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Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
5.91 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
By inhalation
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
150
Modified dose descriptor starting point:
NOAEC
Value:
886.55 mg/m³
Explanation for the modification of the dose descriptor starting point:
Both repeated exposure inhalation and oral studies are available with the read across substance (6:2 FTOH). Although the 90-d oral subchronic study is of longer duration, the 1-month inhalation study will be used as the basis for the inhalation DNEL since it is the more relevant route of exposure. The starting point for the DNEL derivation is a LOAEC of 100 ppm based upon a low incidence of the combined increased in serum ALT and bilirubin levels, and increased liver weights in females exposed to 100 ppm (see discussion for additional details on study findings). Adjustments were applied for study duration (6 hr/day) and normal workday schedule (8 hr/day), and normal human to worker respiratory volume correction for light activity (6.7 m3/10 m3) per REACH guidance R.8.4.2. An additional modification of 1.19 was made to account for the difference in molecular weight between the test substance (432.18) and the read-across substance (364.1).
AF for dose response relationship:
3
Justification:
The dose descriptor is a LOAEL from a 4-week inhalation exposure study in rats. Given the low incidence of the clinical pathology endpoints indicating hepatocellular injury in female rats at 100 ppm, an assessment factor of 3 to extrapolate from a LOAEL to a NOAEL is considered appropriate per REACH guidance R.8.4.3.1.
AF for differences in duration of exposure:
4
Justification:
The observed adverse effects were observed in a 4-week inhalation exposure study and would normally be adjusted by additional factors to address duration of exposure when converting from a 4-wk inhalation study to a chronic bioassay. However, in 28- and 90-day repeated gavage oral studies, the same NOAEL was observed in each with the liver being the target organ. In the 28-day Daikin study, the NOAEL was 5 mg/kg, based on discoloured incisors in females (an indication of fluoride toxicity), and increased relative liver weight and enlargement of the liver in females given 25 mg/kg or more. In the 90-day gavage study by DuPont, changes were observed in the haematology (decreased RBC parameters at 25 mg/kg in males) and clinical chemistry parameters (elevated serum AST consistent with changes in liver weights in females at 25 mg/kg), urine fluoride and hepatic oval cell hyperplasia in females at 25 mg/kg/day. Although there are some qualitative differences in the observed effects and despite a 3-fold longer period of dosing, the NOAELs are the same when evaluating subacute to subchronic exposure. This observation indicates that orally, there is essentially no reduction in the study NOAEL with extended 62 FTOH dosing. Further, repeated exposure toxicokinetic data by the oral and inhalation routes indicate that the test substance is conjugated within minutes of exposure to glucuronide-, sulfo- or glutathione-conjugates and rapidly eliminated. An overall assessment factor of 4 (i.e., subchronic to chronic), is less than the default (i.e., 6) but is justifiable given the comparable conjugate clearance rates by different exposure routes and by the comparable subacute/subchronic NOAEL values for the oral route of exposure. Accordingly, an assessment factor of 4 is an appropriate value for study duration per REACH guidance R8.4.3.2.1.
AF for interspecies differences (allometric scaling):
1
Justification:
Since the starting point is an inhalation study in animals, no further assessment factor for allometric scaling is necessary for inhalation to inhalation route of exposure extrapolation per REACH guidance R.8.4.3.1.
AF for other interspecies differences:
2.5
Justification:
The clinical chemical and histopathological effects produced by the test substance are indicative of systemic toxicity. Since toxicodynamic interactions related to systemic toxicity are not understood, an assessment factor of 2.5 is appropriate for remaining interspecies differences per REACH guidance R.8.4.3.1.
AF for intraspecies differences:
5
Justification:
Metabolism studies in rat, mouse and human hepatocytes indicate that similar metabolites are formed. However, in vitro hepatocyte clearance is faster in rodents than humans. The first step in the metabolism is rapid (within minutes), direct conjugation involving either uridine diphospho-glucuronosyltransferases, sulfotransferases or glutathione-S-transferases with subsequent formation of glucuronide-, sulfonate- and glutathione conjugates, respectively; these are subsequently eliminated, primarily in faeces via the bile. Given the comparable metabolic profiles across species and absence of data indicating potential human polymorphisms in these enzyme systems to support a different value, a default factor of 5 for workers is appropriate according to REACH guidance in R.8.4.3.1.
AF for the quality of the whole database:
1
Justification:
A high quality, robust toxicity database exists. An assessment factor of 1 is appropriate per REACH guidance R.8.4.3.1.
