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Toxicological information

Repeated dose toxicity: inhalation

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Administrative data

Endpoint:
short-term repeated dose toxicity: inhalation
Remarks:
combined repeated dose and reproduction / developmental screening
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Referenceopen allclose all

Reference Type:
study report
Title:
Unnamed
Year:
1993
Report Date:
1993
Reference Type:
secondary source
Title:
Propionaldehyd BUA-Stoffbericht 195
Author:
Beratergremium für umweltrelevante Altstoffe (BUA)
Year:
1996
Bibliographic source:
S. Hirzel Wiss. Verl.-Ges. 1997, Stuttgart

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
Deviations:
yes
Remarks:
only until d20 of gestation exposed, no exposition in lactation period
GLP compliance:
yes
Remarks:
Bushy Run Research Center
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Specific details on test material used for the study:
- Name of test material (as cited in study report): propionaldehyde
- Physical state: water-white odorous liquid
- Analytical purity: 99%
- Lot/batch No.: T-1258
- Storage condition of test material: in a special enclosure under nitrogen atmosphere

Test animals

Species:
rat
Strain:
other: CD®
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Breeding Laboratories (Portage, MI, USA)
- Age at study initiation: about 56 days old
- Weight at study initiation: Males: 230-275 g; Females: 175-210 g
- Fasting period before study: none
- Housing: 1 or 2 / cage
- Diet (e.g. ad libitum): ad libitum except during exposure
- Water (e.g. ad libitum): ad libitum except during exposure
- Acclimation period: approximately 2 weeks

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18.3 - 25
- Humidity (%): 40-70
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: 1991-12-12 To: 1992-02-28

Administration / exposure

Route of administration:
inhalation
Type of inhalation exposure:
whole body
Vehicle:
other: unchanged (no vehicle)
Remarks on MMAD:
MMAD / GSD: no data
Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: Stainless steel and glass, Wahman Manufacturing Company (Timonium, MD)
- Method of holding animals in test chamber: whole body chamber
- System of generating vapor: propionaldehyde was metered from a piston pump (Fluid Metering, Inc., Oyster Bay, NT) into a heated glass evaporator similar in design to that described by Snellings and Dodd (1990). The temperature of the evaporators was maintained at the lowest level sufficient to vaporize the liquid. The resultant vapor was carried into the chamber by a countercurrent air stream that entered the bottom of the evaporator.
- Temperature, humidity in air chamber: 20.5±0.88°C, 47.7±1.52%
- Air flow rate: 1000 liter / min

TEST ATMOSPHERE
- Brief description of analytical method used: Each chamber atmosphere was analyzed for propionaldehyde approximately twice each hour during each 6-hour exposure by flame ionization gas chromatography.
- Samples taken from breathing zone: yes
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Each chamber atmosphere was analyzed for propionaldehyde approximately twice each hour during each 6-hour exposure by flame ionization gas chromatography. The means of daily mean chamber atmosphere concentrations (± standard deviations) were 151 (± 14.1), 745 (± 15.2), and 1522 (± 23.7) ppm (corresponding to 365.4 ± 9.9; 1,802.9 ± 36.8 and 3,683.2 ± 57.4 mg/m3 air), for target concentrations of 150, 750, and 1500 ppm, respectively. No concentration of propionaldehyde above the estimated minimum detection limit of 5 ppm was detected in the control chamber atmosphere during the study.
Duration of treatment / exposure:
males: 52 consecutive days; females: 34 to 48 consecutive days depending on mating time
Frequency of treatment:
daily, 6h/day, 7d/week
Doses / concentrationsopen allclose all
Dose / conc.:
150 ppm (nominal)
Remarks:
362 mg/m³
Dose / conc.:
750 ppm (nominal)
Remarks:
1810 mg/m³
Dose / conc.:
1 500 ppm (nominal)
Remarks:
3620 mg/m³
No. of animals per sex per dose:
15 animals per sex per dose, altogether 120 animals (60/sex)
Control animals:
yes, concurrent no treatment
Details on study design:
Post-exposure period: males: none; females: exposed until day 20 of gestation and sacrificed on day 4 of lactation
Positive control:
none

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily before and after exposure

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: daily before and after exposure

BODY WEIGHT: Yes
- Time schedule for examinations: Body weight data were collected for all males on the morning prior to initiation of the first exposure and weekly thereafter. Female body weight data were collected weekly during the premating phase on Days 0, 7, and 14, during gestation of Days 0, 7, 14, and 21, and Days 0 and 4 of lactation.

FOOD CONSUMPTION:
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes: Food consumption was measured weekly throughout the study for males, except during the 2-week mating period. Female food consumption was measured weekly during the premating period, and at 3 to 4-day intervals during gd 0 through 20.

