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REACH

Potassium perchlorate

EC number: 231-912-9 | CAS number: 7778-74-7

Life Cycle description
Uses advised against

Ecotoxicological information

Toxicity to other aquatic organisms

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Administrative data

Link to relevant study record(s)

Reference

Endpoint:: toxicity to other aquatic vertebrates
Type of information:: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:: key study
Study period:: 2005 - 2006
Reliability:: 2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:: study well documented, meets generally accepted scientific principles, acceptable for assessment
Remarks:: This report summarizes the results from an OECD inter-laboratory study in 2005-2006 to assess the reliability of the amphibian metamorphosis assay for the detection of thyroid system-disrupting substances acting through different pathways. The tests were performed in five different laboratories as non-GLP experiments. The tests don't follow a guideline, but are well-documented.
Justification for type of information:: In water, potassium perchlorate will rapidly dissolve and completely dissociate into the perchlorate anion and the corresponding cation. Toxicity is determined only by the perchlorate moiety of the salt. as potassium is known to be non-toxic. Based on that, read-across is possible to other perchlorate salt dissociating in water without any toxic cation.
Qualifier:: equivalent or similar to guideline
Guideline:: other: OECD 231
Principles of method if other than guideline:: This report summarizes the results from an OECD inter-laboratory study to assess the reliability of the amphibian metamorphosis assay for the detection of thyroid system-disrupting substances acting through different pathways. The Phase 1 validation study, consisted in the optimisation of the protocol and exposure scenario. The Phase 2 of the validation study aimed at an inter-laboratory multi-chemical testing with an harmonised protocol. Three model substances representing different modes of action on the thyroid system were used in Phase-2 studies. These included sodium perchlorate, thyroxine and iopanoic acid. Only sodium perchlorate studies were reported in this robust study summary. The perchlorate anion (PER) is a competetive inhibitor of thyroidal iodide uptake. A total of five experiments with sodium perchlorate (Na-PER) as test substance were performed in five different laboratories (lab 1, lab 2, lab 3, lab 4 and lab 5).
GLP compliance:: no
Analytical monitoring:: yes
Details on sampling:: once a week
Vehicle:: no
Details on test solutions:: one dilution water control
Aquatic vertebrate type (other than fish):: frog
Test organisms (species):: Xenopus laevis
Details on test organisms:: Age at study initiation: tadpoles at premetamorphic stage 51 (criteria of Nieuwkopp and Faber, 1994)
Frequency / Amount: start with at least 600 mg/day/tank (corresponding to 30 mg food/animal), then adjusted with growth of tadpoles
Test type:: flow-through
Water media type:: freshwater
Limit test:: no
Total exposure duration:: 21 d
Test temperature:: 21 - 23 °C
Dissolved oxygen:: at least 40 % of the saturation value
Nominal and measured concentrations:: Nominal concentrations: 0, 62.5, 125, 250 and 500 µg/L of perchlorate anion
Measured concentrations: within 20% of nominal concentrations
Details on test conditions:: TEST SYSTEM
- Test vessel: 4 L with minimum water depth of 10 to 15 cm
- Aeration: aeration of treatment tanks was required when dissolved oxygen concentrations fall below 40% of the air saturation value.
- Type of flow-through (e.g. peristaltic or proportional diluter): no data
- Renewal rate of test solution (frequency/flow rate): 25 mL/min
- No. of organisms per vessel: 20 (but 15 tadpoles per tank after day 7)
- No. of vessels per concentration (replicates): 4
- No. of vessels per control (replicates): 4
- No. of vessels per vehicle control (replicates): not applicable

TEST MEDIUM / WATER PARAMETERS
Locally available and appropriate water demonstrated to promote normal growth and development.

OTHER TEST CONDITIONS
- Adjustment of pH: no data
- Photoperiod: 12 hr light: 12 hr dark
- Light intensity: no data

