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Administrative data

Endpoint:
carcinogenicity, other
Remarks:
oral and dermal
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
test procedure in accordance with generally accepted scientific standards and described in sufficient detail

Data source

Reference
Reference Type:
publication
Title:
Unnamed
Year:
2007

Materials and methods

Principles of method if other than guideline:
Carcinogenicity of sodium bromate was tested in genitically modified mice.
GLP compliance:
yes

Test material

Constituent 1
Chemical structure
Reference substance name:
Sodium bromate
EC Number:
232-160-4
EC Name:
Sodium bromate
Cas Number:
7789-38-0
Molecular formula:
BrHO3.Na
IUPAC Name:
sodium bromate

Test animals

Species:
mouse
Strain:
other: genitically modified mice: Tg AC hemizygous and p53 haploinsufficient
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS:
Male and female FVB/N-TgN(v-Ha-ras) (Tg.AC) hemizygous (Tg.AC hemizygous) and B6.129-Trp53tmlBrd (N5) haploinsufficient (p53 haploinsufficient) mice were obtained from Taconic Laboratory Animals and Services (Germantown, NY) for use in the 26-, 27-, 39-, and 43-week studies. Tg.AC hemizygous mice were quarantined for 16 days before the beginning of the dermal studies and for 13 days before the beginning of the drinking water studies; p53 haploinsufficient mice were quarantined for 14 days before the beginning of the drinking water studies. Five male and five female mice per strain were randomly selected for parasite evaluation and gross observation of disease. Tg.AC hemizygous mice were 6 weeks old and p53 haploinsufficient mice were 6 to 8 weeks old at the beginning of the studies. Blood samples were collected from five male and five female sentinel mice per strain and study group at 4 and 26 weeks, from five male and five female mice from the highest surviving groups at 39 or 43 weeks, and from moribund mice in the 43-week drinking water studies.

ANIMAL MAINTENANCE:
Mice were housed individually and feed and water were available ad libitum. Water consumption was measured weekly by cage during the drinking water studies. Cages and racks were rotated every two weeks.

Administration / exposure

Route of administration:
other: Dermal application or oral via drinking water
Vehicle:
other: 40% USP-grade 95% ethanol/60% water (dermal route); tap water (drinking water, oral route)
Analytical verification of doses or concentrations:
yes
Duration of treatment / exposure:
26 & 39 weeks (dermal route); 27 & 43 weeks (drinking water, oral route)
Frequency of treatment:
daily
Doses / concentrationsopen allclose all
Dose / conc.:
0 mg/kg bw/day
Remarks:
Control, dermal
Dose / conc.:
64 mg/kg bw/day
Remarks:
low dose, dermal
Dose / conc.:
128 mg/kg bw/day
Remarks:
mid dose, dermal
Dose / conc.:
256 mg/kg bw/day
Remarks:
high dose, dermal
Dose / conc.:
0 mg/kg bw/day
Remarks:
Control, oral
Dose / conc.:
80 mg/L drinking water
Remarks:
low dose, oral
Dose / conc.:
400 mg/L drinking water
Remarks:
mid dose, oral
Dose / conc.:
800 mg/L drinking water
Remarks:
high dose, oral
No. of animals per sex per dose:
10 - 15
Control animals:
yes, concurrent vehicle
Positive control:
12-O-Tetradecanoylphorbol-13-acetate (TPA)

Examinations

Observations and examinations performed and frequency:
CLINICAL OBSERVATIONS:
All animals were observed twice daily. Clinical findings and body weights were recorded postdosing on day 1 (dermal studies), initially (drinking water studies), weekly, and at the end of the studies.
In-life observations of papilloma formation on the skin were recorded weekly using the Toxicology Data Management System (TDMS). A papilloma was initially recorded as a mass. The observation “papilloma” was not entered into TDMS for a given animal until the first-observed mass was documented for 3 consecutive weeks. At the third observation, the mass (wart-like in appearance) was entered as a papilloma. Any new mass(es) appearing after the 3-week confirmation period for a given animal at a different site was entered into TDMS first as a mass until the third week, when it was entered as a papilloma. In a few instances, a papilloma that had been previously observed was missing, and therefore not recorded. Reappearance of a mass at a later time was entered into TDMS as a mass until the third observation week, when it was called a papilloma.