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: Yes

WATER CONSUMPTION: No

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: Yes
- Time schedule for collection of blood: blood was taken prior to sacrifice
- Anaesthetic used for blood collection: Yes (identity) : methoxyflurane
- Animals fasted: Yes: all male animals
- How many animals: all animal

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: blood was taken prior sacrifice
- Animals fasted: Yes: all male animals
- How many animals: all animals

URINALYSIS: No

NEUROBEHAVIOURAL EXAMINATION: No
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes: brain, trachea, heart, spleen, adrenal gland as well as, for the males, seminal vesicle, testes and epididymis and, for the females, ovaries, vagina and uterus; the olfactory epithelium was examined histopathologically for all animals.

Results and discussion

Results of examinations

Details on results:
CLINICAL SIGNS AND MORTALITY: No clinical signs and mortality were observed.

BODY WEIGHT AND WEIGHT GAIN: Males: The body weight gain lay in the range of the control group.
Females: The body weight gain were significantly (p < 0.01) decreased in the first exposure week for the females of the middle (750ppm) and high (1500ppm) concentration group. During gestation, the body weight of the high concentration group concentration group were at times decreased significantly (p < 0.01 and 0.05, resp.).

FOOD CONSUMPTION: Males: The feed consumption lay in the range of the control group.
Females: The feed intake were significantly (p < 0.01) decreased in the first exposure week for the females of the middle (750ppm) and high (1500ppm) concentration group. During gestation, the feed consumption of the middle (750ppm) and high (750ppm) concentration group were at times decreased significantly (p < 0.01 and 0.05, resp.).

HAEMATOLOGY: Males: In the high concentration group (1500ppm), the erythrocyte count as well as the monocyte count increased significantly (p < 0.05). An insignificant increase of the hematocrit and of the hemoglobin content was likewise observed. The hematological parameters of the low and middle concentration group were in the range of the controls.

CLINICAL CHEMISTRY: Males: The biochemical parameters of the low and middle concentration group were in the range of the controls.

ORGAN WEIGHTS: Males: The relative kidney weight showed a significant (p < 0.01) increase. The organ weights of the low and middle concentration group were in the range of the controls.

GROSS PATHOLOGY: no effects

HISTOPATHOLOGY: NON-NEOPLASTIC: Males: Substance-related histopathological changes occurred only in the olfactory epithelium of the nasal mucosa: vacuolization was observed in the low and middle concentration group and atrophy in the middle and high concentration group; respectively, 1 and 2 animals of the middle and high concentration group showed squamous metaplasia of the olfactory epithelium.
Females: During autopsy on the 4th lactation day, no substance-related histopathological changes were noted aside from damage of the olfactory epithelium: a vacuolization of the olfactory epithelium was determined mainly in the low and middle concentration group. Atrophy occured in the high concentration group. The lesser damage of the olfactory epithelium of the female animals, compared to the male animals, was attributed to the ca. 6-day exposure-free period (20th gestation day until the 4th Iactation day).

Effect levels

open allclose all
Dose descriptor:
NOAEC
Effect level:
150 ppm (nominal)
Based on:
test mat.
Sex:
male
Basis for effect level:
other: Vacuolization not adverse (at 750 ppm atrophy, adverse effect)
Remarks on result:
other: 362 mg/m³
Dose descriptor:
NOAEC
Effect level:
750 ppm (nominal)
Based on:
test mat.
Sex:
female
Basis for effect level:
other: Vacuolization not adverse (1500 ppm atrophy, adverse effect)
Remarks on result:
other: 3620 mg/m³

Target system / organ toxicity

Critical effects observed:
no

Applicant's summary and conclusion

Conclusions:
The microscopic changes observed in the nasal epithelium, however, are consistent with anticipated effects of chemical irritants. Interestingly, neither the lungs nor other portion of the respiratory tract were adversely affected. The absence of effects in other aspects of the respiratory tract is generally consistent with findings of other aldehydes.
Previous reports of liver damage following six days of exposure to 1300 ppm propionaldehyde were not substantiated under the conditions of this study of 52 days of consecutive exposures.
In summary, repeated exposure to propionaldehyde vapor at concentrations of 0, 150, 750, or 1500 ppm was associated with minimal overt toxicity at the two highest concentrations in females, but males showed no apparent toxicity.
Microscopic assessment of the nasal epithelium, however, revealed treatment-related effects at all concentrations of propionaldehyde exposure in both sexes.
Based on this study, the NOEC for systemic toxicity is 0.36 mg/l. For damage to the nasal cavity, a NOEC could not be established.