EFFECT PARAMETERS MEASURED (with observation intervals if applicable) : A battery of different apical morphological endpoints was analyzed after 7 and 21 days of exposure and histological analysis of thyroid gland tissue was performed with samples obtained after 21 days of exposure:
- Developmental stage: day 0 (all), 7 (subsample) and 21 (all);
- Hind limb length (HLL): day 7 (subsample) and 21 (all);
- Body length (whole body length (WBL) and snout-vent length (SVL)): day 7 (subsample) and 21 (all);
- Wet weight: day 7 (subsample) and 21 (all);
- Mortality: daily observation;
- Thyroid histology: day 21 (5 tadpoles per replicate tank).
Reference substance (positive control):: no
: Key result
Duration:: 21 d
Dose descriptor:: NOEC
Remarks:: NOEC determined by laboratory 1
Effect conc.:: 500 µg/L
Nominal / measured:: nominal
Conc. based on:: act. ingr.
Basis for effect:: other: development
Remarks:: iodide content = 10 µg/L, NOEC = 485 µg/L based on mean measured concentrations
: Key result
Duration:: 21 d
Dose descriptor:: NOEC
Remarks:: NOEC determined by laboratory 2
Effect conc.:: 500 µg/L
Nominal / measured:: nominal
Conc. based on:: act. ingr.
Basis for effect:: other: development
Remarks:: iodide content not determined, NOEC = 473 µg/L based on mean measured concentrations
: Key result
Duration:: 21 d
Dose descriptor:: NOEC
Remarks:: NOEC determined by laboratory 3
Effect conc.:: 62.5 µg/L
Nominal / measured:: nominal
Conc. based on:: act. ingr.
Basis for effect:: other: development
Remarks:: iodide content = 20 µg/L, NOEC = 87 µg/L based on mean measured concentrations
: Key result
Duration:: 21 d
Dose descriptor:: NOEC
Remarks:: NOEC determined by laboratory 4
Effect conc.:: 500 µg/L
Nominal / measured:: nominal
Conc. based on:: act. ingr.
Basis for effect:: other: development
Remarks:: iodide content not determined, NOEC = 524 µg/L based on mean measured concentrations
: Key result
Duration:: 21 d
Dose descriptor:: NOEC
Remarks:: NOEC determined by laboratory 5
Nominal / measured:: nominal
Conc. based on:: act. ingr.
Basis for effect:: other: development
Details on results:: CONTROL GROUP:
- Age of tadpoles at test initiation in the control group: lab 1 = 12 days postfertilization; lab 2 = 11 to 13 days postfertilization; lab 3 = 14 days postfertilization; lab 4 = no data available; lab 5 = 16 dayspostfertilization. Normally, the time required from fertilization to developmental stage 51 should reach within approximately 14 days postfertilization.
- Developmental stage determination in the control group on day 7: lab 1 = 55; lab 2 = 54; lab 3 = 54; lab 4 = 55; lab 5 = 54. Under optimal rearing conditions, control tadpoles should reach early prometamorphic stages 54-55 until study day 7.
- Developmental stage determination in the control group on day 21: lab 1 = 58; lab 2 = 58; lab 3 = 59; lab 4 = 58; lab 5 = 57.
- Daily feeding rates (mg Sera Micron per animal) in the control group: lab 1 = 30 to 67 mg/animal; lab 2 = 10 to 60 mg/animal; lab 3 = 18 to 24 mg/animal; lab 4 = no data available; lab 5 = 40 to 90 mg/animal. It appears that less food was provided to the animals used in lab 3.

EFFECTS OF THE SUBSTANCE ON MORTALITY:
No mortality was observed in any treatment group in lab 3 and lab 5 and mortality was very low (<5%) in tests performed in lab 1, lab 2 and lab 4 (see table 6.1.8/2 in "Any other information on results incl. tables")

EFFECTS OF THE SUBSTANCE ON GROWTH-RELATED ENDPOINTS:
Collectively, data from day 7 and day 21 measurements indicate that treatment of tadpoles with PER did not result in growth retardation. However, results from four of five tests conducted with PER showed significant increases in tadpole size and tadpole weight. Tadpole growth was not affected by PER treatment in lab 2.
Detection of the growth-promoting effects of PER treatment was more robust when the corresponding endpoints were analyzed on study day 21. Results from lab 4 were an exception in this regard, because significant effects at 250 and 500 μg/L PER on size and weight were only detected on study day 7 but not on study day 21. On study day 21, concentration-dependent increases in all three growth-related parameters (WBL, SVL and wet weight) were observed for PER concentrations of 125, 250 and 500 μg/L in lab 1 and for PER concentrations of 250 and 500 μg/L in lab 3. It should be noted that in lab 1, an increased number of control animals already showed development to climax stages which is associated with weight loss and a reduction in body size, thus hampering a sound assessment of growth effects at higher PER concentrations which caused a moderate inhibition of development. Significant increases in tadpole size (at 250 and 500 μg/L PER), but not wet weight, were observed in lab 5.
Overall, the sensitivity of WBL and SVL measurements to detect changes in tadpole size were similar in three tests (lab 1, lab 3 and lab 4), whereas SVL was slightly less sensitive than WBL in one test (lab 5). A less consistent relationship was observed when comparing changes in tadpole size and tadpole weight. In lab 1, significant increases in wet weight were detected in all PER treatments that caused increases in WBL and SVL. In lab 3, wet weight was even increased at PER concentrations (125 μg/l) that did not led to significant effects on WBL and SVL. In contrast, significant changes in tadpole WBL or SVL were not associated with significant changes in wet weight in a test conducted in lab 5.

