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

Repeated dose toxicity: dermal

Administrative data

Endpoint:

short-term repeated dose toxicity: dermal

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1983-03-08 to 1983-03-30

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Guideline study with acceptable restrictions (e.g. purity of test substance not reported)

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1983

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

OECD Guideline 410 (Repeated Dose Dermal Toxicity: 21/28-Day Study)

Deviations:

no

GLP compliance:

no

Remarks:

study performed prior to implementation of GLP

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:

rabbit

Strain:

New Zealand White

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Davidson's Mill Farm; Jamesbury, NJ, U.S.A.
- Age at study initiation: 12 - 14 weeks
- Weight at study initiation: not reported
- Fasting period before study: not reported, fasting prior to collecting of blood samples
- Housing: individually, in hanging wire mesh cages
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: 22 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): not reported
- Humidity (%): not reported
- Air changes (per hr): 11.3 h
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Type of coverage:

occlusive

Vehicle:

other: mineral oil

Details on exposure:

TEST SITE
- Area of exposure: back
- % coverage: 30 % of total skin surface
- Type of wrap if used: gauze bandaging and occlusion with impervious plastic (Prime Wrap II (R)), wrapping of total application site with 3-inch wide Dermiform (R) Tape.
- Time intervals for shavings or clippings: not reported
- plastic collars (E-Jay Saf-T Shields, W.A. Butler, Inc. Columbus, Ohio, U.S.A.) were applied 1 week prior to study initiation and remained for the duration of the study

REMOVAL OF TEST SUBSTANCE
- Washing: tepid water and disposable papertowels
- Time after start of exposure: 6 h


TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 2 mL/kg bw
- Concentration: 0, 25, 75 and 250 mg/mL
- Constant volume or concentration used: no
- For solids, paste formed: no, suspension


VEHICLE
- Justification for use and choice of vehicle: most suitable vehicle for generation of suspensions
- Amount(s) applied (volume or weight with unit): 2 mL/kg bw
- Lot/batch no. : not reported
- Purity: not reported


USE OF RESTRAINERS FOR PREVENTING INGESTION: no, plastic collars (E-Jay Saf-T Shields, W.A. Butler, Inc. Columbus, Ohio, U.S.A.) were applied 1 week prior to study initiation and remained for the duration of the study

Analytical verification of doses or concentrations:

no

Duration of treatment / exposure:

3 weeks

Frequency of treatment:

5 days/week, 6 h/day

Doses / concentrations

Remarks:

Doses / Concentrations:
0,50, 150, 500 mg/kg (m/f)
Basis:
nominal per unit body weight

No. of animals per sex per dose:

6

Control animals:

yes, concurrent no treatment

yes, concurrent vehicle

Details on study design:

Post-exposure period: none

Positive control:

none

Examinations

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily
- Cage side observations checked in table 1 were included.
- Presumably further observations were conducted in addition, but they were not reported in detail

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: daily
- no differentiation was made between cage side observation and clinical observations
- see table 1 for checked observations


DERMAL IRRITATION (if dermal study): Yes
- Time schedule for examinations: once daily
- grading of skin reactions according to Draize score


BODY WEIGHT: Yes
- Time schedule for examinations: at study start and weekly thereafter


FOOD CONSUMPTION:
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: No, but individual food consumption was estimated, based on visual examination of food remaining in the feeder dish


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: once on study day 0 and once at study day 20
- Anaesthetic used for blood collection: No
- Animals fasted: Yes
- How many animals: 6 per group
- Parameters checked in table 2 were examined.


CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: once on study day 0 and once at study day 20
- Animals fasted: Yes
- How many animals: 6 per group
- Parameters checked in table 2 were examined.


URINALYSIS: No


NEUROBEHAVIOURAL EXAMINATION: No

Sacrifice and pathology:

GROSS PATHOLOGY: Yes (see table 3)
HISTOPATHOLOGY: Yes (see table 3)

Results and discussion

Results of examinations

Clinical signs:

effects observed, treatment-related

Dermal irritation:

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):

no effects observed

Food efficiency:

no effects observed

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

no effects observed

Ophthalmological findings:

not examined

Haematological findings:

no effects observed

Clinical biochemistry findings:

no effects observed

Urinalysis findings:

not examined

Behaviour (functional findings):

not examined

Organ weight findings including organ / body weight ratios:

no effects observed

Gross pathological findings:

no effects observed

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Histopathological findings: neoplastic:

no effects observed

Details on results:

CLINICAL SIGNS AND MORTALITY
- occasional findings of ocular and nasal discharges in all groups except the high dose group, nasal discharge very prominent in high dose group
- other signs and findings are incidentally and scattered over the dose groups
- dermal irritation:
- no dermal irritation in the control group
- slight dermal irritation in the vehicle test group (slight erythema and slight to no edema) during the last 7 to 10 days of the study
- significant dermal irritation in the three dose groups showing dose-related progression, dermal irritation increased also with duration of the study in these dose groups (sequence: blanching, fissuring, desquamation, eschar (if present) and exfoliation (if present)
dose signs
50 mg/kg bw/day moderate to marked erythema and edema, blanching, fissuring and desquamation, plus 1/3 of the group showed eschar and exfoliation
150 mg/kg bw/day marked erythema and edema, blanching, fissuring and desquamation eschar and exfoliation
500 mg/kg bw/day marked erythema and edema, blanching, fissuring and desquamation eschar and exfoliation

