Registration Dossier

Administrative data

Key value for chemical safety assessment

Effects on fertility

Description of key information
There are no other reproduction toxicity studies available for pentyl propionate
Link to relevant study records
Reference
Endpoint:
screening for reproductive / developmental toxicity
Type of information:
read-across based on grouping of substances (category approach)
Adequacy of study:
key study
Study period:
2005
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: The study was conducted as per OECD TG 422, EPA OPPTS 870.3650 and in accordance with the Principles of Good Laboratory Practice (GLP)
Justification for type of information:
refer to Category document
Reason / purpose:
reference to other study
Qualifier:
according to
Guideline:
OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
Deviations:
no
Qualifier:
according to
Guideline:
other: USEPA OPPTS 870.3650: Combined Repeated Dose Toxicity Study With the Reproduction/ Developmental Toxicity Screening Test
Deviations:
no
Principles of method if other than guideline:
not applicable
GLP compliance:
yes
Limit test:
no
Species:
rat
Strain:
other: Crl:CD(SD)
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories Inc. (Portage, Michigan)
- Age at study initiation: 8 weeks
- Fasting period before study: no
- Housing: one per cage in stainless steel cages
- Diet: LabDiet Certified Rodent Diet #5002 (PMI Nutrition International, St. Louis, Missouri) in meal form, ad libitum, except during exposure
- Water: municipal water was provided ad libitum, except during exposure
- Acclimation period: at least one week prior to the start of the study

ENVIRONMENTAL CONDITIONS
- Temperature (°C): range of 22 ± 1°C (with a maximum permissible excursion range of ± 3°C)
- Humidity (%): 40-70%
- Air changes (per hr): Room air was exchanged approximately 12-15 times/hour.
- Photoperiod (hrs dark / hrs light): 12- hour light/dark photocycle
Route of administration:
inhalation
Type of inhalation exposure (if applicable):
whole body
Vehicle:
clean air
Details on exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: 4m3 whole-body exposure chambers under dynamic airflow conditions
- Method of holding animals in test chamber: individually housed
- Source and rate of air: room air
- Method of conditioning air: The various concentrations of n-propyl propionate were generated using the glass J tube method. Liquid test material was pumped into the glass J tube assembly and vaporized by heated nitrogen gas passing through the bead bed of the glass J-tube (approximately 20-40 liters per minute). Nitrogen was heated as needed with a flameless heat torch (FHT-4, Master Appliance Corporatio n, Racine, Wisconsin) to the minimum extent necessary to vaporize the test material. The generation system was electrically grounded and the J-tubes were changed as needed. The nitrogen gas and n-propyl propionate vapors were diluted and mixed with room air to achieve an appropriate total flow rate of 900 liters per minute at the desired concentration of n-propyl propionate vapors.
- Temperature, humidity, pressure in air chamber: The chamber temperature and relative humidity were controlled by a system designed to maintain values of approximately 22 ± 3°C and 30-70%, respectively. The chambers were operated at a slight negative pressure relative to the surrounding area.
- Air flow rate: appropriate total flow rate of 900 liters per minute
- Air change rate: 12-15 air changes/hour
- Treatment of exhaust air: All test chamber exhausts were passed through an activated charcoal bed to remove test material from the exhaust system

TEST ATMOSPHERE
- Brief description of analytical method used: The chamber concentrations of n-propyl propionate, measured approximately in the center of the breathing zone of the animals, were determined at least once per hour with a Miran 1A infrared (IR) spectrophotometer (Foxboro/Wilks, South Norwalk, Connecticut) at a wavelength determined pre-exposure. The chamber analytical concentrations were collected from the IR spectrometer, printed and stored using a CAMILE TGâ Data Acquisition and Control System (Camile Products, LLC, Indianapolis, Indiana). The IR spectrophotometer was calibrated and a standard curve was compiled prior to, at the midpoint, and at the end of the study using air standards prepared by vaporizing measured volumes of n-propyl propionate into Tedlar sample bags (Series 233, SKC, Eighty Four, Pennsylvania) along with the metered volumes of dry, compressed air. Analytical concentrations during the exposures were interpolated using the standard curve. The analytical system was checked prior to each exposure with a n-propyl propionate standard of known concentration. The CAMILE TGÒ Data Acquisition and Control System toggled the IR spectrophotometer between the chambers for concentration sampling. The nominal concentration of the test material in each chamber was calculated based on the amount of test material used each day and the total airflow through the chamber for each exposure period. Each of the chambers was checked pre-exposure to ensure that a uniform distribution of vapor was present in the breathing zone of the animals.
- Samples taken from breathing zone: yes
Details on mating procedure:
- M/F ratio per cage: 1:1
- Length of cohabitation: 2 weeks
- Proof of pregnancy: [vaginal plug or sperm in vaginal smear] referred to as [day 0] of pregnancy
- After 14 days of unsuccessful pairing no replacement of first male by another male with proven fertility
- Further matings after two unsuccessful attempts: [no]
- After successful mating each pregnant female was caged: individual
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Nominal concentrations - 0, 50, 250, and 500 ppm
Mean chamber concentrations - 0, 50.8 ± 1.5, 253.3 ± 2.2, and 504.1 ± 7.0 ppm
Duration of treatment / exposure:
Males were exposed six hours per day for at least two weeks prior to mating and continued throughout mating until necropsy for a total of 37 days. Females were exposed six hours per day for 14 days pre-mating, continued throughout mating (two weeks) and gestation (three weeks through gestation day 20).
Frequency of treatment:
six hours per day, seven days/week
Details on study schedule:
Females were observed for signs of parturition beginning on or about GD 20. In so far as possible, parturition was observed for signs of difficulty or unusual duration. The day of parturition was recorded as the first day the presence of the litter was noted and was designated as LD 0. Litters were examined as soon as possible after delivery. The following information was recorded on each litter: the date of parturition, litter size on the day of parturition (LD 0), the number of live and dead pups on days 0, 1, and 4 postpartum, and the sex and the weight of each pup on LD 1 and 4. Any visible physical abnormalities or demeanor changes in the neonates were recorded as they were observed during the lactation period. Any pups found dead were sexed and examined grossly, if possible, for external and visceral defects and then were discarded.
Remarks:
Doses / Concentrations:
0, 50, 250, and 500 ppm (nominal concentrations)
Basis:
other: 0, 50.8 ± 1.5, 253.3 ± 2.2, and 504.1 ± 7.0 ppm (analytical concentrations)
No. of animals per sex per dose:
12 male and 12 female Crl:CD(SD) rats/dose
Control animals:
yes, sham-exposed
Details on study design:
- Dose selection rationale: based on previous study (Supporting study (2)_Repeated dose toxicity: inhalation (14 days)_duPont_2000) and range finding study
- Rationale for animal assignment: random
Positive control:
not applicable
Parental animals: Observations and examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: on all animals once daily throughout the study

