Registration Dossier

Administrative data

Endpoint:
short-term repeated dose toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
1 (reliable without restriction)

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1991
Report Date:
1991

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
OECD Guideline 412 (Subacute Inhalation Toxicity: 28-Day Study)
GLP compliance:
yes
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
As per IUCLID% Sections 1.1. - 1.4.

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
Animals were acquired from Charles River U.K. Ltd, Margate, Kent at approximately 6 weeks of age. Animals were housed 5 of the same sex/cage and acclimated 10 days before being placed on study. The animal room conditions were 18-24 degrees C with 36058% relative humidity and a 12 hr light/dark cycle. When not in exposure chambers the aninmals had free access to standard laboratory rat feed (Biosure Diet LAD 1, Biosure, Cambridgeshire, England) and tap water.

Administration / exposure

Route of administration:
inhalation
Type of inhalation exposure:
whole body
Vehicle:
other: unchanged (no vehicle)
Details on inhalation exposure:
Animals were exposed whole body to a vapour of the test substance in stainless and glass chamber of approximarely 0.5 m3 volume. The vapor was generated by passing liquid 1,6-Hexanediol Diglycidylether (HDDGE) throught a glass sinter containted in a glass flask by infusion pump. Air at approximately 80 degrees C was passed tthrough this flask. The generated vapor was direct to the inhalations by means of the inlet ducts. Target concentrations were 1, 4 and 16 ug/L. Previuos studies had demonstrated that 16 ug/L 91.8 ppm) was the maximal achievable vapor concentration of HDDGE.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Chamber concentration of HDDGE were determined at 1, 3, and 5 hr of exposure during each exposure. Analysis was by gas chromatography.
Duration of treatment / exposure:
6 h/d, 5 d/w, 4 w
Frequency of treatment:
5 days/week
Doses / concentrationsopen allclose all
Remarks:
Doses / Concentrations:
16.16 ug/l
Basis:
analytical conc.
Remarks:
Doses / Concentrations:
4.04 ug/l
Basis:
analytical conc.
Remarks:
Doses / Concentrations:
0.94 ug/l
Basis:

No. of animals per sex per dose:
5
Control animals:
yes
Details on study design:
Animals were exposed by whole body inhalation. Animals were observed for clinical signs before loading into the inhalation chambers and immediately following unloading. Body weights were taken on a weekly basis during the study. Feed consumption was monitored weekly. Blood samples were withdrawn during study week four for analysis.
Positive control:
None

Examinations

Observations and examinations performed and frequency:
Clinical signs twice a day, feed consumption and body weight weekly, hematology and clinical chemistry once during study week four.
Sacrifice and pathology:
At study termination the animals were sacrificed by I. P. injection of pentobarbitone sodium and exsanguniation. During necropsy a detailed macroscopic examination was conducted. The following organs ere taken, trimed and weighted: Thymus, Liver, Adrenals, Lungs, Kidneys and Testes. Tissues removed forr histologiccal examination were preserved in buffered 10% formalin, except the eyes ere fixed in Davidson's fixative. The tissues were stained with hematoxylin and eosin for microscopic examination.
Statistics:
Statistical test included: Barlett's one-wat analysis of variance, Kruskal-Wallis, Student's 't' and Williams'.

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 specified
Water consumption and compound intake (if drinking water study):
no effects observed
Ophthalmological findings:
not specified
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
Description (incidence and severity):
Minimal inflamation of the nasal tract.
Histopathological findings: neoplastic:
no effects observed
Details on results:
Greater adrenal weights from high dose was statistically significant for male rats only and considered to not be toxicologically significant.

Effect levels

open allclose all
Dose descriptor:
NOEL
Effect level:
4.04 mg/L air (analytical)
Sex:
male/female
Dose descriptor:
NOAEL
Effect level:
ca. 16 mg/m³ air
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: Minimal evidence of nasal tract inflammation at the high dose level of 16 mg/m3 with no indication of adverse systemic effects.

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
Exposure of rats to 1, 4, or 16 ug/L HDDGE for 4 weeks did not have any adverse effect on body weight, clinical sign, hematologic or clinical chemical parameters or gross pathology. An increase in adrenal weights in rats exposed to 16 ug/L HDDGE was unlikely to be of toxicological significance because of the absence of microscopic changes in the adrenals. The only treatment-related microscopic changes were minimal inflamation in the vestibule of the nose and minimal, focal changes in the larynx of rats exposed to 16 ug/L HDDGE for 4 weeks. This is characteristic of a mild irritant. Therefore the systemic NOAEL for this study is > 16 mg/m3 (1.8 ppm). Since this repeated-dose inhalation study failed to achieve a Maximum Toleratd Dose (MTD) it is judged to be unsuitable for the establishment of a systemic DNEL. However, due to histopathological evidence of nasal tract irritation at 16 mg/m3, a local (irrritation) DNEL can be established. Based on E.C.H.A. guidance (E.C.H.A. RIP 3.2, Guidance on information requirements and chemical safety assessment, Chapter R.8) the resulting DNEL values for long-term local (irritation) are Worker = 0.44 mg/m3 (0.047 ppm) and General Population = 0.27 mg/m3 (0.029 ppm).
Executive summary:

The repeated-dose inhalation toxicity of 1,6 -Hexanediol Diglycidylether (HDDGE) was examined in a 28 -day rat whole body vapor inhaltion study conducted according to O.E.C.D. Testing Guideline No. 412 with GLP compliance. Exposure of rats to 1, 4, or 16 ug/l HDDGE for 4 weeks (5 days/week) did not have any adverse effect on body weight, clinical sign, hematologic or clinical chemical parameters or gross pathology. An increase in adrenal weights in rats exposed to 16 ug/l HDDGE was unlikely to be of toxicological significance because of the absence of microscopic changes in the adrenals. The only treatment-related microscopic changes were minimal inflamation in the vestibule of the nose and minimal, focal changes in the larynx of rats exposed to 16 ug/l HDDGE for 4 weeks. This is characteristic of a mild irritant. Therefore, the systemic NOAEL for this study is > 16 mg/m3 (1.8 ppm). The results from this study demonstrating local, portal-of-entry, nasal tract irritation are appropriate for the derivation of both worker and general population long-term local (irritation) DNELS.