Registration Dossier

Administrative data

Description of key information

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records
Reference
Endpoint:
sub-chronic toxicity: oral
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: GLP study according to OECD guideline 415 on analogue substance (primary breakdown product 6-2 FTOH)
Justification for type of information:
1. HYPOTHESIS FOR THE ANALOGUE APPROACH
From the toxicokinetic assessment as well as from results of the hydrolysis study it is known that the target chemical 3,3,4,4,5,5,6,6,7,7,8,8,8-tridecafluorooctyl acrylate becomes hydrolysed in vivo to the alcohol and the acrylic acid moiety. Whereas acrylic acid is intensively investigated for health endpoints and does not show repeat dose toxicity, data was required for the corresponding alcohol, 3,3,4,4,5,5,6,6,7,7,8,8,8-tridecafluorooctanol (the source chemical), thereby being in a position to conclude upon long-term toxicity of the target chemical.
2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
Both, source chemical as well as target chemical are of high purity (>90%) and it is expected that study results were not compromised by any impurities being present, considering, that typical impurities do only differ by chain length of the fluorinated part of the alcohol moiety.
3. ANALOGUE APPROACH JUSTIFICATION
Based on the TK assessment as well as from results of the hydrolysis study the target chemical 3,3,4,4,5,5,6,6,7,7,8,8,8-tridecafluorooctyl acrylate breaks down in vivo to the alcohol and the acrylic acid moiety. The resulting alcohol, 3,3,4,4,5,5,6,6,7,7,8,8,8-tridecafluorooctanol (the source chemical), thereby is being formed in vivo rapidly in the gastrointestinal tract and becomes decisive as metabolite for systemic toxicity as distributed in the organism. Hence, using repeat-dose toxicity data from the metabolite 3,3,4,4,5,5,6,6,7,7,8,8,8-tridecafluorooctanol for read-across to 3,3,4,4,5,5,6,6,7,7,8,8,8-tridecafluorooctyl acrylate (target chemical) is justified.
4. DATA MATRIX
Log Pow values are not significantly different (4.54 for source chemical versus 5.07 of target chemical). However, the water solubility of the source chemical is by two orders of magnitude higher (18.8 mg/L) that that of the target chemical (0.185 mg/L) suggesting that distribution in vivo will be quicker reaching reproductive organs, and thus the source chemical may be seen as a worst case surrogate for the target chemical, which requires metabolisation prior to distribution in vivo. In consequence, the data for repeat-dose toxicity of the source chemical may be seen as a worst case surrogate for the target chemical 3,3,4,4,5,5,6,6,7,7,8,8,8-tridecafluorooctyl acrylate, justifying the read-across approach.
Reason / purpose for cross-reference:
reference to same study
Reason / purpose for cross-reference:
read-across source
Qualifier:
according to guideline
Guideline:
other: OECD Guideline 415 (One-Generation Reproduction Toxicity Study)
Deviations:
yes
Remarks:
Offspring in the P litters of each treatment level were randomly selected for continued evaluation until approximately PND 40. Addition of developmental landmarks for F1 generation (males and females) and scheduled sacrifice on postnatal day PND 40.
GLP compliance:
yes
Limit test:
no
Control animals:
yes, concurrent vehicle
Dose descriptor:
NOAEL
Remarks:
(systemic toxicity)
Effect level:
25 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male
Basis for effect level:
other: see 'Remark'
Dose descriptor:
NOAEL
Remarks:
(systemic toxicity)
Effect level:
5 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
female
Basis for effect level:
other: Differences in clinical chemistry and histopathology at 25 mg/kg/day, both of which pertained to the liver and were consistent with observations at 100 mg/kg/day.
Critical effects observed:
not specified
Conclusions:
This study and the conclusions which are drawn from this study on the surrogate substance 3,3,4,4,5,5,6,6,7,7,8,8,8-tridecafluorooctan-1-ol fulfill the quality criteria (validity, reliability, repeatability) and are suitable for a worst case read-across to 3,3,4,4,5,5,6,6,7,7,8,8,8-tridecafluorooctyl acrylate (Target substance).
NOAEL (systemic toxicity; males): 25 mg/kg/day, equivalent to 28.79 mg 3,3,4,4,5,5,6,6,7,7,8,8,8-tridecafluorooctyl acrylate/kg bw/d based on equimolar level
NOAEL (systemic toxicity; females): 5 mg/kg/day, equivalent to 5.76 mg 3,3,4,4,5,5,6,6,7,7,8,8,8-tridecafluorooctyl acrylate/kg bw/d based on equimolar level
Executive summary:

The test substance was administered via gavage to P generation male and female mice during premating, mating, gestation, and lactation, and to F1 generation male and female adults (post-weaning). P adult CD-1 mice (15/sex/group) were administered the test substance daily in a vehicle of 0.1% Tween-80 in 0.5% aqueous methylcellulose at dosages of 0, 1, 5, 25, or 100 mg/kg body weight/day (mg/kg/day) for 10 weeks (males) and 2 weeks (females) during the premating period, and then up until the day before scheduled sacrifice. Following the premating period, the P males and females were co-housed within their respective treatment groups to produce F1 litters. Litters were culled to 4 pups/sex/litter (litter size permitting) on postnatal day 4; all remaining pups were discarded without further evaluation. Dams were allowed to deliver and rear their offspring until weaning on postnatal day (PND) 21. At weaning, selected F1 offspring (one pup/sex/litter when possible) were randomly selected from the 0, 1, 5, and 25 mg/kg/day groups to continue on study as F1 adults. F1 offspring of P animals in the 100 mg/kg/day group were euthanized on PND 21 due to concerns about their viability. The F1 adults from the remaining study groups (0, 1, 5 and 25 mg/kg/day) were administered the test substance from PND 21 until the day before scheduled sacrifice (PND 40-43), and were evaluated for developmental landmarks. Clinical observations, body weight, and food consumption were determined weekly throughout the study. Litter examinations (live or dead pups, individual pup weights, clinical observations) were determined at birth, on PND 4, and weekly during the lactation period. The age and body weight at either vaginal opening or preputial separation were recorded for the F1 generation. P animals surviving to scheduled sacrifice were divided approximately equally into subsets for haematology or clinical chemistry evaluation. Gross postmortem examinations were performed on P and F1 adults and selected organs from P animals were weighed and/or examined microscopically.

Adverse, test substance-related clinical signs and mortality were observed at 100 mg/kg/day in P males and females. One male and two females at this dose level were found dead or humanely euthanized due to clinical abnormalities. Clinical signs in these animals and three additional animals that survived included clonic and tonic convulsions, ataxia, tremors (head/upper body/forelimbs), increased muscle tone, lethargy, pallor, and/or respiratory impairments. When the clinical observations did not result in death, the clinical signs abated within approximately one week. In addition, test substance-related reductions in body weight, body weight gain, food consumption, and food efficiency were observed at this dose level in P males over the course of the study and in P females during the lactation period. Marked reductions in food consumption/efficiency among P females at 100 mg/kg only during the lactation period resulted in mean body weights on day 14 that were 20.4% lower than controls; by comparison, mean final body weights among males in this group were 4.8% lower than controls. There were no effects on any in-life parameter in P or F1 males or females, at dose levels of 25 mg/kg/day and lower. F1 litters of P adults administered 100 mg/kg/day exhibited clinical observations of delayed maturation (closed eyes at lactation day [LD] 21), a 45% reduction in lactation index (pup survival), and reductions in mean pup body weight per litter (64.9% lower on LD 21), compared with controls. The failure to thrive and delayed maturation of the pups were considered to be adverse, test substance-related effects, which were likely a result of the overt systemic toxicity observed in the dams. F1pups at 100 mg/kg/day were euthanized on PND 21 due to concerns about their viability.

Adverse, test substance-related changes in haematology (red and white blood cell) and clinical chemistry (liver-related) parameters were present in P males and females administered 100 mg/kg/day. Changes in liver parameters were also present in one female mouse in the 25 mg/kg/day group. Red blood cell changes in the 100 mg/kg/day groups included minimal to mild decreases in red cell mass parameters (RBC, HGB, and HCT). These changes were slightly higher relative to controls in females compared to males, and in females, were associated with a regenerative response (increased ARET). White blood cell changes in the 100 mg/kg/day male and female groups included minimal to moderate increases in white blood cell parameters (WBC, ALYM, ANEU, and AMON). These changes were likely correlative to the liver effects observed at this dose level. Changes in liver-related clinical chemistry parameters in the 100 mg/kg/day male and female groups included elevations in AST, ALT, ALP, SDH, and TBA. These changes were greater in females compared to males, with elevations of greater than 5-fold for most parameters in females and less than or equal to 5-fold in males. Increases in these same liver parameters in one 25 mg/kg/day female mouse were associated with correlative test substance-related microscopic findings in the liver and were thus also considered test substance related and adverse. Other clinical chemistry changes observed in the 100 mg/kg/day male and female groups included decreases in BUN, CREA, and CHOL (males only). These changes were greater in males than in females and were considered to be secondary to the liver toxicity observed at this dose level. Minimal elevations in serum potassium were also observed in the 100 mg/kg/day male and female groups. There were no adverse test substance-related changes in clinical pathology parameters in male mice administered 25 mg/kg/day or less, or in female mice administered 5 mg/kg/day or less.

