Registration Dossier

Toxicological information

Toxicity to reproduction

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Administrative data

Endpoint:
screening for reproductive / developmental toxicity
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Study period:
2003
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP, guideline study
Cross-referenceopen allclose all
Reason / purpose:
reference to same study
Reason / purpose:
reference to other study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2003

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
Deviations:
no
Remarks:
Not specified in report
Principles of method if other than guideline:
Not applicable
GLP compliance:
yes
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
A final purity of 99.69% +/- 0.01% [determined by gas chromatography with thermal conductivity (GC/TCD)] corrected for water, was reported for the sample. The water content of the sample was 0.05%. Infrared spectroscopy (FTIR) and gas chromatographic mass spectroscopy (GC/MS) were used to confirm the proposed structure.

Source: Angus Chemical
Lot# QF1931LAXX

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
Animals: CD rats (Crl: CD(SD) IGSBR) were approximately eight weeks when treatment was initiated. Examinations performed on all animals prior to the study start revealed that all animals were in good health for study purposes. The animals were acclimated to the laboratory for at least one week prior to the start of the study. Animals had free access to food and water (except during exposure, when both were withheld). Food and water had no contaminants at levels that would interfere with the conduct of this study or interpretation of the results.

Administration / exposure

Route of administration:
inhalation: vapour
Type of inhalation exposure (if applicable):
whole body
Vehicle:
unchanged (no vehicle)
Details on exposure:
Test material atmosphere: Exposure chambers were 2 cubic meter stainless steel and glass Rochester-type whole-body exposure chambers [1.3 meters (m) x 1.2 m wide x 1.2 m deep with a pyramidal top and bottom]. The various concentrations of 1-nitropropane were generated using the glass J-tube method (Miller et al., Am Ind Hyg Assoc J, 41:84-846,1980). Liquid test material was pumped into the glass J-tube assemblies (1 per exposure chamber) and vaporized by the flow of nitrogen gas passing through the bead bed of the glass J-tube. The nitrogen was heated as needed with a flameless heat torch to the minimum extent necessary to vaporize the test material. All chambers (including the filtered air control) received the same amount (20 liters per minute) of supplemental nitrogen. The minimum amount of nitrogen necessary to reach the desired chamber concentrations was used. The generation system was electrically grounded and the J-tubes were changed as needed. The vaporized test material and carrier gas were mixed and diluted with supply air to achieve a total flow of 450 liters per minute at the desired test chamber concentration. This flow rate was sufficient to provide the normal concentration of oxygen to the animals and 12-15 calculated air changes per hour. The chamber temperature and relative humidity were controlled by a system designed to maintain values of approximately 22 +/- 3 degrees C and 30 to 70%, respectively. The chambers were operated at a slightly negative pressure, relative to the surrounding area.


