Iodine pentafluoride

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.122 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

other: DNEL calculated from tolerable daily intake (TDI) for iodine (0.01 mg/kg bw/day) established by WHO on the basis of human data.

Explanation for the modification of the dose descriptor starting point:

Only information on oral route available

Acute/short term exposure

Hazard assessment conclusion:

high hazard (no threshold derived)

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

high hazard (no threshold derived)

Acute/short term exposure

Hazard assessment conclusion:

high hazard (no threshold derived)

DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.175 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

other: DNEL calculated from tolerable daily intake (TDI) for iodine (0.01 mg/kg bw/day) established by WHO on the basis of human data

Explanation for the modification of the dose descriptor starting point:

Only information on oral route available

Acute/short term exposure

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

high hazard (no threshold derived)

Acute/short term exposure

Hazard assessment conclusion:

no DNEL required: short term exposure controlled by conditions for long-term

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:

high hazard (no threshold derived)

Additional information - workers

According to the REACH Guidance on information requirements and chemical safety assessment, a leading DN(M)EL needs to be derived for every relevant human population and every relevant route, duration and frequency of exposure, if feasible.

Short-term toxicity, local toxicity and sensitization

According to the REACH guideline (R8, Appendix R 8-8), a DNEL for acute toxicity should be derived if an acute toxicity hazard (leading to C&L) has been identified and there is a potential risk for high peak exposures. Although acute toxicity studies on iodine pentafluoride (IF5) are not available due to its corrosive properties, information on the decomposition products suggests a classification for acute toxicity is nonetheless warranted. Therefore, the substance is classified for acute dermal, inhalation, and oral toxicity. As a result, DNELs need to be derived for these routes of exposure. However, the long-term DNEL for systemic effects is sufficiently low to ensure that acute systemic toxicity does not occur and, therefore, no DNELs have been derived for systemic effects after short-term exposure.

Regarding local effects:

The substance is classified as corrosive to the skin. However, there are no dose-response data on which a DNEL for local dermal effects can be derived. To protect against local dermal effects all dermal exposure to the substance should be avoided. Although no data is available on whether the test substance could cause irritation to the respiratory tract, based on its physicochemical properties, the substance is likely to be corrosive to the respiratory tract. The long-term inhalation DNEL for systemic effects is considered sufficiently low to prevent possible local effects by inhalation.

The substance is not classified as sensitizing and therefore no DNEL for sensitization is needed.

Long-term toxicity

Iodine pentafluoride violently reacts with moisture and produces hydrofluoric and iodic acids which will undergo rapid dissociation into the respective cations H⁺and anions IO₃^-and F^-. So in reality the information on the iodate and fluoride anions needs to be considered. However, the available repeated dose toxicity data on iodate are limited and are not suitable as a starting point for DNEL derivation. Therefore data on repeated dose toxicity of iodide and fluoride will be used to derive a DNEL.

Fluoride

A comprehensive NTP dataset is available on the repeated dose toxicity of sodium fluoride (NaF). In a 14-day range-finding study with NaF in the rat, mortality was seen at drinking water concentrations of 400 and 800 ppm. Signs of toxicity (reduced weight gain, reduced water consumption, lethargy and dehydration) were noted in surviving animals in these groups. The NOAEL for this study was 200 ppm. In a 14-day range-finding study in the mouse, mortality was seen at the highest dose level of 800 ppm. Signs of toxicity (reduced weight gain, abnormal gait and posture, reduced water consumption) were also apparent at this dose level. A NOAEL of 400 ppm is determined for this study. In a 6-month rat study, the effects of exposure to NaF were limited to reduced weight gain, dental fluorosis, and thickening and ulceration of the gastric mucosa at the highest dose level of 300 ppm. Gastric effects were also seen at 100 ppm. The fluoride content of plasma, bone and teeth increased with dose levels. The NOEL for this study was 30 ppm, however the local gastric effects are considered not to be relevant for the risk assessment and, therefore, a NOAEL of 100 ppm can be determined. In a 6 -month mouse study, mortality attributable to acute nephrosis was seen at the highest dose level of 600 ppm. Skeletal effects were seen in males at the lowest dose level of 50 ppm. No studies of repeated dose dermal toxicity are available. In a published inhalation toxicity study (Sadilova et al, 1974), female rats were exposed to 1 mg/m3 HF 6 hours/day for 1 month. Effects were noted on the teeth, bones and respiratory tract. Two proprietary studies (Placke et al;1990, 1991) are summarised in the EU RAR. However, the data owner is unknown and therefore there is no access to these studies. The EU RAR summary states that an over-all NOAEL for repeated inhalatory exposure in male and female rats was identified as 0.72 mg/m3 (actual HF concentration) for an exposure regimen of 6 hours per day, 5 days per week, for 91 days. No adverse effects were noted at this concentration. At higher concentrations death, tissue irritation, dental malformations, haematological and biological changes and changes in several organ weights were observed. 

