Registration Dossier

Administrative data

Link to relevant study record(s)

Description of key information

Based on overview on Toxicokinetics section from ATSDR's Toxicological profile for perchlorates (2008):
Absorption:
- inhalative: possible (due to aqueous solubility) and has occurred in human studies; extent depends on particle size
- oral: very rapid (excreted from 10 min) and near complete (up to 95%) in humans and animals.
- dermal: expected to be low (ion, poor diffusion across lipid membranes)
Distribution:
- Binds to serum proteins (albumin; weakly to transferrin)
- Distributes broadly
- Concentrates in thyroids (5-10x serum levels) and to a much lower extent salivary gland and skin (both 1-2x) due to active saturable transport mechanism (NIS protein).
- No accumulation: thyroid elimination t1/2 of 10-20h in rat.
- Secreted in the gastric lumen
- Transferred to milk and across the placenta (by possibly saturable mechanisms)
Metabolism:
- no cleavage of chloride or oxygen atoms in radiolabel studies: excreted unchanged
- no covalent binding to thyroid proteins
Elimination/excretion:
- mostly urinary excretion
- milk excretion into milk
- rapid and near complete serum depuration: t1/2 of 8–12 hours in humans and 10–20 hours in rats, possibly due to interspecies differences in binding proteins and/or gastrointestinal transfer by NIS protein
- does not bioaccumulate along prolonged exposure
- probably first-order kinetics in urine
PBPK models:
Not included.

Key value for chemical safety assessment

Bioaccumulation potential:
no bioaccumulation potential

Additional information

Toxicokinetics section (3.4) from ATSDR's Toxicological profile for perchlorates (Wilbur 2008).

3.4.1 Absorption

3.4.1.1 Inhalation Exposure

No studies were found regarding quantitative absorption of perchlorate after inhalation exposure. Occupational studies have measured urinary perchlorate in workers, suggesting that pulmonary absorption may occur (Lamm et al. 1999), although swallowing of particles may have also occurred. Under normal ambient temperatures, the vapor pressure of a perchlorate salt solution is expected to be low, which would reduce the likelihood of exposure to perchlorate fumes or vapors from that source. However, if perchlorate particles were suspended in air, absorption by inhalation would be possible, depending on the particle size. It is also possible that a portion of perchlorate particles suspended in the air could be swallowed and absorbed orally. Given the aqueous solubility of perchlorate salts, it is likely that small particles reaching the alveoli would dissolve and readily enter the systemic circulation.

3.4.1.2 Oral Exposure

Perchlorate has been shown, in both human and animal studies, to be readily absorbed after oral exposure. In human subjects who ingested 10 mg/day perchlorate as potassium perchlorate in drinking water for 14 days (0.14 mg/kg/day), urinary excretion rate of perchlorate was 77% of the dose/day, after 7 days of exposure, indicating that at least 77% of the ingested dosage had been absorbed (Lawrence et al. 2000). Evidence for rapid absorption in humans is provided by studies of elimination patterns. Anbar et al. (1959) detected potassium perchlorate in urine samples collected from four subjects 3 hours after ingestion of 200 mg perchlorate. Durand (1938) gave sodium perchlorate in a single oral dose (784 mg perchlorate per person) to two individuals and found perchlorate in the urine as early as 10 minutes after ingestion. Approximately 30% of the ingested dose had been eliminated in the urine within 3 hours after the dose, and 95% was eliminated within 48 hours. In a study of 13 subjects given 0.5 or 3 mg perchlorate/day for 6 months, serum perchlorate increased from undetected at baseline to an average of

24.5 μg/L in the low-dose group and 77.9 μg/L in the high-dose group over the 6 months (Braverman et al. 2006). The investigators estimated that approximately 65–70% of the daily dose was excreted during a 24-hour period. These results suggest rapid and near complete absorption of perchlorate through the digestive system.