Details on mating procedure:
Animals were bred after approximately two weeks of treatment. Each female was placed with a single male from the same dose level (1:1 mating) until pregnancy occurred or two weeks had elapsed. During the breeding period, daily vaginal lavage samples were evaluated for the presence of sperm as an indication of mating. The day on which sperm were detected or a vaginal copulatory plug was observed in situ was considered gestation day (GD) 0. The sperm- or plug-positive (presumed pregnant) females were then separated from the males and returned to their home cages. If mating did not occur after two weeks, the animals were separated without further opportunity for mating.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
The chamber concentrations of 1-nitropropane, 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 and reported by a strip chart recorder. The IR spectrophotometer was calibrated and a standard curve was compiled prior to and at the midpoint of the study, using air standards prepared by vaporizing measured volumes of 1-nitropropane into Tedlar sample bags 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 1-nitropropane standard gasbag of known concentration. The nominal concentration of the test material in each chamber was estimated based on the amount of test material used and the total airflow through the chamber. Prior to the start of the study, each of the chambers was checked to ensure that a uniform distribution of vapor was present throughout the breathing zone of the animals.
Duration of treatment / exposure:
14 days prior to mating, during mating and to gestation day 19 (females), 14 days prior to mating and during mating (males)
Frequency of treatment:
6 hours/day, 7 days/week
Details on study schedule:
Groups of 12 male and 12 female CD rats were whole-body exposed to target concentrations of 0, 25, 50, and 100 ppm vaporized 1-nitropropane for six hours/day, seven days/week. Female rats were exposed daily for two weeks prior to breeding, through breeding (two weeks), and continuing through gestation day 19. 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 29). 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.
Doses / concentrationsopen allclose all
Remarks:
Doses / Concentrations:
0, 25, 50 and 100 ppm
Basis:
nominal conc.
Remarks:
Doses / Concentrations:
0, 24, 48 and 96 ppm
Basis:
other: actual mean chamber concentrations
No. of animals per sex per dose:
12/sex/dose
Control animals:
yes, concurrent no treatment
Details on study design:
Study contact: Groups of 12 male and 12 female CD rats were whole-body exposed to target concentrations of 0, 25, 50, or 100 ppm vaporized 1-nitropropane for six hours/day, seven days per week. The concentrations used were based on the results of a previous range-finding study. The females were exposed daily for approximately two weeks prior to breeding, continuing through breeding (two weeks) and continuing through gestation day 19. The males were exposed beginning approximately two weeks prior to breeding and continuing through breeding (two weeks) for a minimum exposure period of 28 days.

Animals were bred after approximately two weeks of treatment. Each female was placed with a single male from the same dose level (1:1 mating) until pregnancy occurred or two weeks had elapsed. During the breeding period, daily vaginal lavage samples were evaluated for the presence of sperm as an indication of mating. The day on which sperm were detected or a vaginal copulatory plug was observed in situ was considered gestation day (GD) 0. The sperm- or plug-positive (presumed pregnant) females were then separated from the males and returned to their home cages. If mating did not occur after two weeks, the animals were separated without further opportunity for mating.
Positive control:
No

Examinations

Parental animals: Observations and examinations:
Once each day, a clinical examination was conducted at approximately the same time each afternoon following exposure. This examination included a careful hand-held evaluation of skin, respiration, nervous system function (including tremors and convulsions), swelling, masses, and animal behavior. Cage-side examinations was conducted twice daily and the following parameters were evaluated (if possible): skin, fur, mucous membranes, respiration, nervous system function (including tremors and convulsions), animal behavior, moribundity, mortality, and the availability of feed and water. Detailed clinical observations (DCO) were conducted on all rats pre-exposure, and then weekly throughout the study. Mated females were given detailed examinations on gestation days 0, 7, 14, and 20. Functional tests were conducted pre-exposure and during the last week of the treatment period. For male rats, this took place on test day 26. For female rats, this took place on lactation day (LD) 4. The functional tests included a sensory evaluation, rectal temperature, grip performance, and motor activity.

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 course of the study. Females were weighed weekly during the premating and mating periods. During gestation, females were weighed on days 0, 7, 14, and 20. Females that delivered litters were weighed on days 1 and 4 post-partum. Females that failed to mate or deliver a litter were not weighed during the gestation or lactation phases.

For males and females, feed consumption was determined weekly during the two week pre-breeding period 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 was not measured for males. During gestation, feed consumption was measured for females on days 0-7, 7-14, and 14-20. After parturition, feed consumption was measured on LD 1 and 4. Feed consumption was not recorded for females that failed to mate or deliver a litter.

