Registration Dossier
Registration Dossier
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EC number: 219-376-4 | CAS number: 2426-08-6
Toxicity to reproduction
Administrative data
- Endpoint:
- screening for reproductive / developmental toxicity
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- test procedure in accordance with generally accepted scientific standards and described in sufficient detail
Cross-reference
- Reason / purpose for cross-reference:
- reference to same study
Reference
- Endpoint:
- developmental toxicity
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- test procedure in accordance with generally accepted scientific standards and described in sufficient detail
- Reason / purpose for cross-reference:
- reference to same study
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- other: OECD Guideline 421 (Reproduction / Developmental Toxicity Screening Test)
- Principles of method if other than guideline:
- 20 Osborne-Mendal rats per sex per dose were exposed to air, containing the test substance at a dose of 0, 30, 100, or 200 ppm 6 h/d, 5 d/w for 8 weeks. Animals were observed continiously defore, during and after exposure. Mating begun 2 days after the end of the 8-week exposure for the reproductive effects studies, controls with controls, exposed males with control females, and control males with exposed females. Reproductive effects were evaluated in parental animals and offspring.
- GLP compliance:
- not specified
- Limit test:
- no
- Specific details on test material used for the study:
- SOURCE OF TEST MATERIAL
- Source test material: Alcolac, Inc. (Baltimore, MD)
- Purity test: approximately 99%
STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- The stability of the study material was monitored during the animal studies by gas chromatography and nonaqueous titration of the epoxide group.
- No deterioration of the study material was seen over the course of the studies.
OTHER:
- Apearance: clear, colourless liquid - Species:
- rat
- Strain:
- Osborne-Mendel
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: CAMM Research Institute (Wayne, NJ)
- Females (if applicable) nulliparous and non-pregnant: yes
- Age at study initiation: 8 weeks
- Housing: Single housing, Stainless steel wire (Hazleton Systems, Aberdeen, MD)
- Diet: NIH 07 Rat and Mouse Ration (Zeigler Bros., Inc., Gardners, PA); available ad libitum except during exposure periods
- Water: Automatic watering system (Edstrom Industries, Waterford, WI); available ad libitum
- Acclimation period: 21 days
ENVIRONMENTAL CONDITIONS
- Temperature: 69 tot 80 °F (equivalent to 20.5 to 26.5 °C)
- Humidity (%): 32 to 75
- Photoperiod (hrs dark / hrs light): 12 / 12 - Route of administration:
- inhalation: vapour
- Type of inhalation exposure (if applicable):
- whole body
- Vehicle:
- air
- Details on exposure:
- VAPOUR GENERATION SYSTEM:
No additional preparation of the test item was necessary before introduction into the vapour generation system. The liquid was pumped from a stainless steel reservoir to a vaporizer by a stable micrometering pump with adjustable pump rates. For the concentrations from 10 ppm to 20 ppm, the liquid was vaporized from a fine glass wick on the surface of a cylindrical vaporizer by an electric heater embedded in the cylinder. The vaporizer surface temperatures were set at approximately 90°C. Each cylindrical vaporizer was positioned in the fresh air duct leading directly into the exposure chamber. At exposure concentrations of 4 ppm the liquid test item was drawn from the stainless steel reservoir through a three-way valve into a glass syringe large enough to contain the total amount necessary for a 6-hour exposure. The syringe was attached to a syringe pump unit, and the three-way valve was adjusted to allow flow of the liquid through an injection needle to a cotton wick positioned in the fresh air duct leading directly into the exposure chamber. No additional heating was necessary to generate the vapour.
VAPOUR CONCENTRATION MONITORING:
Concentrations of the test item in the chambers and the exposure room were measured by gas chromatography with a flame ionization detector. Exposure concentrations were within ±10% of the target concentrations
CHAMBER CHARACTERISATION:
Uniformity of vapour concentration in each exposure chamber was measured before the start of the studies and was checked by gas chromatography at intervals of approximately 3 months throughout the studies. In most instances, the vapour concentrations were within 10% of the mean target concentration values at all 12 positions sampled within the chamber, indicating good, homogeneous distribution of the study vapour. - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Samples of the test item exposure at atmospheres were analysed for the presence of potential degradation products by gas chromatography with flame ionization detection. No impurities were observed by gas chromatographic analysis to indicate significant decomposition of the test item under study conditions.
- Details on mating procedure:
- Cohabitation of male and female rats was initiated 2 days after the final exposure. A computer-derived randomization program was used to determine male-female pairings. A single male rat was placed in a cage with a single female rat at 3:00-4:00 p.m. and was removed the following morning at 6:30-7:30. Each female was lavaged with 0.9% saline, which was then examined microscopically for the presence of sperm. The day that sperm were detected was designated day 0 of gestation; no further cohabitation of this pair took place. Cohabitation and lavage for unmated pairs were repeated each day for a period of 7 days until sperm were detected. The day sperm were found was recorded for each male-female pair, Sperm-negative females were recorded as not having mated.
Half of the females in which copulation was detected were assigned to the group to be used for fetal examinations. The remainder were assigned to the group to be used for postnatal examinations. Females selected for the two examination groups were those whose days of mating were representative of those of all mated females at their exposure concentration. Postnatal observations were performed on offspring from pregnant females in which copulation was not detected.
The day after the last exposure, all female rats were placed in stainless steel wire mesh-bottom cages, where they were housed individually throughout the breeding period and during the first 15 days of gestation. - Duration of treatment / exposure:
- 8 weeks
- Frequency of treatment:
- 6 h/d, 5 d/w
- Dose / conc.:
- 30 ppm
- Remarks:
- equivalent to 140 mg/m3
- Dose / conc.:
- 100 ppm
- Remarks:
- equivalent to 467 mg/m3
- Dose / conc.:
- 200 ppm
- Remarks:
- equivalent to 934 mg/m3
- No. of animals per sex per dose:
- 20
- Control animals:
- yes, concurrent vehicle
- Maternal examinations:
- DETAILED CLINICAL OBSERVATIONS:
- Time schedule: continuously during exposure and 2 times per day during nonexposure periods
- Pregnant females were observed twice per day before parturition.
BODY WEIGHT:
- Time schedule for examinations: before study, 1 time per week during the study and at necropsy
- On the 13th day postpartum, the dams were weighed.
POSTMORTEM EXAMINATIONS
- Moribund animals were humanely killed.
