Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.7 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
other: EFSA, Weterings et al., 2016 and ECHA REACH guidance
Overall assessment factor (AF):
0.05
Dose descriptor starting point:
other: Tolerable Daily Intake (TDI)
Value:
4 µg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
0.035 mg/m³
Explanation for the modification of the dose descriptor starting point:

Perchlorate Tolerable Daily Intake (TDI) = 4 µg/kg bw/day (Weterings et al., 2016).


NOAEC (KClO3) = (perchlorate TDI x worker bodyweight / worker respiratory volume) x Molecular Weight KClO3 / Molecular Weight ClO4 = (0.004 mg/kg bw/day x 70 kg / 10 m3/day) x 122.55 / 99.45 = 0.0345 mg/m3

AF for dose response relationship:
0.1
Justification:
According to EFSA CONTAM Panel, a factor of 10 was applied to account for the lower potency of chlorate compared to perchlorate for the inhibition of iodine uptake in humans (critical effect identified by EFSA).
AF for differences in duration of exposure:
1
Justification:
EFSA CONTAM Panel considered the inhibition of thyroid iodine uptake as the critical effect for the chronic hazard characterisation. No further safety factor was considered for duration of exposure.
AF for interspecies differences (allometric scaling):
1
Justification:
The study was performed in human volunteers (Greer et al., 2002).
AF for other interspecies differences:
1
Justification:
The study was performed in human volunteers (Greer et al., 2002).
AF for intraspecies differences:
0.5
Justification:
The study was performed in human volunteers representing general population. Also, the starting point corresponds to a TDI value, intended to general population (an AF of 4 had already been applied by the EFSA CONTAM Panel to the BMDL value to derive the TDI value for perchlorate). As the workers are a more restricted population, a safety factor of 0.5 can be applied to the initial TDI.
AF for the quality of the whole database:
1
Justification:
The study on inhibition of iodine uptake by perchlorate in human volunteers (Greer et al., 2002) was considered appropriate and was validated by EFSA CONTAM Panel.
AF for remaining uncertainties:
1
Justification:
No remaining uncertainties were identified.
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:
5 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
other: EFSA, Weterings et al., 2016 and ECHA REACH guidance
Overall assessment factor (AF):
0.05
Dose descriptor starting point:
other: Tolerable Daily Intake (TDI)
Value:
4 µg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
0.25 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

Perchlorate Tolerated Daily Intake (TDI) = 4 µg/kg bw/day (Weterings et al., 2016).


A maximum dermal absorption value of approximately 2% was found in an in vitro dermal absorption study with human skin at a low dose of 150 µg/cm².


NOAEL (KClO3) = perchlorate TDI / human dermal absorption x Molecular Weight KClO3 / Molecular Weight ClO4 = 0.004 mg/kg bw/day / 0.02 x 122.55 / 99.45 = 0.25 mg/kg bw/day

AF for dose response relationship:
0.1
Justification:
According to EFSA CONTAM Panel, a factor of 10 was applied to account for the lower potency of chlorate compared to perchlorate for the inhibition of iodine uptake in humans (critical effect identified by EFSA).
AF for differences in duration of exposure:
1
Justification:
EFSA CONTAM Panel considered the inhibition of thyroid iodine uptake as the critical effect for the chronic hazard characterisation. No further safety factor was considered for duration of exposure.
AF for interspecies differences (allometric scaling):
1
Justification:
The study was performed in human volunteers (Greer et al., 2002).
AF for other interspecies differences:
1
Justification:
The study was performed in human volunteers (Greer et al., 2002).
AF for intraspecies differences:
0.5
Justification:
The study was performed in human volunteers representing general population. Also, the starting point corresponds to a TDI value, intended to general population (an AF of 4 had already been applied by the EFSA CONTAM Panel to the BMDL value to derive the TDI value for perchlorate). As the workers are a more restricted population, a safety factor of 0.5 can be applied to the initial TDI.
AF for the quality of the whole database:
1
Justification:
The study on inhibition of iodine uptake by perchlorate in human volunteers (Greer et al., 2002) was considered appropriate and was validated by EFSA CONTAM Panel.
AF for remaining uncertainties:
1
Justification:
No remaining uncertainties were identified.
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

Risks for public health related to the presence of chlorate in food was assessed by EFSA CONTAM Panel in 2015 1. Inhibition of iodine uptake in humans was identified as the critical effect for chronic exposure to chlorate and perchlorate. A tolerable daily intake (TDI) was set by read-across from a TDI derived for this effect for perchlorate.


