Troclosene sodium

Repeated dose toxicity: oral

Administrative data

Endpoint:

sub-chronic toxicity: oral

Type of information:

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

Adequacy of study:

key study

Study period:

23 November 1979 to 22 January 1980

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: see 'Remark'

Remarks:

Well documented study which meets basic scientific principles. Justification for read across: The chlorinated isocyanurates (sodium dichloroisocyanurate and sodium dichloroisocynaurate dihydrate) produce free available chlorine, in the form of hypochlorous acid (HOCl) as they dissolve in water. As the equilibria involve all of the possible chlorinated isocyanurates, the toxicity of sodium dichloroisocyanurate (NaDCC) and sodium dichloroisocyanurate dihydrate (NaDCC.2H2O) will be virtually equivalent at the same available chlorine concentration. The parent compound for all chlorinated isocyanurates is isocyanuric acid (cyanuric acid). All of the chlorinated isocyanurates are essentially equivalent, once they are dissolved in water at the low concentrations at which they are used. Therefore read across to sodium dichloroisocyanurate dihydrate is justified.

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1980

Report date:

1980

Materials and methods

Principles of method if other than guideline:

Sodium dichloro-s-triazinetrione dihydrate was administered daily in the drinking water for 59 days to Charles River CD® rats at dosage levels o400, 1200, 4000, and 8000 ppm. Five male and five female rats were initiated in each dosage group and 10 males and 10 females were initiated in a control group. The rats were observed daily for signs of overt toxicity, moribundity and mortality.

GLP compliance:

yes

Test material

Test material information

Constituent 1

Reference substance name:

1,3-dichloro-1,3,5-triazine-2,4,6(1H,3H,5H)-trione sodium salt dihydrate

Cas Number:

51580-86-0

Molecular formula:

C3Cl2N3O3.2H2O.Na

IUPAC Name:

1,3-dichloro-1,3,5-triazine-2,4,6(1H,3H,5H)-trione sodium salt dihydrate

Details on test material:

Name of test material: Sodium dichloro-s-triazinetrione dihydrate
Physical state: coarse white powder.
Lot/batch No.: 56C 919807 (FMC)

Test animals

Species:

rat

Strain:

other: Charles River

Sex:

male/female

Details on test animals or test system and environmental conditions:

Test animals:
Source: Charles River Breeding Laboratories, Inc., Portage, Michigan.
Age at study initiation: 3 weeks
Weight at study initiation: 84-100 g (males) and 84-101 g (females)
Housing: individual housing in suspended wire-mesh cages
Diet: ad libitum
Water: ad libitum
Acclimation period: 9 days

Environmental conditions:
Temperature (°C): 68-70 °F (20-21.1 °C).
Humidity (%): 30-70 %
Photoperiod (hrs dark / hrs light): 12 hours dark / 12 hours light

Administration / exposure

Route of administration:

oral: drinking water

Vehicle:

water

Details on oral exposure:

Preparation of dosing solutions:
A suitable amount of each test compound was dissolved in tap water, on a stir plate, to provide a base solution.

Concentration in vehicle:
Dosage levels of sodium dichloro-s-triazinetrione dihydrate were 400, 1200, 4000 and 8000 ppm.

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Twice during study weeks 1, 2, 3, 4, 6, 7 and 8, duplicate 100-milliliter samples were collected from the control and test solutions prior to dosing. Once during study weeks 5 and 9, duplicate 100-milliliter samples were similarly collected. Duplicate 50-milliliter samples were collected on day 1 of study week 5. These samples were collected 8 days after preparation of the control and test solutions. The other samples were collected from the solutions prepared 4 days prior to dosing.

Samples were sent at room temperature to the sponsor. Prior to shipping, the test solution samples containing sodium dichloro-s-triazinetrione dihydrate were neutralized with sodium thiosulfate. The samples were analyzed for cyanuric acid by Differential Pulse Polarography. In addition, test solutions were assayed for free residual chlorine 4 days after solution preparation by the Iodometric Titration Method.

Duration of treatment / exposure:

28 days extended to 59 days

Frequency of treatment:

Daily in drinking water

Doses / concentrations

Remarks:

Doses / Concentrations:
400, 1200, 4000 and 8000 ppm (males: 42.7, 115.0, 429.1, 866.0 mg/kg bw/d; females: 55.2, 118.0, 492.0, 1459.1 mg/kg bw/d)
Basis:

No. of animals per sex per dose:

5/sex/dose (test) 10/sex/dose (control)

Control animals:

other: Tap water adjusted to pH 7.2 - 7.6 using sodium hydroxide and glacial acetic acid

Details on study design:

Post-exposure period: none

Positive control:

None

Examinations

Observations and examinations performed and frequency:

Cage side observations: Yes
- Time schedule: twice daily

Detailed clinical observations: Yes
- Time schedule: weekly

Body weight: Yes
- Time schedule for examinations: twice weekly

Food consumption:
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes

Water consumption: Yes
- Time schedule for examinations: three times a week

Ophthalmoscopic examination: No

Haematology: Yes
- Time schedule for collection of blood: end of study
- Metabolism cages used for collection of urine: Yes
- Anaesthetic used for blood collection: No
- Animals fasted: No

