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Endpoint:
basic toxicokinetics in vivo
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Principles of method if other than guideline:
Monitoring study to determine absorption and excretion of cyanuric acid after exposure to swimming pool water
Species:
other: Human
Route of administration:
other: oral - swimming pool water and dermal
Details on study design:
Urine samples collected immediately prior to and after exposure were promptly frozen. Participants then collected their urine in sample bottles which were to be used only once and the date and time recorded. All urine samples were frozen (dry ice) as soon as received by the study personnel. Study participants froze or “kept as cold as possible” all overnight specimens as soon as obtained.

The total absorption of the swimmers in the Hall of Fame pool was 3.24 mg/h. Pool concentration was ~30 ppm. The times to 90% cyanuric acid excretion for 23 participants from the Hall of Fame pool, whose compliance was good, was not a function of age or sex. The median time to 90% excretion (approximately 3.5 half-lives) of cyanuric acid absorbed while swimming was ~ 6 h of initial contact (giving a half life of ~1.7 h).

In oral ingestion studies in 2 volunteers, total recovery of cyanuric acid was 21 and 21.2 mg and interpolated 90% excretion was at 3.1 or 3.5 h (t 1/2 ~ 1 h). The volunteers ingested 100 ml of water containing 214 ppm cyanurate (or 21.4 mg cyanurate – thus essentially 100% was recovered in the urine). These were considered consistent with those of swimmers. No further details given.

Dermal absorption alone using total body immersion (to the neck) on 4 males showed the total excretion time was consistent with those described above; further, assuming that these volunteers were immersed for 1 h their mean uptake was 0.25 mg/h. Thus the rates of uptake suggested that much of the swimmers uptake was by the oral route (inadequate detail prevents further analysis). Young swimmers did not appear to absorb more cyanuric acid than older counterparts.

Conclusions:
Orally ingested cyanuric acid appears to be totally excreted unchanged in urine within 24 hours, with t ½ ~1 h. In swimmers, the uptake is largely oral, rates of dermal uptake during immersion (presumably without swimming) being considerably lower. Cyanurate is completely absorbed and excreted unchanged following oral ingestion. When swimming, uptake is largely by oral ingestion.
Endpoint:
basic toxicokinetics in vivo
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Objective of study:
other: absorption and excretion
Principles of method if other than guideline:
The toxicokinetics of CYA in five patients was evaluated and the relationship of CYA elimination to γ-Glutamyl Transpeptidase activity in urine studied.
GLP compliance:
no
Route of administration:
other: oral - swimming pool water and dermal
Details on dosing and sampling:
Total urine was collected and measured for volume and a 20 mL aliquot was used for subsequent chemical and enzymatic analysis.
Toxicokinetic parameters:
half-life 2nd:
Toxicokinetic parameters:
half-life 1st:
Toxicokinetic parameters:
half-life 3rd:
Metabolites identified:
no

The minimum compartmental model found to be statistically consistent with the urine excretion data for cyanuric acid was the one compartment open model with first order input and elimination.  The cumulative excretion curves gave a mean elimination half life of 2.2 h.  Analysis of the data by excretion rate gives an elimination half life of 3.5 h with an average A value of 3.4 mg/h.  The average observed recovery of cyanuric acid after 20 h is 9.8 mg, whereas the value by curve fitting is 11.5 mg (this probably reflected both skin absorption and oral intake). 