Adverse observations of anatomic pathology occurred in the liver and teeth of P males and females at 100 mg/kg/day and in the liver of females at 25 mg/kg/day. Liver changes were generally more severe in females and included hepatocellular hypertrophy, oval cell hyperplasia, single cell necrosis of hepatocytes, and cystic degeneration (females only). Increased liver weight was also observed at 100 mg/kg/day in males and females. In males and females at 100 mg/kg/day, microscopic changes in the incisor teeth consistent with fluoride exposure included degeneration and atrophy of ameloblastic epithelium, lamination of dentin, and incomplete decalcification of enamel and/or dentin. Microscopic findings occurring secondary to the marked decrements in body weight and nutritional parameters in dams administered 100 mg/kg/day included anoestrus with associated atrophic changes in the reproductive tract, and secretory depletion in the mammary gland. The latter change is likely the result of increased duration of nursing in the undernourished pups at the 100 mg/kg/day dose level. Changes considered test substance-related but non-adverse based on lack of association with organ injury or evidence of decreased function included increased kidney weights (100 mg/kg/day males), minimal hepatocellular hypertrophy (5 mg/kg/day males and females, 25 mg/kg/day males), and incomplete decalcification of enamel and dentin (25 mg/kg/day female group). Test substance related gross findings in F1 generation mice were limited to increased incidences of weanlings grossly diagnosed as small. This finding was consistent with the in-life finding of markedly decreased body weight at weaning. There were no adverse pathology findings in P or F1 male mice administered 25 mg/kg/day or less, or in female mice administered 5 mg/kg/day or less.

The no-observed-adverse-effect level (NOAEL) for systemic toxicity was 25 mg/kg/day (males) and 5 mg/kg/day (females). Observations of systemic toxicity in P males and females at 100 mg/kg/day included mortality, clinical abnormalities, and differences in body weight, nutritional parameters, haematology (red and white blood cell), clinical chemistry (liver-related), liver weights, and histopathology (liver, teeth, reproductive tract, and mammary gland). Observations of systemic toxicity in P females at 25 mg/kg/day included differences in clinical chemistry and histopathology, both of which pertained to the liver and were consistent with observations at 100 mg/kg/day.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
5.76 mg/kg bw/day
Study duration:
subchronic
Species:
mouse