- All animals were killed by carbon dioxide, which allows for a more accurate assessment of fetal viability. The dams were weight immediately, and the body weight and time of ill were recorded. The uterus and ovaries were removed and weighed. The ovaries were separated from the uterus, and the corpora lutea were counted. The nongravid uterus was stained with an aqueous solution of 10% ammonium sulfide to locate implantation sites. The rest of the maternal necropsy was conducted according to standard protocol. All maternal tissues were preserved in 10% normal-buffered formalin (NBF). Live and dead fetuses and early, mid, and late resorption sites were counted in each uterine horn. The fetuses and placentas were then removed and numbered for identification.
- When the pups were 21 days old, they and their dams were killed with carbon dioxide and weighed. The ovaries and uteruses of the dams were removed, and the ovaries were examined to enumerate corpora lutea. The uteruses were stained with 10% ammonium sulfide to display implantation sites. All necropsies were performed according to standard protocol.
- Histopathologic examinations were performed on tissues of all control and the highest dose groups and on selected tissues of lower dose groups. - 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 - Fetal examinations:
- - During the first 24 hours after birth, the pups were sexed, weighed, and examined for external abnormalities. This was repeated when the pups were 4 days old.
- The fetuses were killed by an intraperitoneal injection of 0.05 mL of 50 mg/mL sodium pentobarbital. The sex, shape of head, limbs, and number of digits were noted, and the fetus was examined for gross external malformations. The mouth was opened to check for a cleft palate. The fetus and placenta were then weighed. A small incision was made in the abdomen, and each fetus was placed in an individual carton containing Bouin’s fixative. When all fetal examinations had been completed, the results were tabulated and classified as major malformations, minor anomalies, or common variants. Stunting was calculated by multiplying the mean body weight of all pups in a litter by 0.66, omitting the suspected stunted pup. If the suspect pup weighed less than this value, it was considered stunted.
- When the pups were 21 days old they and their dams were killed with carbon dioxide and weighed, and the sex of the pups was verified. - Statistics:
- - Descriptive statistics: mean, standard deviation
- Dunnett's test: p values - Clinical signs:
- no effects observed
- Dermal irritation (if dermal study):
- not examined
- Mortality:
- no mortality observed
- Description (incidence):
- No maternal animals died during the exposure
- Body weight and weight changes:
- no effects observed
- Description (incidence and severity):
- Body weights were not affected in maternal animals
- Food consumption and compound intake (if feeding study):
- not examined
- Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- not examined
- Haematological findings:
- not examined
- Clinical biochemistry findings:
- not examined
- Urinalysis findings:
- not examined
- Behaviour (functional findings):
- not examined
- Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Description (incidence and severity):
- Placental weights, and weights of gravid uteri were not affected in females
- Gross pathological findings:
- no effects observed
- Neuropathological findings:
- not examined
- Histopathological findings: non-neoplastic:
- no effects observed
- Histopathological findings: neoplastic:
- not examined
- Other effects:
- not specified
- Number of abortions:
- no effects observed
- Pre- and post-implantation loss:
- effects observed, treatment-related
- Description (incidence and severity):
- Small but statistically significant reductions were seen in the number of corpora lutea per dam and in the number of implantation sites per dam in females exposed to 200 ppm. The number of implantation sites per dam were statistically significant reduced when the in groups where males were exposed starting from 30 ppm.
- Total litter losses by resorption:
- effects observed, treatment-related
- Early or late resorptions:
- no effects observed
- Dead fetuses:
- effects observed, treatment-related
- Description (incidence and severity):
- The numbers of implantation sites per dam and live fetuses per litter were greatly reduced in dams mated with exposed males in the 30-and 100-ppm groups. None of the females mated with 200-ppm males in the fetal studies became pregnant, and no implantation sites for developing fetuses were found
- Changes in pregnancy duration:
- no effects observed
- Description (incidence and severity):
- Migrated Data from removed field(s)
Field "Effects on pregnancy duration" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsMaternalAnimals.MaternalDevelopmentalToxicity.EffectsOnPregnancyDuration): no effects observed - Changes in number of pregnant:
- effects observed, treatment-related
- Description (incidence and severity):
- The reproductive performance of males exposed to 200 ppm was found to be markedly impaired; the mating behavior of females was not affected at any exposure concentration. The number of pregnant females was statistically significantly reduced in groups where males were exposed starting from 30 ppm.
- Dose descriptor:
- NOAEC
- Remarks:
- systemic toxicity
- Effect level:
- 934 mg/m³ air
- Based on:
- test mat.
- Basis for effect level:
- other: overall effects
- Dose descriptor:
- NOAEC
- Remarks:
- developmental toxicity
- Effect level:
- < 140 mg/m³ air
- Based on:
- test mat.
- Basis for effect level:
- changes in number of pregnant
- pre and post implantation loss
- Abnormalities:
- no effects observed
- Fetal body weight changes:
- no effects observed
- Description (incidence and severity):
- Fetal body weights were not affected.
Migrated Data from removed field(s)
Field "Fetal/pup body weight changes" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.FetalPupBodyWeightChanges): no effects observed
Field "Description (incidence and severity)" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.DescriptionIncidenceAndSeverityFetalPupBodyWeightChanges): No abnormal fetuses were found in the relatively small number of fetuses available for examination which were sired by exposed males. No effects of exposure were seen on the offspring of exposed females. - Reduction in number of live offspring:
- effects observed, treatment-related
- Description (incidence and severity):
- The number of live pups sired by any group of exposed males was significantly lower than that sired by controls.
- Changes in sex ratio:
- not specified
- Changes in litter size and weights:
- no effects observed
- Changes in postnatal survival:
- effects observed, treatment-related
- Description (incidence and severity):
- The number of live pups sired by any group of exposed males was significantly lower than that sired by controls.
- External malformations:
- no effects observed
- Description (incidence and severity):
- Very few malformations were observed in fetal offspring of exposed dams.