Selivanova et al. (1986) examined the absorption of ammonium perchlorate in rats, rabbits, and calves after a single oral dose (2, 20, 200, or 600 mg perchlorate/kg). In rats, a maximum concentration of perchlorate in blood was noted between 30 and 60 minutes after administration (suggesting entrance into the systemic circulation before 30 minutes); in cattle, the maximum blood concentration of perchlorate occurred at 5 hours. In this study, only 8.5% of the administered dose was excreted in feces, and the rest was excreted in the urine, suggesting that >90% of the administered oral dose was absorbed.

3.4.1.3 Dermal Exposure

No studies were found regarding absorption of perchlorate after dermal exposure. As a general rule, electrolytes applied from aqueous solutions do not readily penetrate the skin (Scheuplein and Bronaugh 1983). On this basis, dermal absorption of perchlorate is expected to be low.

This is confirmed by a dermal absorption study on Sodium Chlorate. The dermal absorption of Sodium Chlorate was very low with at most 1.85% (total extent incl. amount in stratum corneum) and 0.446 µg/cm2/hour (rate) over a 24-hour in vitro exposure of human skin, with total recovery (99-101%). This value is extrapolated to Ammonium Perchlorate, based on the structural closeness of both anions (chlorate: ClO3-; perchlorate: ClO4-) and the fact that the toxicity of Ammonium Perchlorate is driven by the perchlorate anion. Furthermore, Perchlorate is expected to penetrate less than the tested Chlorate (solution) due to exposure to solid particles, slightly higher molecular weight, and absence of skin irritant potential.

3.4.2 Distribution

Perchlorate binds to bovine and human serum albumin (Carr 1952; Scatchard and Black 1949). Perchlorate binds only weakly to either of the two binding sites of transferrin (association constants 7 and) (Harris et al. 1998).

Studies conducted in rabbits and rats indicate that perchlorate concentrations in most soft tissues (e.g., kidney, liver, skeletal muscle) are similar to the serum concentrations; tissue:serum concentration ratios >1 have been found in thyroid (5–10) and skin (1–2) (Durand 1938; Yu et al. 2002). Accumulation of perchlorate in the thyroid occurs by a saturable, active transport process (see Section 3.5.1). As a result, thyroid serum concentrations and the amount of perchlorate in the thyroid as a fraction of the absorbed dose decrease with increasing dose (Chow and Woodbury 1970). Elimination of perchlorate from the thyroid gland is relatively rapid, with half-times in rats estimated to be approximately 10–20 hours (Fisher et al. 2000; Goldman and Stanbury 1973; Yu et al. 2002).

Studies conducted in rats administered intravenous injections of perchlorate indicate that perchlorate is secreted into the gastric lumen (Yu et al. 2002). Perchlorate secreted into the gastric lumen may be absorbed in the small intestine.

3.4.2.1 Inhalation Exposure

No studies were found in humans or in animals regarding distribution of perchlorate after inhalation exposure.

3.4.2.2 Oral Exposure

In a survey of 36 healthy lactating volunteers, perchlorate was detected in breast milk at a mean concentration of 10.5 μg/L (range, 0.6–92. μg/L) (Kirk et al. 2005). Exposure of the lactating women was presumed to have occurred mainly from perchlorate in food and drinking water. No correlation was apparent between the concentration of perchlorate in the breast milk and the water that the respective mothers consumed. Serial collection of breast milk from 10 lactating women over a 3 -day period revealed that the concentrations of perchlorate, iodide, and thiocyanate varied significantly over time (Kirk et al. 2007). For perchlorate, the range, mean and median in 147 samples were 0.5–39.5, 5.8, and 4.0 μg/L, respectively. A study of women from three different cities in Chile also detected perchlorate in breast milk at mean concentrations ranging from 17.7 to 95.6 μg/L (Téllez et al. 2005). This study also found no significant correlations between breast milk perchlorate and either urine perchlorate or breast milk iodine concentrations. A study of 57 lactating women in Boston reported a median concentration of perchlorate in milk of 9.1 μg/L (range 1.3–411 μg/L) (Pearce et al. 2007).

