2,4,6-trichloro-1,3,5-triazine

Repeated dose toxicity: inhalation

Administrative data

Endpoint:

sub-chronic toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1990-03-07 to 1990-06-13

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Guideline study with acceptable restrictions (e.g. non-GLP)

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1994

Report date:

1994

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

OECD Guideline 413 (Subchronic Inhalation Toxicity: 90-Day Study)

Version / remarks:

as at 1987

Deviations:

no

GLP compliance:

no

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

2,4,6-trichloro-1,3,5-triazine

EC Number:

203-614-9

EC Name:

2,4,6-trichloro-1,3,5-triazine

Cas Number:

108-77-0

Molecular formula:

C3Cl3N3

IUPAC Name:

trichloro-1,3,5-triazine

Test material form:

solid: particulate/powder

Remarks:

migrated information: powder

Test animals

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: in-house breeding colony
- Age at study initiation: 6-8 weeks
- Weight at study initiation: 145 - 190 g (males), 120 - 160 g (females)
- Fasting period before study: none reported
- Housing: 5 per cage (suspended stainless steel wire mesh cages)
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: 7 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20.5 - 22.5
- Humidity (%): 50 - 65 %
- Air changes (per hr): not reported
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:

inhalation

Type of inhalation exposure:

whole body

Vehicle:

other: unchanged (no vehicle)

Remarks on MMAD:

MMAD / GSD: not applicable to vapour

Details on inhalation exposure:

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: 1 m³ chamber
- Method of holding animals in test chamber: not reported
- Source and rate of air: not reported
- Method of conditioning air: not reported
- System of generating particulates/aerosols:
- vapour generation: cyanuric chloride was sublimated by leading gel dried air through glass tubes (heated to 60 - 90°C with thermostated water on the outside of the tube). The air was filtered to retain particles by plugs of silane treated glass wool. Cyanuric chloride vapour was mixed with dried heated clean air and conducted to the exposure chamber trough glass tubes covered with flexible electric heating tape.
- Temperature, humidity, pressure in air chamber: not reported
- Air flow rate: 120 liters/min
- Air change rate: 7.2 air changes /h
- Method of particle size determination: not reported
- Treatment of exhaust air: not reported


TEST ATMOSPHERE
- Brief description of analytical method used: 5 L air are passed with a flow rate of 0.5 mL/min through 2 mL of toluene in an Impinger gas washing bottle. Afterwards the volume of toluene was refilled to 2 mL. 3 µL of the resulting solution was analysed on a gas chromatography system with nitrogen/phosphorus detector (Hewlett-Packard HP5890A, capillary glass column, HP-1 5m x 0.53 mm x 2.65 µm film thickness, detection range 0.00025 - 0.025 mg/sample). Quantification was reached by comparison to dilutions from weighted amounts of cyanuric chloride dissolved in toluene.
- Samples taken from breathing zone: yes, once every 2 h

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

see above under TEST ATMOSPHERE

Duration of treatment / exposure:

90 days

Frequency of treatment:

6 hours daily, 5 times a week

Doses / concentrations

Remarks:

Doses / Concentrations:
0.01, 0.05 and 0.25 mg/m³
Basis:
analytical conc.

No. of animals per sex per dose:

10

Control animals:

yes

Details on study design:

- Dose selection rationale: doses were selected on a 28 d inhalation study where a NOAEC of 0.08 mg/cbm and a LOAEC of 0.4 mg/cbm were determined
- Rationale for animal assignment: random selecting using a computerized random figure generator
- Rationale for selecting satellite groups: no satellite group
- Post-exposure recovery period in satellite groups: no satellite group

Positive control:

none used

Examinations

Observations and examinations performed and frequency:

General:
Mortality daily; Clinical signs daily before and after exposure; Body weight at study initiation and weekly thereafter; Food consumption.
Clinical pathology:
- Blood chemistry at end of treatment period: aspartate aminotransferase (ASAT), alanine aminotransferase (ALAT), sorbitol dehydrogenase (SDH),
γ-g lutamyl transpeptidase (GGT), alkaline phosphatase (ALP), ornithine carbamoyltransferase (OCT), total billirubin, total protein, albumin, blood
urea nitrogen (BUN), glucose, natrium, potassium, chloride, inorganic phosphate and calcium;
- Hematology at end of treatment period: red blood cell count (RBC), white blood cell count (WBC), hemoglobin, hematocrit value, mean
corpuscular volume (MCV), mean corpuscular hemoglobin concentration (MCHC), platelet count, percentage of reticulocytes and differential
leukocyte count.