- Skeletal malformations:
- not specified
- Visceral malformations:
- not specified
- Other effects:
- not specified
- Dose descriptor:
- NOAEC
- Effect level:
- < 140 mg/m³ air
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- reduction in number of live offspring
- Abnormalities:
- no effects observed
- Developmental effects observed:
- yes
- Lowest effective dose / conc.:
- 140 mg/m³ air
- Treatment related:
- yes
- Relation to maternal toxicity:
- developmental effects in the absence of maternal toxicity effects
- Dose response relationship:
- yes
- Relevant for humans:
- yes
Mean body weights of rats in the eight-week inhalation studies of the reproductive effects
|
Male |
Female |
|
Concentration Male Female (ppm) |
|
Fetal Exam Groups (b) |
Postnatal Exam Groups (c) |
|
Before Exposure |
||
(d)0 |
267 |
187 |
179 |
(e)0 |
265 |
185 |
181 |
30 |
234 |
183 |
185 |
100 |
263 |
177 |
185 |
200 |
269 |
180 |
183 |
|
End of exposure (f) |
||
(d)0 |
419 |
260 |
247 |
(e)0 |
414 |
257 |
247 |
30 |
352 |
240 |
244 |
100 |
337 |
226 |
232 |
200 |
296 |
214 |
216 |
|
Termination (g) |
||
(d)0 |
- |
326 |
281 |
(e)0 |
414 |
360 |
298 |
30 |
371 |
344 |
291 |
100 |
370 |
326 |
289 |
200 |
349 |
332 |
286 |
(b)Groups designated for fetal examination on day 19ofgestation
(c) Groups designated for postnatal examination on day 21 postpartum
(d)Mates for exposed animals
(e)Mates for control animals
(f)Animals were weighed 1day after the end of exposure.
(g)Males were killed 13-14 days after the end of exposure
Summary of pregnancy status of rats after inhalation exposure for8-Weeks
|
Control |
30 ppm |
100 ppm |
200 ppm |
Results when males were exposed (a) |
||||
Number of females examined |
20 |
20 |
20 |
18 |
Percentage sperm-positive |
75 |
90 |
85 |
78 |
Percentage pregnant, sperm-positive |
100 |
**50 |
**23.5 |
**7 |
Percentage sperm-negative |
25 |
10 |
15 |
22 |
Percentage pregnant, sperm-negative |
0 |
0 |
0 |
0 |
Percentage of all females pregnant |
75 |
45 |
**20 |
**6 |
Results when females were exposed(b) |
||||
Number of females examined |
20 |
20 |
20 |
20 |
Percentage sperm-positive |
75 |
85 |
95 |
75 |
Percentage pregnant, sperm-positive |
100 |
100 |
100 |
100 |
Percentage sperm-negative |
25 |
15 |
5 |
25 |
Percentage pregnant, sperm-negative |
0 |
67 |
100 |
40 |
Percentage of all females pregnant |
75 |
95 |
*100 |
85 |
(a)Control female rats were mated with exposed male rats.
(b)Exposed female rats were mated with control male rats.
*P<0.05 vs. the controls by the Fisher exact test
**P<0.01 vs. the controls by the Fisher exact test
Summary of reproductive performance of rats after inhalation exposure for eight weeks
|
|
Results When Males Were Exposed (a)
|
Results When Females Were Exposed (b) |
||||||
Concentration (ppm) |
Day of mating |
Copulations detected (c) |
No. of females impregnated |
No. of litters (d) |
Total Pups/ Litter (e) |
Copulations detected (c) |
No. of females impregnated |
No. of litters (d) |
Total Pups/ Litter (e) |
0 |
1 |
4/20 |
4 |
4 |
14.3±3.1 |
4/20 |
4 |
4 |
14.3±3.1 |
|
2 |
3/16 |
3 |
3 |
14.3±0.6 |
3/16 |
3 |
3 |
14.3±0.6 |
|
3 |
2/13 |
2 |
2 |
14.0±1.4 |
2/13 |
2 |
2 |
14.0±1.4 |
|
4 |
4/11 |
4 |
4 |
13.5±3.1 |
4/11 |
4 |
4 |
13.5±3.1 |
|
5 |
2/7 |
2 |
2 |
12.5±2.1 |
2/7 |
2 |
2 |
12.5±2.1 |
|
6 |
0/5 |
|
|
|
0/5 |
|
|
|
|
7 |
0/5 |
|
|
|
0/5 |
|
|
|
|
Summary |
15/20 |
15 |
15 |
13.8±2.2 |
15/20 |
15 |
15 |
3.8±2.2 |
30 |
1 |
2/20 |
1 |
1 |
6 |
5/20 |
5 |
5 |
13.8±2.4 |
|
2 |
7/18 |
2 |
2 |
1.5±0.7 |
8/15 |
8 |
8 |
12.5±2.2 |
|
3 |
2/11 |
1 |
1 |
1 |
2/7 |
2 |
2 |
13.5±3.5 |
|
4 |
2/9 |
2 |
2 |
5.5±6.4 |
1/5 |
1 |
1 |
12 |
|
5 |
5/7 |
3 |
3 |
10.7± 3.2 |
1 / 4 |
1 |
1 |
15 |
|
6 |
0/7 |
|
|
|
0/3 |
|
|
|
|
7 |
0/7 |
|
|
|
0/3 |
|
|
|
|
Undetected |
|
|
|
|
|
2 |
2 |
|
|
Summary |
18/20 |
9 |
9 |
5.9±4.9 |
17/20 |
19 |
19 |
13±2.1 |
100 |
1 |
1/20 |
0 |
|
|
5/20 |
5 |
5 |
11±2.3 |
|
2 |
3/19 |
0 |
|
|
8/15 |
8 |
8 |
13.4±2.7 |
|
3 |
7/16 |
2 |
2 |
1.0 |
0/7 |
|
|
|
|
4 |
2/9 |
0 |
|
|
1/7 |
1 |
0 |
|
|
5 |
2/7 |
0 |
1 |
|
4/6 |
4 |
4 |
13±2.4 |
|
6 |
1/5 |
1 |
1 |
10 |
1/2 |
1 |
1 |
11 |
|
7 |
1/4 |
1 |
|
10 |
0/1 |
|
|
|
|
Undetected |
|
|
|
|
|
1 |
1 |
13 |
|
Summary |
17/20 |
4 |
4 |
5.3±4.9 |
19/20 |
19 |
19 |
12.7±2.4 |
200 |
1 |
1/18 |
0 |
|
|
1/20 |
1 |
1 |