Iodine

The repeated dose toxicity of iodide was investigated in a 2-year oral (drinking water) study in rats (Takegawa 2000). Male and female F344/DuCrj rats were given potassium iodide (KI) in the drinking water at concentrations of 0, 10, 100 or 1000 ppm for 2 years (corresponding to mean daily intakes in males/females of 0.55/0.66, 5.3/6.7 and 53/67 mg/kg bw/day at the low-, mid- and high-dose, respectively. Survival rates of male rats were decreased in the 100 and 1000 ppm groups. Body weights in the 1000 ppm groups of both sexes were decreased in the latter half of the treatment period. The incidence of thyroid follicular dilatation was increased in the 10, 100 and 1000 ppm groups of both sexes. The incidence of this thyroid lesion did not decrease with decreasing dose levels (1/40, 20/40, 7/40 and 11/40 in males, 3/40, 17/40, 11/40 and 18/40 in females of the control, 10, 100 and 1000 ppm groups, respectively). The authors noted that this thyroid change is not neoplastic and that it resembles the morphological alteration reported to be observed in humans under conditions of chronic exposure to excess iodine. In the submandibular salivary gland of male and female rats treated with 1000 ppm squamous cell carcinomas (SCCs) were observed, along with focal acinar atrophy and/or ductular proliferation, frequently accompanied by squamous metaplasia. The SCCs were seen only at a high dose and did not raise concern with regard to carcinogenicity by different expert groups. Therefore, the SCCs in the thyroid were considered not to be relevant for the DNEL derivation. No KI-related induction of any lesions was apparent in other organs and tissues examined. The lowest dose level of 0.55 mg/kg bw/day was considered to be a LOAEL based on the non-neoplastic thyroid changes.

Reproductive and developmental toxicity effects

The reproductive and developmental toxicity NOAELs are at the same or higher level as for repeated dose toxicity. Therefore, the DNEL derived for repeated dose toxicity will also cover the reproductive and developmental toxic effects. No specific DNELs will be derived for these endpoints.

DNEL derivation

DNELs based on animal toxicity data

As explained above, the long-term DNELs for systemic effects are sufficiently low to protect against short-term systemic effects. Several repeated-dose studies in rats or mice are available for derivation of long-term DNELs for systemic effects. These studies included oral studies with NaF or KI and inhalation studies with HF. The lowest LOAEL of 0.55 mg/kg bw/day was observed in the 2-year drinking water study with KI in rats (in the 6-month drinking water studies with NaF, 100 ppm was a NOAEL in the rat and 50 ppm was a LOAEL in the mouse; these levels corresponded to a daily intake of about 5 mg NaF/kg bw/day, or about 5.5 mg/kg bw when converted to IF₅). The LOAEL for KI was, therefore, used for DNEL calculations. Inhalation studies in rats (lasting between 14 days and 13 weeks) are available, but only for fluoride (HF). It is not known whether inhalation exposure to iodide would result in lower NOAEC/LOAECs than inhalation exposure to fluoride. Therefore, to derive a DNEL for inhalation exposure from the animal toxicity data, route-to-route extrapolation from the 2-year oral study with KI was applied. In the absence of dermal repeated dose toxicity data, route-to-route extrapolation was also used to derive a DNEL for dermal exposure.

As no substance-specific absorption data are available for IF₅, the default absorption factors from the REACH guidance (Chapter 8, R.8.4.2) were used during route-to-route extrapolation to obtain modified dose descriptors (factor 2 for oral to inhalation and factor 1 for oral to dermal).

By applying a correction for molecular weight to the LOAEL for KI from the 2-year oral rat study (0.55 mg/kg bw x 221.90 [Mw IF₅] /166 [Mw KI), a LOAEL of 0.735 mg/kg bw/day can be derived for IF₅.

