Iodine pentafluoride

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Effect on fertility: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

10 mg/kg bw/day

Study duration:

subchronic

Species:

rat

Quality of whole database:

GLP compliant study similar to OECD guideline 416, klimisch 1

Effect on fertility: via inhalation route

Endpoint conclusion:

no study available

Effect on fertility: via dermal route

Endpoint conclusion:

no study available

Additional information

Due to the fact that the substance violently reacts with moisture and produces hydrofluoric and iodic acids, determination of the reproduction toxicological properties of IF5 is based on fluoride and iodine. The reproduction toxicity of fluoride was determined in four studies and of iodine in one study:

In a 2 generation study, female Swiss-Webster mice were fed a low fluoride diet (0.1 -0.3 ppm fluoride) plus drinking water containing 0, 50, 100 or 200 ppm fluoride for 25 weeks from weaning (Messer 1973). Females were mated with untreated males. A high degree of fluoride toxicity was seen at 100 ppm, as evidenced by reduced growth rate and impaired reproduction, and at 200 ppm evidenced by a high mortality rate. Also, at 100 ppm only 9 litters were born over a 10 week period. In the control group a progressive decline in litter production with successive litters occurred in both generations. The results suggest that 50 ppm fluoride in drinking water (approximately 7.5 mg/kg bw/day fluoride) is more adequate to maintain reproductive capacity than the low fluoride control diet without fluoride supplemented drinking water.

The effect of sodium fluoride ingestion was also examined in a two-generation study (Collins 2001). Rats received 0, 25, 100, 175 or 250 ppm sodium fluoride in drinking. Reproduction was not affected by NaF administration, and offspring viability also remained unaffected. The decreased fluid consumption noted in high dose groups was attributed to decreased palatability. Mating, fertility and survival indices were not affected. Sodium fluoride caused an increase in the incidence of whitening of tooth enamel, in a dose-related manner in males and females in the 100, 175 and 250 ppm groups. There was an increase in the development of prominant growth lines in the upper incisors of F0 and F1 adult rats and F1 weanlings. The reproductive NOAEL in rats was therefore 250 ppm (approximately 10 mg/kg bw/day fluoride).

A quantitative examination of the testes of F1 generation males was made, following prolonged exposure to sodium fluoride in the drinking water at 0, 25, 100, 175 or 250 ppm (Sprando 1998). The rats were exposed in utero, during lactation, and directly in their drinking water for 14 weeks after weaning. At the end of the exposure period testicular tissues were perfusion fixed and examined. There were no statistically significant differences between controls and treated rats in almost all the parameters evaluated. A significant decrease in the absolute volume and volume percent of the lymphatic endothelium was observed in the 175 and 250 ppm groups, and in the testicular capsule in the 100ppm group. The authors report that the significance of this finding is not clear, and overall the results suggests that exposure to NaF does not adversely affect testis structure or spermatogenesis in the rat. The NOAEL for male fertility was therefore 250 ppm.

The potential of sodium fluoride (NaF) to affect spermatogenesis and endocrine function was assessed in P and F1 generation male rats (Sprando 1997). Male and female rats received sodium fluoride in their drinking water at 0, 25, 100, 175 or 250 ppm. P generation rats were exposed for 10 weeks, then for 3 weeks during mating. Reproductive tissues were collected from P males 1 week after mating (after approximately 14 weeks of NaF treatment). Pregnant females (P) were exposed to NaF during gestation and lactation. F1 weanling males were exposed to NaF for 14 weeks, at which time reproductive tissues were collected. Dose-related effects were not observed within the P and F1 treatment groups in testis weights, prostate/seminal vesicle weights, non-reproductive organ weights, testicular spermatid counts, sperm production per gram of testis per day, sperm production per gram of testis, LH, FSH or serum testosterone concentrations. Histopathological changes in testicular tissues were not observed. Prolonged exposure to NaF in drinking water up to a dose of 250 ppm does not adversely affect spermatogenesis or endocrine function in P and F1 generation male rats.

