Ammonium perchlorate

Carcinogenicity

Description of key information

Perchlorate has been shown to induce benign thyroid tumours (thyroid follicle epithelial cell adenomas) in rodents in three studies:
- in a Klimisch 4, non-GLP, non-guideline subchronic study in mouse, at the only tested dose of ~1200 mg/kg/day* (Gauss 1972 under 751)
- in a Klimisch 4, non-GLP, non-guideline carcinogenicity study in rat, at the only tested dose of ~630 mg/kg/day* (Kessler 1966 under 77)
- in a Klimisch 2, adequately GLP/guideline-compliant 2-generation study in rat, in 2/30 F1 male pups exposed for 125-142 or up to** 167-184 days at 30 mg/kg/day (York 1999 under 781). This is the most reliable and sensitive value, retained as a basis for a carcinogenicity LOAEL. The NOAEL (3 mg/kg/day) is not retained because of the high dose spacing.
*: indicative dose-level estimated as ammonium perchlorate equivalent by RSS/CSR author, see details in each RSS
**: including or excluding the gestational and lactational periods (in which transplacental and milk transfer to F1 individuals is known, but not quantified)

Key value for chemical safety assessment

Carcinogenicity: via oral route

Link to relevant study records

Reference

Endpoint:

carcinogenicity: oral

Type of information:

migrated information: read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

supporting study

Study period:

Not indicated

Reliability:

4 (not assignable)

Rationale for reliability incl. deficiencies:

other: Prior to GLP; extremely limited sensitivity (see deviations from guideline); very low-detail publication with unclear pathological diagnoses; animals with tumours excluded from group mean values for body and thyroid weight data

Qualifier:

no guideline followed

Guideline:

OECD Guideline 451 (Carcinogenicity Studies)

Deviations:

yes

Remarks:

Only one dose; only one sex; only one organ investigated for lesions incl. tumors; only 11 rats treated for 2 years.

Principles of method if other than guideline:

None. Prior to guidelines.

GLP compliance:

no

Remarks:

prior to GLP

Species:

rat

Strain:

Wistar

Sex:

male

Route of administration:

oral: drinking water

Vehicle:

water

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

Up to 730 days (interim sacrifices at 40, 120, 220 days).

Frequency of treatment:

Continuous

Post exposure period:

None

Remarks:

Doses / Concentrations:
1 %
Basis:
nominal conc.
as KClO4 in water; equivalent Ammonium perchlorate dose-level calculated in conclusion

No. of animals per sex per dose:

F: none
M: 8, 7, 5 and 11 at 40, 120, 220 and 730 days.

Control animals:

yes, concurrent vehicle

Relevance of carcinogenic effects / potential:

Thyroid adenomas most likely due to the persistent TSH stimulation (demonstrated under 7.5 and 7.8 in several shorter studies), in absence of genotoxic effect (demonstrated in genotoxicity studies under 7.6): epigenetic carcinogen.
Mechanism possibly relevant to Human (no data), however the effect will be covered by the respect of DNELs based on anti-thyroid effects.

Dose descriptor:

LOAEC

Effect level:

1 other: % KClO4 in drinking water

Sex:

male

Basis for effect level:

other: Thyroid non-neoplastic (increased absolute and relative weights at all sacrifice timepoints, diffuse goiter evolving into fibrosis) and neoplastic (adenomas in 4/11 rats at 2 years sacrifice) lesions

Remarks on result:

other: Effect type: carcinogenicity (migrated information)

Dose descriptor:

LOAEL

Effect level:

ca. 630 mg/kg bw/day

Based on:

other: equivalent Ammonium Perchlorate dose-level estimated by RSS/CSR author

Sex:

male

Basis for effect level:

other: See details of calculation in executive summary.

Remarks on result:

other: Effect type: carcinogenicity (migrated information)

Conclusions:

Potassium perchlorate is an epigenetic carcinogen in rats. The underlying mechanism (compensation for sustained antithyroid effects) is qualitatively relevant to Human, but quantitatively unlikely due to inter-species differences and the respect of DNELs.

Executive summary:

Potassium perchlorate was provided at 1% in drinking water to young male Wistar rats (mean: 169 g at initiation). The effects were:

• no effect on body weight gain
• 132%, 171%, 72% and 60% increases in thyroid weight at 40, 120, 220 and 730 days (animals bearing adenomas excluded in the publication)
• 190% increased thyroid weight at 730 days when 4 rats with adenomas are reintroduced in the mean by CSR/RSS author
• 4/11 rats with thyroid papillary and/or follicular adenomas at 730 days (above historical control incidence)

CSR/RSS author estimated as follows the equivalent ammonium perchlorate dose-level:

- considering MWs of 138.5 and 117.5 g/mol for KClO4 and NH4ClO4 respectively, 1% KClO4 is equivalent to 8.5 mg/mL of NH4ClO4

- a mean daily water consumption of only 25 mL is hypothesized (in absence of data) based on the low weight of the rats

