Ammonium undecafluorohexanoate

Endpoint summary

Description of key information

Oral (OECD 408), rat: NOAEL (local) = 20 mg/kg bw/day

Read-across from structural analogue source substance sodium undecafluorohexanoate (CAS 2923-26-4)

Oral (OECD 453, combined chronic toxicity/carcinogenicity, read-across), rat: NOAEL systemic (males) = 15 mg/kg bw/day and NOAEL systemic (females) = 30 mg/kg bw/day

Read-across from structural analogue source substance undecafluorohexanoic acid (CAS 307-24-4).

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Reference

Reference 1

Endpoint:

sub-chronic toxicity: oral

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Justification for type of information:

refer to analogue justification provided in IUCLID section 13

Reason / purpose for cross-reference:

read-across source

Key result

Dose descriptor:

NOAEL

Remarks:

local

Effect level:

20 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: No adverse effects observed at 20 mg/kg bw/day

Dose descriptor:

LOAEL

Remarks:

local

Effect level:

100 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

haematology

histopathology: non-neoplastic

Key result

Dose descriptor:

NOAEL

Remarks:

systemic

Effect level:

100 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: No adverse systemic effects observed at 100 mg/kg bw/day.

Dose descriptor:

LOAEL

Remarks:

systemic

Effect level:

500 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

body weight and weight gain

food consumption and compound intake

haematology

histopathology: non-neoplastic

Key result

Critical effects observed:

yes

Lowest effective dose / conc.:

500 mg/kg bw/day (actual dose received)

System:

haematopoietic

Organ:

bone marrow

spleen

Treatment related:

yes

Dose response relationship:

yes

Relevant for humans:

not specified

Conclusions:

An analogue substance approach was used for read-across to the target substance Ammonium undecafluorohexanoate (CAS 21615-47-4). In a combined subchronic repeated dose toxicity study with one-generation reproduction study in rats with source substance Sodium perfluorohexanoate (CAS 2923-26-4), the local NOAEL for subchronic toxicity was 20 mg/kg bw/day, based on microscopic pathology of the nasal tissue (olfactory epithelium degeneration and atrophy) observed at 100 and 500 mg/kg bw/day. Considering the irritating properties (surfactant) of the test substance, local effects observed are assumed to result from gavage procedure and/or reflux of the test substance after gavage. The systemic NOAEL was 100 mg/kg bw/day based on decreased red blood cell parameters, splenic extramedullary hematopoiesis and erythroid hyperplasia in bone marrow and follicular cell hypertrophy in the thyroid gland observed at 500 mg/kg bw/day.
Therefore, the determined local and systemic NOAELs are also applicable for target substance Ammonium undecafluorohexanoate.

Reference 2

Endpoint:

chronic toxicity: oral

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Justification for type of information:

Refer to analogue justification provided in IUCLID section 13

Reason / purpose for cross-reference:

read-across source

Dose descriptor:

LOAEL

Remarks:

systemic

Effect level:

100 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male

Basis for effect level:

other: no adverse effect observed

Dose descriptor:

NOAEL

Remarks:

systemic

Effect level:

15 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male

Basis for effect level:

clinical signs

urinalysis

Dose descriptor:

LOAEL

Remarks:

systemic

Effect level:

200 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

female

Basis for effect level:

other: no adverse effect observed

Dose descriptor:

NOAEL

Remarks:

systemic

Effect level:

30 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

female

Basis for effect level:

clinical signs

histopathology: non-neoplastic

mortality

Critical effects observed:

yes

Lowest effective dose / conc.:

100 mg/kg bw/day (actual dose received)

System:

urinary

Organ:

other: urine pH value

Treatment related:

yes

Dose response relationship:

yes

Relevant for humans:

yes

Conclusions:

Based on the results of the read across study performed with CAS 2923-26-4, the NOAEL for systemic toxicity of the test item was 15 mg/kg bw/day in male and 30 mg/kg bw/day in female rats.