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily
Neither cage side observations nor detailed clinical observations are detailed in the study


DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: daily
The report made no differentiation between cage side observations and detailed clinical observations

BODY WEIGHT: Yes
- Time schedule for examinations: at arrival in the test facility, on day 1 of the study and weekly thereafter


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


FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: No


WATER CONSUMPTION: No


OPHTHALMOSCOPIC EXAMINATION: No


HAEMATOLOGY: Yes
- Time schedule for collection of blood: at the end of the treatment period, in the morning
- Anaesthetic used for blood collection: Yes, ether
- Animals fasted: No
- How many animals: all
- Parameters checked in table 1 were examined.


CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: at the end of the treatment period, in the morning
- Animals fasted: No
- How many animals: all
- Parameters checked in table 1 were examined.


URINALYSIS: No

NEUROBEHAVIOURAL EXAMINATION: No

Sacrifice and pathology:

GROSS PATHOLOGY: Yes (see table 2)
- Macroscopy: external appearance, body orifices, body cavities and their contents
HISTOPATHOLOGY: Yes (see table 2)

Statistics:

Bartlett’s test for homogeneity of variance, ANOVA, Dunnett’s test, Kruskal-Wallis test, Dunn’s summed rank test, Jonkheere’s test for trend and ANCOVA.

Results and discussion

Results of examinations

Clinical signs:

no effects observed

Mortality:

no mortality observed

Body weight and weight changes:

no effects observed

Food consumption and compound intake (if feeding study):

no effects observed

Food efficiency:

not examined

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

not examined

Ophthalmological findings:

not examined

Haematological findings:

effects observed, treatment-related

Description (incidence and severity):

no treatment related effects; small but significantly decrease in hemoglobin in females in the high dose group, but regarded to reflect biological variation; reduced white blood cell count in all treated male groups, but no dose dependency.

Clinical biochemistry findings:

effects observed, treatment-related

Description (incidence and severity):

Statistical significant differences of glucose (males) and phosphatase (females) in the mid dose group are regarded to reflect biological variation.

Urinalysis findings:

not examined

Behaviour (functional findings):

not examined

Organ weight findings including organ / body weight ratios:

no effects observed

Description (incidence and severity):

Occasional statistically significant differences were not dose dependent and regarded to be incidental.

Gross pathological findings:

effects observed, treatment-related

Description (incidence and severity):

see details on results

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Description (incidence and severity):

see details on results

Histopathological findings: neoplastic:

not examined

Details on results:

GROSS PATHOLOGY
- Higher incidence of yellowish exudate in noses of high dose males which was occasionally also found in control and treatment groups of males and females and are a rather common finding in Wistart rats kept at the Institute. These findings might be a result of slight infections of the respiratory tract and therefore not test item related.

HISTOPATHOLOGY: NON-NEOPLASTIC
- Slightly higher incidence of purulent inflamation of the nose combined with accumulation of neutrophils in lumen in the noses of high dose males (correlation with yellowish exudate)
- lymphocytic infiltrations in nasal mucosa in control and exposure groups
- interstitial lymphocyte infiltration in alveolar septa and foamy macrophages in the lumen of alveoli in all treated male groups without a clear dose dependency
- Higher incidence of increased cellularity of BALT in high dose males compared to control and other groups
all above mentioned findings are regarded to be a result of a slight infection of the respiratory tract, which might be slightly enhanced in the high dose group due to the irritating nature of the test item
- minimal increase in the no. of fast red (+) droplets in hepatocytes in males in the high dose male group, but the severity of this findings is not higher than in occasional findings in control animals and no degenerative changes or differences in clinical chemistry parameters of the liver are apparent

Effect levels

1

Dose descriptor:

NOAEC

Remarks:

systemic

Effect level:

0.25 mg/m³ air

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: Value for systemic effects

2

Dose descriptor:

NOAEC

Remarks:

local

Effect level:

0.05 mg/m³ air (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: local effects in the lung due to the corrosive action of cyanuric chloride

Target system / organ toxicity

Critical effects observed:

not specified

Applicant's summary and conclusion

Conclusions:

The present study was conducted according to the OECD guideline 413 as at 1987. Wistar rats were treated repeatedly during 90 d with cyanuric chloride via the inhalation route. No clear treatment related effect became obvious and therefore, the highest tested concentration of 0.25 mg/m³ can be regarded as a level where surely not toxicity occurs. As a LOAEL is missing this value cannot be termed a NOAEL. The true NOAEL might be even higher.