Females were observed for signs of parturition beginning on or about GD 20. Insofar 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 lacation day (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 were discarded.
Oestrous cyclicity (parental animals):
No data
Sperm parameters (parental animals):
The histopathological examination of the testes included a qualitative assessment of stages of spermatogenesis. A cross section through the approximate center of both testes of control and high-dose males were embedded in paraffin, sectioned at 5 microns and stained with modified periodic acid-Schiffs-hematoxylin. The presence and integrity of the 14 stages of spermatogenesis were qualitatively evaluated. Microscopic evaluation included a qualitative assessment of the relationships between spermatogonia, spermatocytes, spermatids, and spermatozoa seen in cross sections of the seminiferous tubules. The progression of these cellular association were defined the cycle of spermatogenesis. In addition, sections of both testes were examined for the presence of degenerative changes (e.g., vacuolation of the germinal epithelium, multinucleated giant cells, a decrease in the thickness of the germinal epithelium, a preponderance of Sertoli cells, sperm stasis, inflammatory changes, mineralization, and fibrosis)
Litter observations:
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 were discarded.
Postmortem examinations (parental animals):
Males were euthanized on test day 29, while females that delivered litters were euthanized on post-partum day 5. Females that did not deliver a litter were euthanized at least 24 days after the last day of the mating period. All pups surviving to LD 4 were euthanized by oral administration of sodium pentobarbital solution, examined for gross external alterations, and then discarded.

Necropsies were conducted on adult animals by a veterinary pathologist assisted by a team of trained individuals. The necropsy included an examination of the external tissues, and all orifices. The head was removed, the cranial cavity opened and the brain, pituitary, and adjacent cervical tissues were examined. The eyes were examined in situ by application of a moistened microscope slide to each cornea. The nasal cavity was flushed via the nasopharyngeal duct, and the lungs were distended to an approximately normal inspiratory volume with neutral, phosphate-buffered 10% formalin using a hand-held syringe and blunt needle. The thoracic and abdominal cavities were opened and the viscera examined. All visceral tissues were dissected from the carcass, re-examined and selected tissues were incised. The uteri of all females were examined and the number of implantation sites were recorded. The uteri of females that did not deliver litters were stained with a 10% solution of sodium sulfide in order to verify pregnancy status. The following tissues were trimmed and weighed: testes, epididymides, ovaries, liver, kidneys, adrenals, thymus, spleen, brain, thyroid/parathyroid (after fixation), and heart. The organ to body weight ratios were calculated. Similar necropsy procedures were followed for animals found dead or moribund with the exception that terminal body weights and organ weights were not collected.

Representative samples of tissues [adrenals, aorta, auditory sebaceous glands, bone (including joint), bone marrow, brain (cerebrum, brainstem and cerebellum), cecum, cervix, coagulating glands, colon, cranial nerve (optic), duodenum, epididymides, esophagus, eyes, gross lesions, heart, ileum (with Peyer's Patch), jejunum, kidneys, lacrimal/Harderian glands, larynx, liver, lungs, mammary gland, mediastinal lymph node, mediastinal tissues, mesenteric lymph node, mestenteric tissues, nasal tissues/pharynx, oral tissues, ovaries, oviducts, pancreas, parathroid glands, peripheral nerve (tibial), pituitary, prostate, rectum, salivary glands, seminal vesicles, skeletal muscle, skin and subcutis, spinal acord (cervical, thoracic, lumbar), spleen, stomach, testes, thymus, thryoid gland, tongue, trachea, urinary bladder, uterus and vagina] were collected and preserved in neutral, phosphate-buffered 10% formalin, except that the testes and epididymides were preserved by immersion in Bouin's fixative. Histopathologic examination of these tissues was conducted on all adult rats from the control and high-dose groups. Examination of tissues from the remaining groups was limited to nasal tissues/pharynx and relevant gross lesions. Selected histopathologic findings were graded to reflect the severity of specific lesions to evaluate: 1) the contribution of a specific lesion to the health status of an animal, 2) exacerbation of common naturally occurring lesions as a result of the test material, and 3) dose-response relationships for treatment related effects. Very slight and slight grades were used for conditions that were altered from the normal textbook appearance of an organ/tissue, but were of minimal severity and usually with less than 25% involvement of the parenchyma. This type of change was not expected to significantly affect the function of the specific organ/tissue or have a significant effect on the overall health of the animal. A moderate grade was used for conditions that were of sufficient severity and/or extent (up to 50% of the parenchyma) that the function of the organ/tissue may have been adversely affected, but not to the point of organ failure. The health status of the animal may or may not have been affected, depending on the organ/tissue involved, but generally lesions graded as moderate were not life threatening. A severe grade was used for conditions that were extensive enough to cause significant organ/tissue dysfunction or failure. This degree of change in a critical organ/tissue may have been life threatening.