Perchlorate also has been detected in dairy milk. A survey of 12 U.S. states showed a mean milk perchlorate level of 5.81 μg/L in 125 samples (FDA 2007a, 2007b), which was lower than a reported mean of 9.39 μg/L for Japanese samples (Dyke et al. 2007). The recent Total Diet Study (TDS) study conducted by the FDA reported a mean concentration of perchlorate of 7 μg/L in eight samples of milk (Murray et al. 2008).

Studies conducted in rabbits and rats indicate that perchlorate concentrations in most soft tissues (e.g., kidney, liver, skeletal muscle) are similar to the serum concentrations; tissue:serum concentration ratios >1 have been found in thyroid (5–10) and skin (1–2) (Durand 1938; Yu et al. 2002). Accumulation of perchlorate in the thyroid occurs by a saturable, active transport process (see Section 3.5.1).

Perchlorate has been shown to cross the placenta of rats. In rats exposed to perchlorate in drinking water, fetal:maternal serum concentration ratios were approximately 1 when the maternal dosage was 1 mg/kg/day or lower, and were <1 when the maternal dosage was 10 mg/kg/day, suggesting the possibility of a dose-dependent limitation in the capacity of transplacental transfer (Clewell et al. 2003a).

3.4.2.3 Dermal Exposure

No studies were found regarding distribution of perchlorate after dermal exposure.

3.4.2.4 Other Routes of Exposure

Several studies have examined the distribution of perchlorate in animals after intravenous, intramuscular, or peritoneal injection (Anbar et al. 1959; Chow and Woodbury 1970; Chow et al. 1969; Durand 1938; Goldman and Stanbury 1973; Yu et al. 2002). These studies have shown that absorbed perchlorate, regardless of the route of exposure, will distribute to soft tissues, including adrenal, brain, kidney, liver, mammary gland, skeletal muscle, spleen, testes, and thyroid. The highest concentrations occur in the thyroid, where tissue:serum concentration ratios of 5–10 have been observed (Chow and Woodbury 1970). The elimination half-time for the thyroid was estimated in rats to be approximately 10–20 hours (Fisher et al. 2000; Goldman and Stanbury 1973; Yu et al. 2002).

Other tissues that appear to concentrate perchlorate are the salivary gland and skin, although not to the same degree as the thyroid (Anbar et al. 1959; Lazarus et al. 1974; Yu et al. 2002). Tissue:blood concentration ratios of 1.5–2 have been observed for the salivary gland (Anbar et al. 1959) and 1–2 for the skin (Yu et al. 2002).

3.4.3 Metabolism

There is no evidence that perchlorate is metabolized in the body. Anbar et al. (1959) assayed for potential metabolites of potassium perchlorate (radiolabeled with 36Cl and 18O4) in the urine of patients 3 hours after a single oral dose (200 mg perchlorate per person). They did not detect any isotopic exchange of the oxygen atoms in excreted perchlorate; furthermore, although they found that 1–3% of the excreted 36Cl was chloride ion, this value was within experimental error. They concluded that the perchlorate excreted after 3 hours was unmodified. There has been no investigation as to whether perchlorate that is eliminated at later time points would exhibit the same isotopic pattern.

Goldman and Stanbury (1973) found that perchlorate reached a maximum concentration (>3% of the administered dose/g tissue) in the thyroid gland of rats 4 hours after an intraperitoneal injection of radiolabeled potassium perchlorate (K 36ClO4; 18 or 24 mg perchlorate/kg). However, trichloroacetic acid precipitates of thyroid homogenates contained only background levels of radioactivity, indicating that perchlorate is not covalently bound to thyroid protein.