The long-term DNELs (worker: inhalation and dermal; general population: oral) calculated from the 2-year rat study, including the assumptions and assessment factors used, are presented in the tables hereafter.These DNELs were not used for the risk characterisation because the DNELs derived from human data (tolerable daily intake for iodine) were considered more appropriate for this purpose.

DNELs based on human data (tolerable daily intake for iodine)

The potential iodine exposure resulting from the long-term DNEL calculated from the rat study (namely 0.7 µg/kg bw/day for worker by inhalation) is considerably lower than the tolerable daily intake (TDI) for iodine of 0.01 mg/kg bw/day as establised by the World Health Organisation (WHO, 2009) and the EU Scientific Committee on Food (EFSA, 2006). This TDI, which is an estimate of the amount of iodine that can be taken in daily over a lifetime without appreciable health risk, is based upon reversible subclinical hypothyroism in healthy children, a sensitive subpopulation. It is supported by studies in elderly adults who may represent another sensitive subpopulation (WHO, 2009). An alternative approach to deriving systemic DNELs would be to use the TDI for iodine as starting point. Applying a correction for molecular weight (126.9 and 221.9 g/mol for iodine and IF₅, respectively), the TDI of 0.010 mg/kg bw/day for iodine corresponds to 0.0175 mg/kg bw/day for IF₅. On this basis, the following DNELs for long-term systemic effects can be derived:

Worker, inhalation: 0.122 mg IF₅/m³

This value is based on the following assumptions: body weight 70 kg, volume of inhaled air 10 m³ in 8 hours, no differences in absorption between routes as molecular iodine and inorganic compounds of iodine are readily and extensively absorbed by both the inhalation and oral routes (WHO, 2009). Calculation: (0.0175 mg IF₅/kg x 70 kg) / 10 m3. To ascertain that this long-term inhalation DNEL based on the critical systemic effect of iodine (hypothyroidism) is low enough to protect against the ciritical effect (skeletal fluorosis) of chronic exposure to fluoride, the DNEL derived from the TDI of iodine is compared with the occupational exposure limit for hydrogen fluoride. The Scientific Committee on Occupational Exposure Limits established an 8-hour TWA of 1.5 mg/m³as fluoride ion for hydrogen fluoride (SCOEL, 1998). Applying a correction for molecular weight (19 and 221.9 g/mol for F and IF₅, respectively), the TWA of 1.5 mg/m³ of fluoride corresponds to 3.5 mg IF₅/m³ which is nearly 30 times higher than the iodine-based DNEL of 0.122 mg IF₅/m³. Hence, the long-term inhalation DNEL for IF₅derived from the TDI for iodine is low enough to protect against systemic effects of the IF₅ metabolite fluoride.

Worker, dermal: 0.175 mg IF₅/kg bw/day

This value is based on the assumption that the ratio oral to dermal absorption is 10:1. Dermal absorption in humans has been experimentally shown to be 1% or less of the applied dose (WHO, 2009). Hence, dermal absorption of iodine is likely to be minimal unless the integrity of the skin is compromised. As IF₅is a corrosive substance, a dermal absorption higher than 1%, namely 10%, was assumed for DNEL derivation.

Calculation: 0.0175 mg IF₅/kg x 10.

The long-term DNELs for systemic effects derived from the TDI for iodine will be taken forward to the risk characterisation.

References

- EFSA (2006). Tolerable upper intake levels for vitamins and minerals. European Food Safety Authority.

- SCOEL (1998). Recommendation from Scientific Committee on Occupational Exposure Limits for Fluorine, Hydrogen Fluoride and Inorganic Fluorides (not uranium hexafluoride).

- WHO (2009). Concise International Chemical Assessment Document 72. Iodine and inorganic iodides: Human health aspects. Geneva, World Health Organization.

Calculation of worker DNELsbased on animal data

Worker, Long-term – inhalation, systemic effects (based on 2-year oral study in rats by Takegawa et al.)