Conclusions:
The cumulative excretion curves gave a mean elimination half life of 2.2 h. Analysis of the data by excretion rate gives an elimination half life of 3.5 h with an average A value of 3.4 mg/h. The average observed recovery of cyanuric acid after 20 h is 9.8 mg, whereas the value by curve fitting is 11.5 mg (this probably reflected both skin absorption and oral intake). When 5 volunteers soaked in a swimming pool for 120 min, recovery was 0.03-2.8 mg cyanuric acid (this probably reflected skin absorption only).
Cyanuric acid is excreted rapidly, with a half life of approximately 3 h.
Endpoint:
basic toxicokinetics in vivo
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Objective of study:
toxicokinetics
Qualifier:
equivalent or similar to
Guideline:
EU Method B.36 (Toxicokinetics)
GLP compliance:
no
Radiolabelling:
yes
Species:
dog
Strain:
Beagle
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Laboratory Research Enterprises, Inc., Kalamazoo, MI, USA
- Age at study initiation: 5.9 - 8.5 months
- Weight at study initiation: 7 - 9 kg
- Fasting period before study: 14 hours
- Housing: Housed in galvanized steel cages until administration of radiolabeled compounds and then transferred to stainless steel metabolism cages
- Individual metabolism cages: yes
- Water: ad libitum
- Acclimation period: At least 1 week to surroundings and for at least 48 hours to food and water conditions


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 23-25
- Humidity (%): 46-55
- Photoperiod: 12 hrs continuous light


Route of administration:
other: oral and intravenous
Vehicle:
water
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:
14C-labeled and unlabeled sodium cyanurate were dissolved in distilled water at 3 mg/mL or suspended in 8% carboxymethyl cellulose (Sigma Chemical Co., St. Louis, MO) in distilled water at 100 mg/L. Solutions or suspensions of the compound were freshly prepared on the day of each experiment and samples were removed for determination of the exact specific activity and for determination of the radiochemical purity of 14C-sodium cyanurate.

HOMOGENEITY AND STABILITY OF TEST MATERIAL:
14C-Sodium cyanurate is stable in solution in distilled water at 2 mg/L. The stability of the compound in dog urine was determined by analysis of urine samples by HPLC. 14C-Sodium cyanurate was determined to be stable at room temperature in distilled water after 16 days and in dog urine after 24 hours.
Remarks:
Doses / Concentrations:
i.v at 5 mg/kg bw
p.o. (oral intubation) at 5 mg/kg bw (in distilled water)
p.o. (oral intubation) at 500 mg/kg bw (in 8% carboxymethylcellulose)
p.o at 5 mg/kg (repeated dose, oral intubation; daily for 15 days, with radiolabelled material only for the last dose)
No. of animals per sex per dose:
2 males and 2 females / group.
Control animals:
no
Details on dosing and sampling:
Sampling times:
Blood – i. v.: 5, 15 and 30 min, 1, 2, 4, 6, 8, 12, 16, 24, 48 and 72 hours. Study terminated at 3 days.
Blood – p. o. dose: 15, and 30 min, 1, 2, 4, 6, 8, 12, 16, 24, 48 and 72 hours and 7 days after administration.
Urine and faeces – i. v.: 0-6, 6-12, 12-24, 24-48 and 48-72 hr.
Urine and faeces – 5 mg/kg single p.o. dose: 0-6, 6-12, 12-24, 24-48 and 48-72 and 72-96 hr.
Urine and faeces – 500 mg/kg p.o.: 0-6, 6-12, 12-24, and then at 24 h intervals for a total of 7 days.
Urine and faeces – 5 mg/kg repeated p.o. dose: 0-6, 6-24, 24-48 and 48-72, 72-96,96-120 and 120-146hr.


Details on absorption:
Sodium cyanurate was totally absorbed after administration at 5 mg/kg p.o but absorption after administration at 500 mg/kg p.o was highly variable ranging from less than 10% of the dose to total absorption with an average of around 50% of the dose absorbed. After repeated administration of the compound at 5 mg/kg p.o absorption of the final 14C-labeled dose was marginally reduced. Absorption was determined by comparison of the urinary recovery of the compound after i.v and p.o administration, and by comparison of the areas under the 0-8 hr blood concentration-time curves after i.v and p.o administration.
Details on distribution in tissues:
The concentrations of sodium cyanurate equivalents in tissues at the time of animal sacrifice were less than the limits of sensitivity for the assay for all treatment regimens.
Details on excretion:
After iv or oral administration at 5 mg/kg sodium cyanurate compound equivalents were primarily excreted via the urinary route during the first 12 h with only marginal excretion occurring after 24 h. The percentage of dose excreted in the urine was similar after either route of administration. Recovery of sodium cyanurate equivalents in the feces was negligible ie 2% of the dose or less except for three of the multiple dose animals in which 6-13% was recovered via the fecal route. The total percentage of the 5 mg/kg dose recovered in the urine and feces of both sexes varied from 80 to 100%. Similar total recoveries were observed after oral administration of the compound at 500 mg/kg. However, the percentage excreted in the urine after the higher dose varied from as low as 14% to a maximum of 73%. Urinary excretion of compound equivalents occurred primarily during the first 24 h after dosing, with only marginal excretion occurring after 48 h. There were no differences between the urinary excretion patterns of males and females.
Metabolites identified:
no
Details on metabolites:
Only parent compound was found in urine indicating that metabolism of sodium cyanurate did not occur or was minimal.