Executive summary:

The potential for the target substance to cause adverse effects following repeated exposure was assessed using an adequate and reliable chronic oral toxicity study of a structural analogue source substance. Oral exposure of male and female rats for 2 years via gavage with the test substance caused treatment -related mortality in females of the high-dose group and systemic toxicity (renal effects, clinical signs) in males and females of the high-dose group. In the high-dose groups, urinalysis parameter changes were noted in males and females and renal papillary necrosis and/or tubular degeneration in females. In addition, local effects observed in the lungs and stomach were observed in animals of all dose groups and considered to be caused by the local irritant effects of the test substance. Based on these findings, a NOAEL for the target substance for repeated dose toxicity after oral exposure was derived to be 15 mg/kg bw/day for males and 30 mg/kg bw/day for females. As explained in the analogue justification, the molecular structure of the target and the source substances are considered to be sufficiently similar to justify the read across application.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEL

15 mg/kg bw/day

Study duration:

subchronic

Species:

rat

Quality of whole database:

The available information comprises two adequate and reliable studies (Klimisch score 1) from reference substances with similar structure and intrinsic properties. Read-across is justified based on common precursors and breakdown products of hydrolysis and consistent trends in environmental fate, ecotoxicological and toxicological profile (refer to endpoint discussion for further details). The selected to study is thus sufficient to fulfil the standard information requirements set out in Annex VIII, 8.6, in accordance with Annex XI, 1.5, of Regulation (EC) No. 1907/2006.

System:

urinary

Organ:

kidney

other: changes in urinary parameters, papillary necrosis and tubular degeneration

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Justification for read-across

There is no data available on the repeated dose toxicity of ammonium undecafluorohexanoate. The assessment of repeated dose toxicity was based on two studies conducted with suitable source substances as part of a read across approach, which is in accordance with Regulation (EC) No. 1907/2006, Annex XI, 1.5. For each specific endpoint the source substance(s) structurally closest to the target substance is/are chosen for read-across, with due regard to the requirements of adequacy and reliability of the available data. Structural similarities and similarities in properties and/or activities of the source and target substance are the basis of read-across. A detailed justification for the analogue read-across approach is provided in the technical dossier (see IUCLID Section 13).

 

Repeated dose toxicity, oral, subchronic

CAS 2923-26-4

Sodium perfluorohexanoate (NaPFHx ) was assessed in a combined subchronic repeated dose oral toxicity study with one-generation reproduction study. The study was performed according to OECD guideline 408 and in compliance with GLP (Chemours, 2009). Ten Crl:CD(SD) rats/sex/dose were administered NaPFHx daily for approximately 90 days by gavage at doses of 0, 20, 100 and 500 mg/kg bw/day. In addition, satellite groups of 10 rats/sex/dose were treated according to the same protocol and sacrificed after a recovery period of 30 days (control and 500 mg/kg bw/day group) and 90 days (control, 20, 100 and 500 mg/kg bw/day group). The mortality/morbidity of the animals was checked daily, clinical signs were assessed daily. The body weights and food consumption were measured weekly. Detailed clinical observations were made weekly. Haematology and clinical chemistry parameters, as well as urinary parameters, were evaluated during weeks 6 and 14 of the dosing period, and near the end of the one-month recovery period. An ophthalmoscopic examination was performed on all rats of the main and 30-day satellite group on Day 10 and prior to sacrifice. Neurobehavioral assessments were performed prior to dosing, during week 13 of dosing, and near the end of the one-month recovery period. At the end of the dosing period, 10 rats/sex/dose were sacrificed. Selected organ weights were recorded, and gross and microscopic pathology examination was performed. One month after the end of the dosing period, the animals in the 30-day satellite control and high dose groups were sacrificed, and 3 months after the end of the dosing period the animals in the 90-day satellite groups were sacrificed. Analytical results demonstrated that the test substance was mixed properly, was at the targeted concentrations, and was stable in the vehicle used in this study.

Test substance related effects compared to control animals were observed on mean body weight (95% to 91.3% of control group) in male rats dosed 90 days with 500 mg/kg bw/day, reversible within 30- and 90-days recovery period. Mean overall food efficiency was significantly decreased in males dosed with 500 mg/kg bw/day compared with the control group, persistent over a 30-day recovery period, but revealed within 90-day recovery period. This effect seems to be related to the body weight decrease in male rats at same dose level, since the food consumption was not affected by the test substance. No toxicologically relevant effects were observed on mean body weight, mean body weight gains, nutritional parameters, mortality, clinical signs, or ophthalmology observations in male rats dosed for 90 days with 20 or 100 mg/kg bw/day or in female rats dosed up to and including 500 mg/kg bw/day of the test substance. No test substance-related effects on forelimb or hindlimb grip strength, sensory motor function, or motor activity were observed in any male or female dose group.