Repeated dose toxicity: inhalation - systemic effects

Link to relevant study records
Reference
Endpoint:
sub-chronic toxicity: inhalation
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
This study was selected as the key study because the information provided for the hazard endpoint is sufficient for the purpose of classification and labelling and/or risk assessment.This study is used for read-across and therefore has been assigned a reliability of 2 (reliable with restrictions). Otherwise the study has a reliability of 1 (reliable without restriction).
Justification for type of information:
1. HYPOTHESIS FOR THE ANALOGUE APPROACH
From the toxicokinetic assessment as well as from results of the hydrolysis study it is known that the target chemical 3,3,4,4,5,5,6,6,7,7,8,8,8-tridecafluorooctyl acrylate becomes hydrolysed in vivo to the alcohol and the acrylic acid moiety. Whereas acrylic acid is intensively investigated for health endpoints and does not show long-term toxicity to men, data was required for the corresponding alcohol, 3,3,4,4,5,5,6,6,7,7,8,8,8-tridecafluorooctanol (the source chemical), thereby being in a position to conclude upon repeated dose toxicity of the target chemical.
2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
Both, source chemical as well as target chemical are of high purity (>90%) and it is expected that study results were not compromised by any impurities being present, considering, that typical impurities do only differ by chain length of the fluorinated part of the alcohol moiety.
3. ANALOGUE APPROACH JUSTIFICATION
Based on the TK assessment as well as from results of the hydrolysis study the target chemical 3,3,4,4,5,5,6,6,7,7,8,8,8-tridecafluorooctyl acrylate breaks down in vivo to the alcohol and the acrylic acid moiety. The resulting alcohol, 3,3,4,4,5,5,6,6,7,7,8,8,8-tridecafluorooctanol (the source chemical), thereby is being formed in vivo rapidly in the gastrointestinal tract and becomes decisive as metabolite for systemic toxicity as distributed in the organism. Hence, using repeated dose toxicity data from the metabolite 3,3,4,4,5,5,6,6,7,7,8,8,8-tridecafluorooctanol for read-across to 3,3,4,4,5,5,6,6,7,7,8,8,8-tridecafluorooctyl acrylate (target chemical) is justified.
4. DATA MATRIX
Log Pow values are not significantly different (4.54 for source chemical versus 5.07 of target chemical). However, the water solubility of the source chemical is by two orders of magnitude higher (18.8 mg/L) than that of the target chemical (0.185 mg/L) suggesting that distribution in vivo will be quicker reaching via blood distribution target organs, and thus the source chemical may be seen as a worst case surrogate for te target chemical, which requires metabolisation prior to distribution in vivo. In consequence, the data for repeated dose toxicity of the source chemical may be seen as a worst case surrogate for the target chemical 3,3,4,4,5,5,6,6,7,7,8,8,8-tridecafluorooctyl acrylate, justifying the read-across approach.
Reason / purpose for cross-reference:
read-across source
Qualifier:
according to guideline
Guideline:
OECD Guideline 412 (Subacute Inhalation Toxicity: 28-Day Study)
Deviations:
yes
Remarks:
Serum gamma glutamyl transpeptidase and ornithine decarboxylase were not evaluated.
Qualifier:
according to guideline
Guideline:
other: EEC Methods for the Determination of Toxicity Method B.8 Directive 92/69/EEC
Deviations:
no
Remarks:
Serum gamma glutamyl transpeptidase was not evaluated.
GLP compliance:
yes
Limit test:
no
Key result
Dose descriptor:
NOAEC
Effect level:
10 ppm
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: Based upon increased serum ALT and bilirubin levels (females) and increased liver weighs in both male and females exposed to 100 ppm.
Dose descriptor:
LOAEC
Effect level:
100 ppm
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: Based upon increased serum ALT and bilirubin levels (females) and increased liver weighs in both male and females exposed to 100 ppm.
Critical effects observed:
not specified
Conclusions:
The study on the read-across 3,3,4,4,5,5,6,6,7,7,8,8,8-tridecafluorooctan-1-ol, a metabolite of the target substance 3,3,4,4,5,5,6,6,7,7,8,8,8-tridecafluorooctyl acrylate, is used in a weight of evidence approach as worst case surrogate for the target chemical, resulting in a NOAEC of 10 ppm and the LOAEC was 100 ppm for male and female rats based upon increased serum ALT and bilirubin levels (females) and increased liver weighs in both male and females exposed to 100 ppm.. The study and the conclusions which are drawn from it fulfil the quality criteria (validity, reliability, repeatability).
Executive summary:

The purpose of this study on the source chemical 3,3,4,4,5,5,6,6,7,7,8,8,8-tridecafluorooctan-1-ol was to provide information on possible adverse effects on rats resulting from repeated exposure to the test substance by inhalation (whole body) over an extended period of time (28 days) and a four weeks recovery period.

Four groups male and female Crl:CD(SD) rats were exposed whole body 6 hours/day, 5 days/week to 0 ± 0, 1.0 ± 0.0084, 10 ± 0.057 or 100 ± 0.33 ppm test substance over a 4-week period for a total of 23 exposures. Ten male and ten female rats exposed to 0 (control) or 100 ppm were then subject to an approximate 4-week recovery period.

There were no adverse effects on body weight, body weight gains, food consumption, or food efficiency, and there were no test substance-related or adverse clinical signs of toxicity in males or females exposed to any concentration over the course of this study.

No adverse effects on motor activity were observed in either males exposed to 1 or 10 ppm or female rats exposed to 1, 10, or 100 ppm. Male rats exposed to 100 ppm demonstrated decreased motor activity during the fourth week of exposure. The decreased motor activity in male rats exposed to 100 ppm had resolved following the 4-week recovery period. In the absence of other neurobehavioral changes in 100 ppm male rats or in female rats, the lower motor activity in 100 ppm males appears to be secondary to other systemic effects of the test substance, instead of a primary effect on the nervous system. There were no adverse effects observed in the ophthalmological evaluations at any exposure level in any of the animals in this study.

Following 4 weeks of exposure, concentration-related and adverse changes in clinical chemistry parameters were observed in male and female rats exposed to 100 ppm. In these animals, increased mean serum bilirubin levels were observed when compared to the control group and several females exposed to 100 ppm exhibited increased alanine aminotransferase (ALT). Following 4 weeks of recovery, group mean values for these clinical pathology parameters in both male and females were similar to the respective control group and not statistically different. No effects on clinical chemistry parameters were observed in males or females exposed to 1 or 10 ppm.