Sodium cyanurate was rapidly absorbed, with peak blood levels 1-3 hours post dose and a single elimination half life of 1.5-2 h.  Absorption was probably rate limiting, thus tmax was later and the terminal half-life was longer in high dose animals.

Sodium cyanurate was completely absorbed following administration at 5mg/kg to dogs, but absorption was highly variable at the 500 mg/kg dose level, averaging ~ 50%.  The absorbed compound was rapidly and almost quantitatively eliminated in the urine.

Metabolism, if it occurred at all, is negligible.

There is no evidence for bioaccumulation of the compound and there are no major changes in the disposition or metabolism of sodium cyanurate following repeated administration.

Conclusions:
There is no evidence for bioaccumulation of the compound and there are no major changes in the disposition or metabolism of sodium cyanurate following repeated administration.
Endpoint:
basic toxicokinetics in vivo
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Qualifier:
equivalent or similar to
Guideline:
EU Method B.36 (Toxicokinetics)
GLP compliance:
no
Radiolabelling:
yes
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Breeding Laboratories, Inc., Wilmington, MA. USA
- Age at study initiation: 8-10 weeks;
- Weight at study initiation: males: 237 - 320 g; females 159 – 227 g
- Fasting period before study:
- Individual metabolism cages: yes
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: At least one week prior to dosing to surroundings and 48 hours to housing


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22-29
- Humidity (%): 33-67
- Photoperiod (hrs dark / hrs light): 12/12


Route of administration:
other: intravenous and oral
Vehicle:
water
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:
14C-labeled and unlabeled sodium cyanurate were dissolved in distilled water at 2 mg/L or suspended in 8% carboxymethyl cellulose in distilled water at 100 mg/L. Solutions of the compound were freshly prepared on the day of each experiment and samples were removed for determination of the exact specific activity and for the determination of the radiochemical purity of the 14C-sodium cyanurate.



HOMOGENEITY AND STABILITY OF TEST MATERIAL:
The stability of 14C-sodium cyanurate in solution in distilled water at 2 mg/mL (the formulation used for adminsitration of the compound to rats at 5 mg/kg p.o or i.v) and in rat urine were determined. The dose formulation was analyzed by HPLC in system B on the day of preparation and after 16 days at room temperature. Rat urine was analyzed by HPLC in systems A and B immediately after spiking with 14C-labeled sodium cyanurate and after 20 hr and 10 days in systems A and B respectively.
Remarks:
Doses / Concentrations:
i.v. at 5 mg/kg bw
p.o. (oral intubation) at 5 mg/kg bw (in distilled water at 2 mg/mL concentration)
p.o. (oral intubation) at 500 mg/kg bw (in 8% carboxymethylcellulose at 100 mg/mL concentration)
p.o at 5 mg/kg (repeated dose, oral intubation; daily for 15 days, with radiolabelled material only for the last dose)
No. of animals per sex per dose:
14C-labeled sodium cyanurate was administered in solution at 5 mg/kg iv to 17 male and 17 female rats and at 5 mg/kg p.o to 17 male and 17 female rats and in suspension at 500 mg/kg p.o to 17 male and 15 female rats.
Five rats from each group were used for blood collection at the time of peak concentration of the compouind (except only 3 females were used at the 500 mg/kg dose level) and 5 were used for urine, feces and tissue collection and 2 for CO2 collection.
Unlabeled sodium cyanurate was adminsistered in solution at 5 mg/kg p.o to 7 male and 7 femlae rats for fourteen days.; on the fifteenth day, 24 hr after the last unlabeled dose, 14C-labeled compound was administered in solution at 5 mg/kg p.o. Five rats from each group were used for urine, feces and tissue collection and two for CO2 collection.
Details on dosing and sampling:
Blood:
i.v.: 5, 15, 30 min, 1, 2, 4, 6, 8, 16, 24, 36, 48, 72 h and 7 days.
p.o.: 30 min, 1, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72 h and 7 days.