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.08 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
100
Modified dose descriptor starting point:
NOAEL
Value:
8.33 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
The NOAEL of 5 mg/kg was derived from a 13-week subchronic oral gavage study in rats with the read-across chemical (6:2 FTOH). The NOAEL was based on RBC changes in males and in liver effects (increased AST and ALP activities and oval cell hyperplasia) ≥ 25 mg/kg/day. Thus, the NOAEL of 5 mg/kg is considered the starting point for dermal DNEL derivation per REACH guidance R.8.4.2. Adjustments to the starting point were applied for study duration (5 days/week instead of 7 days/week). Due to the absence of reliable data, no adjustment was taken for bioavailability differences between oral and dermal routes of exposure or for differences in the absorption between rats and humans. An additional modification of 1.19 was made to account for the difference in molecular weight between the test substance (432.18) and the read-across substance (364.1).
AF for dose response relationship:
1
Justification:
The dose descriptor is a NOAEL from a 13-week oral gavage study in rats. An assessment factor of 1 is appropriate per REACH guidance R.8.4.3.1.
AF for differences in duration of exposure:
2
Justification:
The observed adverse outcomes in a 13-week oral gavage study were considered to be adverse effects resulting from systemic exposure. While the results from 4-week and 13-week repeated exposure gavage studies have the same NOAEL, there is no longer term exposure data to predict effects with chronic exposure. Accordingly, a default assessment factor of 2 is utilized for study duration adjustment per REACH guidance R8.4.3.2.1.
AF for interspecies differences (allometric scaling):
4
Justification:
A default assessment factor of 4 is applied per REACH guidance R.8.4.3.1 since mode of action for the systemic effects is not known. A default value of 4 is used.
AF for other interspecies differences:
2.5
Justification:
The clinical chemical and histopathological effects produced by the test substance are indicative of systemic toxicity. Since toxicodynamic interactions related to systemic toxicity are not understood, an assessment factor of 2.5 is appropriate for remaining interspecies differences per REACH guidance R.8.4.3.1.
AF for intraspecies differences:
5
Justification:
Metabolism studies in rat, mouse and human hepatocytes indicate that similar metabolites are formed. However, in vitro hepatocyte clearance is faster in rodents than humans. The first step in the metabolism is rapid (within minutes), direct conjugation involving either uridine diphospho-glucuronosyltransferases, sulfotransferases or glutathione-S-transferases with subsequent formation of glucuronide-, sulfonate- and glutathione conjugates, respectively; these are subsequently eliminated, primarily in faeces via the bile. Given the comparable metabolic profiles across species and absence of data indicating potential human polymorphisms in these enzyme systems to support a different value, a default factor of 5 for workers is appropriate according to REACH guidance in R.8.4.3.1.
AF for the quality of the whole database:
1
Justification:
A high quality, robust toxicity database exists. An assessment factor of 1 is appropriate per REACH guidance R.8.4.3.1.
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - workers

The key inhalation study is an OECD 412 compliant, 28-d inhalation study in rats with design concentrations of 0, 1, 10, and 100 ppm (see ARF document for justification of read-across). Male and female rats exposed to 100 ppm of 6:2 FTOH demonstrated increased (~20-27%) mean absolute and relative (to body and brain) liver weights one day following the last exposure; by the end of the recovery period, the liver weights were similar to control. In females, 4 of 20 rats exposed to 100 ppm of 6-2 FTOH had ALT (a more specific and sensitive indicator of potential hepatic injury than AST and SDH) values more than double the historical and concurrent control values.  Bilirubin, another indicator of hepatic injury particularly in conjunction with increases in ALT, was minimally but statistically increased (~64% above controls) in 100 ppm females; absent other indicators, bilirubin values alone less than 2-fold above controls are considered to represent biological abnormalities rather than hepatic injury. However, only 1/20 females had an ALT and total bilirubin values more than two-fold above controls suggesting a very low incidence of hepatocellular injury at 100 ppm. In contrast, male rats had ALT values that were slightly increased but within the historical reference range. ALT and total bilirubin values were normal after a 4-week recovery. No histopathological changes were evident in the liver of males or females in any dose group. Nonetheless, the increased liver weights seen in both male and female rats at 100 ppm is considered adverse given the serum ALT levels observed. However, given that two or more enzymatic indicators of liver injury were increased by a factor or 2 or more compared to controls in only 1/20 females, 100 ppm can be considered to be a minimal effect level for hepatocellular injury. Since the clinical pathology changes at 100 ppm were of low incidence and absent histopathological correlates, the 100 ppm LOAEC should be used as the starting point rather than the 10 ppm NOAEC since the actual NOAEC is likely much closer to 100 ppm than 10 ppm.