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Detailed clinical observations (DCO) were conducted on all rats pre-exposure and weekly throughout the study. Mated females received DCO examinations on GD 0, 7, 14, and 20, and lactation day (LD) 3. The DCO was conducted at approximately the same time each examination day, according to an established format. The examination included cage-side, hand-held and open-field observations, which were recorded categorically or using explicitly defined scales (ranks).

BODY WEIGHT: Yes
- Time schedule for examinations: All rats were weighed at least once during the pre-exposure period and on the first day of exposure. Body weights for males were recorded weekly throughout the study. Females were weighed weekly during the pre-breeding period. During gestation, females were weighed on GD 0, 7, 14, and 20. Females that delivered litters were weighed on LD 1 and 4. Females that failed to mate or deliver a litter were not weighed during the gestation or lactation phases. Body weight gains were determined for the following intervals: GD 0-7, 7-14, 14-20, 0-20 and LD 1-4.

FOOD CONSUMPTION: Yes
- Feed consumption was determined pre-exposure and weekly during the two-week prebreeding period for all animals by weighing feed containers at the start and end of a measurement cycle. During breeding, feed consumption was not measured in males or females due to co- housing. Following breeding, feed consumption for males was not measured. For mated females, feed consumption was measured on GD 0, 7, 14 and 20. For females delivering litters, feed consumption was measured on LD 1 and 4. Feed consumption was not measured for females that failed to mate or deliver a litter.

HAEMATOLOGY: Yes
- Time schedule for collection of blood: after last exposure for males and after lactation day 4 for females
- Anaesthetic used for blood collection: Yes - CO2
- Animals fasted: Yes
- How many animals: all animals, except from animals that were euthanized in a moribund condition prior to their scheduled necropsy
- Parameters examined: Blood samples were mixed with ethylenediamine-tetraacetic acid (EDTA), smears were prepared, stained with Wright-Giemsa stain, cover-slipped and filed for evaluation at the discretion of the pathologist. Hematologic parameters were assayed using a Advia 120 Hematology Analyzer (Bayer Corporation, Tarrytown, New York) - Hematocrit (HCT), Hemoglobin (HGB) concentration, Red blood cell (RBC) count, Total white blood cell (WBC) count, Differential WBC count, Platelet (PLAT) count, Reticulocyte (RET) count, RBC indices: Mean Corpuscular Hemoglobin (MCH), Mean Corpuscular Volume (MCV), Mean Corpuscular Hemoglobin Concentration (MCHC), Coagulation - Sample Preparation - Blood samples were collected in sodium citrate tubes, centrifuged and plasma collected and assayed using an ACL9000 (Instrumentation Laboratory, Lexington, Massachusetts). Assay - Prothrombin time

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: after last exposure for males and after lactation day 4 for females
- Animals fasted: Yes
- How many animals: all animals
- Parameters examined: Blood samples were collected and serum was separated from cells as soon as possible. Serum parameters were measured using a Hitachi 912 Clinical Chemistry Analyzer (Roche Diagnostics, Indianapolis, Indiana). Alkaline phosphatase (ALP), Alanine aminotransferase (ALT), Aspartate aminotransferase (AST), Gamma-glutamyl transpeptidase (GGT), Albumin (ALB), Cholesterol (CHOL), Creatinine (CREA), Electrolytes (NA, K, PHOS, CL and CA), Glucose (GLU), Total bilirubin (TBIL), Total protein (TP), Urea nitrogen (UN)

URINALYSIS: Yes
- Time schedule for collection of urine: Urine samples were obtained from all males the week prior to the scheduled necropsy
- Metabolism cages used for collection of urine: Yes
- Animals fasted: Yes
- Parameters examined: The following parameters were examined: Color, appearance, specific gravity (refractometer) and urine volume. Semiquantitative analyses (MultistixÒ Reagent Strips, Bayer Corporation, Elkhardt, Indiana on the Clinitek 200+) of: pH, Bilirubin, Glucose, Protein, Ketones, Blood, Urobilinogen and for microscopic examination - urine samples were also collected from each male by manual compression of the urinary bladder. The urine samples were pooled from each group, and the microsediments were characterized microscopically.