EFFECTS OF THE SUBSTANCE ON DEVELOPMENTAL ENDPOINTS:
At the concentrations used in this study, PER treatment caused developmental delay of tadpoles only in two tests (lab 3 and lab 4). Detection of developmental effects was more robust when the endpoints developmental stage and HLL were analyzed on study day 21 compared to study day 7. On day 7, a weak but significant effects on median stage was only detected for the 500 μg/l PER treatment in lab 1. At day 21, significant effects of PER treatment on tadpole stage were detected for the highest PER concentration (500 μg/l) in lab 4 and for PER concentrations of 125, 250 and 500 μg/l in lab 3.
The tests conducted in lab 3 and lab 4 also revealed a reduction in hind limb growth due to PER treatment. Compared to the control group, mean HLL was significantly lower following 21-day exposure of tadpoles to 250 and 500 μg/l PER in tests from lab 3 and lab 4. In the other three experiments, tadpole development was not significantly affected by the tested PER concentrations as judged from stage determination and HLL measurements.

EFFECTS OF THE SUBSTANCE ON THYROID GLAND HISTOLOGY:
Results from histological evaluation of thyroid tissue were available for four of five experiments. In all four experiments including a histological assessment of thyroid tissue, exposure-related changes in the thyroid gland were detected. The effects pattern observed following 21-day treatment with PER was very consistent among all experiments and included concentration-dependent decreases in colloid content, increases in overall thyroid gland size and hypertrophic and hyperplastic changes in the follicular epithelium. A remarkable finding was that partial colloid depletion, glandular hypertrophy and follicular cell hypertrophy occurred at all tested PER concentrations. Thus, all PER concentrations were effective in altering thyroid histology. Within the tested concentration range of PER, colloid depletion, thyroid gland hypertrophy and changes in follicular epithelium were generally mild to moderate at the lowest concentration (62.5 μg/L) but moderate to severe at the highest concentration (500 μg/L).
A semi-quantitative analysis of the histological alterations was performed using a 3-scale severity grading approach to assess the incidence and severity of three core diagnostic parameters including thyroid gland size, follicular cell hypertrophy and follicular cell hyperplasia. Results from these analyses confirmed the concentration-dependent increase in incidence as well as severity of hypertrophic and hyperplastic changes in the follicular cell epithelium.
In addition, morphometric techniques were used by lab 1 and lab 2 to assess effects of PER treatment on epithelial cell height, thyroid volume and thyroid cross section area. The morphometric data are consistent with the results from the qualitative characterization and the severity grading approach by showing significant increases in epithelial cell height (follicular cell hypertrophy), total glandular volume and maximum cross section area (thyroid gland hypertrophy).

Evaluation of thyroid gland histology was far more sensitive than morphological assessment of test animals in detecting the anti-thyroidal activity of PER. Among all thyroid gland histology parameters (glandular hypertrophy, glandular atrophy, follicular cell hypertrophy, follicular cell hyperplasia, colloid depletion and follicular lumen area), 100% animals were affected at 62.5 µg/L of PER (corrected with control) in the lab 4 for the examination of the follicular lumen area. Based on this effect, the EC50 value can be determined at 31.3 µg/L, corresponding to an arithmetic mean between 0 µg/L and 62.5 µg/L. The NOEC value cannot be determined.
Reported statistics and error estimates:: The statistical protocol used is consistent with the OECD Guidance Document on the Statistical Analysis of Ecotoxicity Experiments.
Validity criteria fulfilled:: not applicable
Conclusions:: Despite inter-laboratory differences in PER effects on developmental parameters, all experiments could detect remarkable effects of PER treatment on thyroid histology including depletion of colloid stores, glandular hypertrophy as well as hypertrophic and hyperplastic changes in the follicular epithelium. Consistent across laboratories, effects were observed already at the lowest tested concentration of 62.5 μg/l PER and incidence and severity of these responses increased in clear concentration-dependent manner.

A geometric mean of three NOEC was then calculated from these results and was determined to be 215 µg/L.