- Mortality: 3 animals died
animal // dose goup // cause of death // test item related
animal 21465 // (150 mg/kg bw/day) // multifocal ulcerative dermatitis and associated debilitating effects // yes
animal 21435 // (vehicle control group) // multifocal renal and pulmonary abscessation // no
animal 21479 // (150 mg/kg bw/day) // severe hepatic necrosis and severe bronchopneumonia // no


BODY WEIGHT AND WEIGHT GAIN
- see table 4
- Body weight losses from study initiation to termination were noted for group 4 males and group 5 males and females
- Body weights of group 5 females were significantly different from both control groups at day 21 of the study
- All noted group mean body weight losses are considered biologically significant and related to the administration of the test article

FOOD CONSUMPTION
- no remarkable changes in the dietary habits of the study animals on the daily visual estimate of food remaining in the dish


HAEMATOLOGY
- No test article related values observed
- statistically significant differences from control group values were considered to be due to normal biological variability

CLINICAL CHEMISTRY
- No test article related values observed
- statistically significant differences from control group values were considered to be due to normal biological variability


URINALYSIS
- not performed

NEUROBEHAVIOUR
- not performed

ORGAN WEIGHTS
- no test article related changes observed
- occasional statistically significant changes either due to low body weights or within normal biological variability

GROSS PATHOLOGY
- no test article related changes observed

HISTOPATHOLOGY: NON-NEOPLASTIC
- all organs except skin:
- generally no test article related changes observed
- additional occasional findings in treated animals were similiar in type and frequency as in the control groups and were therefore considered to be due to normal biological variability
-skin:
- no findings in the untreated control group
- findings in the vehicle control groups included epidermal hyperkeratosis and acanthosis and follicular hyperkeratosis and acanthosis
- numerous test article related microscopic changes in the epidermis, dermis and follicles in treated skin of dosed animals:
- intraepidermal suppuration
- ulceration in the epidermis in groups 4 (mid dose) and 5 (high dose) (more prominent in group 5)
- more pronounced dermal inflammation and follicular acanthosis in dose groups compared to vehicle control
- more pronounced epidermal acanthosis and follicular hyperkeratosis (males only in groups 4 and 5)
- additional microscopic findings were considered not test item related

HISTOPATHOLOGY: NEOPLASTIC (if applicable)
- not applicable

Effect levels

1

Key result

Dose descriptor:

NOAEL

Remarks:

systemic effects

Effect level:

500 mg/kg bw/day

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: no indications for systemic toxicity

2

Key result

Dose descriptor:

LOAEL

Remarks:

local effects (irritation)

Effect level:

50 mg/kg bw/day

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: skin corrosion/irritation

Target system / organ toxicity

Critical effects observed:

not specified

Any other information on results incl. tables

- Table 4: Average body weights and body weight gains during 3 weeks of treatment

Dose rate [mg/kg bw/day]	Body Weights (g)				Total Weight Gain
	Week ‑1	Week 1	Week 2	Week 3	g	% of control
Male
0 group 1	2693 ± 179.7	2906	2984	2968 ± 331.1	275	100
0, vehicle group 2	2733 ± 263.3	2831	2929	2972 ± 141.2	239	87
Low (50) group 3	2686 ± 229.7	2723	2836	2805 ± 335.9	119	43.3
Mid (150) group 4	2672 ± 229.9	2676	2721	2598 ±287.4	- 74	- 23
High (500) group 5	2704 ±239.2	2617	2590	2521 ± 305.6	- 183	- 67
Female
0 group 1	2819 ± 192.9	2986	3142	3076 ±309.0	257	100
0, vehicle group 2	2806 ±127.9	2989	3102	3172 ±255.0	366	142
Low (50) group 3	2799 ± 170.8	2809	2969	2984 ±263.6	185	72.0
Mid (150) group 4	2832 ± 178.9	2817	2962	2935 ±163.2	103	40.1
High (500) group 5	2821 ±226.4	2743	2778	2646 ±292.3 ^1, 4	175	- 68.1

¹  Significantly different (p 0.05) from the control.

² Significantly different (p 0.01) from the control.

³  Significantly different (p 0.05) from the vehicle control.

⁴ Significantly different (p 0.01) from the vehicle control.

Applicant's summary and conclusion

Conclusions:

Under the condition of the present study a LOAEL of 50 mg/kg bw/day could be deduced for local dermal effects. As body weight effects were clearly assigned to reduced food intake due to stress caused by repeated treatment with the corrosive substance and no other indications for systemic toxicity was observed a systemic NOAEL of 500 mg/kg bw/d can be derived.