Tetraethylammonium heptadecafluorooctanesulphonate

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.01 mg/m³

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.08 mg/m³

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.01 mg/m³

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.08 mg/m³

DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.003 mg/kg bw/day

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.003 mg/kg bw/day

DNEL related information

Additional information - workers

Tetraethylammonium perfluorooctanesulfonate (CAS 56773-42-3)

(PFOS)

DNELs

Repeated dose toxicity

A subchronic oral capsule study in monkeys and a dietary chronic toxicity and carcinogenicity study in rats was evaluated for the derivation of DNELs of PFOS

Basis for delineation of the DNEL:

Study (monkey study)

Repeated dose study

monkey, male, female,

subchronic oral capsule study for 182 days

monkey: 0 (control), 0.03, 0.15 or 0.75 mg/kg bw/d – male, female

via capsule

NOAEL, Effects

NOAEL = 0.15 mg/kg bw/d (male and female monkeys)

Effects:

Significant effects occurred only in the 0.75 mg/kg/day dose group and included compound related mortality in 2 of 6 male monkeys, decreased body weights, increased liver weights, lowered serum total cholesterol, lowered triiodothyronine concentrations (without evidence of hypothyroidism), and lowered estradiol levels. Hepatocellular hypertrophy and lipid vacuolation were present at term in the 0.75 mg/kg/day dose group.

Reference:

Seacat AM, Thomford PJ, Hansen KJ, Olsen GW, Case MT, Butenhoff JL (2002)

Subchronic toxicity studies on perfluorooctanesulfonate potassium salt in cynomolgus monkeys

Toxicological Sciences 68, 249-264 (2002)

Reference

Study (rat study)

Repeated dose study

104-Week Dietary Chronic Toxicity and Carcinogenicity Study

rat, male, female,

chronic oral diet study for 104 weeks

rat: 0 (control), 0.5, 2, 5 or 20 ppm

– ca. 0, 0.025, 0.1, 0.25 or 1 mg/kg bw/d

male, female

via diet

Effects, NOAEL

NOAEL = ca. 0.025 mg/kg bw/d (male rats)

NOAEL = ca. 0.1 mg/kg bw/d (female rats)

Effects:

Based on the pathological findings in the liver, (centrilobular hypertrophy, centrilobular eosinophilic hepatocytic granules, centrilobular hepatocytic pigment, or centrilobular hepatocytic vacuolation ) the no-observed-adverse-effect level (NOAEL) for PFOS is considered to be 0.5 ppm in male rats and 2 ppm in female rats; the low observed-adverse-effect level (LOAEL) is 2 ppm in male rats and 5 ppm in female rats.

Reference:

3M Company (2002)

104-Week Dietary Chronic Toxicity and Carcinogenicity Study with Perfluorooctane Sulfonic Acid Potassium Salt (PFOS) in Rats

1.) Long-term tocixity – systemic effects (workers) from the monkey study

Long-term oral or dermal route-systemic effects (worker) using default extrapolation factors:

NOAEL(monkey) from a subchronic toxicity study: 0.15 mg/kg bw/day

Penetration oral compared to dermal (both assumed 100%) 1

For interspecies differences monkey vs. human: 2

For remaining interspecies differences: 2.5

For intraspecies differences in workers: 5

For extrapolation of exposure duration subchronic to chronic: 2

For reliability of dose-response: 1

For quality of whole database: 1

Overall factor: 50

Worker DNEL long-term for oral or dermal route-systemic: 0.0030 mg/kg bw/day

1.) Long-term toxicity – systemic effects (workers) from the rat study

Long-term oral or dermal route-systemic effects (worker) using default extrapolation factors:

NOAEL(rat) from a chronic toxicity study: 0.025 mg/kg bw/day

Penetration oral compared to dermal (both assumed 100%) 1

For interspecies differences rat vs. human: 4

For remaining interspecies differences: 2.5

For intraspecies differences in workers: 5

For extrapolation of exposure duration: 1

For reliability of dose-response: 1

For quality of whole database: 1

Overall factor: 50

Worker DNEL long-term for oral or dermal route-systemic: 0.0005 mg/kg bw/day

Long-term inhalation route-systemic effects (worker) from the monkey study:

NOAEL(monkey) from a subchronic toxicity study: 0.15 mg/kg bw/day

Correction of the starting point according TGD Figure R.8-3:

Corrected inhalatory NAEC = Oral NOAELhuman : 2 (Allometric scaling factor for different species as compared to humans) = NAEL human x 70 kg bw : 10 m³ person

=> NAEC worker = 0.525 mg/m³

For interspecies differences monkey vs. human: 1 (according TGD Table

R.8-4. already covered by correction of starting point)

For remaining interspecies differences: 2.5

For intraspecies differences in workers: 5

For extrapolation of exposure duration subchronic to chronic: 2

For reliability of dose-response: 1

For quality of whole database: 1

Overall factor: 25

Worker DNEL long-term for inhalation exposure: 0.021 mg/m³

Long-term inhalation route-systemic effects (worker):

NOAEL(rat) from a subchronic toxicity study: 0.025 mg/kg bw/day

Correction of the starting point according TGD Figure R.8-3:

Corrected inhalatory NOAEC = Oral NOAEL (0.025 mg/kg) x 1/0.38 m³/kg x 6.7 m³/10m³ x 0.5