Toxicologically relevant hematologic effects were observed at 500 mg/kg bw/day, manifested by mild to moderate decreases (75%, 73%, and 78% of control, respectively, for males; 92%, 94%, and 96% of control, respectively, for females) in red blood cell mass parameters (red blood cell count, hemoglobin and hematocrit) at test days 43/44 and further decreased (69%, 64%, and 69% of control, respectively, for males; 82%, 85%, and 87% of control, respectively, for females) on day 92/93 (males/females). An erythroid regenerative response was observed at 500 mg/kg bw/day by increased reticulocyte count on test days 43/44 and 92/93 (males/females).

Changes of red blood mass parameters were reversible within 30- and 90-day recovery period.

Aspartate aminotransferase (AST) was minimally increased at test day 43 in males administered 500 mg/kg bw/day (133% of control) and at test day 92 in males administered 100 and 500 mg/kg bw/day (125% and 139% of control, respectively). Alanine aminotransferase (ALT) was minimally increased at test day 43 in males administered 20 and 500 mg/kg bw/day (125% and 138% of control, respectively). However, there was no dose-related pattern for the increase in ALT in treated males at test day 43. Changes in ALT and AST were reversible following the 30- and 90-day recovery period. There were no treatment-related adverse findings at doses of 100 mg/kg bw/day or below. The increases in group mean AST and ALT in males at 100 and 500 mg/kg bw/day are considered treatment related but were not toxicologically relevant in view of the generally minimal nature of the differences from controls and also as the underlying pathophysiologic process likely relates to an adaptive response in the liver (i.e., enzyme induction).

Test substance-related microscopic findings were present in the nose, liver, and thyroid gland. In addition, changes occurring secondary to effects on red blood cells were observed in bone marrow and spleen. Degeneration and atrophy of olfactory epithelium, turbinate adhesions and respiratory metaplasia were present in the nose of male and female rats administered 100 a 500 mg/kg bw/day. Minimal changes, including turbinate adhesions, respiratory metaplasia, and microcysts within olfactory epithelium, were still present in the nose following 30 and 90 days recovery. Nasal lesions are considered to be a local effect based on irritant/corrosive properties of the test substance. Respiratory tissues might incidently be exposed to the test substance following gavage procedure and/or by reflux of test substance after gavage.

Increased liver weights and microscopic hepatocellular hypertrophy were present in males and females at 500 mg/kg bw/day and in males at 100 mg/kg bw/day. Liver weight effects in the 500 mg/kg bw/day groups showed some, but not complete recovery after 30- and 90-day treatment-free periods; these changes were reversible after 90 days recovery in males at 100 mg/kg bw/day. These liver effects were consistent with secondary responses to the xenobiotic induction of metabolizing enzymes and/or peroxisome proliferation and were not considered adverse. No test-substance related liver effects were observed in male or female rats at 20 mg/kg bw/day. Relative kidney weights were statistically significantly increased in 500 mg/kg bw/day main study males and females (117% and 1116% for males and females, respectively) and in 100 mg/kg bw/day males (113%), when compared to the control group. In 500 mg/kg bw/day group, kidney weight effects were reversible following the 30-day recovery period in females but not in males. In 100 mg/kg bw/day group effects were reversible following the 30-day recovery period in males. Kidney weights were not determined in the 90-day recovery groups. Kidney weight changes were not associated with microscopic or clinical pathology changes indicative of renal toxicity. Therefore, these changes were considered to be treatment related, but non-adverse. No test-substance related kidney effects were observed in male or female rats at 20 mg/kg bw/day. Follicular cell hypertrophy in the thyroid gland was present at 500 mg/kg bw/day in male and female rats at the end of dosing and after 30-days recovery period. After 90-days recovery period, changes were limited to equivocal hypertrophy in 2/10 males in the 500 mg/kg bw/day group. Thyroid changes were minimal and likely secondary to induction of metabolic enzymes in the liver. Thyroid hypertrophy is a common finding in rats in association with induction of hepatic microsomal enzymes, and in this study was seen only at doses that also produce liver hypertrophy. Therefore, thyroid follicular cell hypertrophy in the current study was considered potentially adverse in the species tested.

