Sodium perchlorate

Carcinogenicity

Description of key information

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.
Mammalian toxicity data of an analogous substance, ammonium perchlorate (CAS no. 7790-98-9), has been used for read across where data gaps for sodium perchlorate exist (repeated toxicity).
Ammonium 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 7.5.1.)
- 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 7.7.)
- 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 7.8.1.). 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

Endpoint conclusion

Dose descriptor:

LOAEL

30 mg/kg bw/day

Justification for classification or non-classification

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.

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