Urine and faeces:
0 - 6, 6 - 12, 12 - 24 h and then 24 h intervals for 7 days.
No sample was collected at 144 h from male rats dosed with 5 mg/kg i.v.

Tissue collection:
7 days after dosing, at sacrifice.

Expired CO2 samples (on 2 animals/group):
5mg/kg i.v.: 0 – 3, 3 – 6, 6 – 12, 12 - 18, 18 – 24, 24 – 48, 48 – 72, (female terminated) 72 – 96 h.
5mg/kg p.o.: single or repeat doses: 0 – 3, 3 – 6, 6 – 12, 12 - 18, 18 – 24, (repeat dose terminated) 24 – 36, 36 – 53 h.
500 mg/kg p.o.: 0 – 3, 3 – 6, 6 – 12, 12 - 18, 18 – 24, 24 – 36, 36 – 52, 52 – 72 and at 24 h intervals up to 7 days.


Details on absorption:
Sodium cyanurate was totally absorbed after administration at 5 mg/kg p.o, but was only partially absorbed (30-45% of the dose) after administration at 500 mg/kg p.o
Details on distribution in tissues:
Radioactivity remaining in tissues and carcass fell below the limit of sensitivity for the assay procedure.
Details on excretion:
5mg/kg i.v.:
Excretion: males – urine 82.68%, faeces 3.51%, cage rinse 2.09%, tissues 0%, total 88.28%; females – urine 76.79%, faeces 3.35%, cage rinse 2.73%, tissues 0%, total 82.96%.

5 mg/kg oral:
Excretion: males – urine 87.88%, faeces 1.41%, cage rinse 0.92%, exhaled CO2 (2 additional animals only) 0.44%, tissues 0%, total 90.21%; females - urine 80.63%, faeces 3.08%, cage rinse 1.10%, exhaled CO2 (2 animals only) 0.94%, tissues 0%, total 84.80%.

500 mg/kg oral (single dose)
Excretion: males – urine 65.11%, faeces 24.79%, cage rinse 1.25%, tissues 0%, exhaled CO2 (2 additional animal only) 9.58%, total 91.16%; females – urine 34.36%, faeces 37.32%, cage rinse 2.11%, exhaled CO2 (2 additional animal only) 5.40%, tissues 0%, total 73.79%.

5 mg/kg (repeat dose)
Excretion: males – urine 84.68%, faeces 2.74%, cage rinse 0.86%, tissues 0%, exhaled CO2 (2 additional animals only) 0.58%, total 88.28%; females – urine 74.67%, faeces 7.792%, cage rinse 1.89%, exhaled CO2 (2 additional animals only) 1.18%, tissues 0%, total 83.95%.
Details on metabolites:
The only substance found in urine co-chromatographed with or had the same retention time as sodium cyanurate on ion exchange chromatography followed by high performance liquid chromatography.
It was suggested that the radiolabelled carbon dioxide, found largely in the study on high dose rats, was due to metabolism by gut/faecal microflora of unabsorbed radiolabelled cyanurate.

Sodium cyanurate was rapidly absorbed, with peak blood levels 0.25-1 hour post dose and an initial elimination half life of 0.53-0.78 h.  A terminal elimination half life was also described.  Absorption was probably rate limiting, thus tmax was later and the terminal half-life was longer in high dose animals.

