repeated dose toxicity: dermal - systemic effects (target organ) digestive: liver

Justification for classification or non-classification

After a 90-day oral exposure and/or after one and three months of recovery, mild hepatocellular necrosis was observed in male rats at all dose levels (10, 60, or 300 mg/kg bw/day). A NOEL was not determined for male rats. The NOEL for female rats was 60 mg/kg/day, based on elevated liver enzymes and thyroid gland hypertrophy observed in female rats administered 300 mg/kg/day. Since the Zonyl test material was ~35.5% solids, the adjusted NOEL is 36 mg a. i. /kg bw/day for female rats and a NOEL was not determined for male rats. The LOEL was determined to be 3.6 mg a. i. /kg bw/day for male rats based on mild hepatocellular necrosis observed among males treated with 3.6 or 36 mg a. i. /kg bw/day at the end of the 90-day dosing period. The histopathological observations were graded as minimal or mild and were not correlated with overt toxicity. Consistent with the CLP guidance minimal necrosis at all dose levels without the observation of any multifocal or moderate necrosis would be considered as a very mild effect using a weight of evidence approach. This conclusion is further supported by the results of the 28-day study on the TNS which resulted in only mild liver and kidney weight increases after 28-days of dosing up to 125 mg a. i. /kg bw/day. Therefore, the following classification applies, Category 2 repeated-dose specific target organ toxicity (STOT repeated) classification has been assigned for effects on the liver with repeated oral administration according to EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No. 1272/2008.