In summary, no effects were observed in the FDA studies (Collins 2001, Sprando 1997 and 1998) following extensive investigation. The two-generation FDA study is of standard design and is comprehensively reported, and it is notable in these studies that the contribution of diet and drinking water to the total fluoride intake was assessed. The EU RAR for HF also considers the data available for the reproductive toxicity of NaF and concludes that the FDA studies are key, for reasons of design, reporting and control of fluoride levels. The EU RAR concludes that the NOAEL for reproductive toxicity is 250 ppm NaF, which corresponds to approximately 10 mg/kg bw/d fluoride. The absence of any apparent effects on the reproductive organs in chronic toxicity studies is also notable.

A combined 28-day repeated dose toxicity study with the reproduction/developmental toxicity screening test was conducted with iodine in rats by oral gavage. The study was performed according to OECD Guideline 422. Based on the results of a 10-day dose range finding study, the dose levels for the main study were selected to be 0.3, 3 and 30 mg/kg. Four groups of ten male and ten female Wistar Han rats were exposed by oral gavage to the test substance at 0, 0.3, 3 and 30 mg/kg. Due to severe toxicity at 30 mg/kg, the dose level of Group 4 was adjusted to 10 mg/kg from Day 4 of the study onwards. Males were exposed for 29 days, i.e. 2 weeks prior to mating, during mating, and up to termination. Females were exposed for 41-47 days, i.e. during 2 weeks prior to mating, during mating, during post-coitum, and during at least 4 days of lactation. No reproduction/developmental toxicity was observed at any dose level. Based on these results, a reproduction and developmental No Observed Adverse Effect Level. (NOAEL) of 10 mg/kg was derived. Based on the absence of functional or morphological disturbances supporting the changes noted for clinical biochemistry parameters, a parental NOAEL of 10 mg/kg bw was established.

Short description of key information:
No studies with iodine pentafluoride are available. However, reliable studies with the read-across substances sodium fluoride and iodine do not indicate reproductive toxicity of fluoride or iodine. A reproductive NOAEL of 10 mg fluoride/kg bw/day was established in a 2-generation study (similar to OECD 416) in rats.

Justification for selection of Effect on fertility via oral route:
Well performed, including both males and females.

Effects on developmental toxicity

Description of key information

No studies with iodine pentafluoride are available. However, reliable studies with the read-across substances sodium fluoride and iodine do not indicate developmental toxicity in rats or rabbits. The lowest NOAEL for developmental toxicity was found in the reproduction/developmental toxicity screening study with iodine in rats, namely 10 mg iodine/kg bw/day (the highest dose level tested).

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

10 mg/kg bw/day

Study duration:

subacute

Species:

rat

Quality of whole database:

GLP compliant, OECD guideline study, klimisch 1.

Effect on developmental toxicity: via inhalation route

Endpoint conclusion:

no study available

Effect on developmental toxicity: via dermal route

Endpoint conclusion:

no study available

Additional information

Due to the fact that the substance violently reacts with moisture and produces hydrofluoric and iodic acids, determination of the developmental toxicological properties of IF5 is based on fluoride and iodine. The reproduction toxicity of fluoride was determined in three studies and of iodine in one study:

Pregnant Sprague-Dawley CD rats were exposed to sodium fluoride in their drinking water at concentrations of 0, 50, 150 or 300 ppm daily between gestation days 6 and 15 (Heindel 1996). Maternal weight gain was significantly reduced at 300 ppm during the first two days of exposure (days 6 to 16). Maternal water consumption (grams/kg/day) during exposure was significantly decreased in the animals exposed to 300ppm NaF. Post-exposure water consumption was normal in these animals indicating the probability of decreased palatability of the 300ppm solution. Necropsy of the maternal animals revealed no effects on kidney or liver weights. NaF exposure did not significantly affect the frequency of post-implantation loss, mean fetal body weight per litter, or external, visceral, or skeletal malformations. This study established a NOAEL for maternal toxicity of 150 ppm (18 mg NaF/kg bw/day, ~8.4mg fluoride/kg bw/day) and a NOAEL of 300 ppm for developmental toxicity (27 mg NaF/kg bw/day, ~12.3 mg fluoride/kg bw/day) administered in drinking water to pregnant CD rats during organogenesis.