Increased incidences of minimal to mild splenic extramedullary hematopoiesis and /or erythroid hyperplasia in bone marrow were present in 500 mg/kg bw/day males and females. These changes were correlative to changes in red cell mass parameters and are an expected finding as part of a regenerative red cell response. As such, these findings were not considered to be primary adverse effects. Consistent with the hematological findings, no compound-related changes were present in spleen or bone marrow in the male or female 500 mg/kg bw/day groups following 30-days recovery.

Under the conditions of this study, the local NOAEL for subchronic toxicity was 20 mg/kg bw/day, based on microscopic pathology of the nasal tissue (olfactory epithelium degeneration and atrophy) observed at 100 and 500 mg/kg bw/day. Considering the irritating properties (surfactant) of the test substance, local effects observed are assumed to result from gavage procedure and/or reflux of the test substance after gavage. The systemic NOAEL was 100 mg/kg bw/day based on decreased red blood cell parameters, splenic extramedullary hematopoiesis and erythroid hyperplasia in bone marrow and follicular cell hypertrophy in the thyroid gland observed at 500 mg/kg bw/day.

 

 

Repeated dose toxicity, oral, chronic

CAS 307-24-4

A second read-across was performed using the structurally similar substance undecafluorohexanoic acid in a combined chronic toxicity/carcinogenicity study (WIL Research Laboratories, 2010). The study was performed in male and female Sprague Dawley rats according to OECD guideline 453 and in compliance with GLP. The analogue substance was dissolved in water and administered by oral gavage at doses of 2.5, 15 and 100 mg/kg bw/day (males); and 5, 30 and 200 mg/kg bw/day (females). Sixty animals per sex and dose group (70 rats for the highest dose group of each sex) were treated daily for a period of 104 weeks. A similar constituted group received the vehicle (water) and served as control. The mortality/morbidity of the animals was checked twice daily, clinical signs were assessed twice daily. The body weights and food consumption were measured weekly until week 14 and every second week thereafter. Detailed clinical observations were made weekly. Haematology and clinical chemistry parameters, as well as urinary parameters, were evaluated during weeks 25-26 and 51-52 of the dosing period. An ophthalmoscopic examination was performed on all rats prior to study start, during week 51 and prior to sacrifice. Neurobehavioral assessments were performed during week 51 of the observation period. At the end of the dosing period the animals were sacrificed. Selected organ weights were recorded, and gross and microscopic pathology examination was performed.

Mortality was observed throughout all treatment groups. Until study termination and excluding accidental death due to mechanical injury and gavage error, percentage survival rates were 31.0, 41.4, 40.4 and 38.1% in males and 36.2, 43.1, 33.3 and 20.6% in females of the control, low, middle and high dose group. Compared to control animals, survival rates were significantly reduced in females administered 200 mg/kg bw/day and included unscheduled and accidental deaths due to reflux injury, mechanical injury or gavage error. Reflux injury was related to the aspiration of compound after the gavage dosing. Deaths due to reflux injury were considered treatment-related and toxicologically relevant, as the test substance has corrosive properties and caused local effects such as inflammation and/or epithelial necrosis in the larynx or pulmonary airway epithelium. Deaths due to mechanical injury were treatment-related but not toxicologically relevant. Deaths due to undetermined reasons may be treatment-related, or may be incidental and not related to systemic toxicity. A significant increase in the mortality rate due to systemic toxicity was observed in females only. The survival rates of males was unaffected by treatment and remained comparable to the control group. Due to the unexpected high mortality rate in the first year of the study no interim kill was performed.

An increased number of animals exhibited toxicologically relevant clinical signs of toxicity in the high dose groups (100 mg/kg bw/day (males) and 200 mg/kg bw/day (females)), compared with the control group. The clinical signs comprised wet and/or dried yellow material in the ventral trunk, anogenital and/or urogenital areas. The observations were made throughout the whole treatment period but more frequently towards the end of the study and were in line with microscopic findings at histopathological examination. In addition, rales and excessive struggling during dosing related to the treatment were observed. The observations were attributed to the acidic nature of the test item.