Sodium cyanurate was completely absorbed following administration at 5 mg/kg to rats, but absorption was ~30 - 45% at the 500 mg/kg dose level, averaging ~ 50%.  The absorbed compound was rapidly and almost quantitatively eliminated in the urine.

Metabolism, if it occurred at all, is negligible at 5 mg/kg.

Conclusions:
There is no evidence for bioaccumulation of the compound and there are no major changes in the disposition or metabolism of sodium cyanurate following repeated administration
Endpoint:
basic toxicokinetics in vivo
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Objective of study:
absorption
Principles of method if other than guideline:
53 Recreational swimmers using a community swimming pool disinfected with cyanuric acid stabilised chlorine. The participants did not swim on the days immediately before or after the test. Swimmers were asked to actively swim for 45 minutes and to collect their urine for the next 24 h. HPLC and porous graphitic carbon columns with UV detection were used to assay the cyanuric acid content of the urine. With the assumption that 100% of the cyanuric acid ingested orally during swimming was passed in the urine collected in the first 24 h, the volume of pool water ingested during swimming was determined for each swimmer
Details on dosing and sampling:
Pool water samples were collected from 4 locations around the pool prior to the start of swimming activities. The sampling locations were on each side of the pool midway between the corners of the pool. 250 mL were collected at a depth of 25 cm in plastic storage bottles, refrigerated at 4ºC, and analysed for cyanuric acid within 1 week.
Urine samples were collected following the swimming event. Each participant was given a sterile one gallon, large mouth container. The participants were directed to collect their urine over the next 24 h and return the specimen containers to the pool manager after that period of time.

Non-adults ingest about twice as much water as adults during a 45 minutes swimming activity.  The average amount swallowed by non-adults and adults was 37 mL and 16 mL, respectively.  This method was effective for measuring the volume of water swallowed during swimming activity. Results from a comparison study by Allen et al. (1982) indicated that young competitive, long-distance swimmers swallowed 3.5 times more water (126 mL) than young recreational swimmers (37 mL).

Endpoint:
basic toxicokinetics in vivo
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Principles of method if other than guideline:
The absorption, distribution, metabolism and excretion of 14C-isocyanurate was examined in male rats following oral and dermal administration
Radiolabelling:
yes
Species:
rat
Strain:
Wistar
Sex:
male
Details on test animals and environmental conditions:
TEST ANIMALS
- Age at study initiation: For single oral dose: 12 weeks; for repeat oral dose: 5 weeks; for percutaneous absorption, excretion to expiration and bile: 15 weeks
- Weight at study initiation: For single oral dose: 207 ± 13 g; for repeat oral dose: 144 ± 11g; for percutaneous absorption, excretion to expiration and bile: 240 ± 8 g

Route of administration:
other: dermal, oral and iv
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:
14C - 2, 4, 6- cyanuric chloride was dissolved in water at 90°C for 4 hours to convert to 14C-2,4,6-ICA and the solutions of required concentration were prepared by an addition of carrier solution. The radiochemical purity of the heated solution was verified to be pure quality by thin layer chromatography and isotope dilution method using the reference standard of ICA and cyanuric chloride.



Duration and frequency of treatment / exposure:
For repeat oral administration rats were given solution twice a day for 20 days.
Remarks:
Doses / Concentrations:
For oral exposure: 50 μCi/0.410 mg/mL/kg (by gavage).
For dermal exposure: 0.497 mg / 0.8 mL.
No. of animals per sex per dose:
Single oral administration: 6 groups of 3 rats per time point
Repeat oral administration: 4 groups of 3 rats per time point
Percutaneous absorption: 3 groups of 3 rats per time point
Details on dosing and sampling:
Single oral administration: Radioactivity in tissues and organs measured in groups of 3 rats sacrificed at 0.25, 0.5, 1, 3, 6 and 12 h post dose

Repeat oral administration: Urine and feces were collected everyday at 30 min and at 1, 3, 12 hours after last dosing each group was dissected.