The developmental toxicity of sodium fluoride was determined in rats. Mated females were exposed to sodium fluoride in the drinking water at concentrations of 0, 25, 100, 175 and 250 ppm on gestation days 0 -20 (Collins 1995). Caesarean sections were performed on gestation day 20 and foetuses were examined. Sodium fluoride was not teratogenic at any dose tested. There was no effect on the development of specific bones including sternebrae. Foetal growth was not affected by sodium fluoride, even in dams exhibiting significantly decreased food and water consumption (250ppm; decreased feed and water consumption, 175ppm decreased water consumption). A significant increase was seen in the average number of foetuses with three or more skeletal variations in the 250 ppm group, however the number of affected litters was not significantly increased. There was no dose related effect on sodium fluoride on the incidence of soft tissue variations. Therefore the developmental NOAEL was determined to be 250 ppm. (~11.1 mg fluoride/kg bw/day)

Pregnant New Zealand White rabbits were exposed to sodium fluoride in their drinking water at concentrations of 0, 100, 200 or 400 ppm daily between gestation days 6 and 19 (Heindel 1996). There was evidence of minimal maternal toxicity but no definitive evidence of developmental toxicity with levels of sodium fluoride in drinking water as high as 400ppm (resulting in an average exposure of 29 mg/kg bw/d) although the palatabillity of a 400 ppm sodium fluoride solution apparently reduced water consumption. This study established a NOAEL for maternal toxicity at 200 ppm NaF in drinking water (approximately 18 mg/kg bw/d) and a NOAEL for developmental toxicity of 400ppm NaF in drinking water (approximately 29 mg/kg bw/d, ~13.2 mg fluoride/kg bw/day) administered to pregnant NZW rabbits during organogenesis.

A combined 28-day repeated dose toxicity study with the reproduction/developmental toxicity screening test was conducted with iodine in rats by oral gavage. The study was performed according to OECD Guideline 422. Based on the results of a 10-day dose range finding study, the dose levels for the main study were selected to be 0.3, 3 and 30 mg/kg. Four groups of ten male and ten female Wistar Han rats were exposed by oral gavage to the test substance at 0, 0.3, 3 and 30 mg/kg. Due to severe toxicity at 30 mg/kg, the dose level of Group 4 was adjusted to 10 mg/kg from Day 4 of the study onwards. Males were exposed for 29 days, i.e. 2 weeks prior to mating, during mating, and up to termination. Females were exposed for 41-47 days, i.e. during 2 weeks prior to mating, during mating, during post-coitum, and during at least 4 days of lactation. No reproduction/developmental toxicity was observed at any dose level. Based on these results, a reproduction and developmental NOAEL of 10 mg/kg was derived. Based on the absence of functional or morphological disturbances supporting the changes noted for clinical biochemistry parameters, a parental NOAEL of 10 mg iodine/kg bw was established.

In summary, reliable studies (three developmental toxicity studies (similar to OECD Guideline 414) with sodium fluoride in rats or rabbits and a reproduction/developmental toxicity screening test (OECD Guideline 422) with iodine in rats) do not indicate developmental toxicity of fluoride or iodine. The NOAELs for developmental toxicity were about 11 -13 mg fluoride/kg bw/day (sodium fluoride studies) or 10 mg iodine/kg bw/day. When these values are converted to iodine pentafluoride (based on molecular weights of 19 for fluoride, 254 for iodine and 222 for iodine pentafluoride), the developmental NOAEL would be about 140 mg iodine pentafluoride/kg bw/day based on the studies with sodium fluoride and about 9 mg iodine pentafluoride/kg bw/day based on the study with iodine. As the lowest developmental NOAEL was obtained in the screening test with iodine, this study was selected as key study.

Justification for selection of Effect on developmental toxicity: via oral route:
Lowest NOAEL was observed in this study.

Justification for classification or non-classification

Due to the fact that the substance violently reacts with moisture and produces hydrofluoric and iodic acids, classification for toxicity is based on fluoride and iodine. Since no adverse effects were observed in the studies with iodine and fluoride, classification of IF5 according to EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No. 1272/2008 and EU Directive 67/548/EEC is not warranted.