The histopathological examination of the testes included a qualitative assessment of stages of spermatogenesis. A cross section through the approximate center of both testes of control and high-dose males were embedded in paraffin, sectioned at 5 microns and stained with modified periodic acid-Schiffs-hematoxylin. The presence and integrity of the 14 stages of spermatogenesis were qualitatively evaluated. Microscopic evaluation included a qualitative assessment of the relationships between spermatogonia, spermatocytes, spermatids, and spermatozoa seen in cross sections of the seminiferous tubules. The progression of these cellular association were defined the cycle of spermatogenesis. In addition, sections of both testes were examined for the presence of degenerative changes (e.g., vacuolation of the germinal epithelium, multinucleated giant cells, a decrease in the thickness of the germinal epithelium, a preponderance of Sertoli cells, sperm stasis, inflammatory changes, mineralization, and fibrosis).

Postmortem examinations (offspring):
Any pups found dead were sexed and examined grossly, if possible, for external and visceral defects and were discarded.
Statistics:
Statistical analyses of body weights and body weight gains during gestation were performed using data collected on days 0, 7, 14, and 20. Statistical analyses of body weight and body weight gains during the post-partum period were performed using data collected on days 1 and 4.

Statistics continued below.
Reproductive indices:
The female and male mating, conception, and fertility indices and gestation index were calculated.
Offspring viability indices:
The gestation survival index, Day 1 or 4 pup survival index and post implatation loss were calculated.

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):
Exposure to 1-nitropropane resulted in treatment-related decreases in body weight in males exposed to 100 ppm (6.9% on day 7). Body weights of the mid- and low-dose males were not altered by exposure to 1-nitropropane. There were no treatment-related differences in body weight or body weight gains of females at any exposure level tested during the premating, gestation or lactation periods..
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
Statistically- identified decreases in feed consumption were noted during the pre-breeding phase on test days 1-7 and 7-14 in the 100 ppm males and on days 1-7 in the 100 ppm females. There were no significant effects on food consumption at anytime in the 50 or 25 ppm exposure groups. There were no significant differences in the amount of feed consumed by any of the exposed groups when compared to their respective controls throughout the gestation or lactation periods.
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
no effects observed
Behaviour (functional findings):
no effects observed
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
Males exposed to 100 ppm had statistically identified higher relative brain and testes weights. The alterations in relative brain and testes weights were reflective of the treatment-related lower body weights at the 100 ppm dose level. Males exposed to 25 ppm had statistically identified lower absolute and relative thymus weights. The alterations in thymus weights were interpreted to not be treatment related because of the lack of a dose response. There were no histopathologic correlations to any of the statistically- identified organ weight changes. There were no statistically identified alterations in final body weights or organ weights of females at any exposure level. Small increases in female heart weights correlated positively with dose but were interpreted to be of no biologic significance and likely due to chance for the following reasons: lack of statistical significance, lack of similar effect in males, and the absence of gross or histopathologic changes in the heart in either sex at any dose.
Gross pathological findings:
no effects observed
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
Treatment-related histopathologic effects were noted in the nasal tissues of males exposed to 100 ppm and females exposed to 50 or 100 ppm. The nasal tissue effects consisted of very slight or slight degeneration of the olfactory epithelium, and slight chronic active inflammation of the squamous
epithelium. The olfactory degeneration was characterized by thinning and/or a disarray of olfactory epithelial cells located in the anterior portions of the dorsal meatus or the dorsal portions of the nasoturbinates. Other features of olfactory degeneration in some affected animals consisted of accompanying inflammation in the olfactory epithelium and submucosa, and exfoliation of olfactory epithelial cells into the nasal lumen. Inflammation of the nasal squamous epithelium was characterized by accumulations of neutrophils and lymphocytes in the anterior portion of the squamous epithelium of the ventral meatus. Exfoliation of inflammatory cells and keratin was present in some affected animals. All other histopathologic observations were considered to be spontaneous alterations, unassociated with exposure to 1-nitropropane.
Histopathological findings: neoplastic:
not examined
Other effects:
not examined