Percutaneous absorption: At 6, 9 and 12 hours after application the applied area of skin was wiped thoroughly with a piece of gauze containing water, then at 21 hours after application rats were sacrificed. Meanwhile blood and urine were sampled every 3 hours.
Details on absorption:
Percutaneous absorption: Essentially very little radioactivity had been taken into or passed through the skin
Details on distribution in tissues:
Single oral dose: Radioactivity was distributed rapidly and evenly throughout the body, with highest levels in tissues at 0.5 h. By 6 h radioactivity had been eliminated from most tissues. It persisted slightly longer in stomach. Radioactivity was eliminated almost entirely in urine

Repeat oral dose: Distribution of radioactivity was similar to that following a single oral dose. 94.2 ± 0.6% of the dose appeared in urine and 3.37 ± 0.25% in faeces.

Table 1: Distribution of Radioactivity Following Single Oral Doses of Radiolabelled Isocyanurate

Tissue, etc

Time After Administration (h)

0.25

0.5

1

3

6

12

% of dose

Stomach wall

               contents

2.72

42.68

1.45

10.19

2.07

12.21

0.27

5.65

0.06

0.42

0.02

0.01

Upper small intestine wall

                contents

2.61

8.87

1.13

3.68

0.74

1.36

0.15

0.22

0.04

0.04

0.01

0.00

Lower small intestine wall

               contents

0.85

1.46

0.81

1.82

0.99

1.86

0.22

0.09

0.02

0.18

0.01

0.04

Large intestine wall

contents

0.47

0.21

0.69

0.37

0.23

0.19

0.09

0.09

0.02

0.18

0.00

0.03

Rest of carcass*

40.13

70.38

61.26

29.96

12.26

9.63

Excreta

Urine

Faeces

-

9.43

9.44

-

19.09

19.08

0.005

63.26

63.23

0.03

86.78

86.54

0.24

90.25

88.85

1.41

. . . Table 2: Distribution of Radioactivity Following Repeated Oral Doses of Radiolabelled Isocyanurate

Tissue, etc

Time After Administration (h)

0.5

1

3

6

% of dose

Stomach wall

               contents

2.55

39.93

1.94

23.13

0.93

5.97

0.02

0.01

Upper small intestine wall

                contents

1.82

4.87

0.91

1.60

0.30

0.32

0.02

0.01

Lower small intestine wall

               contents

1.13

5.02

0.66

2.49

0.14

1.44

0.02

0.06

Large intestine wall

contents

0.22

0.15

0.17

0.19

0.05

0.09

0.01

0.11

Rest of carcass*

25.08

43.17

47.74

7.61

Excreta

19.27

25.74

43.02

92.13

Table 3: Percutaneous absoprtion of radioactivity at 21 hours after application to rat skin (% of dose)

Length of Application

(Hours)

