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Toxicological information

Repeated dose toxicity: inhalation

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Administrative data

Endpoint:
sub-chronic toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Cross-reference
Reason / purpose:
reference to same study

Data source

Reference
Reference Type:
secondary source
Title:
Unnamed
Year:
2010

Materials and methods

Test guidelineopen allclose all
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
Deviations:
yes
Remarks:
(Extention of the exposure period, additional repeated dose group for females and a 4-week recovery period (males))
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 413 (Subchronic Inhalation Toxicity: 90-Day Study)
GLP compliance:
yes
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female

Administration / exposure

Route of administration:
inhalation: vapour
Type of inhalation exposure:
whole body
Vehicle:
air
Analytical verification of doses or concentrations:
yes
Duration of treatment / exposure:
Males: 16 wks (10 weeks premating)
Females: 13 wks
(post exposure observation time: 4 weeks)
Frequency of treatment:
6 hours/day, 5 days/week
Doses / concentrationsopen allclose all
Dose / conc.:
0 ppm
Dose / conc.:
50 ppm
Remarks:
0.21 mg/L nominal conc.
Dose / conc.:
150 ppm
Remarks:
0.61 mg/L nominal conc.
Dose / conc.:
450 ppm
Remarks:
After 10 weeks exposure, the level was reduced to 400 ppm due to slight mortality and the perceived additional stress of mating (females).
1.84/1.64 mg/L nominal conc.
No. of animals per sex per dose:
15 (10 animals/sex/dose in the main group; 5 animals/sex/dose in the recovery group)
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: no data
- Post-exposure recovery period in satellite groups: 4 weeks, 5 rats/sex/dose

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes

DETAILED CLINICAL OBSERVATIONS: Yes

BODY WEIGHT: Yes

FOOD CONSUMPTION: Yes

OPHTHALMOSCOPIC EXAMINATION: Yes

HAEMATOLOGY: Yes
- Time schedule for collection: After 5 weeks (5 animals/sex/group), 13 weeks (10/females/group), 18 weeks (10 males/group), and after the 4-week recovery period (5 animals/sex/group) were selected for blood collection

CLINICAL CHEMISTRY: Yes
- Time schedule for collection: After 5 weeks (5 animals/sex/group), 13 weeks (10/females/group), 18 weeks (10 males/group), and after the 4-week recovery period (5 animals/sex/group) were selected for blood collection

URINALYSIS: Yes

NEUROBEHAVIOURAL EXAMINATION: Yes
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes
Complete necropsies were performed on all rats and specific organs and tissues were weighed and examined microscopically.

Results and discussion

Results of examinations

Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
In the weekly detailed clinical observations, no compound related effects were seen. However, in observations conducted immediately post-exposure, adverse clinical signs such as decreased activity and prostration were seen in a few animals (both sexes) in the 450/400 ppm exposure group. Please also refer to Table 1.
Mortality:
mortality observed, non-treatment-related
Description (incidence):
Single males were found dead at 450 ppm on Days 37,38 and 60 of the study. A single female rat was euthanized in extremis on Day 17. One female was found dead on Day 31. No cause of death could be determined.
Body weight and weight changes:
no effects observed
Description (incidence and severity):
No compound related effects were seen.
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
No compound related effects were seen.
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
no effects observed
Description (incidence and severity):
No compound related effects were seen.
Haematological findings:
no effects observed
Description (incidence and severity):
No compound related effects were seen.
Clinical biochemistry findings:
no effects observed
Description (incidence and severity):
No compound related effects were seen.
Urinalysis findings:
no effects observed
Description (incidence and severity):
No compound related effects were seen.
Behaviour (functional findings):
no effects observed
Description (incidence and severity):
No compound related effects were seen.
Immunological findings:
not specified
Organ weight findings including organ / body weight ratios:
no effects observed
Description (incidence and severity):
No compound related effects were seen.
Gross pathological findings:
no effects observed
Description (incidence and severity):
No compound related effects were seen.
Neuropathological findings:
not specified
Histopathological findings: non-neoplastic:
no effects observed
Description (incidence and severity):
No compound related effects were seen.
Histopathological findings: neoplastic:
not specified
Other effects:
not specified

Effect levels

open allclose all
Key result
Dose descriptor:
NOAEC
Remarks:
(systemic toxicity)
Effect level:
0.61 mg/L air (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
clinical signs
Dose descriptor:
LOAEC
Effect level:
1.64 mg/L air (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
mortality

Target system / organ toxicity

Key result
Critical effects observed:
no

Any other information on results incl. tables

Table 1: Mortality

 

Test group 0

0 ppm

(0 mg/L)

Test group 1

50 ppm#

(0.21 mg/L)

Test group 2

150 ppm

(0.610 mg/L)

Test group 3

450/400 ppm+

(1.84/1.64 mg/L)

Males

0/15

1/15

0/15

3/15

Females

0/15

1/15

0/15

2/15

#50 ppm group: incidentally, one male died during blood collection on Day 126 and one female was found dead on Day 32.

+450/400 ppm: 3 males were found dead on Days 37, 38 and 60; 1 female was found dead on Day 31 and 1 female was euthanizedin extremison Day 17. Clinically decreased activity, prostration, and difficult breathing were seen prior to death.

Applicant's summary and conclusion