NEUROBEHAVIOURAL EXAMINATION: Yes
- Time schedule for examinations: The functional tests (sensory evaluation, rectal temperature, grip performance and motor activity) were conducted pre-exposure and during the last week of exposures. Postexposure testing in the females took place on LD 4.
- Dose groups that were examined: all groups
Oestrous cyclicity (parental animals):
not examined
Sperm parameters (parental animals):
not examined
Litter observations:
Females were observed for signs of parturition beginning on or about GD 20. In so far as possible, parturition was observed for signs of difficulty or unusual duration. The day of parturition was recorded as the first day the presence of the litter was noted and was designated as LD 0. Litters were examined as soon as possible after delivery. The following information was recorded on each litter: the date of parturition, litter size on the day of parturition (LD 0), the number of live and dead pups on days 0, 1, and 4 postpartum, and the sex and the weight of each pup on LD 1 and 4. Any visible physical abnormalities or demeanor changes in the neonates were recorded as they were observed during the lactation period. Any pups found dead were sexed and examined grossly, if possible, for external and visceral defects and then were discarded.
Postmortem examinations (parental animals):
GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes
Postmortem examinations (offspring):
Litters were examined as soon as possible after delivery. The following information was recorded on each litter: the date of parturition, litter size on
the day of parturition (LD 0), the number of live and dead pups on days 0, 1, and 4 postpartum, and the sex and the weight of each pup on LD 1 and 4. Any visible physical abnormalities or demeanor changes in the neonates were recorded as they were observed during the lactation period.Any pups found dead were sexed and examined grossly, if possible, for external and visceral defects and then were discarded. All pups surviving to LD 4 were euthanized by oral administration of sodium pentobarbital solution, examined for gross external alterations, and then discarded
Statistics:
Standard statistical methods were employed
Reproductive indices:
Female mating index, Male mating index, female conception index, male conception index, female fertility index, male fertility index and gestation index, post implantation index
Offspring viability indices:
gestation survival index, day 1 and 4 pup survival index
Clinical signs:
no effects observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Organ weight findings including organ / body weight ratios:
no effects observed
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
Male and female rats exposed to 50, 250 or 500 ppm n-propyl propionate had a degeneration of the olfactory epithelium of the nasal turbinates that was very slight in degree, focal or multifocal and unilateral or bilateral in distribution.
Other effects:
not specified
Reproductive function: oestrous cycle:
not examined
Reproductive function: sperm measures:
not examined
Reproductive performance:
no effects observed
CLINICAL SIGNS AND MORTALITY - No treatment-related effects on behavior or demeanor were observed in any phase of the study at any exposure level. In addition, there were no treatment-related clinical observations or external morphological anomalies in the offspring. Male (2218) was euthanized on day 22 of test following an accidental injury to the tail and concern for humane treatment. All remaining animals survived until termination.

BODY WEIGHT AND WEIGHT GAIN - There were no effects on male body weights at any exposure concentration at any time. The body weights of females in the 250 and 500 ppm group were slightly lower (4-7%) than those of controls during the pre-mating phase, corresponding with decreased feed consumption in these animals during this phase of the study. Body weights of the latter females were also decreased slightly during the first two weeks of gestation. These lower body weights were statistically identified on pre-mating day 14 and gestation days 7 and 14 in the 500 ppm females, but only on pre- mating day 14 in the 250 ppm females. Slight, non-statistically significant decreases (3-6%) in body weights of the 250 and 500 ppm females were also evident on lactation day 1 and 4. Consistent with the very slight nature of the body weight effects in the 250 and 500 ppm group females, there were no statistically significant effects on gestation or lactation body weight gains in these groups.

FOOD CONSUMPTION - There were no treatment-related effects on male feed consumption at any time in any of the exposure groups. During the pre-mating phase, mean feed consumption of females in the 250 and 500 ppm groups was slightly lower (7-8%) than that of control females (Text Table 2). Although only the value for the 500 ppm group females on days 7-14 was statistically identified, these slight decreases in food consumption correlated with slightly decreased body weights during the same period and, thus, were considered treatment related. There were no statistically significant effects on food consumption during gestation or lactation in the 250 or 500 pm group females, nor at any time in the 50 ppm group females.

HAEMATOLOGY - There were no treatment related hematologic effects at any exposure level.

CLINICAL CHEMISTRY - There were no treatment-related changes for males and females at any exposure level. Males exposed to 500 ppm had a statistically identified increase in aspartate aminotransferase activity that was slightly outside of the historical control range for our laboratory. A similar increase in this enzyme did not occur in males at lower dose levels or females at any dose level. This slightly higher enzyme activity was interpreted not to be toxicologically significant due to the absence of microscopic necrosis in the heart, liver and/or skeletal muscle and the fact that significant increases in aspartate aminotransferase activity are normally associated with 2- to 3-fold increases in activity, rather than the minor increase observed in this study.

URINALYSIS - There were no treatment-related changes at any exposure level.

NEUROBEHAVIOUR - There were no treatment-related changes at any exposure level.

ORGAN WEIGHTS - There were no treatment-related alterations in the final body weights and organ weights of males at any exposure level. However, the final body weights of females of the 500 ppm group were significantly lower (8%) than those of controls. Males exposed to 50 or 500 ppm had statistically identified increases in absolute and relative adrenal weights. These adrenal weight differences were interpreted not to be treatment related because the weights were within the historical control range, there was no clear dose-response relationship, there was a lack of a similar response in the females, and there was no histopathologic correlate to the decreased adrenal weights.

GROSS PATHOLOGY - Five females exposed to 500 ppm had a pale focus involving the right medial lobe of the liver, compared to an incidence of zero in the control females. This alteration is commonly observed in rats in this specific location, consists of a very focal vacuolation of hepatocytes and is also known as tension lipidosis. This alteration was interpreted to be a spontaneous change that has no toxicologic significance, and was not related to exposure to n-propyl propionate. There were no treatment-related gross pathologic observations. One male (2218) exposed to 50 ppm was euthanized (Day 22) due to a traumatic injury to the tail.