11 |
|
2 |
1/17 |
0 |
|
|
711 |
7 |
7 |
13.0±0.8 |
|
3 |
3/16 |
0 |
|
|
511 |
5 |
5 |
12.8±1.1 |
|
4 |
2/13 |
0 |
|
|
0/7 |
|
|
|
|
5 |
5/11 |
0 |
|
|
1I7 |
1 |
1 |
12 |
|
6 |
2/6 |
1 |
1 |
8 |
116 |
1 |
1 |
10 |
|
7 |
0/4 |
0 |
0/5 |
|
|
7 |
|
|
|
Undetected |
|
|
|
|
|
2 |
2 |
10 |
|
Summary |
14/18 |
1 |
1 |
8 |
15/20 |
17 |
17 |
12.1±1.5 |
|
|
|
|
|
|
|
|
|
|
(a)Data from control females mated with exposed males
(b)Data from exposed females mated with control males
(c)Number of copulations detected/number of females
(d)Litters examined at d 19 of gestation or within 24 h after birth
(e) Mean±standard deviation
Reproductive status of maternal rats and postnatal survival of Offspring of rats exposed for eight weeks (before mating)
|
Control |
30 ppm |
100 ppm |
200 ppm |
||||
|
Number (a) |
Mean (b) |
Number (a) |
Mean (b) |
Number (a) |
Mean (b) |
Number (a) |
Mean (b) |
Results when maleswereexposed (c) |
||||||||
Length of gestation (days) |
7 |
23.1 ±0.9 |
3 |
23.7 ± 0.6 |
0 |
|
1 |
23 |
Implantation sites per dam |
7 |
14.0 ± 4.6 |
5 |
*6.4 ± 5.7 |
0 |
|
1 |
10 |
Pups alive on day 1 |
7 |
11.6 ± 5.5 |
3 |
6.3 ± 4.0 |
0 |
|
1 |
8 |
Pups alive on day 4 |
7 |
8.9 ±4.7 |
3 |
0.7 ± 1.2 |
0 |
|
1 |
8 |
Pups alive on day 21 |
7 |
8.9 ± 4.7 |
3 |
0.7 ± 1.2 |
0 |
|
|
8 |
Pups alive on day 1per implantation site (percent) |
7 |
74.2 ± 35.6 |
3 |
81.5 ± 17. |
0 |
|
1 |
80 |
Pups alive on day 4 per pups alive on day 1(percent) |
6 |
77.0 ± 17.7 |
3 |
33.3 ± 57.7 |
0 |
|
1 |
100.0 |
Pups alive on day 21 per pups alive on day 4 (percent) |
6 |
100.0 ± 0.0 |
1 |
100.0 ± 0.0 |
0 |
|
1 |
100.0 |
Results when females were exposed (d) |
||||||||
Length of gestation (days) |
7 |
23.1 ±0.9 |
8 |
22.6 ± 0.7 |
9 |
22.8 ± 0.4 |
7 |
22.7 ± 0.5 |
Implantation sites per dam |
7 |
14.0 ±4.6 |
10 |
15.0 ± 1.9 |
10 |
14.4 ± 1.7 |
9 |
13.6 ± 1.1 |
Pups alive on day 1 |
7 |
11.6 ± 5.5 |
10 |
12.4 ± 2.1 |
10 |
12.7 ± 2.7 |
9 |
12.1 ± 1.4 |
Pups alive on day 4 |
7 |
8.9 ±4.7 |
10 |
11.3 ± 4.1 |
10 |
11.1 ± 4.0 |
9 |
11.9 ±1.5 |
Pups alive on day 21 |
7 |
8.9 ± 4.7 |
10 |
11.2 ± 4.2 |
10 |
11.1± 4.0 |
9 |
11.9 ±1.5 |
Pups alive on day 1per implantation site (percent) |
7 |
74.2 ±35.6 |
10 |
83.4 ± 14.7 |
10 |
88.3 ± 15.6 |
9 |
89.4 ± 8.3 |
Pups alive on day 4 per pups alive on day 1(percent) |
6 |
77.0 ± 17.7 |
10 |
88.0 ± 31.6 |
10 |
84.6 ± 17.5 |
9 |
98.0 ± 3.9 |
Pups alive on day 21 per pups alive on day 4 (percent) |
6 |
100.0 ± 0.0 |
10 |
99.0 ± 3.0 |
10 |
100.0 ±0.0 |
9 |
100.0 ± 0.0 |
(a)Number of dams or litters
(b)Mean±standard deviation
(c)Control female rats were mated with exposed male rats.
(d)Exposed female rats were mated with control male rats.
*P<0.05 vs. the controls by Dunnett’s test (Dunnett, 1980); statistical analysis performed on length of gestation andimplantation sites per dam only.
Mean body weights of offspring of rats exposed for eight weeks by inhalation to allyl glycidyl ether before mating (a)
|
|
Control |
|
30 ppm |
|
100 ppm |
|
200 ppm |
|
|
Days Post Patrum |
Number (a) |
Mean (b) |
Number (a) |
Mean (b) |
Number (a) |
Mean (b) |
Number (a) |
Mean (b) |
Results when males were exposed (c) |
|||||||||
Male offspring |
1 |
6 |
6.2± 0.3 |
2 |
6.6± 1.0 |
0 |
|
1 |
8.0 |
Female offspring |
1 |
6 |
6.0 ±0.4 |
2 |
6.3± 0.8 |
0 |
|
1 |
7.6 |
Male offspring |
4 |
6 |
10 ±0.5 |
1 |
10.1 |
0 |
|
1 |
12.8 |
Female offspring |
4 |
6 |
9.7 ±0.7 |
1 |
10.9 |
0 |
|
1 |
12.4 |
Male offspring |
21 |
6 |
54.6± 9.0 |
1 |
65.0 |
0 |
|
1 |
65.2 |
Female offspring |
21 |
6 |
52.1 ± 8.4 |
1 |
60.0 |
0 |
|
1 |
61.0 |
Results when females were exposed (d) |
|||||||||
Male offspring |
1 |
6 |
6.2± 0.3 |
10 |
6.7±0.5 |
10 |
6.7±0.4 |
9 |
*6.8±0.5 |
Female offspring |
1 |
6 |
6.0 ±0.4 |
10 |
6.3±0.5 |
10 |
6.5±0.3 |
9 |
6.5±0.4 |
Male offspring |
4 |
6 |
10 ±0.5 |
9 |
9.8±1.1 |
10 |
10.2±1.1 |
9 |
10.4±0.7 |
Female offspring |
4 |
6 |
9.7 ±0.7 |
9 |
9.7±0.8 |
10 |
9.8±1.4 |
9 |
9.8±0.7 |
Male offspring |
21 |
6 |
54.6± 9.0 |
9 |
48.8±5.8 |
10 |
52.5±7.8 |
9 |
53.2±4.6 |
Female offspring |
21 |
6 |
52.1 ± 8.4 |
9 |
46.1±5.4 |
10 |
50±8.7 |
9 |
79.4±3.9 |
(a) Number of dams or litters
(b) Mean ± standard deviation in grams
(c)Control female rats were mated with exposed male rats.
(d)Exposed female rats were mated with control male rats.