There were no test item-related effects on the body weight, food consumption and food efficiency of the animals. Body weight changes below 10% were observed in all dose groups but a dose-response relationship was lacking and there was no consistent group response over time. Occasional week to week fluctuations in food consumption and food efficiency were considered not treatment-related.

Hematological findings included a significantly reduced mean number of red blood cells (8.1%) and haemoglobin (5.2%) in females administered 200 mg/kg bw/day after one year of treatment. The levels were comparable to those of the control group at terminal necropsy and thus not considered to be toxicologically relevant. Reticulocyte levels of this dose group were significantly increased in study weeks 25 (21.8%) and 51 (26.3%) and remained slightly, non-significantly increased until study termination. Due to the lack of histopathological findings and the absence of haematological effects in males, the observations were considered toxicologically not relevant.

Some changes in clinical chemistry parameters were reported: reduced triglyceride levels 47.4% and 42.8%) and reduced fatty acids (21.1% and 19.4%) in males administered 2.5 and 100 mg/kg bw/day, as well as increased levels of inorganic phosphate (8.5% and 6.8%) and sodium (0.7%) in males administered 15 and 100 mg/kg bw/day after one year of treatment. Females administered 200 mg/kg bw/day showed increased triglyceride levels in study week 26 (66.3%) and 52 (27.2%), as well as significantly reduced low density lipoprotein (LDL) and very low density lipoprotein (VLDL) cholesterol concentrations. However, the observed changes were considered to be incidental, were not dose-dependent and/or not associated with histopathological changes and therefore not considered to be toxicologically relevant. Furthermore, hormone levels (testosterone and luteinizing hormone) levels were slightly reduced in males at all dose groups after26 weeks of dosing, but the effects were not dose-related and turned to control conditions within one year of treatment.

Urinalysis indicated lower urinary pH values in males of the high dose group when compared to control animals. The effect was attributed to the acidic nature of the test substance and considered to be toxicologically relevant. Treatment-related findings in females included a higher urine volume and lower specific gravity. The findings were attributed to treatment-related renal effects and supported by histopathological findings.

Gross pathological analysis showed primarily pulmonary findings. Failure of the lungs to collapse was found in 11/46 males and 11/56 females of the high dose group and in 5/42 males and 3/39 females of the vehicle control group. The findings correlated with hemorrhage, edema, increased alveolar macrophages or other evidence of accidental aspiration of the test substance. In addition, local irritation caused by the acidic test compound were found the stomach of the high dose group animals.

Neuromuscular, sensory and related activities were investigated with the functional observational battery. Two females administered 200 mg/kg bw/day showed impaired mobility and/or abnormal gait at the study week 51 evaluation. The study authors state that observations were probably due to excessive struggling during dosing on the previous day and transient excessive body weight loss with concomitant physical debilitation, and were not representative for the other animals of this dose group. Therefore, this effect is not toxicologically relevant. Minor findings were lower mean grip strength of females treated at 5 mg/kg bw/day, an increased number of male rats, which were asleep or lying on their side or less animals with eye lids wide open in the dosage group treated at 100 mg/kg bw/day. The findings were considered to be a result of normal biological variation as a dose-response relationship was lacking and no effects on locomotor activity were seen. 

Histopathological findings of toxicological relevance were predominantly observed in kidneys of female rats administered 200 mg/kg bw/day. The findings comprised severe papillary necrosis in 17/56 females, compared with 0/39 females in the control group. In addition, minimal to moderate renal tubular degeneration was observed in 3/46 males and 7/56 females of the high dose group and in 4/42 males and 1/39 females of the control group. The findings correlated with clinical signs (yellow material at the urogenital and anogenital area), alterations of urine parameters and a decreased survival rate. Microscopic findings were further observed in the lungs, liver and stomach of the high dose group animals. The findings were explained by accidental aspiration of the dosing formulations and were accompanied by mucosal irritation due to the physical properties of the test item.