HISTOPATHOLOGY - Male and female rats exposed to 50, 250 or 500 ppm n-propyl propionate had a degeneration of the olfactory epithelium of the nasal turbinates that was very slight in degree, focal or multifocal and unilateral or bilateral in distribution. The incidence of olfactory degeneration increased with exposure concentration. These degenerative changes were primarily observed in Level 2 of the nasal turbinates and affected the medial and lateral aspects of the dorsal portion of the nasoturbinates turbinates and infrequently the maxilloturbinates (Level 1) and ethmoturbinates (Level 3 and 4). Females exposed to 500 ppm also had very slight degenerative effects involving olfactory epithelium in Level 1. Very slight, focal or multifocal, squamous metaplasia of olfactory or respiratory epithelium was also noted in two males exposed to 500 ppm, two females exposed to 50 ppm and two females exposed to 250 ppm. These effects were interpreted to be primary treatment-related effects that were attributed to n-propyl propionate.
Males exposed to 500 ppm and females exposed to ³ 50 ppm had a higher incidence of adipose tissue atrophy than the controls. The toxicologic significance of these observations was questionable given that they were graded as very slight or slight, and they were not associated with any marked changes in body weights.
Key result
Dose descriptor:
NOAEC
Effect level:
500 ppm
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: based on no reproductive effects and neurological function observed at 500 ppm
Key result
Dose descriptor:
LOAEC
Effect level:
50 ppm (analytical)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
histopathology: non-neoplastic
Clinical signs:
no effects observed
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:
no effects observed
Histopathological findings:
not examined
There were no treatment-related effects at any exposure level on reproductive indices, time to mating, gestation length, post-implantation loss, pup survival, or pup sex ratio. Although there was a statistically identified decrease in postnatal day (PND) 4 survival, this was not considered to be toxicologically significant as the values were well within the laboratory’s historical control range (Text Table 7) and the statistical significance was largely influenced by the very high value of 100% in the control group. In fact, only four pups died during the early postnatal period, which is not unexpected for this sample size.In addition, there were no statistically identified differences on litter size, PND 1 survival, or other reproductive end points that would be indicative of a reproductive effect. There were no treatment related effects on litter or pup body weights at any exposure level tested.
Key result
Dose descriptor:
NOAEC
Generation:
F1
Effect level:
500 ppm (analytical)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No treatment related effects on litter or pup body weights at any exposure level tested.
Key result
Reproductive effects observed:
no

None

Conclusions:
Exposure to n-propyl propionate resulted in slight reductions in food consumption and body weight throughout the study in females exposed to 250 and 500 ppm. Treatmentrelated histopathologic effects were also evident in the nasal tissues of males and females exposed to all test concentrations. The nasal tissue effects consisted of very slight degeneration of the olfactory epithelium. In addition males exposed to 500 ppm and females exposed to ³ 50 ppm had a higher incidence of adipose tissue atrophy than the controls. This was interpreted to have questionable significance. No treatment-related effects were seen in reproductive performance, pup survival and growth, neurologic function, clinical chemistry, or hematology. Therefore, the no-observed-effect concentration (NOEC) for general toxicity could not be determined for male and female rats. The NOEC for reproductive effects and neurological function was 500 ppm, the highest concentration tested.
Executive summary:

This study evaluated n-propyl propionate in the OECD 422 study design. Groups of 12 male and 12 female Crl:CD(SD) rats were whole-body exposed to target concentrations of 0, 50, 250 or 500 ppm vaporized n-propyl propionate for six hourslday, seven dayslweek. Female rats were exposed daily for two weeks prior to breeding, through breeding (up to two weeks), and continuing through gestation day 20. Females were necropsied on post-partum day 5. The males were exposed for two weeks prior to breeding and continuing through breeding (two weeks) until necropsy (test day 38). Effects on reproductive and neurological function as well as general toxicity were evaluated. In addition, post mortem examinations included a gross necropsy of the adults with collection of organ weights and extensive histopathologic examination of tissues. Litter size, pup survival, sex, body weight, and the presence of gross external abnormalities were also assessed.

Exposure to n-propyl propionate resulted in slight reductions in food consumption and body weight throughout the study in females exposed to 250 and 500 ppm. Treatment-related histopathologic effects were also evident in the nasal tissues of males and females exposed to all test concentrations. The nasal tissue effects consisted of very slight degeneration of the olfactory epithelium. In addition males exposed to 500 ppm and females exposed to 2 50 ppm had a higher incidence of adipose tissue atrophy than the controls. This was interpreted to have questionable significance. No treatment-related effects were seen in reproductive performance, pup survival and growth, neurologic function, clinical chemistry, or hematology parameters.

Therefore, the no-observed-effect concentration (NOEC) for general toxicity could not be determined for male and female rats. The NOEC for reproductive effects and neurological function was 500 ppm, the highest concentration tested.

Effect on fertility: via oral route
Endpoint conclusion:
no study available
Effect on fertility: via inhalation route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEC
2 411 mg/m³
Study duration:
subchronic
Species:
rat
Quality of whole database:
good
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

There are no reproduction toxicity studies available for pentyl propionate, however there is a reproduction/developmental toxicity study for propyl propionate and a 90-days repeated dose toxicity study available for n-butyl propionate.

Reproduction toxicity data on n-propyl propionate:

In a reproduction/developmental toxicity screening study (OECD TG 422) available, exposure to n-propyl propionate resulted in slight reductions in food consumption and body weight throughout the study in females exposed to 250 and 500 ppm. Treatment related histopathologic effects were also evident in the nasal tissues of males and females exposed to all test concentrations. The nasal tissue effects consisted of very slight degeneration of the olfactory epithelium. In addition males exposed to 500 ppm and females exposed to ≥ 50 ppm had a higher incidence of adipose tissue atrophy than the controls. This was interpreted to have questionable significance. No treatment-related effects were seen in reproductive performance, pup survival and growth, neurologic function, clinical chemistry, or hematology. Therefore, the low-observed-effect concentration (LOEC) for general toxicity for male and female rats was considered to be 500 ppm and the NOEC for reproductive effects and neurological function was 500 ppm (2411 mg/m3), the highest concentration tested.

Reproduction toxicity data on n-butyl propionate:

There are no reproduction toxicity studies available for n-butyl propionate and in aGLP study conducted according to EPA OTS 798.2450 (90 -day Inhalation Toxicity), where groups of male and female Sprague Dawley rats were exposed (whole body) to vapours of butyl propionate over a period of 13 weeks at levels of 250, 750 and 1500 ppm for 6 hours/day, 5 days/week, there were no effects noted in organs (testes, ovaries) of the male and female reproductive system. (refer to repeted dose toxicity section)

Conclusion:

 

In all the available studies on category members there is an absence of any (or any significant) reproduction toxicity . Therefore, it is concluded that pentyl propionate is unlikely to cause any reproduction toxicity.