*P<0.05vs. the controls by Dunnett’s test (Dunnett,1980)
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 1 990
- Report date:
- 1990
Materials and methods
Test guideline
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- OECD Guideline 421 (Reproduction / Developmental Toxicity Screening Test)
- Principles of method if other than guideline:
- 20 Osborne-Mendal rats per sex per dose were exposed to air, containing the test substance at a dose of 0, 30, 100, or 200 ppm 6 h/d, 5 d/w for 8 weeks. Animals were observed continiously defore, during and after exposure. Mating begun 2 days after the end of the 8-week exposure for the reproductive effects studies, controls with controls, exposed males with control females, and control males with exposed females. Reproductive effects were evaluated in parental animals and offspring.
- GLP compliance:
- not specified
- Limit test:
- no
Test material
- Reference substance name:
- Allyl 2,3-epoxypropyl ether
- EC Number:
- 203-442-4
- EC Name:
- Allyl 2,3-epoxypropyl ether
- Cas Number:
- 106-92-3
- Molecular formula:
- C6H10O2
- IUPAC Name:
- Allyl 2,3-epoxypropyl ether
Constituent 1
- Specific details on test material used for the study:
- SOURCE OF TEST MATERIAL
- Source test material: Alcolac, Inc. (Baltimore, MD)
- Purity test: approximately 99%
STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- The stability of the study material was monitored during the animal studies by gas chromatography and nonaqueous titration of the epoxide group.
- No deterioration of the study material was seen over the course of the studies.
OTHER:
- Apearance: clear, colourless liquid
Test animals
- Species:
- rat
- Strain:
- Osborne-Mendel
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: CAMM Research Institute (Wayne, NJ)
- Females (if applicable) nulliparous and non-pregnant: yes
- Age at study initiation: 8 weeks
- Housing: Single housing, Stainless steel wire (Hazleton Systems, Aberdeen, MD)
- Diet: NIH 07 Rat and Mouse Ration (Zeigler Bros., Inc., Gardners, PA); available ad libitum except during exposure periods
- Water: Automatic watering system (Edstrom Industries, Waterford, WI); available ad libitum
- Acclimation period: 21 days
ENVIRONMENTAL CONDITIONS
- Temperature: 69 tot 80 °F (equivalent to 20.5 to 26.5 °C)
- Humidity (%): 32 to 75
- Photoperiod (hrs dark / hrs light): 12 / 12
Administration / exposure
- Route of administration:
- inhalation: vapour
- Type of inhalation exposure (if applicable):
- whole body
- Vehicle:
- air
- Details on exposure:
- VAPOUR GENERATION SYSTEM:
No additional preparation of the test item was necessary before introduction into the vapour generation system. The liquid was pumped from a stainless steel reservoir to a vaporizer by a stable micrometering pump with adjustable pump rates. For the concentrations from 10 ppm to 20 ppm, the liquid was vaporized from a fine glass wick on the surface of a cylindrical vaporizer by an electric heater embedded in the cylinder. The vaporizer surface temperatures were set at approximately 90°C. Each cylindrical vaporizer was positioned in the fresh air duct leading directly into the exposure chamber. At exposure concentrations of 4 ppm the liquid test item was drawn from the stainless steel reservoir through a three-way valve into a glass syringe large enough to contain the total amount necessary for a 6-hour exposure. The syringe was attached to a syringe pump unit, and the three-way valve was adjusted to allow flow of the liquid through an injection needle to a cotton wick positioned in the fresh air duct leading directly into the exposure chamber. No additional heating was necessary to generate the vapour.
VAPOUR CONCENTRATION MONITORING:
Concentrations of the test item in the chambers and the exposure room were measured by gas chromatography with a flame ionization detector. Exposure concentrations were within ±10% of the target concentrations
CHAMBER CHARACTERISATION:
Uniformity of vapour concentration in each exposure chamber was measured before the start of the studies and was checked by gas chromatography at intervals of approximately 3 months throughout the studies. In most instances, the vapour concentrations were within 10% of the mean target concentration values at all 12 positions sampled within the chamber, indicating good, homogeneous distribution of the study vapour. - Details on mating procedure:
- Cohabitation of male and female rats was initiated 2 days after the final exposure. A computer-derived randomization program was used to determine male-female pairings. A single male rat was placed in a cage with a single female rat at 3:00-4:00 p.m. and was removed the following morning at 6:30-7:30. Each female was lavaged with 0.9% saline, which was then examined microscopically for the presence of sperm. The day that sperm were detected was designated day 0 of gestation; no further cohabitation of this pair took place. Cohabitation and lavage for unmated pairs were repeated each day for a period of 7 days until sperm were detected. The day sperm were found was recorded for each male-female pair, Sperm-negative females were recorded as not having mated.
Half of the females in which copulation was detected were assigned to the group to be used for fetal examinations. The remainder were assigned to the group to be used for postnatal examinations. Females selected for the two examination groups were those whose days of mating were representative of those of all mated females at their exposure concentration. Postnatal observations were performed on offspring from pregnant females in which copulation was not detected.
The day after the last exposure, all female rats were placed in stainless steel wire mesh-bottom cages, where they were housed individually throughout the breeding period and during the first 15 days of gestation. - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Samples of the test item exposure at atmospheres were analysed for the presence of potential degradation products by gas chromatography with flame ionization detection. No impurities were observed by gas chromatographic analysis to indicate significant decomposition of the test item under study conditions.
- Duration of treatment / exposure:
- 8 weeks
- Frequency of treatment:
- 6 h/d, 5 d/w
- Details on study schedule:
- - Mating was begun 2 days after the end of the 8-week exposure period
- Mated animals were approximately 16 weeks old at the initiation of the mating procedure
Doses / concentrationsopen allclose all
- Dose / conc.:
- 30 ppm
- Remarks:
- equivalent to 140 mg/m3
- Dose / conc.:
- 100 ppm
- Remarks:
- equivalent to 467 mg/m3
- Dose / conc.:
- 200 ppm
- Remarks:
- equivalent to 934 mg/m3
- No. of animals per sex per dose:
- 20
- Control animals:
- yes, concurrent vehicle
Examinations
- Parental animals: Observations and examinations:
- DETAILED CLINICAL OBSERVATIONS:
- Time schedule: continuously during exposure and 2 times per day during nonexposure periods
- Pregnant females were observed twice per day before parturition.
BODY WEIGHT:
- Time schedule for examinations: before study, 1 time per week during the study and at necropsy
- On the 13th day postpartum, the dams were weighed. - Sperm parameters (parental animals):
- - Sperm was examined microscopically for evaluation of motility
- Sperm was counted in caude epididymides suspensions
- Sperm was examined for abnormalities - Litter observations:
- During the first 24 hours after birth, the pups were sexed, weighed, and examined for external abnormalities. This was repeated when the pups were 4 days old.