There were no test substance-related adverse effects on gross pathological evaluation in male or females at any exposure level. Male and female rats exposed to 100 ppm demonstrated increased mean absolute liver weights as well as increased mean liver weights relative to body and brain weight one day following the last exposure. By the end of the recovery period, the liver weights were similar to control.

There were no test substance related adverse microscopic findings at any of the exposure concentrations tested. Test substance-related, but non-adverse, microscopic findings were present in the teeth (incisors) and sections of long bones (femur and tibia) at the termination of exposure and following the 1-month recovery period. These changes consisted of increased lamination of dentin of the incisor teeth and incomplete decalcification of enamel of the incisors and the bone trabeculae in the tibia and femur. These findings were consistent with exposure to a fluorine-containing test substance and were not associated with any histopathological changes suggestive of tissue injury or any adverse functional consequences in these tissues. Therefore, these microscopic findings were not considered to be adverse.

There were no portal of entry effects noted in this study; no adverse findings were observed in the respiratory tract tissues at any exposure level. Therefore, the adverse effects observed in this study are considered to be systemic effects and are consistent with those observed in a previous oral repeated dose study with the test substance.

Under the conditions of this study, the no-observed-adverse-effect concentration (NOAEC) for the test substance 3,3,4,4,5,5,6,6,7,7,8,8,8-tridecafluorooctan-1-ol was 10 ppm for male and female rats based upon increased serum ALT and bilirubin levels (females) and increased liver weights in both male and females exposed to 100 ppm. These results are considered valid for assessing the risk posed by 3,3,4,4,5,5,6,6,7,7,8,8,8-tridecafluorooctyl acrylate, the target substance.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEC
428 mg/m³
Study duration:
subacute
Species:
rat
Quality of whole database:
Systemic effects were observed in this read-across study on 3,3,4,4,5,5,6,6,7,7,8,8,8-tridecafluorooctan-1-ol at the high-dose group, limited to increased serum ALT and bilirubin levels (females) and increased liver weights in both male and females exposed to 100 ppm. Therefore, the NOAEC was set to 25 ppm (estimated by conversion, considering molecular weight differences as 428 mg/m3) in this surrogate study for the target substance 3,3,4,4,5,5,6,6,7,7,8,8,8-tridecafluorooctyl acrylate.
Organ:
liver