Effects on developmental toxicity

Description of key information
There are no developmental toxicity studies available for pentyl propionate, however there are studies for other substances in the category (refer to the justification for read-across attached to section 13 of the dataset). There is an inhalation developmental toxicity study available for butyl propionate.
Link to relevant study records
Reference
Endpoint:
developmental toxicity
Type of information:
read-across based on grouping of substances (category approach)
Adequacy of study:
key study
Study period:
1996
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: The study was conducted according to EPA OTS 798.4900 (Prenatal Developmental Toxicity Study) and in accordance with the Principles of Good Laboratory Practice (GLP)
Justification for type of information:
refer to Category document
Qualifier:
according to
Guideline:
EPA OTS 798.4900 (Prenatal Developmental Toxicity Study)
Deviations:
no
Principles of method if other than guideline:
not applicable
GLP compliance:
yes
Limit test:
no
Species:
rat
Strain:
Sprague-Dawley
Details on test animals and environmental conditions:
- Source: Charles River Laboratories Inc.
- Age at study initiation: approximately 10 weeks old at receipt and approximately 12 weeks when paired for breeding
- Weight at study initiation: minimum of 220 grams
- Housing: individually housed and the animals were paired for mating in the home cage of the male.
- Diet: ad libitum, Purina Certified Rodent Chow #5002 was provided ad libitum, except during the exposure periods and during the period of fasting prior to blood collection
- Water: ad libitum, tap water was provided ad libitum except during the exposure periods
- Acclimation period: 12 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 70.0 °F to 73.22 °F
- Humidity (%): 33.7-57.8%
- Air changes (per hr): 10 fresh air changes/hour
- Photoperiod (hrs dark / hrs light): 12 hours light/dark cycle
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: Exposures were conducted in four 1.0 m3 stainless steel and glass whole body inhalation chambers
- Method of holding animals in test chamber: Animals were individually caged in stainless steel wire mesh caging during the exposures.
- Source and rate of air: chamber supply air provided from a HEPA and charcoal filtered, temperature and humidity controlled source. The cage batteries were rotated through various cage positions in the chambers to help ensure a similar exposure for all animals within each group over the duration of the xposure period.
- System of generating vapour: Test material was metered from a reservoir using positive displacement pumps at a known and constant rate to a glass vaporization column (24 mm ID glass tube approximately 20 cm long) filled with 8 and 12-mm glass beads. The vaporization column was wrapped with a 206-watt flexible heating tape operated from a temperature controller. Vaporization air was metered to the bottom of the column using a mass flow meter. The concentrated vapors were piped to the chamber inlet where the concentration was diluted to the target level by the chamber ventilation airflow.
- Temperature, humidity, pressure in air chamber: Temperature, relative humidity, chamber ventilation rate and negative pressure within the chambers were continually monitored and generally recorded every 35 minutes through an appropriate software. Chamber temperature and relative humidity were monitored by RTD and polymeric sensors. Airflow through the chamber was monitored by the pressure drop across a sharp-edge orifice plate as measured by differential pressure gauges (calibrated) and was set such that there were 12-15 air changes/hour.
- Air change rate: 12-15 air changes/hour
- Treatment of exhaust air: Treatment of exhaust air consisted of activated charcoal and a HEPA filtration.

TEST ATMOSPHERE
- Brief description of analytical method used: Actual exposure concentrations were measured using gas chromatographic (GC) methods. Sapmples of the exposure atmospheres from each chamber were automatically collected at approximately 35 minute intervals using a loop and computer-controlled gas sampling and multiposition valves. The instrument conditions were as follows -
Instrument: Hewlett Packard 5890 Series II with a FID and a 3396 Series II integrator
Detector: Flame ionization at 250 °C
Column: 10' x 1/8" stainless steel; 10% SP-1000 on 80/100 mesh Supelcoport
Gases: Carrier - Helium; Pressure - 60 psig, Flow rate - 30 ml/min
Temperature (°C) - Column 150, isothermal; Detector - 250
Injection volume: 0.25 ml
Retention time (min.): approximately 1.6
- Samples taken from breathing zone: yes
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Target conentrations - 0, 500, 1000 and 2000 ppm
Daily nominal concentrations means for the entire study - 0, 542, 1159 and 2116 ppm
Mean analytical concentrations - 0, 495, 1011 and 2000 ppm
Details on mating procedure:
- Impregnation procedure: cohoused
- M/F ratio per cage: 1:1 male:female
- Further matings after two unsuccessful attempts: no
- Proof of pregnancy: vaginal plug / sperm in vaginal smear referred to as day 0 of pregnancy
Duration of treatment / exposure:
10 consecutive days (gestation days 6-15)
Frequency of treatment:
6 hours/day
Duration of test:
April 23, 1996 - July 3, 1996
No. of animals per sex per dose:
24 Sprague Dawley rats/dose
Control animals:
yes, sham-exposed
Details on study design:
- Dose selection rationale: based on range finding study - A Combined 2-Week Range-Finding Inhalation Toxicity and Developmental Toxicity Study of n-Butyl Propionate in Rats; Report no. 228009 and Company Study no. - HET K-012981-008 listed under references.