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): Yes
- Time schedule for examinations: weekly

HAEMATOLOGY: Yes
Blood was collected from the retroorbital sinus of all mice except positive controls at the end of the 26 and 27-week studies for hematology. Hematocrit; hemoglobin concentration; erythrocyte, reticulocyte, and platelet counts; mean cell volume; mean cell hemoglobin; mean cell hemoglobin concentration; and leukocyte count and differentials were determined.
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
Necropsies and microscopic examinations were performed on all mice except the positive controls. The heart, right kidney, liver, lung, right testis, and thymus were weighed. At necropsy, all organs and tissues were examined for grossly visible lesions, and all major tissues were fixed and preserved in 10% neutral bufferedforma lin, processed and trimmed, embedded in paraffin, sectioned to a thickness of 5 µm, and stained with hematoxylin and eosin for microscopic examination. For all paired organs (e.g., adrenal gland, kidney, ovary), samples from each organ were examined.

HISTOPATHOLOGY: Yes
Histopathology was performed on all mice except positive controls. In addition to gross lesions and tissue masses, the following tissues were examined: adrenal gland, brain, large intestine (cecum, colon), small intestine (duodenum, jejunum, ileum), kidney, liver, lung, lymph nodes (mandibular and mesenteric), mammary gland, ovary, pituitary gland, skin, spleen, stomach (forestomach), testis (with epididymis), thymus, thyroid gland, and uterus.
Statistics:
- Survival Analyses:
The probability of survival was estimated by the product-limit procedure of Kaplan and Meier (1958).Statistical analyses for possible dose-related effects on survival used Cox’s (1972) method for testing two groups for equality and Tarone’s (1975) life table test to identify dose-related trends. All reported P values for the survival analyses are two sided.

- Calculation and analysis of lesion incidence:
The incidences of neoplasms or nonneoplastic lesions are presented as the numbers of animals bearing such lesions at a specific anatomic site and the numbers of animals with that site examined microscopically. The Fisher exact test (Gart et al., 1979), a procedure based on the overall proportion of affected animals, was used to determine significance.

Results and discussion

Results of examinations

Clinical signs:
no effects observed
Description (incidence and severity):
No clinical findings were attributed to sodium bromate administration in both dermal and oral route.
Dermal irritation (if dermal study):
no effects observed
Mortality:
mortality observed, non-treatment-related
Description (incidence):
Survival of all dosed groups was similar to that of the vehicle control groups in both dermal and oral routes
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
not examined
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
no effects observed
Ophthalmological findings:
not examined
Haematological findings:
effects observed, treatment-related
Description (incidence and severity):
26- and 39-WEEK DERMAL STUDIES IN Tg.AC HEMIZYGOUS MICE:
Minimal decreases in hematocrit and hemoglobin concentration values occurred in 128 mg/kg females and 256 mg/kg males and females at 26 weeks. A minimal decrease in erythrocyte count also occurred in 256 mg/kg males. These decreases in erythron were accompanied by a minimal decrease in mean cell hemoglobin and mean cell hemoglobin concentration values, primarily in the females. Reticulocyte counts were significantly increased in 128 mg/kg females and 256 mg/kg males and females.