Thus, compared to the assessment of morphological endpoints, evaluation of thyroid gland histology provided the most sensitive and consistent endpoint responses across the individual experiments.
Executive summary:: This report summarizes the results from an OECD inter-laboratory study to assess the reliability of the amphibian metamorphosis assay for the detection of thyroid system-disrupting substances acting through different pathways. The Phase 1 validation study, consisted in the optimisation of the protocol and exposure scenario. The Phase 2 of the validation study aimed at an inter-laboratory multi-chemical testing with an harmonised protocol. Three model substances representing different modes of action on the thyroid system were used in Phase-2 studies. These included sodium perchlorate, thyroxine and iopanoic acid. Only sodium perchlorate studies were reported in this robust study summary. The perchlorate anion (PER) is a competetive inhibitor of thyroidal iodide uptake. A total of five non-GLP experiments with sodium perchlorate (Na-PER) as test substance were performed in five different laboratories (lab 1, lab 2, lab 3, lab 4 and lab 5).

Tadpoles (initiated at premetamorphic stage 51) of the South African clawed frogXenopus laevis(20 tadpoles per replicate tank with 4 replicates per test concentration and control) were exposed during 21 days at four concentrations of the test substance (62.5, 125, 250 and 500 µg/L perchlorate anion) plus a dilution water control. Chemical treatment was accomplished by aqueous exposure of tadpoles in a flow-through system (flow rate 25 mL/min) and test chemicals concentrations were verified by analytical chemistry one a week. A battery of different apical morphological endpoints (developmental stage, hind limb length, whole body length, snout-vent length, wet weight) was analyzed after 7 and 21 days of exposure. Mortality was observed every day and histological analysis of thyroid gland tissue was performed with samples obtained after 21 days of exposure.

Analysis of growth-related parameters and mortality rates did not reveal signs of systemic toxicity for any of the tested perchlorate concentrations. Results from stage determination and hind limb length measurements showed perchlorate treatment to cause developmental delay in two experiments (lab 3 and lab 4) giving NOEC values ranging between 62.5 µg/L and 500 µg/L in nominal concentration. Macroscopic effects determined in laboratories with iodine concentrations measured to be > 1.5 µg/L have been considered as key values. A geometric mean of three NOEC was then calculated from these results and was determined to be 215 µg/L.

Histological assessment of thyroid tissue was performed in four labs. Perchlorate treatment elicited marked effects on thyroid gland histology in all four studies. Incidence and severity of histological changes occurred in a concentration-dependent manner and provided strong evidence for disruption of the thyroid system by perchlorate, including depletion of colloid stores, glandular hypertrophy as well as hypertrophic and hyperplastic changes in the follicular epithelium. Consistent across laboratories, effects were observed already at the lowest tested concentration of 62.5 μg/L perchlorate. Thus, compared to the assessment of morphological endpoints, evaluation of thyroid gland histology provided the most sensitive and consistent endpoint responses across the individual experiments.

Description of key information

Despite inter-laboratory differences in PER effects on developmental parameters, all experiments could detect remarkable effects of PER treatment on thyroid histology including depletion of colloid stores, glandular hypertrophy as well as hypertrophic and hyperplastic changes in the follicular epithelium. Consistent across laboratories, effects were observed already at the lowest tested concentration of 62.5 μg/l PER and incidence and severity of these responses increased in clear concentration-dependent manner.

A geometric mean of three NOEC was then calculated from these results and was determined to be 215 µg/L.

Thus, compared to the assessment of morphological endpoints, evaluation of thyroid gland histology provided the most sensitive and consistent endpoint responses across the individual experiments.

Additional information

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Nominal concentration (µg/L)	Lab 1	Lab 2	Lab 3	Lab 4	Lab 5
0.0	0	0	0	0	0
62.5	0	1 (1.25%)	0	2 (2.5%)	0
125	1 (1.25%)	0	0	0	0
250	1 (1.25%)	0	0	0	0
500	3 (3.75%)*	0	0	0	0

	Lab 1	Lab 2	Lab 3	Lab 4	Lab 5
Total iodide content in dilution water	10 µg/L	n.d.	20 µg/L	1.5 µg/L	n.d.
Effective PER concentration leading to developmental delay	> 500 µg/L	> 500 µg/L	125 µg/L	500 µg/L	> 500 µg/L
Effective PER concentration leading alterations in thyroid histology	62.5 µg/L	62.5 µg/L	62.5 µg/L	62.5 µg/L	n.d.