1,3,5-tris(oxiranylmethyl)-1,3,5-triazine-2,4,6(1H,3H,5H)-trione

Repeated dose toxicity: inhalation

Administrative data

Endpoint:

short-term repeated dose toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1991

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: all relevant data available

Cross-reference

Cross-reference 1

Reason / purpose for cross-reference:

reference to same study

Cross-reference 2

Reason / purpose for cross-reference:

reference to other study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1991

Report date:

1991

Materials and methods

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 412 (Subacute Inhalation Toxicity: 28-Day Study)

Deviations:

yes

Remarks:

similar to subchronic inhalation study but designed as RF-study

Principles of method if other than guideline:

similar to subchronic inhalation study but designed as RF-study

GLP compliance:

yes

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

1,3,5-tris(oxiranylmethyl)-1,3,5-triazine-2,4,6(1H,3H,5H)-trione

EC Number:

219-514-3

EC Name:

1,3,5-tris(oxiranylmethyl)-1,3,5-triazine-2,4,6(1H,3H,5H)-trione

Cas Number:

2451-62-9

Molecular formula:

C12H15N3O6

IUPAC Name:

tris[(oxiran-2-yl)methyl]-1,3,5-triazinane-2,4,6-trione

Details on test material:

TGIC (technical grade, batch-no. 177108)

Test animals

Species:

mouse

Strain:

CD-1

Sex:

male

Details on test animals or test system and environmental conditions:

exact strain designation: CD-1(ICR)BR strain
Mice were housed two per cage in stainless-steel wire-mesh cages at 18.9 – 22.2 °C, a relative humidity of 47 - 61 %, and at a 12-hour datk/light cycle. Food and water was provided ad libitum. Individual numbering was by tail tattoo.
Acclimatization period was at least 5 days.

Administration / exposure

Route of administration:

inhalation: dust

Type of inhalation exposure:

whole body

Vehicle:

other: unchanged (no vehicle)

Details on inhalation exposure:

4 groups of 12 male mice were exposed to TGIC at 0. 100, 350 and 750 mg/m3 air, 6 hours/day, for 5 consecutive days (whole-body exposure), followed by a 14-day recovery period for further observations.
The volume of the inhalation chamber was 1330 l, and the mouse inhalation cages were placed inside the chamber; air flow was 300 l/min, and dust was generated by an Auger Dust Feeder (Spring Tool Co., Schoolcraft, MI, USA), and concentrations (gravimetric on fiber filters) as well as particle size (using a cascade impactor) were measured several times during each daily exposure.

Analytical verification of doses or concentrations:

no

Duration of treatment / exposure:

6 hours / day, Whole body exposure

Frequency of treatment:

on 5 consecutive days

Doses / concentrations

Remarks:

Doses / Concentrations:
0, 100, 350, 750 mg/m3 air
Basis:
nominal conc.

No. of animals per sex per dose:

12 male mice / group

Control animals:

yes, sham-exposed

Details on study design:

Body weights were measured shortly before the first exposure, and shortly after the last exposure, and on days 7 and 14 post exposure. Gross necropsy was performed after sacrifice on all organs , and gross lesions were preserved in 10% neutral formalin. All parameters measured were statistically analysed with appropriate methods.

Positive control:

none

Examinations

Observations and examinations performed and frequency:

Body weights were measured shortly before the first exposure, and shortly after the last exposure, and on days 7 and 14 post exposure.

Sacrifice and pathology:

Necropsy was performed after sacrifice on all organs , and gross lesions were preserved in 10% neutral formalin. All parameters measured were statistically analysed with appropriate methods.

Statistics:

yes

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):

not examined

Food efficiency:

not examined

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

not examined

Ophthalmological findings:

not examined

Haematological findings:

not examined

Clinical biochemistry findings:

not examined

Urinalysis findings:

not examined

Behaviour (functional findings):

no effects observed

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Gross pathological findings:

effects observed, treatment-related

Histopathological findings: non-neoplastic:

not examined

Histopathological findings: neoplastic:

not examined

Details on results:

Mortality (or sacrifice in moribund condition) was observed in all three dose groups:
at 100 mg/m3 5/12 (days 5-9),
at 350 mg/m3 12/12 (days 3-11), and
at 750 mg/m3 11/12 (days 2-4).

Clinical signs were found in all dose groups and included unkemptness, audible respiration, gasping, blepharospasm, swollen periocular tissue, and dehydration, and perioral wetness was observed at 350 and 750 mg/m3 air.

Body weights were reduced in all dose groups in a concentration-related manner, even during the recovery period additional weight loss was observed at 100 mg/m3 air.

At necropsy gas accumulation in all TGIC-treated animals was found in the gastro-intestinal tract, hyperinflation of the lungs at 350 and 750 mg/m3 air, decreased splee sizein all groups. Also treatment-related were crusts on the skin, perioral areas, perinasal area, and periocular aerea as well as color changes in the lungs.

Effect levels

Dose descriptor:

NOAEL

Effect level:

<= 100 mg/m³ air (nominal)

Sex:

male

Basis for effect level:

other: mortality

Remarks on result:

not determinable

Remarks:

no NOAEL identified

Target system / organ toxicity

Critical effects observed:

not specified

Any other information on results incl. tables

No NOAEL or NOEL was determined

Applicant's summary and conclusion

Conclusions:

6-hour inhalation exposure for 5 consecutive days caused mortality among the male mice exposued
at 100 mg/m3 5/12 (days 5-9),
at 350 mg/m3 12/12 (days 3-11), and
at 750 mg/m3 11/12 (days 2-4).
In addition clinical signs and reduced body weights were observed in a dose-related manner.
No NOAEL or NOEL was determined
The NOEL for this study is below 100 mg/m3 air of TGIC

Executive summary:

6-hour inhalation exposure for 5 consecutive days caused mortality among the male mice exposued at 100 mg/m3 5/12 (days 5-9), at 350 mg/m3 12/12 (days 3-11), and at 750 mg/m3 11/12 (days 2-4). In addition clinical signs and reduced body weights were observed in a dose-related manner. No NOAEL or NOEL was determined The NOEL for this study is below 100 mg/m3 air of TGIC