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:
no effects observed
Reproductive function: sperm measures:
no effects observed
Reproductive performance:
no effects observed

Details on results (P0)

Test material: Mean chamber concentration values for the study were 0, 24.4 +/- 1.8, 48.4 +/- 1.8, and 96.3 +/- 2.6 ppm. Actual mean chamber concentration values deviated 2-4% from the targeted values of 0, 25, 50, and 100 ppm. Chamber airflow in all four chambers was maintained throughout the study duration. Mean chamber temperatures for all chambers were maintained between 20 and 23 C. Mean chamber relative humidity was maintained in the range of 33-44% for all exposure chambers. On one exposure day the mean relative humidity of the 25, 50, and 100 ppm chambers was below 30% (29.4, 29.4, and 28.1%, respectively). This single, minor excursion from the protocol-specified range of 30-70% is not considered to have affected the integrity of the study.

Effects at 96 ppm: All animals survived until termination. There were no treatment-related effects at any exposure level on reproductive indices, time to mating, gestation length, post-implantation loss, pup survival, pup sex ratio or histological examination of reproductive organs. Although conception and fertility indices of males and females exposed to 96 ppm 1-nitropropane (83.3%) were numerically (but not statistically) lower than those of the controls, this was most likely due to the fact that the control group values were quite high (100%). The conception and fertility indices in the 96 ppm group were within the range of historical control values from four OECD 422 studies conducted by the laboratory from 2000 - 2004 (83.3 -100%). The mean number of pups born live (11.9/litter) and the mean number of pups on day 1 and 4 postpartum (both 11.8/litter) were less than controls (14.0/litter and 13.8/litter, respectively). Although these differences were not statistically significant, each of these values was outside the range of the historical control data from recently completed OECD 422 studies (13.3 - 15.6 fetuses born live/litter, 12.8 - 15.5 alive on day 1/litter and 12.5 - 15.5 alive on day 4/litter). Inspection of the individual animal data revealed that 3 of 10 dams in this group had litter sizes of fewer than 12 pups, whereas in the control, 24 and 48 ppm groups the number of dams producing fewer than 12 pups was 1/12, 1/12 and, 0/10, respectively. Mean male and female pup weights were increased relative to the controls on days 1 (7.3 and 6.9 g in exposed males and females compared to 6.7 and 6.3 g in control males and females) and 4 postpartum (10.4 and 9.7 g in exposed males and females compared to 9.2 and 8.8 g in control males and females) in dams exposed to 96 ppm 1-nitropropane. The mean pup weight values at 96 ppm were within the historical control range from recently completed OECD 422 studies, while the control values were outside the historical range. Therefore, the changes in pup body weights were not considered adverse.

Feed consumption was reduced during the pre-breeding phase on test days 1-7 and 7-14 in males and on days 1-7 in females. Average body weight of males was decreased (6.9%) on test day 7. Males exposed to 96 ppm had higher relative brain and testes weights. There were no treatment related gross pathologic observations. Treatment-related histopathologic effects were noted in the nasal tissues of one male and one to seven females exposed to 96 ppm (see Section 5.4 for additional details. The severity of all lesions was graded very slight to slight. There was no effect of treatment on histopathology of any reproductive organ examined.

Effects at 48 ppm: Treatment-related histopathologic effects were noted in the nasal tissues of a few females exposed to 48 ppm (see Section 5.4 for additional details). There was no effect of exposure on histopathology of reproductive organs. Although conception and fertility indices of males and females exposed to 48 ppm 1-nitropropane (83.3%) were numerically (but not statistically) lower than those of the controls, this was most likely due to the fact that the control group values were quite high (100%). The conception and fertility indices in the 96 ppm group were within the range of historical control values from four OECD 422 studies conducted by the laboratory from 2000 - 2004 (83.3 -100%).