3.4.4 Elimination and Excretion

The few studies of the elimination and excretion of perchlorate, described in the sections that follow, suggest that it is rapidly eliminated from the body through the urinary tract. Similar results have been obtained after oral exposure or after intravenous or intraperitoneal injection; the specific cation appears not to influence the pattern of excretion.

3.4.4.1 Inhalation Exposure

A study in two workers occupationally exposed to perchlorate found that the urinary perchlorate concentration increased over 3 days of perchlorate exposure, but there was a decrease between the 12-hour work shifts (Lamm et al. 1999). Excretion after the last exposure appeared to follow a first-order kinetics pattern, particularly when the urinary perchlorate concentration was between 0.1 and 10 mg/L. The average elimination half-life for the two workers was approximately 8 hours. No information was located regarding excretion of perchlorate in animals following inhalation exposure.

3.4.4.2 Oral Exposure

In adult human subjects who ingested potassium perchlorate in drinking water (0.14 mg/kg/day) for 14 days, urinary excretion rate of perchlorate was 77% of the dose/day after 7 days of exposure, indicating that urine is the main excretory pathway for absorbed perchlorate (Lawrence et al. 2000). The urinary excretion rate of perchlorate returned to control levels (<0.5 mg/day) within 14 days after exposure to perchlorate was terminated (Lawrence et al. 2000). Perchlorate was detected in the urine of two adults at 10 minutes after a single oral dose of sodium perchlorate (784 mg perchlorate per person); urinary excretion as a percentage of the dose was 30% at 3 hours, 50% in at 5 hours, 85% at 24 hours, and 95% at 48 hours (Durand 1938). This suggests an excretion half-time of approximately 12 hours. The latter estimate is consistent with the elimination kinetics of perchlorate from serum. The elimination halftime for perchlorate in serum was estimated to be approximately 8 hours in adult human subjects who ingested potassium perchlorate in drinking water (0.5 mg/kg/day) for 14 days (Greer et al. 2002). In another study in adult humans, it was estimated that approximately 65–70% of a daily dose of 0.5–3 mg perchlorate/day was excreted over a 24-hour period (Braverman et al. 2006). Thus, in humans, perchlorate is rapidly eliminated and would not be expected to accumulate in the body with prolonged exposure. Based on an elimination half-time of approximately 8–12 hours, a steady state would be achieved within 3–4 days of continuous exposure. The detection of perchlorate in breast milk from lactating women (Kirk et al. 2005; Pearce et al. 2007; Téllez et al. 2005) also indicates breast milk as an excretion route in humans.

Studies conducted in a variety of experimental animals, including rats, rabbits, and calves, have shown that absorbed perchlorate is rapidly and nearly completely excreted in the urine (Fisher et al. 2000; Selivanova et al. 1986; Yu et al. 2002).

Studies conducted in rats have shown that perchlorate is excreted in mammary milk (Clewell et al. 2003b). Perchlorate has also been detected in dairy milk (Howard et al. 1996; Kirk et al. 2005).

3.4.4.3 Dermal Exposure

No studies were found regarding elimination or excretion of perchlorates after dermal exposure.

3.4.4.4 Other Routes of Exposure

Studies in which rats received intravenous or intraperitoneal injections of perchlorate provide additional support for the rapid excretion of perchlorate in urine. Rats that received a single intravenous injection of 0.01, 0.1, 1.0, or 3.0 mg/kg perchlorate (as ammonium perchlorate) excreted 85, 86, 80, or 79% of the administered dose, respectively, in urine (Fisher et al. 2000). The elimination half-time for intravenously injected perchlorate (approximately 0.04 mg, 0.18–0.25 mg/kg, as potassium perchlorate) from serum, and the urinary excretion half-time were estimated in rats to be approximately 20 hours (Goldman and Stanbury 1973). Similarly, rats injected with sodium perchlorate (2, 8, or 49 mg perchlorate/kg) excreted 50% of the administered dose in urine during the first 6 hours and had excreted 93–97% of the dose by 60 hours (Eichler and Hackenthal 1962); in this study, higher doses of perchlorate were eliminated at a faster rate than lower doses. Similar results were obtained in rats that received a single intravenous dose of 3.3 mg/kg perchlorate as ammonium perchlorate; urinary excretion of perchlorate was essentially complete within 12 hours (Yu et al. 2002). Possible contributors to the relatively longer elimination half-life of perchlorate in rats than in humans include differences in serum protein binding or perhaps the NIS protein in the gastrointestinal tract may sequester perchlorate temporarily to a greater degree in the rat than human.