- Postmortem examinations (parental animals):
- - Moribund animals were humanely killed.
- All male animals were killed 13-14 days after the last exposure
- All animals were killed by carbon dioxide, which allows for a more accurate assessment of fetal viability. The dams were weight immediately, and the body weight and time of ill were recorded. The uterus and ovaries were removed and weighed. The ovaries were separated from the uterus, and the corpora lutea were counted. The nongravid uterus was stained with an aqueous solution of 10% ammonium sulfide to locate implantation sites. The rest of the maternal necropsy was conducted according to standard protocol. All maternal tissues were preserved in 10% normal-buffered formalin (NBF). Live and dead fetuses and early, mid, and late resorption sites were counted in each uterine horn. The fetuses and placentas were then removed and numbered for identification.
- When the pups were 21 days old, they and their dams were killed with carbon dioxide and weighed. The ovaries and uteruses of the dams were removed, and the ovaries were examined to enumerate corpora lutea. The uteruses were stained with 10% ammonium sulfide to display implantation sites. All necropsies were performed according to standard protocol.
- Histopathologic examinations were performed on tissues of all control and the highest dose groups and on selected tissues of lower dose groups. - Postmortem examinations (offspring):
- - The fetuses were killed by an intraperitoneal injection of 0.05 mL of 50 mg/mL sodium pentobarbital. The sex, shape of head, limbs, and number of digits were noted, and the fetus was examined for gross external malformations. The mouth was opened to check for a cleft palate. The fetus and placenta were then weighed. A small incision was made in the abdomen, and each fetus was placed in an individual carton containing Bouin’s fixative. When all fetal examinations had been completed, the results were tabulated and classified as major malformations, minor anomalies, or common variants. Stunting was calculated by multiplying the mean body weight of all pups in a litter by 0.66, omitting the suspected stunted pup. If the suspect pup weighed less than this value, it was considered stunted.
- When the pups were 21 days old they and their dams were killed with carbon dioxide and weighed, and the sex of the pups was verified. - Statistics:
- - Descriptive statistics: mean, standard deviation
- Dunnett's test: p values
Results and discussion
Results: P0 (first parental generation)
General toxicity (P0)
- Clinical signs:
- no effects observed
- Dermal irritation (if dermal study):
- not examined
- Mortality:
- mortality observed, non-treatment-related
- Description (incidence):
- 2 of 20 male rats exposed to 200 ppm died before the end of the 8-week studies of reproductive effects. It is not explicitly specified that the deaths are related to the exposure of the animals to the test item.
- Body weight and weight changes:
- no effects observed
- Description (incidence and severity):
- Body weights were not affected in parental animals.
- Food consumption and compound intake (if feeding study):
- not examined
- Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- not examined
- Haematological findings:
- not examined
- Clinical biochemistry findings:
- not examined
- Urinalysis findings:
- not examined
- Behaviour (functional findings):
- not examined
- Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Histopathological findings: non-neoplastic:
- no effects observed
- Histopathological findings: neoplastic:
- not examined
Reproductive function / performance (P0)
- Reproductive function: oestrous cycle:
- not examined
- Reproductive function: sperm measures:
- effects observed, treatment-related
- Description (incidence and severity):
- Exposure had no effect on sperm motility or on number of sperm recovered from the cauda epididymis 13-14 days after the last exposure. The percentage of abnormal sperm was significantly increased in males exposed to 200.0 ppm
- Reproductive performance:
- effects observed, treatment-related
- Description (incidence and severity):
- The reproductive performance of males exposed to 200.0 ppm was found to be markedly impaired. The mating behavior of females was not affected at any exposure concentration. Small but statistically significant reductions were seen in the number of corpora lutea per dam and in the number of implantation sites per dam in females exposed to 200 ppm. The number of implantation sites per dam were statistically significant reduced when the in groups where males were exposed starting from 30 ppm. The number of pregnant females was statistically significantly reduced in groups where males were exposed starting from 30 ppm.
Effect levels (P0)
open allclose all
- Dose descriptor:
- NOAEC
- Remarks:
- fertility
- Effect level:
- < 140 mg/m³ air
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- reproductive performance
- Dose descriptor:
- NOAEC
- Remarks:
- systemic toxicity
- Effect level:
- 934 mg/m³ air
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: overall effects
Target system / organ toxicity (P0)
- Critical effects observed:
- no
Results: F1 generation
General toxicity (F1)
- Clinical signs:
- no effects observed
- Description (incidence and severity):
- Very few malformations were observed in fetal offspring of exposed dams.No abnormal fetuses were found in the relatively small number of fetuses available for examination which were sired by exposed males. No effects of exposure were seen on the offspring of exposed females.
- Dermal irritation (if dermal study):
- not examined
- Mortality / viability:
- mortality observed, treatment-related
- Description (incidence and severity):
- The number of live pups sired by any group of exposed males was significantly lower than that sired by controls.
- Body weight and weight changes:
- no effects observed
- Description (incidence and severity):
- Fetal body weights were not affected.
- 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:
- no effects observed
- Organ weight findings including organ / body weight ratios:
- not examined
- Gross pathological findings:
- effects observed, treatment-related
- Description (incidence and severity):
- Very few malformations were observed in fetal offspring of exposed dams. No abnormal fetuses were found in the relatively small number of fetuses available for examination which were sired by exposed males.
- Histopathological findings:
- not examined
- Other effects:
- not specified
- Description (incidence and severity):
- No effects of exposure were seen on the offspring of exposed females.