Effects at 24 ppm: Very slight, chronic, active, multifocal or focal inflammation of the squamous epithelium of the nasal tissue was noted in one female. There were no effects on any reproductive parameter.

Effects in controls: Very slight, chronic, active, multifocal or focal inflammation of the squamous epithelium of the nasal tissue was noted in one and two females, respectively. There were no effects on any reproductive parameter.

Effect levels (P0)

open allclose all
Key result
Dose descriptor:
NOEC
Remarks:
general toxicity
Effect level:
50 ppm (nominal)
Based on:
test mat.
Sex:
male
Basis for effect level:
other: Based on histologic changes in the nasal tissues.
Key result
Dose descriptor:
NOEC
Remarks:
general toxicity
Effect level:
25 ppm (nominal)
Based on:
test mat.
Sex:
female
Basis for effect level:
other: Based on histologic changes in the nasal tissues.
Key result
Dose descriptor:
NOEC
Remarks:
reproductive effects
Effect level:
50 ppm (nominal)
Based on:
test mat.
Sex:
female
Basis for effect level:
other: Based on differences in litter size between high-dose animals and controls.
Key result
Dose descriptor:
NOEC
Remarks:
neurologic function
Effect level:
100 ppm (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: The highest concentration tested.

Target system / organ toxicity (P0)

Key result
Critical effects observed:
yes
Lowest effective dose / conc.:
50 ppm
System:
respiratory system: upper respiratory tract
Organ:
nasal cavity
Treatment related:
yes
Dose response relationship:
yes
Relevant for humans:
not specified

Results: F1 generation

General toxicity (F1)

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

Developmental neurotoxicity (F1)

Behaviour (functional findings):
not examined

Developmental immunotoxicity (F1)

Developmental immunotoxicity:
not examined

Details on results (F1)

In the high-exposure group, the mean number of pups born live and the mean number of pups on day 1 and 4 postpartum were less than controls. Although these differences were not statistically significant, each of these values was outside the range of the historical control data from recently completed OECD 422 studies. Inspection of the individual animal data revealed that 3 of 10 dams in this group had litter sizes of fewer than 12 pups, whereas in the control, 25 and 50 ppm groups the number of dams producing fewer than 12 pups was 1/12, 1/12 and, 0/10, respectively. The toxicological significance of this finding is equivocal, as there were no apparent effects on any other reproductive parameter examined, nor were there any corroborating findings revealed at gross or histopathological examination. When considered together, these results suggest that the slightly reduced litter size in animals exposed to 100 ppm 1-nitropropane was likely secondary to maternal toxicity and/or stress associated with nasal irritation.

Mean Litter Size
Exposure Level (ppm)
Parameter (mean values) 0 25 50 100
No. Born Live 14.0 14.3 15.1 11.9
Day 1 13.8 14.3 15.1 11.8
Day 4 13.8 14.1 15.1 11.8

Historical Control Data for Mean Litter Size
Study #
Year 1 2 3 4 Range
2000 2003 2004 2004 (Average)

No. Born Live 13.6 15.1 15.6 13.3 13.3-15.6 (14.4)
Day 1 13.4 15.1 15.5 12.8 12.8-15.5 (14.2)
Day 4 13.4 14.9 15.5 12.5 12.5-15.5 (14.1)


Mean male and female pup weights were statistically identified as increased relative to the controls on days 1 and 4 postpartum in dams exposed to 100 ppm 1-nitropropane. The increase in mean pup weights at 100 ppm was most likely secondary to the smaller litter size in the 100 ppm group, as pup weight varies inversely with litter size. The mean pup weight values at 100 ppm were within the historical control range from recently completed OECD 422 studies, while the control values were outside the historical range. Therefore, the changes in pup body weights were not considered adverse. No significant differences were noted at the lower exposure levels.