- the mean body weight was 169 g (beginning of study) and 383 g (end of study)

- therefore, the estimated dose-level ranges 550 (end of study) to 1260 (beginning of study) mg/kg/day, with a time-weighed average around 630 mg/kg/day.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LOAEL

30 mg/kg bw/day

Study duration:

chronic

Species:

rat

Quality of whole database:

The summarised study was performed prior to GLP, with extremely limited sensitivity (see deviations from guideline); very low-detail publication with unclear pathological diagnoses; animals with tumours excluded from group mean values for body and thyroid weight data

Carcinogenicity: via inhalation route

Endpoint conclusion

Endpoint conclusion:

no study available

Carcinogenicity: via dermal route

Endpoint conclusion

Endpoint conclusion:

no study available

Justification for classification or non-classification

Perchlorate is a goitrogen; goitrogens are known to induce thyroid stimulation, possible benign tumours at extreme exposure levels/durations, but a causal relationship with malignant thyroid tumours is not established and seems unlikely from the expert positions below:

The National Academy of Sciences panel on perchlorate concluded that perchlorate is unlikely to cause cancer (National Academy of Sciences report, "Health Implications of Perchlorate Ingestion," January 2005):

• "The committee concludes that the thyroid tumors in the (rat) offspring were most likely treatment related, but that thyroid cancer in humans resulting from perchlorate exposure is unlikely because of the hormonally mediated mode of action and species differences (between humans and rats) in thyroid function." (p 7)
• "The committee notes, however, that on the basis of its understanding of the biology of human and rodent thyroid tumors, it is unlikely that perchlorate poses a risk of thyroid cancer in humans." (p 73)
• "It is unlikely that perchlorate poses a risk of cancer in humans." (p 95)
• "Specifically, the development of thyroid tumors as an ultimate result of perchlorate exposures is an unlikely outcome in humans." (p 109)

This is consistent with the view of US FDA (Poirer et al., "An FDA Review of Sulfamethazine toxicity", December 1999):

• "The pathogenesis of thyroid tumors in rats and humans is different. There is no evidence for a primary causative role of TSH in thyroid tumor formation in humans; however, TSH at normal levels may play some necessary, but incomplete role in human thyroid tumor development. Accordingly, there are few examples of thyroid carcinogens in humans. X-irradiation and radioactive iodine are the only clearly known human thyroid carcinogens; there are no other chemicals known to induce thyroid tumors in humans."

This is further consistent with the previous US FDA expert paper "Assessment of thyroid follicular cell tumours", ref. EPA/630/R-97/002, March 1998:

• "Treatments of rodents that cause thyroid-pituitary disruption result in chronic reduction in circulating thyroid hormone levels, increase in TSH levels and the development of increased cell division, increased size and numbers of thyroid cells, increased thyroid gland weight and, finally, tumors of the thyroid. [...] Cessation of treatment early in the process before tumor development results in reversal of processes back towards normal." (p.1) "Rodents show significant increases in cancer with thyroid-pituitary disruption; humans show little, if any." (p.11) "when thyroid-pituitary disruption is the sole mode of action, [...] rodents appear to be more sensitive to this carcinogenic mode of action than humans." (p.2) "When treatment with a goitrogen alone leads to tumor formation, TSH increases cell division among normal cells, which leads to increases in the overall chance of a spontaneous initiating mutation and then promotes the altered cells that retain responsiveness to TSH; carcinogenesis in these cases would be free of chemically induced mutagenic effects." (p.8) "In spite of the potential qualitative similarities, there is evidence that humans may not be as sensitive quantitatively to thyroid cancer development from thyroid-pituitary disruption as rodents. Rodents readily respond to reduced iodide intake with the development of cancer; humans develop profound hyperplasia with “adenomatous” changes with only suggestive evidence of malignancy. Even with congenital goiters due to inherited blocks in thyroid hormone production, only a few malignancies have been found in humans." (p. 13)

Additional information

The benign tumours (thyroid follicle adenomas) evidenced in rodents (rat and mouse) were never evidenced to progress to malignancy. They are considered to correspond to the consequences of excessive, prolonged compensation (thyroid follicle hypertrophy and hyperplasia) of perchlorate's antithyroid effects. As these non-neoplastic follicle activation lesions were evidenced to be reversible upon cessation of exposure, it may be expected that the thyroid adenomas also are reversible. Based on the likely mechanism, supported by the fact that perchlorate is devoid of mutagenic potential, these adenomas are considered to represent epigenetic/non-genotoxic/promoter, threshold carcinogenicity. At the retained LOAEL there was a minimal incidence of 2/30 rats, with a total of 3 thyroid adenomas (benign), and its relevance when compared with historical data has been debated. It is reported only for transparency.

Justification for selection of carcinogenicity via oral route endpoint:
This study was the only study available to assess the corresponding endpoint

Carcinogenicity: via oral route (target organ): glandular: thyroids