The established TDI was based on a BMDL05 for thyroid iodine uptake inhibition by perchlorate from a study performed in human volunteers (Greer et al., 2002), multiplied by a an overall assessment factor of 4.


When comparing the NOAEL and LOAEL for thyroid follicular cell hypertrophy in rats, perchlorate is about 10 times more potent than chlorate. Therefore, the CONTAM Panel established a TDI for chlorate of 3 μg/kg bw/day, based on the TDI established for perchlorate (0.3 μg/kg bw/day) and by multiplying by a factor of 10 for the difference in potency between the two substances.


Then, Weterings et al.2 demonstrated that the physiological intraindividual variation in iodine uptake is much larger than 5%. Therefore, a Benchmark Response (BMR) of 20% was proposed for benchmark dose analysis of human thyroidal iodine uptake data, to take the inherent variation in relative thyroidal uptake of radioactive iodine data into account. The derived TDI from the BMDL20 for perchlorate was then 4 µg/kg bw/day, which is the starting point used to calculate potassium chlorate DNELs.


 


Worker - DNEL inhalation long-term systemic toxicity


Modified starting point:


Route to route extrapolation was done from the TDI for perchlorate to obtain a NOAEC for potassium chlorate:


NOAEC (KClO3) = (perchlorate TDI x worker bodyweight / worker respiratory volume) x Molecular Weight KClO3 / Molecular Weight ClO4 = (0.004 mg/kg bw/day x 70 kg / 10 m3/day) x 122.55 / 99.45 = 0.0345 mg/m3


Assessment factors:


As applied by the EFSA CONTAM Panel, an assessment factor of 0.1 was used to take into account the 10 times lower potency of chlorate compared to perchlorate towards thyroid function.


Also, the TDI is calculated for the general population while worker population corresponds to a more restricted population. According to ECHA guidance Chapter R.8, an assesment factor of 10 is generally used to take into account intraspecies variability in general population while an assessment factor of 5 is generally used for workers. Therefore, the assessment factor for intraspecies variability in workers was reduced by a factor of 0.5.


The global assessment factor applied to the modified starting point was therefore 0.05.


 


DNEL inhalation long-term systemic toxicity = 0.0345 mg/m3 / 0.05 = 0.70 mg/m3


 


Worker - DNEL dermal long-term systemic toxicity


Modified starting point:


Route to route extrapolation was done from the TDI for perchlorate to obtain a NOAEL for potassium chlorate:


A maximum dermal absorption value of approximately 2% was found in an in vitro dermal absorption study with human skin at a low dose of 150 µg/cm².


NOAEL (KClO3) = perchlorate TDI / human dermal absorption x Molecular Weight KClO3 / Molecular Weight ClO4 = 0.004 mg/kg bw/day / 0.02 x 122.55 / 99.45 = 0.25 mg/kg bw/day


Assessment factors:


As applied by the EFSA CONTAM Panel, an assessment factor of 0.1 was used to take into account the 10 times lower potency of chlorate compared to perchlorate towards thyroid function.


Also, the TDI is calculated for the general population while worker population corresponds to a more restricted population. According to ECHA guidance Chapter R.8, an assesment factor of 10 is generally used to take into account intraspecies variability in general population while an assessment factor of 5 is generally used for workers. Therefore, the assessment factor for intraspecies variability in workers was reduced by a factor of 0.5.


The global assessment factor applied to the modified starting point was therefore 0.05.


 


DNEL dermal long-term systemic toxicity = 0.25 mg/kg bw/day / 0.05 = 5 mg/kg bw/day


 


1 EFSA CONTAM Panel (EFSA Panel on Contaminants in the Food Chain), 2015. Scientific Opinion on risks for public health related to the presence of chlorate in food. EFSA Journal 2015;13(6):4135, 103 pp. doi:10.2903/j.efsa.2015.4135


2 Weterings PJ, Loftus C, Lewandowski TA. Derivation of the critical effect size/benchmark response for the dose-response analysis of the uptake of radioactive iodine in the human thyroid. Toxicol Lett. 2016 Aug 22;257:38-43.
doi: 10.1016/j.toxlet.2016.06.004. PMID: 27268963

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
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:
no hazard identified
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:
0.05 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
other: EFSA, Weterings et al., 2016 and ECHA REACH guidance
Overall assessment factor (AF):
0.1
Dose descriptor starting point:
other: Tolerable Daily Intake (TDI)
Value:
4 µg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
5 µg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

The initial study was performed in human volunteers by oral route with perchlorate. The only modification needed is about the difference in molecular weight between perchlorate and potassium chlorate.