Repeated dose toxicity: inhalation - local effects

Link to relevant study records
Reference
Endpoint:
sub-chronic toxicity: inhalation
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
This study was selected as the key study because the information provided for the hazard endpoint is sufficient for the purpose of classification and labelling and/or risk assessment.This study is used for read-across and therefore has been assigned a reliability of 2 (reliable with restrictions). Otherwise the study has a reliability of 1 (reliable without restriction).
Justification for type of information:
1. HYPOTHESIS FOR THE ANALOGUE APPROACH
From the toxicokinetic assessment as well as from results of the hydrolysis study it is known that the target chemical 3,3,4,4,5,5,6,6,7,7,8,8,8-tridecafluorooctyl acrylate becomes hydrolysed in vivo to the alcohol and the acrylic acid moiety. Whereas acrylic acid is intensively investigated for health endpoints and does not show long-term toxicity to men, data was required for the corresponding alcohol, 3,3,4,4,5,5,6,6,7,7,8,8,8-tridecafluorooctanol (the source chemical), thereby being in a position to conclude upon repeated dose toxicity of the target chemical.
2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
Both, source chemical as well as target chemical are of high purity (>90%) and it is expected that study results were not compromised by any impurities being present, considering, that typical impurities do only differ by chain length of the fluorinated part of the alcohol moiety.
3. ANALOGUE APPROACH JUSTIFICATION
Based on the TK assessment as well as from results of the hydrolysis study the target chemical 3,3,4,4,5,5,6,6,7,7,8,8,8-tridecafluorooctyl acrylate breaks down in vivo to the alcohol and the acrylic acid moiety. The resulting alcohol, 3,3,4,4,5,5,6,6,7,7,8,8,8-tridecafluorooctanol (the source chemical), thereby is being formed in vivo rapidly in the gastrointestinal tract and becomes decisive as metabolite for systemic toxicity as distributed in the organism. Hence, using repeated dose toxicity data from the metabolite 3,3,4,4,5,5,6,6,7,7,8,8,8-tridecafluorooctanol for read-across to 3,3,4,4,5,5,6,6,7,7,8,8,8-tridecafluorooctyl acrylate (target chemical) is justified.
4. DATA MATRIX
Log Pow values are not significantly different (4.54 for source chemical versus 5.07 of target chemical). However, the water solubility of the source chemical is by two orders of magnitude higher (18.8 mg/L) than that of the target chemical (0.185 mg/L) suggesting that distribution in vivo will be quicker reaching via blood distribution target organs, and thus the source chemical may be seen as a worst case surrogate for te target chemical, which requires metabolisation prior to distribution in vivo. In consequence, the data for repeated dose toxicity of the source chemical may be seen as a worst case surrogate for the target chemical 3,3,4,4,5,5,6,6,7,7,8,8,8-tridecafluorooctyl acrylate, justifying the read-across approach.
Reason / purpose for cross-reference:
read-across source
Qualifier:
according to guideline
Guideline:
OECD Guideline 412 (Subacute Inhalation Toxicity: 28-Day Study)
Deviations:
yes
Remarks:
Serum gamma glutamyl transpeptidase and ornithine decarboxylase were not evaluated.
Qualifier:
according to guideline
Guideline:
other: EEC Methods for the Determination of Toxicity Method B.8 Directive 92/69/EEC
Deviations:
no
Remarks:
Serum gamma glutamyl transpeptidase was not evaluated.
GLP compliance:
yes
Limit test:
no
Key result
Dose descriptor:
NOAEC
Effect level:
10 ppm
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: Based upon increased serum ALT and bilirubin levels (females) and increased liver weighs in both male and females exposed to 100 ppm.
Dose descriptor:
LOAEC
Effect level:
100 ppm
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: Based upon increased serum ALT and bilirubin levels (females) and increased liver weighs in both male and females exposed to 100 ppm.
Critical effects observed:
not specified
Conclusions:
The study on the read-across 3,3,4,4,5,5,6,6,7,7,8,8,8-tridecafluorooctan-1-ol, a metabolite of the target substance 3,3,4,4,5,5,6,6,7,7,8,8,8-tridecafluorooctyl acrylate, is used in a weight of evidence approach as worst case surrogate for the target chemical, resulting in a NOAEC of 10 ppm and the LOAEC was 100 ppm for male and female rats based upon increased serum ALT and bilirubin levels (females) and increased liver weighs in both male and females exposed to 100 ppm.. The study and the conclusions which are drawn from it fulfil the quality criteria (validity, reliability, repeatability).
Executive summary:

The purpose of this study on the source chemical 3,3,4,4,5,5,6,6,7,7,8,8,8-tridecafluorooctan-1-ol was to provide information on possible adverse effects on rats resulting from repeated exposure to the test substance by inhalation (whole body) over an extended period of time (28 days) and a four weeks recovery period.

Four groups male and female Crl:CD(SD) rats were exposed whole body 6 hours/day, 5 days/week to 0 ± 0, 1.0 ± 0.0084, 10 ± 0.057 or 100 ± 0.33 ppm test substance over a 4-week period for a total of 23 exposures. Ten male and ten female rats exposed to 0 (control) or 100 ppm were then subject to an approximate 4-week recovery period.

There were no adverse effects on body weight, body weight gains, food consumption, or food efficiency, and there were no test substance-related or adverse clinical signs of toxicity in males or females exposed to any concentration over the course of this study.

No adverse effects on motor activity were observed in either males exposed to 1 or 10 ppm or female rats exposed to 1, 10, or 100 ppm. Male rats exposed to 100 ppm demonstrated decreased motor activity during the fourth week of exposure. The decreased motor activity in male rats exposed to 100 ppm had resolved following the 4-week recovery period. In the absence of other neurobehavioral changes in 100 ppm male rats or in female rats, the lower motor activity in 100 ppm males appears to be secondary to other systemic effects of the test substance, instead of a primary effect on the nervous system. There were no adverse effects observed in the ophthalmological evaluations at any exposure level in any of the animals in this study.

Following 4 weeks of exposure, concentration-related and adverse changes in clinical chemistry parameters were observed in male and female rats exposed to 100 ppm. In these animals, increased mean serum bilirubin levels were observed when compared to the control group and several females exposed to 100 ppm exhibited increased alanine aminotransferase (ALT). Following 4 weeks of recovery, group mean values for these clinical pathology parameters in both male and females were similar to the respective control group and not statistically different. No effects on clinical chemistry parameters were observed in males or females exposed to 1 or 10 ppm.