- A range-finding study of n-Butyl Propionate in rats was conducted to determine exposure concentrations for subsequent 13-week and developmental toxicity studies. The range-finding study consisted of two phases: a subchronic toxicity phase and a developmental toxicity phase. For the subchronic toxicity phase, the test article was administered via whole-body inhalation to four groups, each comprised of five male and five female Sprague-Dawley Crl:CD BR rats, for six hours per day, five days per week, for two consecutive weeks. For the developmental toxicity phase, the test article was administered via whole-body inhalation to four groups of 12 bred female rats each for six hours per day for 10 consecutive days (gestation days 6-15). Target exposure concentrations were 250, 500, 2500 and 4000 ppm (parts per million). For each phase, a concurrent control group of identical design was exposed to clean, filtered air on a comparable regimen. Throughout the study period, all rats were observed daily for appearance and behavior prior to exposure, for clinical signs during and within approximately one hour after exposure, and for mortality and moribundity. Body weights and food consumption were recorded at appropriate intervals. For the subchronic toxicity phase, necropsies were performed on all animals, and selected organs were weighed. A microscopic examination was performed on nasal tissues from all animals. For the developmental toxicity phase, a laparotomy and macroscopic examination were performed on each animal on gestation day 20. The uteri and ovaries were examined, and numbers of fetuses, early and late resorptions, total implantations and corpora lutea were recorded. Mean gravid uterine weights and net body weight changes were recorded for each group.
Test article exposure had no adverse effect at any exposure level on survival, organ weight data (subchronic toxicity phase), intrauterine survival (developmental toxicity phase) or at the macroscopic examination. Test article-related clinical signs were noted in the 2500 and 4000 ppm groups and consisted primarily of drooping eyelids and salivation during exposure, and red or brown material or staining around the nose and/or mouth one hour following exposure. In both phases, body weight gain and food consumption were inhibited in the 2500 and 4000 ppm groups generally throughout the treatment period. Mean gravid uterine weights, net body weights and net body weight gains in these groups were also reduced in the developmental toxicity phase. Exposure-related lesions were noted at the microscopic examination of nasal tissues in the subchronic toxicity phase. These consisted of cytoplasmic vacuolation, necrosis and/or atrophy of the olfactory epithelium (with or without dilatation of Bowman's glands) in nasal sections III, IV, V and VI of the 2500 and 4000 ppm groups. Based on the results of this study, target concentrations of 500, 1000 and 2000 ppm were
selected for the definitive developmental toxicity study of n-Butyl Propionate in rats.
Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily for moribundity and mortality

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: daily prior to exposure, during the exposure period and one hour following completion of the exposure period.

BODY WEIGHT: Yes
- Time schedule for examinations: maternal body weights were recorded on gestation days 0, 6, 16 and 20

FOOD CONSUMPTION: Yes
- Food consumption for each animal determined and mean diet consumption calculated as g/animal/day and g/kg/day: Yes

WATER CONSUMPTION: No

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 20
- Organs examined: the thoracic, abdominal and pelvic cavities were opened by a ventral midline incision and the contents were examined
Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: Yes
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes
-Other: Uteri with no macroscopic evidence of nidation were excised, opened and subsequently placed in 10% ammonium sulfide solution for detection of early implantation loss.
Fetal examinations:
- External examinations: Yes: all per litter
- Soft tissue examinations: Yes: all per litter
- Skeletal examinations: Yes: all per litter
- Head examinations: Yes: all per litter
Statistics:
Standard statistical methods were employed
Indices:
Postimplantation loss on group mean litter and a proportional litter basis, and fetal devlopmental findings were summarized
Historical control data:
Yes
Details on maternal toxic effects:
Maternal toxic effects:yes

Details on maternal toxic effects:
All maternal animals survived to the scheduled necropsy on gestation day 20. The predominant exposure-related clinical signs observed during exposure included dose-related incidences of slightly drooping eyelids and salivation in the 1000 and 2000 ppm groups. Sporadic occurrences of half-closed (and/or completely closed) eyelids and lacrimation also were observed in these animals during exposure. Wet tan or yellow matting on various body surfaces was noted primarily in the 2000 ppm group one hour following exposure on the first two days of test article administration. Other clinical signs noted in the treated groups were observed infrequently and/or at a similar frequency in the control group.

In the 500, 1000 and 2000 ppm groups, slightly reduced mean body weight gains (500 and 1000 ppm groups) or a mean body weight loss (2000 ppm group) occurred during gestation days 6-9. The differences from the control group were statistically significant p < 0.05 or p < 0.01). During the remainder of the exposure period (gestation days 9-12 and 12-16) and the post-exposure period (gestation days 16-20), mean body weight gains in the exposed groups were similar to the control group values. When the entire treatment period (gestation days 6-16) was evaluated, mean body weight gains in all of the exposed groups were slightly reduced relative to the control group value; the differences in the 1000 and 2000 ppm groups were statistically significant p < 0.01). Mean body weights in all of the exposed groups were slightly reduced from gestation days 7 through 20; the differences from the control group values were often statistically significant p < 0.05 or p < 0.01). Slight reductions in net body weight gain were observed in the 1000 and 2000 ppm groups relative to the control group value; the difference between the control and 2000 ppm groups was statistically significant p < 0.05). Mean gravid uterine weight and net body weight (the day 20 body weight minus the weight of the uterus and contents) were unaffected by treatment with the test article. Differences between the control and treated groups were slight and were not statistically significant.

Food consumption, evaluated as g/animal/day and g/kg/day, was slightly reduced in a dose-related manner in all of the treated groups relative to the control group values during gestation days 6-9, 9-12 and 12-16, and when the entire treatment period (gestation days 6-16) was evaluated. The differences from the control group values were generally statistically significant (p < 0.05 or p < 0.01). During the post-treatment period (gestation days 16-20), food consumption in the treated groups was similar to that in the control group; differences were slight and were not statistically significant. At the scheduled necropsy, no treatment-related findings were observed at any exposure level. Dark red lungs (all lobes) were observed in animal nos. 48997 and 49026 in the 1000 and 2000 ppm groups, respectively. In the 500 ppm group, animal no. 48965 had reddening of the cervical lymph nodes. No other remarkable internal findings were noted in animals in the treated groups.
Key result
Dose descriptor:
NOAEL
Effect level:
2 000 ppm (nominal)
Based on:
test mat.
Basis for effect level:
other: developmental toxicity
Key result
Dose descriptor:
LOAEL
Effect level:
500 ppm (nominal)
Based on:
test mat.
Basis for effect level:
other: maternal toxicity
Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:no effects

Details on embryotoxic / teratogenic effects:
Intrauterine growth and survival were unaffected by treatment with the test article at exposure levels of 500, 1000 and 2000 ppm. Parameters evaluated included postimplantation loss, live litter size, fetal body weights, fetal sex ratios and the numbers of corpora lutea and implantation sites. Differences between the control and treated groups were slight and were not statistically significant.