27- AND 43-WEEK DRINKING WATER STUDIES IN Tg.AC HEMIZYGOUS MICE:
Minimal decreases in hematocrit, hemoglobin concentration, and erythrocyte count values occurred primarily in 400 and 800 mg/kg females at 27 weeks. There were also decreases in mean cell hemoglobin and mean cell hemoglobin concentration values, but these occurred primarily in treated males. Reticulocyte counts were increased in 400 mg/kg males and 800 mg/kg males and females.
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
26- and 39-WEEK DERMAL STUDIES IN Tg.AC HEMIZYGOUS MICE:
Absolute testis weights in 256 mg/kg males and absolute kidney weights in 256 mg/kg females were decreased at 39 weeks.

27- and 43-WEEK DRINKING WATER STUDIES IN Tg.AC HEMIZYGOUS MICE:
Absolute kidney weights were significantly decreased in 800 mg/L females and relative kidney weights were increased in 400 and 800 mg/L males at 27 weeks. Absolute testis weights were significantly decreased in 800 mg/L males at 43 weeks.
Gross pathological findings:
effects observed, treatment-related
Description (incidence and severity):
26- and 39-WEEK DERMAL STUDIES IN Tg.AC HEMIZYGOUS MICE:
Nephropathy occurred in 14 of 15 males receiving 128 and 256 mg/kg at 26 weeks and in all 256 mg/kg females in both studies. In the thyroid gland, the incidences of follicular cell hypertrophy in all dosed groups of males and females, follicular secretory depletion in 128 and 256 mg/kg females, and lymphocytic cellular infiltrate in 256 mg/kg females were significantly increased in both studies. Splenic hematopoietic cell proliferation occurred with a significantly increased incidence in 128 and 256 mg/kg females at 26 weeks. The incidence of germinal epithelium degeneration in the testis was significantly increased in 256 mg/kg males at 39 weeks.

27- AND 43-WEEK DRINKING WATER STUDIES IN Tg.AC HEMIZYGOUS MICE:
Thyroid gland follicular cell hypertrophy and follicular secretory depletion occurred in most 400 and 800 mg/L males and females at 27 weeks and in most exposed females at 43 weeks, and the incidences of thyroid gland follicular cell hypertrophy were significantly increased in all exposed groups of males at 43 weeks. The incidences of thyroid gland lymphocytic cellular infiltrates were significantly increased in 400 and 800 mg/L females in both studies and in 800 mg/L males at 43 weeks. The incidences of nephropathy were significantly increased in all exposed groups of males and in 400 and 800 mg/L females at 27 weeks. Renal tubule degeneration occurred with significantly increased incidences in 800 mg/L males and females in both studies. The incidences of renal tubule hypertrophy were significantly increased in 400 and 800 mg/L females at 27 weeks and in 800 mg/L males and females at 43 weeks. Pituitary gland pars distalis hypertrophy occurred with a significantly increased incidence in 800 mg/L females in both studies. The incidence of hyperkeratosis of the forestomach epithelium was significantly increased in 800 mg/L females at 43 weeks. The incidences of tubular degeneration of the epididymis and germinal epithelium degeneration of the testis were significantly increased in 800 mg/L males at 43 weeks.
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
26- and 39-WEEK DERMAL STUDIES IN Tg.AC HEMIZYGOUS MICE:
Nephropathy occurred in 14 of 15 males receiving 128 and 256 mg/kg at 26 weeks and in all 256 mg/kg females in both studies. In the thyroid gland, the incidences of follicular cell hypertrophy in all dosed groups of males and females, follicular secretory depletion in 128 and 256 mg/kg females, and lymphocytic cellular infiltrate in 256 mg/kg females were significantly increased in both studies. Splenic hematopoietic cell proliferation occurred with a significantly increased incidence in 128 and 256 mg/kg females at 26 weeks. The incidence of germinal epithelium degeneration in the testis was significantly increased in 256 mg/kg males at 39 weeks.