Rinsed Skin

Bloood Samples

Total Urine

Gauze and Rinsing Water

6

2.24 ± 0.60

Not detected

0.008 ± 0.006

85.29 ± 0.60

9

2.71 ± 1.14

Not detected

0.007 ± 0.001

82.02 ± 1.14

12

1.24 ± 0.23

Not detected

0.009 ± 0.006

85.48 ± 0.23

Conclusions:
14C-Isocyanuric acid, given orally to rats, distributed rapidly, showing highest radioactivity concentrations in blood, liver and kidney.  Maximum concentrations occurred 0.5 h after dosing.  Thereafter radioactivity decreased rapidly, with half lives of approximately 1 h.  The radioactivity was excreted almost entirely in urine as unchanged substance.  When administered dermally, very little radiolabelled isocyanurate was taken up.
Endpoint:
basic toxicokinetics in vitro / ex vivo
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Objective of study:
absorption
Principles of method if other than guideline:
In order to quantify the dermal penetration of cyanuric acid under simulated swimming pool exposure conditions an automated in vitro dermal absorption (AIDA) method was used. Skin from humans and two animal species were tested to determine the relationship between dermal absorption in animal models to humans. In addition, a tissue cultured human-derived skin was evaluated as an alternative to human skin. A donor solution was used to simulate swimming pool water and contained 14C-cyanuric acid, while the receiver solution simulated blood and consisted of Hank’s or Ringer’s solution. Receiver samples were harvested and analyzed.
GLP compliance:
not specified
Radiolabelling:
yes
Species:
other: rat, guinea pig, human tissue (human-derived skin strain)
Strain:
other: Rat: Sprague Dawley, Guinea pig: hairless, Human: caucasian, tissues cultured human-derived skin: Testskin®
Route of administration:
dermal
Details on exposure:
TEST SITE:
Rat: skin specimens were obtained from the shaved mid-dorsal region immediately post-euthanasia with barbiturate and were dermatomed
Hairless guinea pig: skin specimens were obtained from the back region immediately post-euthanasia with barbiturate and were dermatomed
Human: abdominal skin from a Caucasian female was obtained viable from a local hospital and was mounted in the AIDA chamber within 1 h of surgery and was dermatomed.
Tissue cultured human-derived skin: not specified
Remarks:
Doses / Concentrations:
The donor solution simulated the swimming pool water and consisted of 100 ml distilled water containing either 1 µCi or 100 µCi of 14C-CYA, unlabelled CYA at 55 ppm and chlorine at 1.5 ppm. The concentrations of unlabelled CYA and chlorine were selected as being representative of standard pool conditions.
Positive control:
14C-DEET (diethyl-m-toluamide; SA 4.4 mCi/mM, radiochemical purity >95%)
Details on dosing and sampling:
The donor solution was pumped in re-circulating fashion over the outer epidermal side of the skin at a rate of 5 mL/min with a peristaltic pump. Donor solution was maintained at 37ºC.
Ringer’s or Hank’s receiver solution, simulating blood, was adjusted to pH 7.4 with 1 N NaOH, passed through a 0.2 μm filter and pumped at 40μL/min over the inner dermal side of the skin. Receiver samples were analysed by liquid scintillation counting.



The Receiver solution simulating blood samples were harvested in a fraction collector every 2 h for 24 h, methanol skin washes and tissue digests of the skin were sampled at 24 h post-application
Details on absorption:
In all cases the % dermal absorption, cumulative amount of cyanuric acid and the maximum rate of permeation ranged from non-detectable to minimal. Where human skin was tested with a pool concentration of unlabelled cyanuric acid and chlorine, only 0.06 μg/cm2 total cumulative absorption was detected over the 24 h exposure period. Employing a value of 1.83 m2 for the total body surface area of a 70 kg human, 0.06 μg/cm2 would imply an exposure of 1.1 mg for a 24 h exposure period. Assuming a worse case maximum exposure time of 5 h daily the data suggests that 0.2 mg/day would be absorbed through a swimmer’s skin. For a standard water cyanuric acid concentration of 55 ppm, 0.2 g of cyanuric acid would be contained in 3.6 mL of pool water. Therefore exposure by the oral route could easily supersede that of dermal.
The presence of unlabelled cyanurate in the “pool” markedly affected the calculations when expressed as μg of cyanurate. Permeation rates with the rat skin with Ringer’s and rat skin with Hank’s were similar, but the Rp values were different due to the larger total dose of cyanuric acid in the latter study

Where human skin was tested with a pool concentration of unlabelled cyanuric acid and chlorine, only 0.06 μg/cm2 total cumulative absorption was detected over the 24 h exposure period.  Employing a value of1.83 m2 for the total body surface area of a human, would imply an exposure of 1.1 mg for a 24 h exposure period.  Assuming a worse case maximum exposure time of 5 h daily the data suggests that 0.2 mg/day would be absorbed through a swimmers skin.  For a standard water cyanuric acid concentration of 55 ppm, 0.2g of cyanuric acid would be contained in 3.6 mL pool water.  Therefore exposure by the oral route could easily supersede that of dermal.