The numbers of fetuses (litters) available for fetal morphological examination were 372(24), 3 18(22), 341 (24) and 353(24) in the control, 500, 1000 and 2000 ppm groups, respectively. The numbers of fetuses (litters) with malformations were 2(2), 0(0), 4(4) and l(1) in these same exposure groups, respectively.

External malformations were observed in 3 and 1 fetuses in the 1000 and 2000 ppm groups, respectively. Fetus nos. 49001-06 and 49030-06 in the 1000 and 2000 ppm groups, respectively, had vertebral agenesis. Fetus nos, 49017-01 and 49062-03 in the 1000 ppm group had microphthalrnia (unilateral or bilateral). No external developmental variations were observed in fetuses at any exposure level.

Soft tissue malformations were observed in two fetuses each in the control and 1000 ppm groups. Fetus no. 48983-06 in the control group and fetus no. 48997-05 in the 1000 ppm group had situs inversus. Fetus no. 48997-05 also had a heart and great vessel anomaly (the aortic arch was interrupted, the right carotid and subclavian arteries arose from the ascending and descending aorta, respectively, and the interventricular septum was absent) and lobular agenesis of the lungs (only one lobe was present on each side). Fetus no. 49001-06 in the 1000 ppm group had malpositioned testes and kidneys, fused kidneys and fused adrenals. Fetus no. 49032-02 in the control group had a heart and great vessel anomaly (situs inversus [heart]; the ascending aorta arose from the smaller ventricle on the left side, and the pulmonary trunk arose from the larger ventricle on the right side). Soft tissue developmental variations were not observed in fetuses at any exposure level.

Skeletal malformations were not observed in fetuses at any exposure level in this study. Skeletal developmental variations were observed in all of the exposure groups, including the control group. None of the occurrences were attributed to exposure to the test article. The incidence (percent per litter) of ossification of cervical centrum no. 1 was reduced in the 2000 ppm group relative to the control group value; the difference was statistically significant p < 0.05). However, because of the absence of other indications of developmental delay in these fetuses (e.g. reduced mean fetal body weight), the reduced incidence of ossification of cervical centrum no. 1 was not attributed to the test article. Statistically significant (p < 0.05 or p < 0.01) increases were observed in the incidence of reduced ossification of the 13th ribs in the 500, 1000 and 2000 ppm groups (numbers of litters and percent per litter). However, the incidences expressed as percent per litter (3.2, 6.6 and 5.1 percent per litter in the 500, 1000 and 2000 ppm groups, respectively) were well within the range in the WIL historical control data (0.0-11.5 percent per litter), and no dose-response relationship was apparent; therefore, the increases were not attributed to the test article. The only other statistically significant (p < 0.05) difference between the control and treated groups was an increase in the number of litters in the 1000 ppm group with unossified sternebra(e) no. 5 andlor 6. Because the incidence (3.7 percent per litter) was well within the range in the WIL historical control data (0.6-37.5 %), and because a similar increase was not observed in the 2000 ppm group, the difference was attributed to biological variation. Other skeletal developmental variations that occurred in the treated groups were observed infrequently and/or at similar frequencies in the control group.

Fetal external, soft tissue and/or skeletal malformations were observed in 2(2), 0(0), 4(4) and l(1) fetuses (litters) in the control, 500, 1000 and 2000 ppm groups, respectively, and were considered to be spontaneous in origin. Differences between the control and treated groups in the total numbers of malformations were not statistically significant. Statistically significant (p < 0.05) differences in the incidences of various skeletal developmental variations were noted between the control and treated groups. However, in all cases, the incidences were within the range in the WIL historical control data, were not observed when the data were expressed on a percent per litter basis andlor were not observed to occur in a dose-related manner. Therefore, the increased incidences were attributed to biological variation. Other developmental variations noted in the treated groups were observed infrequently and/or at similar frequencies in the control group.
Key result
Dose descriptor:
NOAEL
Effect level:
2 000 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: no treatment-related developmental toxic effects were noted for the three tested exposure concentrations.
Abnormalities:
not specified
Developmental effects observed:
not specified

None

Conclusions:
Based on effects on body weight and food consumption observed at exposure concentrations, a NOAEL (no observed adverse effect level) for maternal toxicity was not determined. The exposure concentration of 500 ppm was considered to be the LOAEL (lowest observed adverse effect level) for maternal toxicity. Alternatively, no treatment-related developmental toxic effects were noted for the three tested exposure concentrations. Therefore, the highest exposure 2000 ppm, was considered to be the NOAEL for developmental toxicity.
Executive summary:

The potential maternal toxicity and development toxicity of n-Butyl Propionate were evaluated in this study. Three groups of 24 bred Sprague-Dawley Crl:CD BR rats were exposed to the test article by whole body inhalation for a 6 hour period each day for 10 consecutive days (gestation days 6-15) Target concentrations were 500, 1000 and 2000 ppm (parts per million.) The actual mean measured exposure concentrations were observed daily for appearance and behavior prior to exposure, for clinical signs during and within approximately one hour after completion of exposure and for mortality and moribundity. Body weights and food consumption were recorded at appropriate intervals. On gestation day 20, a laparohysterectomy was performed on all animals. The uteri and ovaries were examined and the numbers of fetuses, early and late resorptions, total implantations and corpora lute were recorded. Mean gravid uterine weights and net body weight changes were calculated for each group. The fetuses were weighed, sexed and examined for external, soft tissue skeletal malformations and variations.

 

All maternal animals survived to the scheduled necropsy on gestation day 20. The predominant treatment related clinical signs observed were dose-related incidences of slightly dropping eyelids and salivation, noted during exposure in the 1000 and 2000 ppm groups. Body weight gain and food consumption were inhibited in the 500, 1000, 2000 ppm groups during the first three days of exposure. Food consumption remained reduced in all of the treated groups throughout the remainder of the exposure period. No treatment-related necropsy findings were noted at any exposure level on gestation day 20.

