Registration Dossier

Administrative data

Endpoint:
fertility, other
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
Reference Type:
secondary source
Title:
No information
Author:
TSCATS
Year:
1993
Bibliographic source:
Doc. I.D.: 86-930000198, Microfiche No: OTS0538178
Report Date:
1993

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:
SOURCE OF TEST MATERIAL
- Source: Union Carbide Chemicals and Plastics Company Inc.
- Lot No.of test material: T-1258
- Purity: Approximately 99%
- Appearance: Water-white odorous liquid

STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: In the original containers (55-gallon stainless steel drums) in a special enclosure under a 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)
- Females nulliparous and non-pregnant: yes
- Age at study initiation: about 56 days old
- Weight at study initiation: Males: 234-275 g; Females: 177-209 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 (if applicable):
whole body
Vehicle:
unchanged (no vehicle)
Details on 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 bottem 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
Details on mating procedure:
- M/F ratio per cage: 1/1
- Length of cohabitation: 7 days, after the first 7 days of the mating period, females of unsuccessfully mated pairs were randomly placed with another male in the same exposure group.
- Proof of pregnancy: vaginal plug or sperm in vaginal smear referred to as day 0 of gestation
- After 7 days of unsuccessful pairing replacement of first male by another male with proven fertility.
- Further matings after two unsuccessful attempts: no data
- After successful mating each pregnant female was caged (how): individually
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 (±t 4.1), 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
Premating exposure period (males): 14 days
Premating exposure period (females): 14 days
Duration of test: until postnatal day 4
Frequency of treatment:
daily, 6h/day, 7d/week
Details on study schedule:
- Age at mating of the mated animals in the study: about 12 weeks
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 and control, altogether 120 animals (60/sex)
Control animals:
yes, concurrent no treatment
Positive control:
no positive control

Examinations

Parental animals: Observations and examinations:
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.

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 wa taken prior sacrifice
- Animals fasted: Yes: all male animals
- How many animals: all animals
Sperm parameters (parental animals):
Parameters examined in P male parental generations:
testis weight, epididymis weight
Litter observations:
STANDARDISATION OF LITTERS
- Performed on day 4 postpartum: yes
- If yes, all pups examined.


PARAMETERS EXAMINED
The following parameters were examined in F1 offspring:
number and sex of pups, stillbirths, live births, postnatal mortality, presence of gross anomalies, weight gain, physical or behavioural abnormalities


GROSS EXAMINATION OF DEAD PUPS:
yes, for external and internal abnormalities; possible cause of death was/was not determined for pups born or found dead
Postmortem examinations (parental animals):
SACRIFICE
- Male animals: All surviving animals after 52day of exposure.
- Female animals: All surviving animals after day 4 of lactation

GROSS NECROPSY
- Gross necropsy consisted of external and internal examinations including the cervical, thoracic, and abdominal viscera.

HISTOPATHOLOGY / ORGAN WEIGHTS
The tissues indicated in Table [1] were prepared for microscopic examination and weighed, respectively.
Postmortem examinations (offspring):
SACRIFICE
- The F1 offspring were sacrificed at 4 days of age.
- These animals were all discarded without a pathologic examination.
Reproductive indices:
mating index: males and females
fertility index: males and females
gestational index
Offspring viability indices:
live birth index
4-day survival index

Results and discussion

Results: P0 (first parental animals)

General toxicity (P0)

Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
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 and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
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.).
Haematological findings:
effects observed, non-treatment-related
Description (incidence and severity):
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 biochemistry findings:
no effects observed
Description (incidence and severity):
Males: The biochemical parameters of the low and middle concentration group were in the range of the controls.
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
Males: The relative kidney weight (p < 0.01) and the mean absolute thymic region weight showed a significant increase at the highest test group (1500 ppm). The organ weights of the low and middle concentration group were in the range of the controls.
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
Males: Substance-related histopathological changes occurred only in the olfactory epithelium of the nasal mucosa: vacuolizatian 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).
Other effects:
not examined

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:
not examined
Reproductive function: sperm measures:
not examined
Reproductive performance:
no effects observed

Effect levels (P0)

Dose descriptor:
NOEC
Effect level:
>= 1 500 ppm (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
reproductive performance

Target system / organ toxicity (P0)

Critical effects observed:
no

Results: F1 generation

General toxicity (F1)

Clinical signs:
not examined
Mortality / viability:
no mortality observed
Body weight and weight changes:
no effects observed
Sexual maturation:
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
not examined
Histopathological findings:
not examined

Details on results (F1)

Litter size and viability were similar among the groups. Pup body weights on postnatal days 0 and 4 were not affected by exposure although the high concentration body weight gain for that period was slightly depressed.

Effect levels (F1)

Dose descriptor:
NOAEC
Generation:
F1
Effect level:
>= 1 500 ppm (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
viability
mortality
body weight and weight gain
other: litter size and sex ratio

Target system / organ toxicity (F1)

Critical effects observed:
no

Overall reproductive toxicity

Reproductive effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
Repeated exposure to propionaldehyde vapor at concentrations of 0, 150, 750 or 1500 ppm was associated with minimal 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. Reproductive parameters were not affected at any concentration. A slight decrease in body weight gain in the 1500 ppm offspring was the only finding of possible significance in neonates.