Clinical chemistry: Yes
- Time schedule for collection of blood: end of study
- Metabolism cages used for collection of urine: Yes
- Animals fasted: No

Urinalysis: Yes
- Time schedule for collection of urine: end of study
- Metabolism cages used for collection of urine: Yes
- Animals fasted: No

Neurobehavioural examination: No

Sacrifice and pathology:

Gross pathology and histopathology: Yes

Other examinations:

Organ weights

Results and discussion

Results of examinations

Clinical signs:

effects observed, treatment-related

Mortality:

mortality observed, treatment-related

Body weight and weight changes:

effects observed, treatment-related

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Food efficiency:

not examined

Water consumption and compound intake (if drinking water study):

effects observed, treatment-related

Ophthalmological findings:

not examined

Haematological findings:

effects observed, treatment-related

Clinical biochemistry findings:

effects observed, treatment-related

Urinalysis findings:

effects observed, treatment-related

Behaviour (functional findings):

not examined

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Gross pathological findings:

effects observed, treatment-related

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Histopathological findings: neoplastic:

not specified

Details on results:

Clinical signs
Animals treated with 4000 and 8000 ppm demonstrated laboured breathing, emaciation, accumulation of yellow material in the anogenital region, decreased activity and death.

Mortality
Deaths occurred as early as week 1 for some animals in animals treated with 4000 and 8000 ppm. Survival at termination is shown in table 1.

Body weight gain
A dosage related decrease in group mean body weight was noted for the 4000 ppm and 8000 ppm groups (males and females). The decrease was significantly different for males at 4 or 8 weeks.

Food consumption and compound intake
A dosage related decrease was noted in average food consumption in males and females treated with 4000 ppm and 8000 ppm

A dosage related decrease in mean water consumption was noted in all treated groups. This difference was statistically significant for almost all groups at 4 and 8 weeks of study.

Haematology
All values were within the normal range. Occasional values were statistically significant but the absolute differences were small and the numbers of animals surviving for blood collection were minimal.


Clinical chemistry
All values were within the normal range. Occasional values were statistically significant but the absolute differences were small and the numbers of animals surviving for blood collection were minimal.


Urinalysis
All values were within the normal range. Occasional values were statistically significant but the absolute differences were small and the numbers of animals surviving for urine collection were minimal. Urine volume and urine creatinine were significantly decreased in the high dose males, which may be due to decreased water consumption and mean body weight in this group.


Organ weights
A statistically significant decrease in absolute liver weights at 8000 ppm was noted and was probably treatment related due to the decrease in body weight gains.

Gross and histopathology: No gross or microscopic lesions of treatment-related significance were noted.

Other findings: No other significant effects were described.

Effect levels

1

Dose descriptor:

NOAEL

Effect level:

115 mg/kg bw/day (nominal)

Sex:

male

2

Dose descriptor:

NOAEL

Effect level:

178 mg/kg bw/day (nominal)

Sex:

female

3

Dose descriptor:

LOAEL

Effect level:

429 mg/kg bw/day (nominal)

Sex:

male

4

Dose descriptor:

LOAEL

Effect level:

492 mg/kg bw/day (nominal)

Sex:

female

Target system / organ toxicity

Critical effects observed:

not specified

Any other information on results incl. tables

Table 1:Survival at study termination

Group	Dosage level	Number surviving/number initiated
		Males	Females
I	0 (control)	10/10	10/10
II	400	5/5	5/5
III	1200	5/5	5/5
IV	2000	4/5	4/5
V	4000	2/5	1/5

At eight weeks of study, compound related signs were noted for male and female rats treated with sodium dichloro-s-triazinetrione dihydrate at 4000 and 8000 ppm, demonstrating laboured breathing, emaciation, accumulation of yellow material in the anogenital region, decreased defecation, decreased activity and death. Deaths occurred in groups treated with sodium dichloro-s-triazinetrione dihydrate at 4000 and 8000 ppm.

Compound related decreases in mean body weight, food consumption and water consumption were noted in groups treated with sodium dichloro-s-triazine dihydrate. Urine volumes and urine creatinine were decreased in high dose males treated with sodium dichloro-s-triazinetrione dihydrate. All male groups treated with sodium dichloro-s-triazine dihydrate had decreased liver weights as did females treated with sodium dichloro-s-triazinetrione dihydrate at 4000 and 8000 ppm. Although statistical significance was claimed for several effects at lower doses the values obtained were within the normal range of historic control values

Applicant's summary and conclusion

Conclusions:

LO(A)EL: 4000 ppm (males 429 mg/kg bw/d; females 492 mg/kg bw/d) (emaciation, deaths)
NO(A)EL: 1200 ppm (males 115 mg/kg/d; females 178 mg/kg bw/d)