Description	Value		Remark
Step 1) Relevant dose-descriptor	LOAEL: 0.55 mg/kg bw/day		LOAEL potassium iodide based on non-neoplastic change in thyroid
Step 2) Modification of starting point	KI: 166 g/mol IF5: 221.9 g/mol   2           0.38 m^3/kg bw           6.7 m^3/10 m^3		Correction for molecular weight.     The REACH Guidance on information requirements and chemical safety assessment (R.8.4.2) prescribes a default factor of 2 in case of oral to inhalation extrapolation.   Standard respiratory volume of a rat, corrected for 8 h exposure, as proposed in the REACH Guidance on information requirements and chemical safety assessment (R.8.4.2).   Correction for activity driven differences of respiratory volumes in workers compared to workers in rest.
Modified dose-descriptor	(0.55*221.9/166) / 2 / 0.38 x (6.7/10) = 0.65 mg/m^3
Step 3) Assessment factors
Interspecies	2.5	For inhalation studies only a factor 2.5 for remaining interspecies differences is used, and no correction is made for differences in body size, because extrapolation is based on toxicological equivalence of a concentration of a chemical in the air of experimental animals and humans; animals and humans breathe at a rate depending on their caloric requirements.
Intraspecies	5	Default AF for workers
Exposure duration	1	2-year study
Dose response	3	Default AF to extrapolate from LOAEL to NOAEL
Quality of database	2	Read-across
DNEL	Value
	0.65 / (2.5 x 5 x 1 x 3 x 2) = 0.65 / 75 =8.6µg IF5/m^3 (corresponding to 0.7 µg I or 0.5 µg F/kg bw/day, based on 70 kg body weight and 10 m^3air inhaled in 8 hours)

Worker, Long-term – dermal, systemic effects (based on 2-year oral study in rats by Takegawa et al.)

Description	Value	Remark
Step 1) Relevant dose-descriptor	LOAEL: 0.55 mg/kg bw/day	LOAEL potassium iodide based on non-neoplastic change in thyroid
Step 2) Modification of starting point	KI: 166 g/mol IF5: 221.9 g/mol	Correction for molecular weight.
Modified dose-descriptor	0.55*221.9/166 = 0.735 mg/kg bw/day
Step 3) Assessment factors
Interspecies	4 x 2.5	Assessment factor for allometric scaling and remaining interspecies differences.
Intraspecies	5	Default AF for workers
Exposure duration	1	2-year exposure
Dose response	3	Default AF to extrapolate from LOAEL to NOAEL
Quality of database	2	Read-across
DNEL	Value
	0.735 / (4 x 2.5 x 5 x 1 x 3 x 2) = 0.735 / 300 =2.5 µg IF5/kg bw/day (corresponding to 1.4 µg I or 1.0 µg F/kg bw/day)

General Population - Hazard via inhalation route

Systemic effects

Acute/short term exposure

DNEL related information

Local effects

Acute/short term exposure

DNEL related information

General Population - Hazard via dermal route

Systemic effects

Acute/short term exposure

DNEL related information

General Population - Hazard via oral route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.018 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

other: DNEL calculated from tolerable daily intake (TDI) for iodine (0.01 mg/kg bw/day) established by WHO on the basis of human data.

Acute/short term exposure

Hazard assessment conclusion:

high hazard (no threshold derived)

DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:

high hazard (no threshold derived)

Additional information - General Population

According to the REACH Guidance on information requirements and chemical safety assessment, a leading DN(M)EL needs to be derived for every relevant human population and every relevant route, duration and frequency of exposure, if feasible.

Short-term toxicity, local toxicity and sensitization

According to the REACH guideline (R8, Appendix R 8-8), a DNEL for acute toxicity should be derived if an acute toxicity hazard (leading to C&L) has been identified and there is a potential risk for high peak exposures. Although acute toxicity studies on iodine pentafluoride (IF5) are not available due to its corrosive properties, information on the decomposition products suggests a classification for acute toxicity is nonetheless warranted. Therefore, the substance is classified for acute dermal, inhalation, and oral toxicity. As a result, DNELs need to be derived for these routes of exposure. However, the long-term DNEL for systemic effects is sufficiently low to ensure that acute systemic toxicity does not occur and, therefore, no DNELs have been derived for systemic effects after short-term exposure.

Regarding local effects:

The substance is classified as corrosive to the skin. However, there are no dose-response data on which a DNEL for local dermal effects can be derived. To protect against local dermal effects all dermal exposure to the substance should be avoided. Although no data is available on whether the test substance could cause irritation to the respiratory tract, based on its physicochemical properties, the substance is likely to be corrosive to the respiratory tract. The long-term inhalation DNEL for systemic effects is considered sufficiently low to prevent possible local effects by inhalation.

The substance is not classified as sensitizing and therefore no DNEL for sensitization is needed.