Macroscopical abnormalities of toxicological relevance were found in the lungs of males and females of the high dose group. The findings comprised acute pulmonary congestion in 5/42, 9/36, 9/37 and 19/46 males in the control, low-, mid-, and high-dose groups and in 8/39, 6/35, 1/40 and 2/56 females the control, low-, mid-, and high-dose group and/or haemorrhage in 1/42, 5/36, 5/37 and 9/46 males in the control, low-, mid-, and high-dose groups and in 2/39, 3/35, 0/40 and 3/56 females the control, low-, mid-, and high-dose group and increased pulmonary alveolar macrophages in 4/42, 5/36, 8/37 and 5/46 males in the control, low-, mid-, and high-dose groups and in 2/39, 4/35, 6/40 and 18/56 females the control, low-, mid-, and high-dose group. Erosion and/or ulceration in the stomach was observed primarily in females (5/39, 3/35, 4/40 and 16/56 females and in 4/39, 0/35, 6/40 and 0/56 females in the control, low-, mid-, and high-dose group), as well as hepatocellular necrosis (2/39, 0/35, 3/40 and 11/56 females the control, low-, mid-, and high-dose group). The latter findings were consistent with ischemia and primarily found in dead animals. There were no neoplastic histopathological alterations observed.

Based on the observed adverse effects, the NOAEL for systemic toxicity was 15 mg/kg bw/day for males and 30 mg/kg bw/day for females.

Conclusion oral repeated dose toxicity:

A NOAEL for local toxicity of 20 mg/kg bw/day was derived in the 90-day subchronic repeated dose toxicity study performed with the source substance sodium undecafluorohexanoate, and a NOAEL for systemic toxicity of 15 mg/kg bw/day in male and a NAOEL for systemic toxicity of 30 mg/kg bw in female rats was derived in the chronic repeated dose toxicity study performed with the source substance undecafluorohexanoic acid. Based on the read- across application, the target substance ammonium undecaflurohexanoate is expected to show the same local and systemic effects at the same dose levels.

Justification for classification or non-classification

Two read across studies with structurally similar compounds were performed to investigate the oral repeated dose toxicity of ammonium undecafluorohexanoate (CAS 21615-47-4). In the first study with the source substance sodium perfluorohexanoate (CAS 2923-26-4) local effects on the olfactory epithelium were observed at a lowest observed adverse effect concentration (LOAEL) of 100 mg/kg bw/day in male and female rats. Based on this finding a no observed adverse effect level (NOAEL) of 20 mg/kg bw/day was derived. Considering the irritating properties of sodium perfluorohexanoate, local effects are assumed to result from gavage procedure and/or reflux injury and are therefore not relevant for classification. Systemic toxicity of sodium perfluorohexanoate was observed at a LOAEL of 500 mg/kg bw/day, comprising decreased red blood cell parameters, splenic extramedullary hematopoiesis and erythroid hyperplasia in bone marrow and follicular cell hypertrophy in the thyroid gland.

In the second study, the source substance undecafluorohexanoic acid (CAS 307-24-4) was shown to have renal effects in female rats, leading to clinical signs related to renal effects, and inducing papillary necrosis and tubular degeneration. The systemic LOAEL was 200 mg/kg bw/day for females. Based on this finding a systemic NOAEL of 30 mg/kg bw/day was derived for female rats. In male animals a decreased pH value of the urine and clinical signs related to kidney effects was noted at a systemic LOAEL of 100 mg/kg bw/day. A NOAEL of 15 mg/kg bw/day was derived for male rats.

According to the criteria of Regulation (EC) No. 1272/2008 (CLP), Annex I, Section 3.9, a LOAEL guidance value of ≤ 100 mg/kg bw/day based on data obtained in a sub-chronic (90-day) repeated dose toxicity study is used to indicate the necessity for classification as specific target organ toxicant after repeated exposure. As the LOAEL in male rats was observed at 100 mg/kg bw/day, a classification of ammonium undecafluorohexanoate may be considered. However, there were no histopathological findings in the kidneys of male animals, and the relevant study is a 2-year chronic toxicity study.

Based on these considerations, the available data on repeated dose toxicity following oral exposure for 104 weeks according to OECD 453, ammonium perfluorohexanoate (CAS 307-24-4) is considered not to meet the classification criteria according to Regulation (EC) No. 1272/2008 (CLP) for specific target organ toxicity after repeated exposure. The data are conclusive but not sufficient for classification.