Iodine pentafluoride

Repeated dose toxicity: oral

Administrative data

Endpoint:

repeated dose toxicity: oral

Remarks:

combined repeated dose and carcinogenicity

Type of information:

migrated 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: Data published in a peer-reviewed journal, adequate for assessment.

Data source

Reference

Reference Type:

publication

Title:

Studies on the carcinogenicity of potassium iodide in F344 rats

Author:

Takegawa, K et al.

Year:

2000

Bibliographic source:

Food and Chemical Toxicology 38 (2000) 773-781

Materials and methods

Test guideline

Qualifier:

no guideline followed

Principles of method if other than guideline:

Combined repeated dose and carcinogenicity 2 year study.

GLP compliance:

no

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Potassium iodide

EC Number:

231-659-4

EC Name:

Potassium iodide

Cas Number:

7681-11-0

IUPAC Name:

potassium iodide

Test material form:

solid: particulate/powder

Remarks:

migrated information: powder

Details on test material:

- Supplier: Nacalai Tesque (Kyoto, Japan).
- Purity: >99%

Test animals

Species:

rat

Strain:

Fischer 344/DuCrj

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Japan (Atsugi, Japan)
- Age at initiation of treatment: 6 weeks
- Housing: Two or three to a polycarbonate cage with wood chips (Softchip, Sankyo Laboratory Service, Tokyo, Japan) for bedding,
- Diet (e.g. ad libitum): CRF-1 diet (Oriental Yeast, Tokyo, Japan), ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 1 week

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 24±1
- Humidity (%): 55±5
- Air changes (per hr): 18
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:

oral: drinking water

Vehicle:

water

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

2 years

Frequency of treatment:

Continuous in drinking water

Doses / concentrations

Remarks:

Doses / Concentrations:
10, 100, 1000 ppm
Basis:
nominal in water

No. of animals per sex per dose:

0 and 1000 ppm: 60 animals
10 and 100 ppm: 40 animals

Control animals:

yes, concurrent vehicle

Details on study design:

Both sexes were divided into four groups, each consisting of 60, 40, 40 and 60 rats after the acclimatization, and given KI in the drinking water at concentrations of 0, 10, 100 and 1000 ppm for 2 year, respectively. 1000 ppm was set as the highest dose, exceeding the 260 ppm which has been reported to induce colloid goitres (Kanno J., Onodera H., Furuta K., Maekawa A., Kasuga T. and Hayashi Y. (1992) Tumor-promoting effects of both iodine deficiency and iodine excess in the rat thyroid. Toxicologic Pathology 20, 226-235.). The lowest dose, 10 ppm, was also higher as compared to the optimal one for the rat, namely 0.2 ppm (Kanno et al., 1992).

Examinations

Observations and examinations performed and frequency:

During the treatment period, general condition was checked daily, and water consumption was recorded every 2 weeks up to 12 weeks, and every 4 weeks thereafter. Body weights were recorded at the same times.

Sacrifice and pathology:

In the 0 and 1000 ppm groups, five rats each were necropsied 3, 6, 12 and 18 months after the initiation of the treatment. All survivors were fasted overnight prior to necropsy, which was performed after exsanguination from the aorta under ether anesthesia. Livers, kidneys, lungs, hearts, spleens, adrenals, brains, pituitaries and thyroids were fixed in 10% neutral buffered formalin, for the interim necropsy. For animals treated for 2 year, in addition to the organs described above, testes, noses, tongues, tracheas, salivary glands, esophagus, stomachs, small and large intestines, pancreas, urinary bladders, prostates, seminal vesicles, ovaries, uteri, vaginae, mammary glands, lymph nodes, sternums, femurs, spinal cords, eye balls, skin and skeletal muscles were fixed in the same manner. Grossly visible lesions were also separately fixed. Histopathological examination was performed on hematoxylin-eosin (HE)-stained specimens processed routinely. Animals that died or were killed in a moribund condition were also necropsied and examined histopathologically. White blood cell count (WBC), red blood cell count (RBC), hemoglobin (Hb), hematocrit (Ht) and platelet count (PLT) were recorded with the aid of an automated hematology analyzer (Sysmex M-2000, Toa Medical Electronics Co., Ltd, Hyogo, Japan).