TDI (KClO3) = TDI perchlorate x MW KClO3 / MW ClO4 = 0.004 mg/kg bw/day x 122.55 / 99.45 = 0.005 mg/kg bw/day.

AF for dose response relationship:
0.1
Justification:
According to EFSA CONTAM Panel, a factor of 10 was applied to account for the lower potency of chlorate compared to perchlorate for the inhibition of iodine uptake in humans (critical effect identified by EFSA).
AF for differences in duration of exposure:
1
Justification:
EFSA CONTAM Panel considered the inhibition of thyroid iodine uptake as the critical effect for the chronic hazard characterisation. No further safety factor was considered for duration of exposure.
AF for interspecies differences (allometric scaling):
1
Justification:
The study was performed in human volunteers (Greer et al., 2002).
AF for other interspecies differences:
1
Justification:
The study was performed in human volunteers (Greer et al., 2002).
AF for intraspecies differences:
1
Justification:
The study was performed in human volunteers representing general population. Also, the starting point corresponds to a TDI value, intended to general population (an AF of 4 had already been applied by the EFSA CONTAM Panel to the BMDL value to derive the TDI value for perchlorate).
AF for the quality of the whole database:
1
Justification:
The study on inhibition of iodine uptake by perchlorate in human volunteers (Greer et al., 2002) was considered appropriate and was validated by EFSA CONTAM Panel.
AF for remaining uncertainties:
1
Justification:
No remaining uncertainties were identified.
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

Risks for public health related to the presence of chlorate in food was assessed by EFSA CONTAM Panel in 2015 1. Inhibition of iodine uptake in humans was identified as the critical effect for chronic exposure to chlorate and perchlorate. A tolerable daily intake (TDI) was set by read-across from a TDI derived for this effect for perchlorate.


The established TDI was based on a BMDL05 for thyroid iodine uptake inhibition by perchlorate from a study performed in human volunteers (Greer et al., 2002), multiplied by a an overall assessment factor of 4.


When comparing the NOAEL and LOAEL for thyroid follicular cell hypertrophy in rats, perchlorate is about 10 times more potent than chlorate. Therefore, the CONTAM Panel established a TDI for chlorate of 3 μg/kg bw/day, based on the TDI established for perchlorate (0.3 μg/kg bw/day) and by multiplying by a factor of 10 for the difference in potency between the two substances.


Then, Weterings et al.2 demonstrated that the physiological intraindividual variation in iodine uptake is much larger than 5%. Therefore, a Benchmark Response (BMR) of 20% was proposed for benchmark dose analysis of human thyroidal iodine uptake data, to take the inherent variation in relative thyroidal uptake of radioactive iodine data into account. The derived TDI from the BMDL20 for perchlorate was then 4 µg/kg bw/day, which is the starting point used to calculate potassium chlorate DNELs.


 


General population - DNEL oral long-term systemic toxicity


Modified starting point:


The initial study was performed in human volunteers by oral route with perchlorate. The only modification needed is about the difference in molecular weight between perchlorate and potassium chlorate.


TDI (KClO3) = TDI perchlorate x MW KClO3 / MW ClO4 = 0.004 mg/kg bw/day x 122.55 / 99.45 = 0.005 mg/kg bw/day.


Assessment factors:


As applied by the EFSA CONTAM Panel, an assessment factor of 0.1 was used to take into account the 10 times lower potency of chlorate compared to perchlorate towards thyroid function.


The global assessment factor applied to the modified starting point was therefore 0.1.


 


DNEL oral long-term systemic toxicity = 0.005 mg/kg bw/day / 0.1 = 0.05 mg/kg bw/day


 


1 EFSA CONTAM Panel (EFSA Panel on Contaminants in the Food Chain), 2015. Scientific Opinion on risks for public health related to the presence of chlorate in food. EFSA Journal 2015;13(6):4135, 103 pp. doi:10.2903/j.efsa.2015.4135


2 Weterings PJ, Loftus C, Lewandowski TA. Derivation of the critical effect size/benchmark response for the dose-response analysis of the uptake of radioactive iodine in the human thyroid. Toxicol Lett. 2016 Aug 22;257:38-43.
doi: 10.1016/j.toxlet.2016.06.004. PMID: 27268963