27- AND 43-WEEK DRINKING WATER STUDIES IN Tg.AC HEMIZYGOUS MICE:
Thyroid gland follicular cell hypertrophy and follicular secretory depletion occurred in most 400 and 800 mg/L males and females at 27 weeks and in most exposed females at 43 weeks, and the incidences of thyroid gland follicular cell hypertrophy were significantly increased in all exposed groups of males at 43 weeks. The incidences of thyroid gland lymphocytic cellular infiltrates were significantly increased in 400 and 800 mg/L females in both studies and in 800 mg/L males at 43 weeks. The incidences of nephropathy were significantly increased in all exposed groups of males and in 400 and 800 mg/L females at 27 weeks. Renal tubule degeneration occurred with significantly increased incidences in 800 mg/L males and females in both studies. The incidences of renal tubule hypertrophy were significantly increased in 400 and 800 mg/L females at 27 weeks and in 800 mg/L males and females at 43 weeks. Pituitary gland pars distalis hypertrophy occurred with a significantly increased incidence in 800 mg/L females in both studies. The incidence of hyperkeratosis of the forestomach epithelium was significantly increased in 800 mg/L females at 43 weeks. The incidences of tubular degeneration of the epididymis and germinal epithelium degeneration of the testis were significantly increased in 800 mg/L males at 43 weeks.

27- AND 43-WEEK DRINKING WATER STUDIES IN p53 HAPLOINSURFFICIENT MICE:
Non-neoplastic lesions in male or female p53 haploinsufficient mice were attributed to exposure to sodium bromate in either study.
Histopathological findings: neoplastic:
no effects observed

Effect levels

open allclose all
Dose descriptor:
NOAEL
Effect level:
256 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: Effect type: carcinogenicity
Remarks on result:
other: dermal study
Dose descriptor:
NOAEL
Effect level:
800 mg/L drinking water
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: Effect type: carcinogenicity
Remarks on result:
other: oral study

Target system / organ toxicity

Critical effects observed:
no

Applicant's summary and conclusion

Conclusions:
In a NTP carcinogenicity study performed with Tg.AC hemizygous and p53 deficent mice, sodium bromate did not show evidence of carcinogenic activity in p53 deficient mice and there were no treatment-related increased incidences of neoplams in all genetically modified mice. However, it should be mentioned that the suitable read-across partner potassium bromate (CAS No. 7758-01-2) caused cancer in non-genetically modified male rats in two carcinogenicity assays (2-year drinking water studies). Furthermore, IARC classified potassium bromate in Group 2B. Therefore, under considerations of the classification from the structural analogue potassium bromate, sodium bromate is suspected to be a carcinogen and classification as Carc. 2 (H351) according to CLP Regulation 1272/2008 is warranted.

Executive summary:

In a NTP carcinogenicity study, sodium bromate was administered to genetically modified male and female mice (Tg.AC hemizygous and p53 deficient) in water at dose levels of 0, 80, 400 and 800 mg/L for 27 or 43 weeks. Solutions containing sodium bromate were also applied to the backs of male and female Tg.AC mice at dose level of 0, 64, 128, or 256 mg/kg for 26 or 39 weeks. Exposure to sodium bromate either through the skin or by drinking water decreased body weights in groups given the highest concentrations. Furthermore, in none of the tests in which this substance was dermally applied to both sexes of transgenic mice (Tg.AC mice) at up to 256 mg/kg/day for up to 39 weeks, and tests in which it was administered by drinking water to both sexes of two strains of transgenic mice (p53 deficient mice or Tg.AC mice) at up to 800 mg/L for up to 43 weeks, there was no increase in tumour incidence, and no evidence of carcinogenicity was shown.

However, it should be mentioned that the suitable read-across partner potassium bromate (CAS No. 7758-01-2) caused cancer in non-genetically modified male rats in two carcinogenicity assays (2-year drinking water studies). Furthermore, IARC classified potassium bromate in Group 2B. Therefore, under considerations of the classification from the structural analogue potassium bromate, sodium bromate is suspected to be a carcinogen and classification as Carc. 2 (H351) according to CLP Regulation 1272/2008 is warranted.