Table 1: In vitro recovery data from skin following exposure to 14C-cyanurate in a model swimming pool

Species

R & H

Wash

Digest

Wash + Digest

Rat

R

0.23 ± 0.12

0.05 ± 0.02

0.28 ± 0.14

Rat

H

0.01 ± 0.01

0.01 ± 0.01

0.01 ± 0.01

Rat

R

0.01 ± 0.02

0.01 ± 0.01

0.02 ± 0.02

Guinea pig

R

0.00 ± 0.00

0.17 ± 0.04

0.17 ± 0.04

Guinea pig

H

0.00 ± 0.01

0.01 ± 0.01

0.01 ± 0.02

Human

R

0.00 ± 0.00

0.00 ± 0.00

0.00 ± 0.00

Human

H

0.00 ± 0.00

0.00 ± 0.00

0.00 ± 0.00

Testskin®

R

0.00 ± 0.00

0.00 ± 0.00

0.00 ± 0.00

Table 2: In vitro pharmacokinetic data for different species of animal skin following exposure to 14C-cyanurate in a model swimming pool

Species

R & H*

Skin Thickness (mm)

Skin Permeation

(%)

Cumulative Absorption

in 24h (μg/cm2)

Maximum Rate of Skin Penetration

(μg/cm2/h)

Rat

R

0.50 ± 0.01

0.003 ± 0.00

0.00 ± 0.00

0.00 ± 0.00

Rat

H

0.64 ± 0.05

0.004 ± 0.00

1.12 ± 0.97

0.06 ± 0.05

Rat

R

0.50 ± 0.00

0.070 ± 0.08

0.30 ± 0.37

0.07 ± 0.10

Guinea Pig

R

0.31± 0.01

0.076± 0.02

0.01 ± 0.00

0.00 ± 0.00

Guinea Pig

H

0.50 ± 0.01

0.001 ± 0.00

0.20 ± 0.34

0.01 ± 0.02

Human

R

0.50 ± 0.01

0.000 ± 0.00

0.02 ± 0.01

0.00 ± 0.00

Human

H

0.51 ± 0.01

0.000 ± 0.00

0.06 ± 0.04

0.00 ± 0.00

Testskin®

R

0.30 ± **

0.000 ± 0.00

0.02 ± 0.03

0.00 ± 0.00

* Ringers or Hanks receiver solution

** Data provided by Organogenesis Inc.

Conclusions:
An in vitro model system indicates that cyanurate is poorly absorbed through the skin in all the species tested.

Description of key information

Studies conducted on cyanuric acid and sodium cyanurate monohydrate.

Key value for chemical safety assessment

Bioaccumulation potential:
no bioaccumulation potential

Additional information

Studies have been conducted on the absorption, distribution, metabolism and excretion of radiolabelled sodium cyanurate (equivalent to 77.5% CYA) after single i.v. and repeated oral administration. No metabolism or accumulation was demonstrated in either of the two animal studies in dogs and rats with 100% of the radioactive label recovered in urine and faeces. Over 98% of the cyanuric acid was absorbed from the GI tract. The findings of the animal studies are upheld in a pilot study in humans ingesting swimming pool water where > 98% of a measured dose of CYA was recovered in urine within 24 hours of dosing (Dufour et al (2006). In oral ingestion studies in 2 volunteers, total recovery of cyanuric acid was 21 and 21.2 mg and interpolated 90% excretion was at 3.1 or 3.5 h (t1/2~ 1 h). The volunteers ingested 100 ml of water containing 214 ppm cyanurate (or 21.4 mg cyanurate) thus essentially 100% was recovered in the urine. 

In dermal absorption studies where human skin was tested with a pool concentration of unlabelled cyanuric acid and chlorine, only 0.06 μg/cm2total cumulative absorption was detected over the 24 h exposure period (Moody 1993). Employing a value of 1.83 m2for the total body surface area of a 70 kg human, would imply an exposure of 1.1 mg for a 24 h exposure period. Assuming a worse case maximum exposure time of 5 h daily the data suggests that 0.2 mg/day would be absorbed through a swimmers skin. For a standard water cyanuric acid concentration of 55 ppm, 0.2 g of cyanuric acid would be contained in 3.6 mL pool water. Therefore exposure by the oral route could easily supersede that of dermal.