=> NOAEC worker = 0.022 mg/m³

For interspecies differences rat vs. human: 1 (according TGD Table

R.8-4. already covered by correction of starting point)

For remaining interspecies differences: 2.5

For intraspecies differences in workers: 5

For extrapolation of exposure: 1

For reliability of dose-response: 1

For quality of whole database: 1

Overall factor: 12.5

Worker DNEL long-term for inhalation exposure: 0.00176 mg/m³

The differences in the DNELs derived from the monkey and the rat study are caused by the different no-observed adverse effect levels (NOEALs ) of PFOS found in monkeys and rats. In both species effects on the liver (hypertrophy) as the most susceptible organ was found. However, rats accumulate PFOS in the target organ, whereas in monkeys an accumulation of PFOS in the liver was not substantiated. Thus the concentrations of PFOS in the liver are essential which may be different from serum levels in various species.

From limited human data it can be concluded, the ratio of the concentrations of PFOS in liver and serum in humans and monkeys is similar.

Therefore the data of the monkey study are more reliable.

The German MAK Commission defined in 2010 a workplace limit value of 0.01 mg/m³ ((DFG 2010). This value is lower, but overall in line with the values derived with the above mentioned calculations. Taking into consideration the uncertainties regarding species extrapolation this value of 0.01 mg/m³ will be used as long-term DNEL for workers for inhalation exposure.

2.) Short-term toxicity – systemic effects (workers)

Concerning the systemic effects an exceeding factor of 8 for inhalation toxicity based on the DNEL for long term exposure seems justified. For oral and dermal toxicity no exceeding factor is recommend.

Worker DNELshort-term for oral or dermal route-systemic: 0.003 mg/kg bw/day

Worker DNEL short-term for inhalation exposure: 0.08 mg/m³

Conclusion (systemic effects):

Worker DNEL long-term for oral or dermal route-systemic: 0.003 mg/kg bw/day

Worker DNEL long-term for inhalation exposure: 0.01 mg/m³

Worker DNELshort-term for oral or dermal route-systemic: 0.003 mg/kg bw/day

Worker DNEL short-term for inhalation exposure: 0.08 mg/m³

3.) Reproductive Toxicity – systemic effects (workers)

In a 2 generation study on rats a NOAEL of 0.4 mg/kg bw/ d for developmental toxicity was found.

For the developmental toxicity/teratogenicity a NOAEL of 0.3 mg/kg bw/d for pre- and postnatal toxicity was determined. In a prenatal immunotoxicty study in mice the NOAEL was 0.1 mg/kg bw/d.

Therefore the derivation of a separate DNEL for reproductive toxicity is not necessary, because the DNEL for repeated dose toxicty (0.025 mg/kg bw/d in rats) covers both endpoints.

4. Long-term and short-term dermal or inhalation route - local effects (worker)

In rabbits, PFOS was not irritating to the skin (OECD TG 404), and not irritating to the eyes (OECD TG 405).

A LLNA in mice (OECD 429 and 406) was negative up to and including a 50% concentration.

Therefore the DNELs for systemic effects also applies to local effects:

Conclusion (local effects):

Worker DNEL long-term for oral or dermal route: 0.003 mg/kg bw/day

Worker DNEL long-term for inhalation exposure: 0.01 mg/m³

Worker DNELshort-term for oral or dermal route: 0.003 mg/kg bw/day

Worker DNEL short-term for inhalation exposure: 0.08 mg/m³

References:

• Seacat AM, Thomford PJ, Hansen KJ, Olsen GW, Case MT, Butenhoff JL –Subchronic toxicity studies on perfluorooctanesulfonate potassium salt in cynomolgus monkeys, Toxicol Sci 68, 249-264 (2002)

• Mihail F, Tetraaethylammoniumperfluoroctansulfonat - Untersuchungen auf Reizwirkung an der Haut und am Auge von Kaninchen, Bayer - Institut fuer Toxikologie Wuppertal-Elberfeld, 1975

• Luebker DJ, Case MT, York RG, Moore JA, Hansen KJ, Butenhoff JL (2005), Two-generation reproduction and cross-foster studies of perfluorooctanesulfonate (PFOS) in rats, Toxicology 215, 126-148

• Butenhoff JL, , Ehresman DJ, Chang SC, Parker FA,, Stump DG (2009), Gestational and lactational exposure to potassium perfluorooctanesulfonate (K+PFOS) in rats: developmental neurotoxicity. Reprod Toxicol 27, 319-330

• Keil DE, Mehlmann T, Butterwoth L, Peden-Adams MM (2008), Gestational exposure to perfluorooctane sulfonate suppresses immune function in B6C3F1 mice, Toxicol Sci 103, 77-85

• ECHA – Guidance on information requirements and chemical safety assessment, Chapter R. 8, Characterisation of dose [concentration]-response for human health, page 64

General Population - Hazard via inhalation route

Systemic effects

Acute/short term exposure

DNEL related information

Local effects

Acute/short term exposure

DNEL related information

General Population - Hazard via dermal route

Systemic effects

Acute/short term exposure

DNEL related information

General Population - Hazard via oral route

Systemic effects

Acute/short term exposure

DNEL related information

Additional information - General Population

tetraethylammonium heptadecafluorooctanesulfonate is only used in idustrial processes (e.g. metal (chromium) plating) and the general population is not exposed to the compound. Therefore the derivation of a DNEL for the general population is not necessary.