Developmental neurotoxicity (F1)
- Behaviour (functional findings):
- not examined
Developmental immunotoxicity (F1)
- Developmental immunotoxicity:
- not examined
Effect levels (F1)
- Dose descriptor:
- NOAEC
- Generation:
- F1
- Effect level:
- < 140 mg/m³ air
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- viability
Target system / organ toxicity (F1)
- Critical effects observed:
- no
Overall reproductive toxicity
- Reproductive effects observed:
- yes
- Lowest effective dose / conc.:
- 140 mg/m³ air
- Treatment related:
- yes
- Relation to other toxic effects:
- reproductive effects in the absence of other toxic effects
- Dose response relationship:
- yes
- Relevant for humans:
- yes
Any other information on results incl. tables
Mean body weights of rats in the eight-week inhalation studies of the reproductive effects
|
Male |
Female |
|
Concentration Male Female (ppm) |
|
Fetal Exam Groups (b) |
Postnatal Exam Groups (c) |
|
Before Exposure |
||
(d)0 |
267 |
187 |
179 |
(e)0 |
265 |
185 |
181 |
30 |
234 |
183 |
185 |
100 |
263 |
177 |
185 |
200 |
269 |
180 |
183 |
|
End of exposure (f) |
||
(d)0 |
419 |
260 |
247 |
(e)0 |
414 |
257 |
247 |
30 |
352 |
240 |
244 |
100 |
337 |
226 |
232 |
200 |
296 |
214 |
216 |
|
Termination (g) |
||
(d)0 |
- |
326 |
281 |
(e)0 |
414 |
360 |
298 |
30 |
371 |
344 |
291 |
100 |
370 |
326 |
289 |
200 |
349 |
332 |
286 |
(b)Groups designated for fetal examination on day 19 of gestation
(c) Groups designated for postnatal examination on day 21 postpartum
(d)Mates for exposed animals
(e)Mates for control animals
(f)Animals were weighed 1day after the end of exposure.
(g)Males were killed 13-14 days after the end of exposure
Summary of pregnancy status of rats after inhalation exposure for 8-Weeks
|
Control |
30 ppm |
100 ppm |
200 ppm |
Results when males were exposed (a) |
||||
Number of females examined |
20 |
20 |
20 |
18 |
Percentage sperm-positive |
75 |
90 |
85 |
78 |
Percentage pregnant, sperm-positive |
100 |
**50 |
**23.5 |
**7 |
Percentage sperm-negative |
25 |
10 |
15 |
22 |
Percentage pregnant, sperm-negative |
0 |
0 |
0 |
0 |
Percentage of all females pregnant |
75 |
45 |
**20 |
**6 |
Results when females were exposed (b) |
||||
Number of females examined |
20 |
20 |
20 |
20 |
Percentage sperm-positive |
75 |
85 |
95 |
75 |
Percentage pregnant, sperm-positive |
100 |
100 |
100 |
100 |
Percentage sperm-negative |
25 |
15 |
5 |
25 |
Percentage pregnant, sperm-negative |
0 |
67 |
100 |
40 |
Percentage of all females pregnant |
75 |
95 |
*100 |
85 |
(a)Control female rats were mated with exposed male rats.
(b)Exposed female rats were mated with control male rats.
*P<0.05 vs. the controls by the Fisher exact test
**P<0.01 vs. the controls by the Fisher exact test
Summary of reproductive performance of rats after inhalation exposure for eight weeks
|
|
Results When Males Were Exposed (a)
|
Results When Females Were Exposed (b) |
||||||
Concentration (ppm) |
Day of mating |
Copulations detected (c) |
No. of females impregnated |
No. of litters (d) |
Total Pups/ Litter (e) |
Copulations detected (c) |
No. of females impregnated |
No. of litters (d) |
Total Pups/ Litter (e) |
0 |
1 |
4/20 |
4 |
4 |
14.3±3.1 |
4/20 |
4 |
4 |
14.3±3.1 |
|
2 |
3/16 |
3 |
3 |
14.3±0.6 |
3/16 |
3 |
3 |
14.3±0.6 |
|
3 |
2/13 |
2 |
2 |
14.0±1.4 |
2/13 |
2 |
2 |
14.0±1.4 |
|
4 |
4/11 |
4 |
4 |
13.5±3.1 |
4/11 |
4 |
4 |
13.5±3.1 |
|
5 |
2/7 |
2 |
2 |
12.5±2.1 |
2/7 |
2 |
2 |
12.5±2.1 |
|
6 |
0/5 |
|
|
|
0/5 |
|
|
|
|
7 |
0/5 |
|
|
|
0/5 |
|
|
|
|
Summary |
15/20 |
15 |
15 |
13.8±2.2 |
15/20 |
15 |
15 |
3.8±2.2 |
30 |
1 |
2/20 |
1 |
1 |
6 |
5/20 |
5 |
5 |
13.8±2.4 |
|
2 |
7/18 |
2 |
2 |
1.5±0.7 |
8/15 |
8 |
8 |
12.5±2.2 |
|
3 |
2/11 |
1 |
1 |
1 |
2/7 |
2 |
2 |
13.5±3.5 |
|
4 |
2/9 |
2 |
2 |
5.5±6.4 |
1/5 |
1 |
1 |
12 |
|
5 |
5/7 |
3 |
3 |
10.7± 3.2 |
1 / 4 |
1 |
1 |
15 |
|
6 |
0/7 |
|
|
|
0/3 |
|
|
|
|
7 |
0/7 |
|
|
|
0/3 |
|
|
|
|
Undetected |
|
|
|
|
|
2 |
2 |
|
|
Summary |
18/20 |
9 |
9 |
5.9±4.9 |
17/20 |
19 |
19 |
13±2.1 |
100 |
1 |
1/20 |
0 |
|
|
5/20 |
5 |
5 |
11±2.3 |
|
2 |
3/19 |
0 |
|
|
8/15 |
8 |
8 |
13.4±2.7 |
|
3 |
7/16 |
2 |
2 |
1.0 |
0/7 |
|
|
|
|
4 |
2/9 |
0 |
|
|
1/7 |
1 |
0 |
|
|
5 |
2/7 |
0 |
1 |
|
4/6 |
4 |
4 |
13±2.4 |
|
6 |
1/5 |
1 |
1 |
10 |
1/2 |
1 |
1 |
11 |
|
7 |
1/4 |
1 |
|
10 |
0/1 |
|
|
|
|
Undetected |
|
|
|
|
|
1 |
1 |
13 |
|
Summary |
17/20 |
4 |
4 |
5.3±4.9 |
19/20 |
19 |
19 |
12.7±2.4 |
200 |
1 |
1/18 |
0 |
|
|
1/20 |