There were no test substance-related adverse effects on gross pathological evaluation in male or females at any exposure level. Male and female rats exposed to 100 ppm demonstrated increased mean absolute liver weights as well as increased mean liver weights relative to body and brain weight one day following the last exposure. By the end of the recovery period, the liver weights were similar to control.

There were no test substance related adverse microscopic findings at any of the exposure concentrations tested. Test substance-related, but non-adverse, microscopic findings were present in the teeth (incisors) and sections of long bones (femur and tibia) at the termination of exposure and following the 1-month recovery period. These changes consisted of increased lamination of dentin of the incisor teeth and incomplete decalcification of enamel of the incisors and the bone trabeculae in the tibia and femur. These findings were consistent with exposure to a fluorine-containing test substance and were not associated with any histopathological changes suggestive of tissue injury or any adverse functional consequences in these tissues. Therefore, these microscopic findings were not considered to be adverse.

There were no portal of entry effects noted in this study; no adverse findings were observed in the respiratory tract tissues at any exposure level. Therefore, the adverse effects observed in this study are considered to be systemic effects and are consistent with those observed in a previous oral repeated dose study with the test substance.

Under the conditions of this study, the no-observed-adverse-effect concentration (NOAEC) for the test substance 3,3,4,4,5,5,6,6,7,7,8,8,8-tridecafluorooctan-1-ol was 10 ppm for male and female rats based upon increased serum ALT and bilirubin levels (females) and increased liver weights in both male and females exposed to 100 ppm. These results are considered valid for assessing the risk posed by 3,3,4,4,5,5,6,6,7,7,8,8,8-tridecafluorooctyl acrylate, the target substance.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEC
1 711 mg/m³
Study duration:
subacute
Species:
rat
Quality of whole database:
No acute effects were observed in this read-across study on 3,3,4,4,5,5,6,6,7,7,8,8,8-tridecafluorooctan-1-ol and the NOAEC was derived based on systemic effects only. The 100 ppm high dose group showing no acute effects can be estimated by conversion, considering molecular weight differences as 1711 mg/m3.

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

A one generation reproduction study on analogue substance FT-OH (3,3,4,4,5,5,6,6,7,7,8,8,8-tridecafluorooctan-1-ol) showed adverse, test substance-related clinical signs and mortality at 100 mg/kg/day in parental males and females. One male and two females at this dose level were found dead or humanely euthanized due to clinical abnormalities. Clinical signs in these animals and three additional animals that survived included clonic and tonic convulsions, ataxia, tremors (head/upper body/forelimbs), increased muscle tone, lethargy, pallor, and/or respiratory impairments.

Adverse, test substance-related changes in haematology (red and white blood cell) and clinical chemistry (liver-related) parameters were present in P males and females administered 100 mg/kg/day. Changes in liver parameters were also present in one female mouse in the 25 mg/kg/day group. Red blood cell changes in the 100 mg/kg/day groups included minimal to mild decreases in red cell mass parameters (RBC, HGB, and HCT). These changes were slightly higher relative to controls in females compared to males, and in females, were associated with a regenerative response (increased ARET). White blood cell changes in the 100 mg/kg/day male and female groups included minimal to moderate increases in white blood cell parameters (WBC, ALYM, ANEU, and AMON). These changes were likely correlative to the liver effects observed at this dose level. Changes in liver-related clinical chemistry parameters in the 100 mg/kg/day male and female groups included elevations in AST, ALT, ALP, SDH, and TBA. These changes were greater in females compared to males, with elevations of greater than 5-fold for most parameters in females and less than or equal to 5-fold in males. Increases in these same liver parameters in one 25 mg/kg/day female mouse were associated with correlative test substance-related microscopic findings in the liver and were thus also considered test substance related and adverse.

Adverse observations of anatomic pathology occurred in the liver and teeth of P males and females at 100 mg/kg/day and in the liver of females at 25 mg/kg/day. Liver changes were generally more severe in females and included hepatocellular hypertrophy, oval cell hyperplasia, single cell necrosis of hepatocytes, and cystic degeneration (females only). Increased liver weight was also observed at 100 mg/kg/day in males and females. In males and females at 100 mg/kg/day, microscopic changes in the incisor teeth consistent with fluoride exposure included degeneration and atrophy of ameloblastic epithelium, lamination of dentin, and incomplete decalcification of enamel and/or dentin.