 

A 90-day repeated dose oral gavage study was conducted in rats with 6:2 FTOH at dosages of 0, 5, 25, 125, and 250 mg/kg/day (see ARF document for justification of read-across). The NOAEL is 5 mg/kg/day. At 25 mg/kg/day and higher, changes were observed in the haematology and clinical chemistry parameters, urinalysis parameters (female rats only), urine fluoride and varied histopathological effects in the liver. At 125 and 250 mg/kg/day, 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. Adverse clinical signs (primarily dental effects) were also increased in these groups, body weights and body weight changes were significantly reduced, plasma fluoride levels were increased and there was a test substance-related effect on the ameloblastic epithelium of the tooth. Feed consumption values were also significantly reduced in the female rats and increased apoptosis in the acinar cells at sacrifice in the male rats at 250 mg/kg/day. Therefore, the findings of the 90-day oral study are sufficient for the identification of hazard benchmarks for the purposes of risk assessment for workers including route-to-route extrapolation for potential inhalation exposure.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.03 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
200
Modified dose descriptor starting point:
NOAEL
Value:
5.95 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
The NOAEL of 5 mg/kg was derived from a 13-week subchronic oral gavage study in rats. The NOAEL was based on RBC changes in males and in liver effects (increased AST and ALP activities and oval cell hyperplasia) at ≥ 25 mg/kg/day. Thus, the NOAEL of 5 mg/kg is considered the starting point for dermal DNEL derivation per REACH guidance R.8.4.2. No adjustments to the starting point were applied for study duration since rats were dosed daily in the key study. Due to the absence of reliable data, no adjustment was taken for bioavailability differences between oral and dermal routes of exposure or for differences in the absorption between rats and humans. A modification of 1.19 was made to account for the difference in molecular weight between the test substance (432.18) and the read-across substance (364.1). Accordingly, the total adjustment factor is 1.19, consistent with REACH R.8.4.2 guidance.
AF for dose response relationship:
1
Justification:
The dose descriptor is a NOAEL from a 13-week oral gavage study in rats. An assessment factor of 1 is appropriate per REACH guidance R.8.4.3.1.
AF for differences in duration of exposure:
2
Justification:
The observed adverse outcomes in a 13-week oral gavage study were considered to be adverse effects resulting from systemic exposure. While the results from 4-week and 13-week repeated exposure gavage studies have the same NOAEL, there is no data from longer term studies to predict effects and NOAEL values associated with chronic expsoure. Accordingly, a default assessment factor of 2 is utlized for study duration adjustment per REACH guidance R8.4.3.2.1.
AF for interspecies differences (allometric scaling):
4
Justification:
A default assessment factor of 4 is applied per REACH guidance R.8.4.3.1 since mode of action for the systemic effects is not known. A default value of 4 is used.
AF for other interspecies differences:
2.5
Justification:
The clinical chemical and histopathological effects produced by the test substance are indicative of systemic toxicity. Since toxicodynamic interactions related to systemic toxicity are not understood, an assessment factor of 2.5 is appropriate for remaining interspecies differences per REACH guidance R.8.4.3.1.
AF for intraspecies differences:
10
Justification:
Metabolism studies in rat, mouse and human hepatocytes indicate that similar metabolites are formed. However, in vitro hepatocyte clearance is faster in rodents than humans. The first step in the metabolism is rapid (within minutes), direct conjugation invovling either uridine diphospho-glucuronosyltransferases, sulfotransferases or glutathione-S-transferases with subsequent formation of glucuronide-, sulfonate- and glutathione conjugates, respectively; these are subsequently eliminated, primarily in feces via the bile. Given the comparable metabolic profiles across species and absence of data indicating potential human polymorphisms in these enzyme systems to support a different value, a default factor of 10 for the general population is appropriate according to REACH guidance in R.8.4.3.1.
AF for the quality of the whole database:
1
Justification:
A high quality, robust toxicity database exists. An assessment factor of 1 is appropriate per REACH guidance R.8.4.3.1.
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - General Population

A 90-day repeated dose oral gavage study in rats was conducted with 6:2 FTOH at dosages of 0, 5, 25, 125, and 250 mg/kg/day (see ARF document for justification of read-across). The NOAEL is 5 mg/kg/day. At 25 mg/kg/day and higher, changes were observed in the haematology and clinical chemistry parameters, urinalysis parameters (female rats only), urine fluoride and varied histopathological effects in the liver. At 125 and 250 mg/kg/day, 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. Adverse clinical signs (primarily dental effects) were also increased in these groups, body weights and body weight changes were significantly reduced, plasma fluoride levels were increased and there was a test substance-related effect on the ameloblastic epithelium of the tooth. Feed consumption values were also significantly reduced in the female rats and increased apoptosis in the acinar cells at sacrifice in the male rats at 250 mg/kg/day. Therefore, the findings of the 90-day oral study are sufficient for the identification of hazard benchmarks for the purposes of risk assessment for the general population including route-to-route extrapolation for potential inhalation exposure.