Long-term toxicity

Iodine pentafluoride violently reacts with moisture and produces hydrofluoric and iodic acids which will undergo rapid dissociation into the respective cations H⁺and anions IO₃^-and F^-. So in reality the information on the iodate and fluoride anions needs to be considered. However, the available repeated dose toxicity data on iodate are limited and are not suitable as a starting point for DNEL derivation. Therefore data on repeated dose toxicity of iodide and fluoride will be used to derive a DNEL.

Fluoride

A comprehensive NTP dataset is available on the repeated dose toxicity of sodium fluoride (NaF). In a 14-day range-finding study with NaF in the rat, mortality was seen at drinking water concentrations of 400 and 800 ppm. Signs of toxicity (reduced weight gain, reduced water consumption, lethargy and dehydration) were noted in surviving animals in these groups. The NOAEL for this study was 200 ppm. In a 14-day range-finding study in the mouse, mortality was seen at the highest dose level of 800 ppm. Signs of toxicity (reduced weight gain, abnormal gait and posture, reduced water consumption) were also apparent at this dose level. A NOAEL of 400 ppm is determined for this study. In a 6-month rat study, the effects of exposure to NaF were limited to reduced weight gain, dental fluorosis, and thickening and ulceration of the gastric mucosa at the highest dose level of 300 ppm. Gastric effects were also seen at 100 ppm. The fluoride content of plasma, bone and teeth increased with dose levels. The NOEL for this study was 30 ppm, however the local gastric effects are considered not to be relevant for the risk assessment and, therefore, a NOAEL of 100 ppm can be determined. In a 6 -month mouse study, mortality attributable to acute nephrosis was seen at the highest dose level of 600 ppm. Skeletal effects were seen in males at the lowest dose level of 50 ppm. No studies of repeated dose dermal toxicity are available. In a published inhalation toxicity study (Sadilova et al, 1974), female rats were exposed to 1 mg/m3 HF 6 hours/day for 1 month. Effects were noted on the teeth, bones and respiratory tract. Two proprietary studies (Placke et al;1990, 1991) are summarised in the EU RAR. However, the data owner is unknown and therefore there is no access to these studies. The EU RAR summary states that an over-all NOAEL for repeated inhalatory exposure in male and female rats was identified as 0.72 mg/m3 (actual HF concentration) for an exposure regimen of 6 hours per day, 5 days per week, for 91 days. No adverse effects were noted at this concentration. At higher concentrations death, tissue irritation, dental malformations, haematological and biological changes and changes in several organ weights were observed. 

Iodine

The repeated dose toxicity of iodide was investigated in a 2-year oral (drinking water) study in rats (Takegawa 2000). Male and female F344/DuCrj rats were given potassium iodide (KI) in the drinking water at concentrations of 0, 10, 100 or 1000 ppm for 2 years (corresponding to mean daily intakes in males/females of 0.55/0.66, 5.3/6.7 and 53/67 mg/kg bw/day at the low-, mid- and high-dose, respectively. Survival rates of male rats were decreased in the 100 and 1000 ppm groups. Body weights in the 1000 ppm groups of both sexes were decreased in the latter half of the treatment period. The incidence of thyroid follicular dilatation was increased in the 10, 100 and 1000 ppm groups of both sexes. The incidence of this thyroid lesion did not decrease with decreasing dose levels (1/40, 20/40, 7/40 and 11/40 in males, 3/40, 17/40, 11/40 and 18/40 in females of the control, 10, 100 and 1000 ppm groups, respectively). The authors noted that this thyroid change is not neoplastic and that it resembles the morphological alteration reported to be observed in humans under conditions of chronic exposure to excess iodine. In the submandibular salivary gland of male and female rats treated with 1000 ppm squamous cell carcinomas (SCCs) were observed, along with focal acinar atrophy and/or ductular proliferation, frequently accompanied by squamous metaplasia. The SCCs were seen only at a high dose and did not raise concern with regard to carcinogenicity by different expert groups. Therefore, the SCCs in the thyroid were considered not to be relevant for the DNEL derivation. No KI-related induction of any lesions was apparent in other organs and tissues examined. The lowest dose level of 0.55 mg/kg bw/day was considered to be a LOAEL based on the non-neoplastic thyroid changes.

Reproductive and developmental toxicity effects

The reproductive and developmental toxicity NOAELs are at the same or higher level as for repeated dose toxicity. Therefore, the DNEL derived for repeated dose toxicity will also cover the reproductive and developmental toxic effects. No specific DNELs will be derived for these endpoints.