Statistics:

Body weight, water consumption, organ weight and hematology data were analyzed for homogeneity of variance using Bartlett's test. When they proved to be homogeneous, one-way analysis of variance was applied. If significant heterogeneity of variance (P≤0.01) was apparent, the equivalent non-parametric statistical method of Kruskal-Wallis was employed. Where significant differences between the groups were detected, a multiple comparison test (Dunnett's test or Scheffe's method) was used. Final survival rates and the incidences of tumors were compared with the Fisher's exact probability test.

Results and discussion

Results of examinations

Details on results:

Survival rates of male rats were decreased in the 100 and 1000 ppm groups as compared to the control from around 80 weeks after the initiation of the treatment. The rates for females of any treated groups were similar to that of the controls. Body weights in the 1000 ppm groups of both sexes were depressed in the latter half of the treatment period. Water consumption in all treated groups was similar to the control level, and KI consumption was accordingly dose dependent. Hematological examination did not reveal any effects of the treatments. On histopathological examination, the incidence of thyroid follicular dilatation was found to be increased in the 10, 100 and 1000 ppm groups of both sexes (the incidence did not decrease with decreasing dose levels). This change is however not neoplastic. This lesion was composed of increased colloid in the lumen and flattened epithelia due to the compression. Thyroid proliferative lesions derived from follicular epithelia were not increased by KI treatment, although examples were observed in each group. It was therefore concluded that long-term treatment of KI per se does not result in thyroid tumor induction in rats. In the salivary gland, focal acinar atrophy, ductular proliferation and squamous metaplasias were frequently observed, and squamous cell carcinomas were noted in four males and three females of the 1000 ppm group. SCCs of the submandibular gland were unlikely to affect the survival rate, since the incidence was low. Lobular atrophies were well-circumscribed from the surrounding tissue and triangular in shape, suggesting focal lesions related to single ducts, and accompanied by ductular proliferation in most cases. Squamous metaplasias were observed in the epithelium of proliferating ductules, and the morphological continuum to squamous cell carcinomas were observed in these metaplasias. No KI-related induction of any lesions was apparent in the other organs or tissues. Lesions with incidences more than 25% in one or more groups were, foci of cellular alteration in the liver and hyperplasias of the pituitary in both sexes, C-cell hyperplasias of the thyroid, medullary hyperplasias and pheochromocytomas of the adrenals, and interstitial cell tumors of the testis in males, and cystic endometrial hyperplasias and endometrial stromal polyps of the uterus in females. However, these are all known to spontaneously occur and neither increase in their incidence nor special types of lesions were observed in the treated groups. With regard to animals necropsied 3, 6, 12 and 18 months after the initiation of the treatment, the numbers with follicular dilatation in the thyroid were apparently increased in the 1000 ppm group as compared to the controls from 3 months. No treatment-related effects were evident in other organs.
The cause of decreased survival at the end of the treatment period in males of the 100 ppm and 1000 ppm groups in the long-term carcinogenicity study was not considered to be directly related to compression of the respiratory tract due to thyroid enlargement, since follicular dilatation of the thyroid did not show such a marked thyroidal enlargement. Overall, no possible causes for the depressed survival rates were clear. Furthermore, KI does not appear to have systemic toxic effects, other than the effect on the thyroid, at concentrations of 10 and 100 ppm, since body weight gain was not inhibited at this level of exposure.

Effect levels

Dose descriptor:

LOAEL

Effect level:

0.55 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: Thyroid findings

Target system / organ toxicity

Critical effects observed:

not specified

Applicant's summary and conclusion

Conclusions:

A LOAEL of 0.55 mg/kg bw/day was determined in a 2-year drinking water study with potassium iodide in rats.

Executive summary:

In a chronic toxicity study male and female F344/DuCrj rats received potassium iodide (KI) in the drinking water at concentrations of 0, 10, 100 or 1000 ppm for 2 years. The average daily intakes (males - females) were 0, 0.55 - 0.66, 5.31 - 6.73. and 53.03 - 66.59 mg/kg bw/day. Survival rates of male rats were decreased in the100 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 non-neoplastic lesion did not decrease with decreasing dose levels). In the submandibular salivary gland of male adn female rats of the 1000 ppm group squamous cell carcinomas were observed, along with focal acinar atrophy and/or ductular proliferation, frequently accompanied by squamous metaplasia. No KI-related induction of any lesions was apparent in any other organ or tissue. The lowest dose level of 0.55 mg/kg bw/day was considered to be a LOAEL based on the non-neoplastic thyroid change.