Mean Pup Weights
Exposure Level (ppm)
Parameter (mean values) 0 25 50 100
1 Female (g) 6.3 6.5 6.2 6.9*
1 Male (g) 6.7 6.9 6.6 7.3*

4 Female (g) 8.8 9.2 8.6 9.7*
4 Male (g) 9.2 9.7 9.2 10.4*

* Statistically different from control mean by Dunnett’s test, alpha = 0.05.

Historical Control Data for Mean Pup Weights
Study # 1 2 3 4 Range
Year 2000 2003 2004 2004 (Average)

1 Female (g) 6.9 6.5 6.6 7.0 6.5-7.0 (6.8)
1 Male (g) 7.3 7.0 7.0 7.4 7.0-7.4 (7.2)

4 Female (g) 9.8 9.1 9.1 10.1 9.1-10.1 (9.5)
4 Male (g) 10.2 9.6 9.7 10.7 9.6-10.7 (10.1)

Effect levels (F1)

open allclose all
Key result
Dose descriptor:
LOEC
Generation:
F1
Effect level:
100 ppm (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
viability
Key result
Dose descriptor:
NOEC
Generation:
F1
Effect level:
50 ppm (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: no effects observed

Overall reproductive toxicity

Reproductive effects observed:
not specified

Any other information on results incl. tables

This summary only describes procedures and results related to fertility.  Repeated dose and developmental data are discussed in Sections 5.4 and 5.8.2, respectively.

The authors considered the toxicological significance of reduced litter sizes at 96 ppm as equivocal, as there were no apparent effects on any other reproductive parameter examined, nor were there any corroborating findings revealed at gross or histopathological examination.
  The authors suggested that the slightly reduced litter size in animals exposed to 96 ppm 1-nitropropane was likely secondary to maternal toxicity and/or stress associated with nasal irritation. The authors also stated that the increases in mean pup weights at 96 ppm were most likely secondary to the smaller litter size in the 96 ppm group, as pup weight varies inversely with litter size.

Applicant's summary and conclusion

Conclusions:
The no-observed-effect concentration (NOEC) for general toxicity, based on histologic changes in the nasal tissues, was 50 ppm for males and 25 ppm for females. The NOEC for reproductive effects, based on differences in litter size between high-dose animals and controls, was 50 ppm. The NOEC for neurologic function was 100 ppm, the highest concentration tested.
Executive summary:

This study evaluated 1-nitropropane in the OECD 422 study design. Groups of 12 male and 12 female CD rats were whole-body exposed to target concentrations of 0, 25, 50, and 100 ppm vaporized 1-nitropropane for six hours/day, seven days/week. Female rats were exposed daily for two weeks prior to breeding, through breeding (two weeks), and continuing through gestation day 19. 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 29). 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 1-nitropropane resulted in treatment-related decreases in body weight in males exposed to 100 ppm. Treatment-related histopathologic effects were noted in the nasal tissues of males exposed to 100 ppm and females exposed to either 50 or 100 ppm. The nasal tissue effects consisted of very slight or slight degeneration of the olfactory epithelium, and slight chronic active inflammation of the squamous epithelium. No treatment effects were seen in reproductive performance, pup survival and growth, neurologic function, clinical chemistry, or haematology. A very slight decrease in litter size was seen in animals exposed to 100 ppm 1-nitropropane. However, given the lack of other effects on reproductive performance or gross/histologic findings in the reproductive organs, the slight decrease in litter size may have been secondary to maternal toxicity and/or stress in the high-dose females.

The no-observed-effect concentration (NOEC) for general toxicity, based on histologic changes in the nasal tissues, was 50 ppm for males and 25 ppm for females. The NOEC for reproductive effects, based on differences in litter size between high-dose animals and controls, was 50 ppm. The NOEC for neurologic function was 100 ppm, the highest concentration tested.