DNEL derivation

As there is no consumer use for iodine pentafluoride (only manufacturing and use as intermediate), no long-term inhalation and dermal DNELs for the general population were calculated.

DNELs based on animal toxicity data

As explained above, the long-term DNELs for systemic effects are sufficiently low to protect against short-term and local effects. Several repeated-dose studies in rats or mice are available for derivation of long-term DNELs for systemic effects. These studies included oral studies with NaF or KI and inhalation studies with HF. The lowest LOAEL of 0.55 mg/kg bw/day was observed in the 2-year drinking water study with KI in rats (in the 6-month drinking water studies with NaF, 100 ppm was a NOAEL in the rat and 50 ppm was a LOAEL in the mouse; these levels corresponded to a daily intake of about 5 mg NaF/kg bw/day, or about 5.5 mg/kg bw when converted to IF₅). The LOAEL for KI was, therefore, used for DNEL calculation. By applying a correction for molecular weight to the LOAEL for KI from the 2-year oral rat study (0.55 mg/kg bw x 221.9 [Mw IF₅] /166 [Mw KI), a LOAEL of 0.735 mg/kg bw/day can be derived for IF₅.

The long-term DNEL (general population: oral) calculated from the 2-year rat study, including the assumptions and assessment factors used, is presented in the table hereafter. This DNEL was not used for the risk characterisation because the DNEL derived from human data (tolerable daily intake for iodine) was considered more appropriate for this purpose.

DNEL based on human data (tolerable daily intake for iodine)

The potential iodine exposure resulting from the long-term DNEL calculated from the rat study (namely 0.7 µg/kg bw/day for general population by the oral route) is considerably lower than the tolerable daily intake (TDI) for iodine of 0.01 mg/kg bw/day as establised by the World Health Organisation (WHO, 2009) and the EU Scientific Committee on Food (EFSA, 2006). This TDI, which is an estimate of the amount of iodine that can be taken in daily over a lifetime without appreciable health risk, is based upon reversible subclinical hypothyroism in healthy children, a sensitive subpopulation. It is supported by studies in elderly adults who may represent another sensitive subpopulation (WHO, 2009).

An alternative approach to deriving systemic DNELs would be to use the TDI for iodine as starting point. Applying a correction for molecular weight (126.9 and 221.9 g/mol for iodine and IF₅, respectively), the TDI of 0.010 mg/kg bw/day for iodine corresponds to 0.0175 mg/kg bw/day for IF₅. On this basis, the following DNEL for long-term systemic effects can be derived:

General population, oral: 0.0175 mg IF₅/kg bw/day

As the TDI for iodine is based on oral exposure, no modifications for route-to-route extrapolation or absorption differences are needed. The long-term DNEL for systemic effects derived from the TDI for iodine will be taken forward to the risk characterisation.

References

-  EFSA (2006). Tolerable upper intake levels for vitamins and minerals. European Food Safety Authority.

- SCOEL (1998). Recommendation from Scientific Committee on Occupational Exposure Limits for Fluorine, Hydrogen Fluoride and Inorganic Fluorides (not uranium hexafluoride).

- WHO (2009). Concise International Chemical Assessment Document 72. Iodine and inorganic iodides: Human health aspects. Geneva, World Health Organization.

Calculation of general population DNEL based on animal data

General population, Long-term – oral, systemic effects (based on 2-year oral study in rats by Takegawa et al.)

Description	Value	Remark
Step 1) Relevant dose-descriptor	LOAEL: 0.55 mg/kg bw/day	LOAEL potassium iodide based on non-neoplastic change in thyroid
Step 2) Modification of starting point	KI: 166 g/mol IF5: 221.9 g/mol	Correction for molecular weight.
Modified dose-descriptor	0.55*221.9/166 = 0.735 mg/kg bw/day
Step 3) Assessment factors
Interspecies	4 x 2.5	Assessment factor for allometric scaling and remaining interspecies differences.
Intraspecies	10	Default AF general population
Exposure duration	1	2-year exposure
Dose response	3	Default AF to extrapolate from LOAEL to NOAEL
Quality of database	2	Read-across
DNEL	Value
	0.735 / (4 x 2.5 x 10 x 1 x 3 x 2) = 0.735 / 600 =1.2 µg IF5/kg bw/day (corresponding to 0.7 µg I or 0.5 µg F/kg bw/day)