3.4.5 Physiologically Based Pharmacokinetic (PBPK)/Pharmacodynamic (PD) Models

PBPK models have been developed for perchlorate in rats and humans. Since the actual model algorithm was not available, since the risk assessment for human health is based on worker long-term toxicological data, and since use of PBPK models to refine standard assessment factors complicates the assessment process, models description and results have not been included.

Read-across use of sodium chlorate dermal uptake data

 

The dermal absorption of Sodium Chlorate was very low with at most 1.85% (total extent incl. amount in stratum corneum) and 0.446 µg/cm2/hour (rate) over a 24-hourin vitroexposure of human skin, with total recovery (99-101%). This value is extrapolated to Ammonium Perchlorate, based on the structural closeness of both anions (chlorate: ClO3-; perchlorate: ClO4-) and the fact that the toxicity of Ammonium Perchlorate is driven by the perchlorate anion. This extrapolation is supported by the following table summarizing differential features of (Sodium) Chlorate and (Ammonium) Perchlorate and their impact on dermal absorption (based on ECHA's Guidance on information requirements and chemical safety assessment, Table R.7.12-3, 2008):

Determinants of dermal penetration: differential analysis between Sodium Chlorate and Ammonium perchlorate

 

Determinant of dermal penetration

Influence on penetration:favours (+) or limits (-)

Differential influence: AP when compared with SC:higher (+), lower (-) or similar (=) penetration

Physical state

- Liquid / solution

+ (quicker)

-(AP: solid/SC: solution)

- Solid

-(slower)

Molecular weight below 100

+ (quicker)

-to = (Perchlorate= 99.5 / Chlorate= 83.5; AP= 117.5 / SC = 106.4)

Structural alerts for skin binding*

-(bound = non absorbable)

= (neither AP nor SC present such alerts)

Water solubility

+ above 0.1 g/L

= (20°C: AP= 200g/L vs. SC= 696-736 g/L***)

Calculated log Kow**

-below -1 (low solubility instratum corneum)

= (AP: <-1.8**** / SC<-2.9***)

Vapour pressure

-above 100 Pa (volatilizes)

= (AP: not applicable, solid / SC: <3.5 10-5 Pa***)

Surface active properties

+ below 10 mN/m

= (neither AP nor SC are surface active)

Skin irritation potential

+ (damages skin)

-(AP: non-irritant / SC skin irritant***)

SC: sodium chlorate as tested in the dermal penetration study under 7.1.2: formulations in water

AP: Ammonium Perchlorate as in actual use i.e. solid particles (no formulation is used)

*: metal ions, acrylates, quaternary ammonium ions, heterocyclic ammonium ions, sulphonium salts, quinines, dialkyl sulphides, acid chlorides, halotriazines, dinitro or trinitro benzenes

**: calculated as log (Solubility in n-octanol in g/L/Solubility in water in g/L)

***: taken from EC, Draft Assessment Report (DAR) - Chlorate, 2008

****: n-propanol used due to lacking data on solubility in n-octanol (therefore log Kow overestimated)

Based on the above table, the dermal penetration of Perchlorate and Chlorate anions is essentially similar and in both cases very low because the log Kow <-1 shows a negligible ability to crossstratum corneum. Furthermore, Perchlorate is expected to penetrate less than the tested Chlorate (solution) due to exposure to solid particles, slightly higher molecular weight, and absence of skin irritant potential.