The no-observed-adverse-effect level (NOAEL) for systemic toxicity was 25 mg/kg/day (males) and 5 mg/kg/day (females). Observations of systemic toxicity in P males and females at 100 mg/kg/day included mortality, clinical abnormalities, and differences in body weight, nutritional parameters, haematology (red and white blood cell), clinical chemistry (liver-related), liver weights, and histopathology (liver, teeth, reproductive tract, and mammary gland). Observations of systemic toxicity in parental females at 25 mg/kg/day included differences in clinical chemistry and histopathology, both of which pertained to the liver and were consistent with observations at 100 mg/kg/day.

This study was used as a read-across to fulfil the data gap for the test substance. The underlying hypothesis for the read-across between the test substance and 6:2 FTOH is that the source chemical is the primary initial metabolite of the target chemical, and both substances will therefore undergo identical distribution, metabolism and elimination from this point forwards. Any toxicity expressed by the source chemical in toxicological studies including, but not necessarily limited to, one generation reproductive toxicity study in the rat and pre-natal developmental toxicity, will be directly representative of the toxicity of the target chemical (see additional details in the attached document).

In a 90-day subchronic study on analogue FT-OH, male and female rats were given 6:2 FTOH via gavage at doses of 0, 5, 25, 125, or 250 mg/kg/day for 90 days, with 1- and 3-month recovery periods. A NOEL of 5 mg/kg/day was established. At ≥25 mg/kg/day, changes were observed in the haematology and clinical chemistry parameters, urinalysis parameters (female rats only), urine fluoride and varied histopathological effects in the liver. Mortality was observed in one female rat at 125 mg/kg/day and six or more rats in each of the sexes at 250 mg/kg/day. Therefore, on the basis of these results on the analogue FT-OH, the substance NOAEL could be considered to be 5 mg/kg/day. Considering that only slight effects in females were observed at 25 mg/kg bw/d, whereas effects at 100 mg/kg bw/d were clearly adverse, a classification as STOT Repeat Exposure Category 2 is justified. In support thereof, a 28-day subacute study on the substance itself, performed in 2014, showed that liver weights were increased in the 30 and 120 mg/kg/day groups and hypertrophy of the hepatocytes was observed in the 120 mg/kg group; however, no histopathological change was noted in the 30 mg/kg group. No kidney histopathological changes were noted at any dose levels. No adverse effects were noted in the 30 mg/kg group. This result came from a shorter exposure, but it is on the substance itself and not read-across. Therefore, also considering this additional information and giving a weight to all these oral studies, the substance can be classified as STOT-RE Category 2, with effects on liver and teeth.

Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint: This is a 1-generation reproduction study in mice (Guideline, GLP study) on 6:2 FTOH (CAS 647-42-7), which is the primary breakdown product of the target substance and thus a good candidate for read-across. The resulting NOAEL is the same as the subchronic 90 days study in rats (read across as well), but this was selected due to more pronunciated adverse effects in order to perform a more conservative classification for the substance.

No studies on the substance itself are available for the dermal route of exposure or for inhalation exposure. However, 3,3,4,4,5,5,6,6,7,7,8,8,8-tridecafluorooctan-1-ol, the direct metabolite of 3,3,4,4,5,5,6,6,7,7,8,8,8-tridecafluorooctyl acrylate, has been investigated for repeated dose toxicity by inhalation in a subacute study applying whole body exposure to rats. Within this study the liver appeared to be the target organ for systemic effects and changes were slight in the highest dose group tested (100 ppm equivalent to approximately 1’509 mg/m3). No acute effects were observed.

Justification for selection of repeated dose toxicity dermal – systemic as well as local effects endpoint: According to Regulation (EC) No 1907/2006, the results of repeated dose toxicity test only need to be provided for the most appropriate route of administration. For the test item, the oral route is considered as the most likely exposure route for human and animals. Therefore, a test via other routes can be omitted. Repeated dose toxicity: via oral and inhalation route - systemic effects (target organ) digestive: liver

Justification for classification or non-classification

Based on the liver effects (weight, clinical pathology, and histopathological changes) observed in female mice at ≥25 mg/kg/day, as well as teeth effects (microscopic changes) observed in male and female mice at 100 mg/kg, after approximately 70 days of dosing in the 1-generation mouse gavage study with analogue substance 6:2 FTOH, the substance is classified as Xn; R48/22 (Harmful: danger of serious damage to health by prolonged exposure if swallowed) according to EU Directive 67/548/EEC and STOT-RE Cat 2 (H373: May cause damage to organs [liver; teeth] through prolonged or repeated oral exposure) according to EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No. 1272/2008.