 

Intrauterine growth and survival were unaffected by exposure to the test article at levels of 500, 1000 and 2000 ppm. The malformations and developmental variations observed in this study occurred infrequently, at similar frequencies in the control group or at frequencies that were within the range of the WIL historical control data, and were not considered to be related to test article exposure.

 

Based on effects on body weight and food consumption observed at exposure concentrations, a NOAEL (no observed adverse effect level) for maternal toxicity was not determined. The exposure concentration of 500 ppm was considered to be the LOAEL (lowest observed adverse effect level) for maternal toxicity. Alternatively, no treatment-related developmental toxic effects were noted for the three tested exposure concentrations. Therefore, the highest exposure 2000 ppm, was considered to be the NOAEL for developmental toxicity.

Effect on developmental toxicity: via oral route
Endpoint conclusion:
no study available
Effect on developmental toxicity: via inhalation route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEC
10 808 mg/m³
Study duration:
subacute
Species:
rat
Quality of whole database:
good
Effect on developmental toxicity: via dermal route
Endpoint conclusion:
no study available
Additional information

There are no developmental toxicity studies available for pentyl propionate, however there is an inhalation developmental toxicity studies available for butyl propionate.

In a GLP study conducted according to EPA OTS 798.4900 (Prenatal Developmental Toxicity Study), groups of Sprague Dawley rats were exposed (whole body) via inhalation to vapours of butyl propionate at levels of 500, 1000 and 2000 ppm for 6 hours/day, 10 consecutive days (gestation days 6-15). Based on effects on body weight and food consumption observed at exposure concentrations, a NOAEL (no observed adverse effect level) for maternal toxicity was not determined. The exposure concentration of 500 ppm was considered to be the LOAEL (lowest observed adverse effect level) for maternal toxicity. Alternatively, no treatment-related developmental toxic effects were noted for the three tested exposure concentrations. Therefore, the highest exposure 2000 ppm, was considered to be the NOAEL for developmental toxicity.

In a GLP study conducted according to OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test), groups of male and female Crl:CD(SD) rats were exposed via inhalation (whole body) to vapours of propyl propionate at levels of 0, 250, 500 and 1000 ppm for 6 hours/day, 7 days/week for a period of approximately 6-8 weeks.Treatment related histopathologic effects were also evident in the nasal tissues of males and females exposed to all test concentrations. The nasal tissue effects consisted of very slight degeneration of the olfactory epithelium. No treatment-related effects were seen in reproductive performance, pup survival and growth, neurologic function, clinical chemistry, or hematology. Therefore, the low-observed-effect concentration (LOEC) for general toxicity for male and female rats was considered to be 500 ppm and the NOEC for reproductive effects and neurological function was 500 ppm, the highest concentration tested.

 

On the basis of the studies conducted it can be concluded that pentyl propionate is unlikely to cause any developmental toxicity.

Compound tested

Species tested

Duration of exposure

GLP status

Doses tested

Guideline

Result - Maternal toxicity

Result - Developmental toxicity

Butyl propionate

SD rats

GD 6-15, 6 hours/day

Yes

0, 500, 1000, 2000 ppm

EPA OTS 798.4900

LOAEL – 500 ppm

NOAEL – 2000 ppm

Propyl propionate

SD rats

Approximately 6-8 weeks

Yes

0, 250, 500, 1000 ppm

OECD 422

LOEC – 500 ppm

NOEC – 500 ppm

Developmental toxicity data on n-butyl propionate:

In this GLP study conducted according to EPA OTS 798.4900 (Prenatal Developmental Toxicity Study), groups of Sprague Dawley rats were exposed (whole body) via inhalation to vapours of butyl propionate at levels of 500, 1000 and 2000 ppm for 6 hours/day, 10 consecutive days (gestation days 6-15). Based on effects on body weight and food consumption observed at exposure concentrations, a NOAEL (no observed adverse effect level) for maternal toxicity was not determined. The exposure concentration of 500 ppm was considered to be the LOAEL (lowest observed adverse effect level) for maternal toxicity. Alternatively, no treatment-related developmental toxic effects were noted for the three tested exposure concentrations. Therefore, the highest exposure 2000 ppm, was considered to be the NOAEL for developmental toxicity.

Developmental toxicity data on n-propyl propionate:

In a reproduction/developmental toxicity screening study (OECD TG 422) available, exposure to n-propyl propionate resulted in slight reductions in food consumption and body weight throughout the study in females exposed to 250 and 500 ppm. Treatment related histopathologic effects were also evident in the nasal tissues of males and females exposed to all test concentrations. The nasal tissue effects consisted of very slight degeneration of the olfactory epithelium. In addition males exposed to 500 ppm and females exposed to ≥ 50 ppm had a higher incidence of adipose tissue atrophy than the controls. This was interpreted to have questionable significance. No treatment-related effects were seen in reproductive performance, pup survival and growth, neurologic function, clinical chemistry, or hematology. Therefore, the low-observed-effect concentration (LOEC) for general toxicity for male and female rats was considered to be 500 ppm and the NOEC for reproductive effects and neurological function was 500 ppm, the highest concentration tested.

 

Conclusion:

In all the available studies on catgegory substances there is an absence of any (or any significant) developmental toxicity. Therefore, it is concluded that pentyl propionate is unlikely to cause any developmental toxicity.

Justification for selection of Effect on developmental toxicity: via inhalation route:
Key study on a category member

Toxicity to reproduction: other studies

Additional information

There are no other reproduction toxicity studies available for pentyl propionate.

Justification for classification or non-classification

In the absence of any effects observed in the reproduction screening test for propyl propionate and the developmental toxicity test for butyl propionate and based on the Guidance to Regulation (EC) No. 1272/2008 on Classification, Labelling and Packaging of substances and mixtures, pentyl propionate will not be classified for reproduction and developmental toxicity.