1 |
1 |
11 |
|
2 |
1/17 |
0 |
|
|
711 |
7 |
7 |
13.0±0.8 |
|
3 |
3/16 |
0 |
|
|
511 |
5 |
5 |
12.8±1.1 |
|
4 |
2/13 |
0 |
|
|
0/7 |
|
|
|
|
5 |
5/11 |
0 |
|
|
1I7 |
1 |
1 |
12 |
|
6 |
2/6 |
1 |
1 |
8 |
116 |
1 |
1 |
10 |
|
7 |
0/4 |
0 |
0/5 |
|
|
7 |
|
|
|
Undetected |
|
|
|
|
|
2 |
2 |
10 |
|
Summary |
14/18 |
1 |
1 |
8 |
15/20 |
17 |
17 |
12.1±1.5 |
|
|
|
|
|
|
|
|
|
|
(a)Data from control females mated with exposed males
(b)Data from exposed females mated with control males
(c)Number of copulations detected/number of females
(d)Litters examined at d 19 of gestation or within 24 h after birth
(e) Mean ± standard deviation
Reproductive status of maternal rats and postnatal survival of Offspring of rats exposed for eight weeks (before mating)
|
Control |
30 ppm |
100 ppm |
200 ppm |
||||
|
Number (a) |
Mean (b) |
Number (a) |
Mean (b) |
Number (a) |
Mean (b) |
Number (a) |
Mean (b) |
Results when maleswereexposed (c) |
||||||||
Length of gestation (days) |
7 |
23.1 ±0.9 |
3 |
23.7 ± 0.6 |
0 |
|
1 |
23 |
Implantation sites per dam |
7 |
14.0 ± 4.6 |
5 |
*6.4 ± 5.7 |
0 |
|
1 |
10 |
Pups alive on day 1 |
7 |
11.6 ± 5.5 |
3 |
6.3 ± 4.0 |
0 |
|
1 |
8 |
Pups alive on day 4 |
7 |
8.9 ±4.7 |
3 |
0.7 ± 1.2 |
0 |
|
1 |
8 |
Pups alive on day 21 |
7 |
8.9 ± 4.7 |
3 |
0.7 ± 1.2 |
0 |
|
|
8 |
Pups alive on day 1per implantation site (percent) |
7 |
74.2 ± 35.6 |
3 |
81.5 ± 17. |
0 |
|
1 |
80 |
Pups alive on day 4 per pups alive on day 1(percent) |
6 |
77.0 ± 17.7 |
3 |
33.3 ± 57.7 |
0 |
|
1 |
100.0 |
Pups alive on day 21 per pups alive on day 4 (percent) |
6 |
100.0 ± 0.0 |
1 |
100.0 ± 0.0 |
0 |
|
1 |
100.0 |
Results when females were exposed (d) |
||||||||
Length of gestation (days) |
7 |
23.1 ±0.9 |
8 |
22.6 ± 0.7 |
9 |
22.8 ± 0.4 |
7 |
22.7 ± 0.5 |
Implantation sites per dam |
7 |
14.0 ±4.6 |
10 |
15.0 ± 1.9 |
10 |
14.4 ± 1.7 |
9 |
13.6 ± 1.1 |
Pups alive on day 1 |
7 |
11.6 ± 5.5 |
10 |
12.4 ± 2.1 |
10 |
12.7 ± 2.7 |
9 |
12.1 ± 1.4 |
Pups alive on day 4 |
7 |
8.9 ±4.7 |
10 |
11.3 ± 4.1 |
10 |
11.1 ± 4.0 |
9 |
11.9 ±1.5 |
Pups alive on day 21 |
7 |
8.9 ± 4.7 |
10 |
11.2 ± 4.2 |
10 |
11.1± 4.0 |
9 |
11.9 ±1.5 |
Pups alive on day 1per implantation site (percent) |
7 |
74.2 ±35.6 |
10 |
83.4 ± 14.7 |
10 |
88.3 ± 15.6 |
9 |
89.4 ± 8.3 |
Pups alive on day 4 per pups alive on day 1(percent) |
6 |
77.0 ± 17.7 |
10 |
88.0 ± 31.6 |
10 |
84.6 ± 17.5 |
9 |
98.0 ± 3.9 |
Pups alive on day 21 per pups alive on day 4 (percent) |
6 |
100.0 ± 0.0 |
10 |
99.0 ± 3.0 |
10 |
100.0 ±0.0 |
9 |
100.0 ± 0.0 |
(a)Number of dams or litters
(b)Mean ± standard deviation
(c)Control female rats were mated with exposed male rats.
(d)Exposed female rats were mated with control male rats.
*P<0.05 vs. the controls by Dunnett’s test (Dunnett, 1980); statistical analysis performed on length of gestation and implantation sites per dam only.
Mean body weights of offspring of rats exposed for eight weeks by inhalation to allyl glycidyl ether before mating (a)
|
|
Control |
|
30 ppm |
|
100 ppm |
|
200 ppm |
|
|
Days Post Patrum |
Number (a) |
Mean (b) |
Number (a) |
Mean (b) |
Number (a) |
Mean (b) |
Number (a) |
Mean (b) |
Results when males were exposed (c) |
|||||||||
Male offspring |
1 |
6 |
6.2± 0.3 |
2 |
6.6± 1.0 |
0 |
|
1 |
8.0 |
Female offspring |
1 |
6 |
6.0 ±0.4 |
2 |
6.3± 0.8 |
0 |
|
1 |
7.6 |
Male offspring |
4 |
6 |
10 ±0.5 |
1 |
10.1 |
0 |
|
1 |
12.8 |
Female offspring |
4 |
6 |
9.7 ±0.7 |
1 |
10.9 |
0 |
|
1 |
12.4 |
Male offspring |
21 |
6 |
54.6± 9.0 |
1 |
65.0 |
0 |
|
1 |
65.2 |
Female offspring |
21 |
6 |
52.1 ± 8.4 |
1 |
60.0 |
0 |
|
1 |
61.0 |
Results when females were exposed (d) |
|||||||||
Male offspring |
1 |
6 |
6.2± 0.3 |
10 |
6.7±0.5 |
10 |
6.7±0.4 |
9 |
*6.8±0.5 |
Female offspring |
1 |
6 |
6.0 ±0.4 |
10 |
6.3±0.5 |
10 |
6.5±0.3 |
9 |
6.5±0.4 |
Male offspring |
4 |
6 |
10 ±0.5 |
9 |
9.8±1.1 |
10 |
10.2±1.1 |
9 |
10.4±0.7 |
Female offspring |
4 |
6 |
9.7 ±0.7 |
9 |
9.7±0.8 |
10 |
9.8±1.4 |
9 |
9.8±0.7 |
Male offspring |
21 |
6 |
54.6± 9.0 |
9 |
48.8±5.8 |
10 |
52.5±7.8 |
9 |
53.2±4.6 |
Female offspring |
21 |
6 |
52.1 ± 8.4 |
9 |
46.1±5.4 |
10 |
50±8.7 |
9 |
79.4±3.9 |
(a) Number of dams or litters
(b) Mean ± standard deviation in grams
(c)Control female rats were mated with exposed male rats.
(d)Exposed female rats were mated with control male rats.
*P<0.05 vs. the controls by Dunnett’s test (Dunnett,1980)
Applicant's summary and conclusion
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