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Toxicological information

Repeated dose toxicity: inhalation

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Administrative data

Endpoint:
repeated dose toxicity: inhalation
Remarks:
other: inhalation during developmental toxicity study (GD 6-15)
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Developmental toxicity study comparable to guideline study (OECD Guideline 414) with sufficient documentation, well documented;
Cross-reference
Reason / purpose:
reference to same study

Data source

Reference
Reference Type:
publication
Title:
Developmental toxicity evaluation of inhaled citral in Spraque-Dawley rats.
Author:
Gaworksi C.L., Vollmuth T.A., York R.G., Heck J.D., Aranyi C.
Year:
1992
Bibliographic source:
Fd Chem. Toxic. 30, 269-275

Materials and methods

Principles of method if other than guideline:
Mortalities, clinical signs of intoxication, body weight gains and gross lesions were investigated as signs of maternal toxicity during a developmental toxicity study.
GLP compliance:
not specified
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): Citral
- Lot/batch No.: 9966
- Analytical purity: 90%
- Impurities (identity and concentrations): not identified
- Composition of test material, percentage of components: approx. 90% purity representing a commercial product
- Isomers composition: 35% neral, 55% geranial

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
female
Details on test animals and environmental conditions:
see Section 7.8.2

Administration / exposure

Route of administration:
inhalation
Type of inhalation exposure:
whole body
Vehicle:
other: nitrogen
Remarks on MMAD:
MMAD / GSD: 4.2 µm / 1.9
Details on inhalation exposure:
see Section 7.8.2
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
see Section 7.8.2
Duration of treatment / exposure:
from gestation day 6 - 15
Frequency of treatment:
daily, 6 h/d
Doses / concentrationsopen allclose all
Remarks:
Doses / Concentrations:
10, 34, 68 ppm
Basis:
other: nominal conc. corresponding to 63, 215 and 430 mg/m3 (=MW*ppm/24.1*1000); MW=152,2 g/mol
Remarks:
Doses / Concentrations:
10.2 +- 0.9, 34.4 +- 4.1 ppm citral as vapour
Basis:
analytical conc.
Remarks:
Doses / Concentrations:
68 ppm: composed of 30.7 +- 4.2 ppm as aerosol and 37.0 +- 14.1 ppm as vapour
Basis:
analytical conc.
No. of animals per sex per dose:
25
Control animals:
yes, sham-exposed
Details on study design:
- Dose selection rationale: highest selected to produce maternally toxic effects

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice a day

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: twice a day

BODY WEIGHT: Yes
- Time schedule for examinations: days 0, 2 4, 6, 8 (exposure days), 12, 16, 20 (post-exposure period)

FOOD CONSUMPTION: No data

WATER CONSUMPTION: No data

OPHTHALMOSCOPIC EXAMINATION: No /

HAEMATOLOGY: No

CLINICAL CHEMISTRY: No

URINALYSIS: No

NEUROBEHAVIOURAL EXAMINATION: No
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
Statistics:
Maternal body weights and body-weight gains were analysed by a one-way analysis of variance (ANOVA), followed by a Dunnett's when applicable ( Steel and Torrie, 1960).

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):
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
not examined
Histopathological findings: non-neoplastic:
not examined
Histopathological findings: neoplastic:
not examined
Details on results:
CLINICAL SIGNS AND MORTALITY
68 ppm: moribund condition of 1/25 animals (killed on gestation day 17); ocular opacity, difficulty in breathing during the exposure phase of the study indicating stress of severe respiratory tract irritation; normal breathing returned in most of affected animals by gestation day 20; other frequently observed clinical signs: nasal discharge, salivation, redness around eyes, discolored facial fur, scrubby hair coat

BODY WEIGHT AND WEIGHT GAIN
68 ppm:
- Body weight loss during exposure period from gestation day (GD) 6 to 15; after exposure period body weight gain was comparable to other groups;
- overall mean body weight (GD 20) significantly decreased
- Body weight gain (GD0-20) decreased by 39% compared to controls.


Evaluation: In the 68 ppm dose group, significant signs of maternal toxicity as mortality, decreased body weight gain and clinical signs of toxicity were attributable to the stress produced by severe respiratory tract irritation. Weight loss on the third day of exposure was followed by constantly decreased body weight throughout the exposure. However, after completion of the exposure period recovery of body weight and clinical signs of toxicity occurred. At 10 and 34 ppm, findings were incidental and not siginficantly different from control animals.

Effect levels

open allclose all
Dose descriptor:
NOAEC
Effect level:
34 ppm
Sex:
female
Basis for effect level:
other: corresponds to 215 mg/m3
Dose descriptor:
LOAEC
Effect level:
68 ppm
Sex:
female
Basis for effect level:
other: severe respiratory tract irritation with reduced body weight gain and clinical signs as secondary effects in pregant rats; corresponds to 430 mg/m3

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion