Registration Dossier
Registration Dossier
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EC number: 231-837-1 | CAS number: 7758-23-8
Developmental toxicity / teratogenicity
Administrative data
- Endpoint:
- developmental toxicity
- Type of information:
- experimental study
- Adequacy of study:
- weight of evidence
- Study period:
- No data
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- comparable to guideline study with acceptable restrictions
- Remarks:
- Study performed 1974 before guidelines were available but meets generally accepted scientific standards with acceptable restrictions. Deficinencies are: food consumption not reported; uterine weights and corpora lutea not determined; one third used for visceral examination, should be 50%; test substance identification (batch etc) missing; no details on housing conditions/source of animals; administration only during periods of organogenesis; no explanation for dose choice, no statistics, no historical data
Cross-referenceopen allclose all
- Reason / purpose for cross-reference:
- reference to same study
Reference
- Endpoint:
- developmental toxicity
- Type of information:
- experimental study
- Adequacy of study:
- weight of evidence
- Study period:
- No data
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- comparable to guideline study with acceptable restrictions
- Remarks:
- Study performed 1974 before guidelines were available but meets generally accepted scientific standards with acceptable restrictions. Deficinencies are: food consumption not reported; uterine weights and corpora lutea not determined; one third used for visceral examination, should be 50%; test substance identification (batch etc) missing; no details on housing conditions/source of animals; administration only during periods of organogenesis; no explanation for dose choice, no statistics, no historical data
- Reason / purpose for cross-reference:
- reference to same study
- Reason / purpose for cross-reference:
- reference to same study
- Qualifier:
- no guideline followed
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- OECD Guideline 414 (Prenatal Developmental Toxicity Study)
- Version / remarks:
- 2001
- Deviations:
- yes
- Remarks:
- food consumption not reported; uterine weights and corpora lutea not determined; one third used for visceral examination; test substance identification missing; administration only during periods of organogenesis, no statistics, no historical data
- Principles of method if other than guideline:
- Adult female albino CD-1 mice were mated with young adult males. Observation of a vaginal sperm plug was considered as Day 0 of gestation. Dosing by oral intubation with a control (vehicle at level equivalent to group receiving the highest dose or aspirin at 150 mg/kg) or test article in a water suspension (10 mL/kg bw) at 4.65, 21.6, 100.0 and 465.0 mg/kg bw was carried out daily on Days 6 to 15 of gestation. Observations of body weight, appearance, behaviour, and food consumption were performed. On Day 17 of gestation all dams underwent Caesarean section. Implantation sites, resorption sites and live/dead foetuses recorded. Body weights of live pups recorded. Urogenital tract of each dam examined for anatomical normality. All foetuses examined grossly for presence of external congenital abnormalities. One third foetuses of each litter underwent detailed visceral examination and the remaining two thirds were cleared in potassium hydroxide, stained with alizarin red S dye and examined for skeletal defects.
- GLP compliance:
- no
- Remarks:
- Study predates GLP
- Limit test:
- no
- Species:
- mouse
- Strain:
- other: albino CD-1
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Outbred
- Age at study initiation: No data
- Weight at study initiation: 29.2 - 30.6 g
- Housing: Gang housing in disposable plastic cages
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: No data
ENVIRONMENTAL CONDITIONS
- Temperature (°C): No data, temperature controlled rooms
- Humidity (%): No data, humidity controlled rooms
IN-LIFE DATES: No data - Route of administration:
- oral: gavage
- Vehicle:
- water
- Details on exposure:
- PREPARATION OF DOSING SOLUTIONS:
VEHICLE: Water
- Amount of vehicle (if gavage): 10 mL/kg bodyweight - Analytical verification of doses or concentrations:
- not specified
- Details on mating procedure:
- - Impregnation procedure: cohoused
- Proof of pregnancy: vaginal plug referred to as day 0 of pregnancy - Duration of treatment / exposure:
- 10 days (Day 6 to Day 15 of gestation)
- Frequency of treatment:
- Daily
- Duration of test:
- 17 days
- Dose / conc.:
- 4.65 mg/kg bw/day (actual dose received)
- Remarks:
- test substance
- Dose / conc.:
- 21.6 mg/kg bw/day (actual dose received)
- Remarks:
- test substance
- Dose / conc.:
- 100 mg/kg bw/day (actual dose received)
- Remarks:
- test substance
- Dose / conc.:
- 465 mg/kg bw/day (actual dose received)
- Remarks:
- test substance
- Dose / conc.:
- 150 mg/kg bw/day (actual dose received)
- Remarks:
- Aspirin
- No. of animals per sex per dose:
- Table 1 Number of animals dosed
Material Dose (mg/kg) Total
Mated Pregnant
Sham 0.0 25 22
Aspirin 150.0 25 20
FDA 71-81 4.65 25 24
21.6 26 19
100.0 23 22
465.0 25 23 - Control animals:
- yes, sham-exposed
- other: positive control: 150 mg/kg bw aspirin
- Maternal examinations:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Appearence, behaviour, food consumption and weight observed daily.
DETAILED CLINICAL OBSERVATIONS: No
BODY WEIGHT: Yes
- Time schedule for examinations: Body weights recorded on days 0, 6, 11, 15 and 17.
POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 17
- Organs examined: uterus and urogenital tract - Ovaries and uterine content:
- The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: No
- Number of corpora lutea: No
- Number of implantations: Yes
- Number of resorptions: Yes - Fetal examinations:
- - External examinations: Yes: one third per litter
- Soft tissue examinations: Yes: one third per litter
- Skeletal examinations: Yes: two thirds per litter
- Head examinations: Yes: two thirds per litter - Statistics:
- No data
- Indices:
- No data
- Historical control data:
- No
- Clinical signs:
- not specified
- Mortality:
- no mortality observed
- Body weight and weight changes:
- no effects observed
- Food consumption and compound intake (if feeding study):
- not specified
- 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:
- not examined
- Gross pathological findings:
- not specified
- Description (incidence and severity):
- Urogenital tract was observed but no data regarding this point were described in the report.
- Neuropathological findings:
- not examined
- Histopathological findings: non-neoplastic:
- not examined
- Histopathological findings: neoplastic:
- not examined
- Other effects:
- not examined
- Number of abortions:
- no effects observed
- Description (incidence and severity):
- For sham- and test substance treated animals no abortions were observed. In the control group with Aspirin 1 animal died or aborted.
- Pre- and post-implantation loss:
- no effects observed
- Description (incidence and severity):
- Implant sites (total number/average per dam):
0 mg/kg bw: 261 / 11.9
4.65 mg/kg bw: 283 / 11.8
21.6 mg/kg bw: 225 / 11.8
100 mg/kg bw: 244 / 11.1
465 mg/kg bw: 265 / 11.5
Aspirin: 224 / 11.8 - Total litter losses by resorption:
- no effects observed
- Description (incidence and severity):
- Resorptions:
Group (mg(kg bw): 0 4.65 21.6 100 465 Aspirin
Total number: 8 19 4 12 28 20
Dams with >=1 site resorbed: 7 13 3 10 12 9
Dams with all sites resobred: - - - - 1 -
% partial resorption: 31.8 54.2 15.8 45.5 52.2 47.4
% complete resorption: - - - - 4.35 - - Early or late resorptions:
- not examined
- Dead fetuses:
- no effects observed
- Description (incidence and severity):
- Dead fetuses:
Group (mg/kg bw): 0 4.65 21.6 100 465 Aspirin
Total: 1 - - 2 4 3
Dams with 1 or more dead: 1 - - 2 3 3
Dams with all dead: - - - - - -
% partial dead: 4.55 - - 9.09 13.0 15.8
% all dead: - - - - - - - Changes in pregnancy duration:
- not examined
- Description (incidence and severity):
- Migrated Data from removed field(s)
Field "Effects on pregnancy duration" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsMaternalAnimals.MaternalDevelopmentalToxicity.EffectsOnPregnancyDuration): not examined - Changes in number of pregnant:
- not examined
- Key result
- Dose descriptor:
- NOAEL
- Remarks:
- maternal toxicity
- Effect level:
- > 465 mg/kg bw/day
- Based on:
- test mat.
- Basis for effect level:
- body weight and weight gain
- clinical signs
- mortality
- Key result
- Dose descriptor:
- NOAEL
- Remarks:
- developmental toxicity
- Effect level:
- > 465 mg/kg bw/day
- Based on:
- test mat.
- Basis for effect level:
- dead fetuses
- necropsy findings
- number of abortions
- pre and post implantation loss
- Key result
- Abnormalities:
- no effects observed
- Fetal body weight changes:
- not examined
- Description (incidence and severity):
- Fetal body weights after Caesarean section were determined. The average body weights of fetuses were similar in all groups (see table 2 below).
Migrated Data from removed field(s)
Field "Fetal/pup body weight changes" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.FetalPupBodyWeightChanges): not examined - Reduction in number of live offspring:
- no effects observed
- Description (incidence and severity):
- see table 2 for details
- Changes in sex ratio:
- no effects observed
- Description (incidence and severity):
- see tabel 2 for details
- Changes in litter size and weights:
- not examined
- Changes in postnatal survival:
- not examined
- External malformations:
- not examined
- Skeletal malformations:
- effects observed, non-treatment-related
- Description (incidence and severity):
- increase of incomplete ossification of sternebrae and extremities was observed in the highest dose group (see table 3 below for details)
- Visceral malformations:
- no effects observed
- Description (incidence and severity):
- see details in table 4 below
- Key result
- Dose descriptor:
- NOAEL
- Remarks:
- fetal toxicity
- Effect level:
- >= 465 mg/kg bw/day
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- reduction in number of live offspring
- Key result
- Dose descriptor:
- NOAEL
- Remarks:
- developmental toxicity
- Effect level:
- >= 465 mg/kg bw/day
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- skeletal malformations
- visceral malformations
- Key result
- Abnormalities:
- no effects observed
- Key result
- Developmental effects observed:
- no
- Conclusions:
- Under the conditions of the study, the test material administered to pregnant mice for 10 days up to a dose level of 465 mg/kg bw showed no maternal or developmental toxicity. The NOAEL for both maternal and developmental toxicity is > 465 mg/kg bw.
Table 2 Reproduction data
Dose (mg/kg) |
Sham |
Aspirin |
4.65 |
21.6 |
100.0 |
465.0 |
Pregnancies |
|
|
|
|
|
|
Total No. |
22 |
20 |
24 |
19 |
22 |
23 |
Died or aborted (before Day 17) |
0 |
1 |
0 |
0 |
0 |
0 |
To term (on Day 17) |
22 |
19 |
24 |
19 |
22 |
23 |
Live litters |
|
|
|
|
|
|
Total No.* |
22 |
19 |
24 |
19 |
22 |
22 |
Implant Sites |
|
|
|
|
|
|
Total No. |
261 |
224 |
283 |
225 |
244 |
265 |
Average/dam* |
11.9 |
11.8 |
11.8 |
11.8 |
11.1 |
11.5 |
Resorptions |
|
|
|
|
|
|
Total No* |
8 |
20 |
19 |
4 |
12 |
28 |
Dams with 1 or more sites resorbed |
7 |
9 |
13 |
3 |
10 |
12 |
Dams with all sites resorbed |
-- |
-- |
-- |
-- |
-- |
1 |
Per cent partial resorptions |
31.8 |
47.4 |
54.2 |
15.8 |
45.5 |
52.2 |
Per cent complete resorptions |
-- |
-- |
-- |
-- |
-- |
4.35 |
Live foetuses |
|
|
|
|
|
|
Total No |
252 |
201 |
261 |
221 |
230 |
233 |
Average/dam* |
11.5 |
10.6 |
10.9 |
11.6 |
10.5 |
10.1 |
Sex ratio (M/F) |
1.02 |
0.88 |
0.78 |
0.92 |
1.13 |
0.93 |
Dead Foetuses |
|
|
|
|
|
|
Total No.* |
1 |
3 |
-- |
-- |
2 |
4 |
Dams with 1 or more dead |
1 |
3 |
-- |
-- |
2 |
3 |
Dams with all dead |
-- |
-- |
-- |
-- |
-- |
-- |
Per cent partial dead |
4.55 |
15.8 |
-- |
-- |
9.09 |
13.0 |
Per cent all dead |
-- |
-- |
-- |
-- |
-- |
-- |
Average foetus weight (g) |
0.84 |
0.81 |
0.88 |
0.87 |
0.82 |
0.85 |
* Includes only those dams examined at term
** Positive control: 150 mg/kg
Table 3 Summary of skeletal findings
Findings |
Dose (mg/kg) |
|||||
Sham |
Aspirin |
4.65 |
21.6 |
100.0 |
465.0 |
|
Live foetuses examined (at term) |
179/22 |
141/19 |
186/24 |
155/19 |
162/22 |
164/22 |
Sternebrae |
|
|
|
|
|
|
Incomplete oss. |
10/8 |
31/10 |
18/9 |
27/15 |
22/10 |
28/15 |
Scrambled |
|
|
|
|
|
|
Bipartite |
8/7 |
3/3 |
11/8 |
9/7 |
10/8 |
9/6 |
Fused |
|
|
|
|
|
|
Extra |
|
6/3 |
|
|
|
|
Missing |
23/10 |
28/11 |
13/9 |
13/6 |
32/14 |
23/7 |
Other |
|
|
|
|
|
|
Ribs |
|
|
|
|
|
|
Incomplete oss. |
|
|
|
|
|
9/4 |
Fused/split |
|
2/2 |
|
|
|
|
Wavy |
|
1/1 |
2/2 |
|
|
|
Less than 12 |
1/1 |
|
1/1 |
|
|
1/1 |
More than 13 |
48/18 |
30/12 |
42/18 |
18/11 |
32/15 |
34/17 |
Other |
|
|
|
|
|
|
Vertebrae |
|
|
|
|
|
|
Incomplete oss. |
9/6 |
9/3 |
2/2 |
1/1 |
11/4 |
13/4 |
Scrambled |
|
|
|
|
|
|
Fused |
|
|
|
|
|
|
Extra ctrs. oss. |
|
|
|
|
|
|
Scoliosis |
|
|
|
|
|
|
Tail defects |
|
|
|
|
|
|
Other |
|
|
|
|
|
|
Skull |
|
|
|
|
|
|
Incomplete closure |
|
2/2 |
|
|
|
|
Missing |
|
|
1/1 |
|
|
|
Craniostosis |
|
|
|
|
|
|
Other; facial bones, inc |
|
|
|
|
|
2/1 |
Extremities |
|
|
|
|
|
|
Incomplete oss. |
7/5 |
5/3 |
2/2 |
|
10/5 |
14/4 |
Missing |
|
|
|
|
|
|
Extra |
|
|
|
|
|
|
Miscellaneous |
|
|
|
|
|
|
Hyoid; missing |
37/16 |
33/11 |
31/15 |
22/12 |
52/15 |
33/13 |
Hyoid; reduced |
17/11 |
25/12 |
17/11 |
21/14 |
15/11 |
27/14 |
* Numerator = Number of foetuses affected; Denominator = Number of litters affected
** Positive control: 150 mg/kg
Table 4 Summary of soft tissue abnormalities
Material |
Dose level (mg/kg) |
Dam |
Number of pups |
Description |
Aspirin |
150.0 |
A 6068 |
1 |
Cleft palate; gastroschisis |
- Reason / purpose for cross-reference:
- reference to same study
Reference
- Endpoint:
- developmental toxicity
- Type of information:
- experimental study
- Adequacy of study:
- weight of evidence
- Study period:
- No data
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- comparable to guideline study with acceptable restrictions
- Remarks:
- Study performed 1974 before guidelines were available but meets generally accepted scientific standards with acceptable restrictions. Deficinencies are: food consumption not reported; uterine weights not determined; test substance identification (batch etc) missing; no details on housing conditions/source of animals; administration only during periods of organogenesis, not until day before pregnancy; no explanation for dose choice, no statistics, no historical data; animal number too low
- Reason / purpose for cross-reference:
- reference to same study
- Reason / purpose for cross-reference:
- reference to same study
- Qualifier:
- no guideline followed
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- OECD Guideline 414 (Prenatal Developmental Toxicity Study)
- Version / remarks:
- 2001
- Deviations:
- yes
- Remarks:
- food consumption not reported; uterine weights not determined; administration only during periods of organogenesis, no statistics, no historical data; animal number too low
- Principles of method if other than guideline:
- Adult female Dutch-belted rabbits were dosed on Day 0 with a single injection of 0.4 mL human chorionic gonadotropin (400 IU) via the marginal ear vein. After three hours each doe was artificially inseminated with 0.3 mL diluted semen from a donor buck using 20E06 motile sperm. Dosing by oral intubation with a control (vehicle at level equivalent to group receiving the highest dose) or test article in a water suspension (10 mL/kg bw) at 2.17, 10.10, 46.7 and 217.0 mg/kg was carried out daily on Days 6 to 18 of gestation. The positive control 6-aminonicotinamide at 2.5 mg/kg bw was dosed on Day 9. Observations of body weight, appearence, behaviour, and food consumption were performed. On Day 29 all does underwent Caesarean section. Number of corpora lutea, implantation sites, resorption sites and live/dead foetuses recorded. Body weights of live pups recorded. Urogenital tract of each dam examined for anatomical normality. All foetuses examined grossly for presence of external congenital abnormalities. Live foetuses of each litter were then placed in an incubator for 24 hours for evaluation of neonatal survival. All pups underwent detailed visceral examination. All foetuses were cleared in potassium hydroxide, stained with alizarin red S dye and examined for skeletal defects.
- GLP compliance:
- no
- Remarks:
- Study predates GLP
- Limit test:
- no
- Species:
- rabbit
- Strain:
- Dutch
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Outbred
- Age at study initiation: No data
- Weight at study initiation: 1.84 - 2.21 kg
- Housing: Individually housed in mesh-bottomed cages
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: No data
ENVIRONMENTAL CONDITIONS
- Temperature (°C): No data, temperature controlled rooms
- Humidity (%): No data, humidity controlled rooms
IN-LIFE DATES: No data - Route of administration:
- oral: gavage
- Vehicle:
- water
- Details on exposure:
- PREPARATION OF DOSING SOLUTIONS:
VEHICLE: Water
- Amount of vehicle (if gavage): 1 mL/kg bw at doses equal to or below 250 mg/kg bw and 2 mL/kg at doses up to 500 mg/kg bw - Analytical verification of doses or concentrations:
- not specified
- Details on mating procedure:
- - Impregnation procedure: artificial insemination
- Proof of pregnancy: No data - Duration of treatment / exposure:
- 13 days (Day 6 to Day 18 of gestation)
- Frequency of treatment:
- Daily
- Duration of test:
- 29 days
- Dose / conc.:
- 2.17 mg/kg bw/day (actual dose received)
- Dose / conc.:
- 10.1 mg/kg bw/day (actual dose received)
- Dose / conc.:
- 46.7 mg/kg bw/day (actual dose received)
- Dose / conc.:
- 217 mg/kg bw/day
- Dose / conc.:
- 2.5 mg/kg bw/day (actual dose received)
- Remarks:
- positive control (6-aminoicotinamide)
- No. of animals per sex per dose:
- Table 1 Number of animals dosed
Material Dose (mg/kg) Total
Mated Pregnant
Sham 0.0 21 12
6-AN 2.5 18 9
FDA 71-81 2.17 21 12
10.10 27 17
46.7 15 10
217.0 27 10 - Control animals:
- yes, sham-exposed
- other: positive control: 2.5 mg/kg 6-aminonicotinamide (6-AN)
- Maternal examinations:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Appearence, behaviour, food consumption and weight observed daily.
DETAILED CLINICAL OBSERVATIONS: No
BODY WEIGHT: Yes
- Time schedule for examinations: Body weights recorded on days 0, 6, 12, 18 and 29.
POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 29
- Organs examined: uterus and urogenital tract - Ovaries and uterine content:
- The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: No
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of resorptions: Yes - Fetal examinations:
- - External examinations: Yes
- Soft tissue examinations: Yes
- Skeletal examinations: Yes
- Head examinations: Yes - Statistics:
- No data
- Indices:
- No data
- Historical control data:
- No
- Clinical signs:
- not specified
- Mortality:
- mortality observed, non-treatment-related
- Description (incidence):
- Total died/Total in group:
0 mg/kg bw 2/21
2.17 mg/kg bw 2/21
10.10 mg/kg bw 5/27
46.7 mg/kg bw 1/15
217 mg/kg bw 0/27
6-AN mg/kg bw 2/18 - Body weight and weight changes:
- no effects observed
- Food consumption and compound intake (if feeding study):
- not specified
- 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:
- not examined
- Gross pathological findings:
- not specified
- Description (incidence and severity):
- Urogenital tract was observed but no data regarding this point were described in the report.
- Neuropathological findings:
- not examined
- Histopathological findings: non-neoplastic:
- not examined
- Histopathological findings: neoplastic:
- not examined
- Number of abortions:
- effects observed, non-treatment-related
- Description (incidence and severity):
- for details see table 2 below
- Pre- and post-implantation loss:
- no effects observed
- Description (incidence and severity):
- for details see table 2 below
- Total litter losses by resorption:
- no effects observed
- Description (incidence and severity):
- for details see table 2 below
- Early or late resorptions:
- not examined
- Dead fetuses:
- no effects observed
- Description (incidence and severity):
- for details see table 2 below
- Changes in pregnancy duration:
- not examined
- Description (incidence and severity):
- Migrated Data from removed field(s)
Field "Effects on pregnancy duration" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsMaternalAnimals.MaternalDevelopmentalToxicity.EffectsOnPregnancyDuration): not examined - Changes in number of pregnant:
- not examined
- Other effects:
- effects observed, non-treatment-related
- Description (incidence and severity):
- decreased number of corpora lutea in highest dose group observed (see table 2 below)
- Key result
- Dose descriptor:
- NOAEL
- Remarks:
- maternal toxicity
- Effect level:
- > 217 mg/kg bw/day
- Based on:
- test mat.
- Basis for effect level:
- body weight and weight gain
- mortality
- Key result
- Dose descriptor:
- NOAEL
- Remarks:
- developmental toxicity
- Effect level:
- > 217 mg/kg bw/day
- Based on:
- test mat.
- Basis for effect level:
- dead fetuses
- number of abortions
- pre and post implantation loss
- total litter losses by resorption
- Key result
- Abnormalities:
- no effects observed
- Fetal body weight changes:
- no effects observed
- Description (incidence and severity):
- for details see table 2 below
Migrated Data from removed field(s)
Field "Fetal/pup body weight changes" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.FetalPupBodyWeightChanges): not examined - Reduction in number of live offspring:
- no effects observed
- Description (incidence and severity):
- for details see table 2 below
- Changes in sex ratio:
- no effects observed
- Description (incidence and severity):
- for details see table 2 below
- Changes in litter size and weights:
- not examined
- Changes in postnatal survival:
- not examined
- External malformations:
- no effects observed
- Description (incidence and severity):
- for details see table 3 below
- Skeletal malformations:
- no effects observed
- Description (incidence and severity):
- for details see table 3 below
- Visceral malformations:
- no effects observed
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- >= 217 mg/kg bw/day
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- reduction in number of live offspring
- changes in sex ratio
- fetal/pup body weight changes
- external malformations
- skeletal malformations
- visceral malformations
- Key result
- Abnormalities:
- no effects observed
- Key result
- Developmental effects observed:
- no
- Conclusions:
- Under the conditions of the study, the test material administered to pregnant rabbits for 13 days up to a dose level of 217 mg/kg bw showed no maternal or developmental toxicity. The NOAEL for both maternal and developmental toxicity is > 217 mg/kg bw.
Table 2 Reproduction data
Dose (mg/kg) |
Sham |
6-AN |
2.17 |
10.10 |
46.7 |
217.0 |
Pregnancies |
|
|
|
|
|
|
Total No. |
12 |
9 |
12 |
17 |
10 |
10 |
Died or aborted (before Day 29) |
2 |
0 |
1 |
4 |
0 |
0 |
To term (on Day 29) |
10 |
9 |
11 |
13 |
10 |
10 |
Corpora Lutea |
|
|
|
|
|
|
Total no. |
160 |
117 |
132 |
191 |
110 |
121 |
Average/dam mated |
11.4 |
9.75 |
9.43 |
9.55 |
8.46 |
6.37 |
Live litters |
|
|
|
|
|
|
Total No.* |
10 |
8 |
10 |
13 |
9 |
8 |
Implant Sites |
|
|
|
|
|
|
Total No. |
58 |
57 |
62 |
79 |
50 |
49 |
Average/dam* |
5.80 |
6.33 |
5.64 |
6.08 |
5.00 |
4.90 |
Resorptions |
|
|
|
|
|
|
Total No* |
7 |
6 |
9 |
3 |
7 |
4 |
Dams with 1 or more sites resorbed |
4 |
4 |
2 |
2 |
4 |
2 |
Dams with all sites resorbed |
-- |
1 |
1 |
-- |
1 |
2 |
Per cent partial resorptions |
40.0 |
44.4 |
18.2 |
15.4 |
40.0 |
20.0 |
Per cent complete resorptions |
-- |
11.1 |
9.09 |
-- |
10.0 |
20.0 |
Live foetuses |
|
|
|
|
|
|
Total No |
51 |
49 |
49 |
76 |
43 |
45 |
Average/dam* |
5.10 |
5.44 |
4.45 |
5.85 |
4.30 |
4.50 |
Sex ratio (M/F) |
0.96 |
1.13 |
1.29 |
1.30 |
0.87 |
1.05 |
Dead Foetuses |
|
|
|
|
|
|
Total No.* |
-- |
2 |
4 |
-- |
-- |
-- |
Dams with 1 or more dead |
-- |
2 |
1 |
-- |
-- |
-- |
Dams with all dead |
-- |
-- |
-- |
-- |
-- |
-- |
Per cent partial dead |
-- |
22.2 |
9.09 |
-- |
-- |
-- |
Per cent all dead |
-- |
-- |
-- |
-- |
-- |
-- |
Average foetus weight (g) |
39.6 |
37.0 |
39.3 |
39.7 |
36.0 |
39.7 |
* Includes only those dams examined at term
** Positive control: 2.5 mg/kg 6-AN dosed on Day 9
Table 3 Summary of skeletal findings
Findings |
Dose (mg/kg) |
|||||
Sham |
6-AN |
2.17 |
10.10 |
46.7 |
217.0 |
|
Live foetuses examined (at term) |
51/10 |
49/8 |
49/10 |
76/13 |
43/9 |
44/8 |
Sternebrae |
|
|
|
|
|
|
Incomplete oss. |
1/1 |
|
|
1/1 |
1/1 |
|
Scrambled |
|
|
|
|
|
|
Bipartite |
|
|
|
|
|
|
Fused |
|
|
|
|
|
|
Extra |
|
|
|
|
3/1 |
1/1 |
Missing |
|
|
|
|
|
1/1 |
Other |
|
|
|
|
|
|
Ribs |
|
|
|
|
|
|
Incomplete oss. |
|
|
|
|
|
|
Fused/split |
|
|
|
|
|
|
Wavy |
|
|
|
|
|
|
Less than 12 |
|
|
|
|
|
|
More than 13 |
|
|
|
|
|
|
Other |
|
|
|
|
|
|
Vertebrae |
|
|
|
|
|
|
Incomplete oss. |
|
|
|
|
|
|
Scrambled |
|
|
|
|
|
|
Fused |
|
|
|
|
|
|
Extra ctrs. oss. |
|
|
|
|
|
|
Scoliosis |
|
|
|
|
|
|
Tail defects |
|
1/1 |
|
1/1 |
1/1 |
|
Other |
|
|
|
|
|
|
Skull |
|
|
|
|
|
|
Incomplete closure |
|
|
|
3/1 |
|
|
Missing |
|
|
|
|
|
|
Craniostosis |
|
|
|
|
|
|
Other; facial bones, inc |
|
|
|
|
|
|
Extremities |
|
|
|
|
|
|
Incomplete oss. |
|
|
|
|
|
|
Missing |
|
|
|
|
|
|
Extra |
|
|
|
|
|
|
Miscellaneous |
|
|
|
|
|
|
* Numerator = Number of foetuses affected; Denominator = Number of litters affected
** Positive control: 2.5 mg/kg 6-AN dosed on Day 9 No soft tissue abnormalities observed.Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 1 974
- Report date:
- 1973
Materials and methods
Test guidelineopen allclose all
- Qualifier:
- no guideline followed
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- OECD Guideline 414 (Prenatal Developmental Toxicity Study)
- Version / remarks:
- 2001
- Deviations:
- yes
- Remarks:
- food consumption not reported; uterine weights and corpora lutea not determined; one third used for visceral examination; test substance identification missing; administration only during periods of organogenesis, no statistics, no historical data
- Principles of method if other than guideline:
- Adult female albino (Wistar derived stock) rats were mated with young adult males. Observation of a vaginal sperm plug was considered as Day 0 of gestation. Dosing by oral intubation with a control (vehicle at level equivalent to group receiving the highest dose or aspirin at 250 mg/kg) or test article in a water suspension at 4.1, 19.1, 88.5 and 410.0 mg/kg was carried out daily on Days 6 to 15 of gestation. Observations of body weight, appearence, behaviour, and food consumption were performed. Daily room temperature was recorded. On Day 20 of gestation all dams underwent Caesarean section. Number of implantation sites, resorption sites and live/dead foetuses recorded. Body weights of live pups recorded. Urogenital tract of each dam examined for anatomical normality. All foetuses examined grossly for presence of external congenital abnormalities. One third foetuses of each litter underwent detailed visceral examination and the remaining two thirds were cleared in potassium hydroxide, stained with alizarin red S dye and examined for skeletal defects.
- GLP compliance:
- no
- Remarks:
- Study predates GLP
- Limit test:
- no
Test material
- Reference substance name:
- calcium dihydrogenorthophosphate monohydrate
- IUPAC Name:
- calcium dihydrogenorthophosphate monohydrate
- Reference substance name:
- 10031-30-8
- EC Number:
- 600-059-8
- Cas Number:
- 10031-30-8
- Molecular formula:
- Ca.2H3O4P
- IUPAC Name:
- 10031-30-8
- Details on test material:
- - Name of test material (as cited in study report): FDA 71-81 (Monocalcium phosphate; monohydrate)
- Physical state: Fine white crystalline material
Constituent 1
Constituent 2
Test animals
- Species:
- rat
- Strain:
- Wistar
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Outbred
- Age at study initiation: No data
- Weight at study initiation: 216 - 224 g
- Housing: Individual housing in mesh bottom cages
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: No data
ENVIRONMENTAL CONDITIONS
- Temperature (°C): Not recorded, temperature controlled rooms
- Humidity (%): Not recorded, humidity controlled rooms
IN-LIFE DATES: From: 12/01/1975 To: 06/02/1975
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- water
- Details on exposure:
- PREPARATION OF DOSING SOLUTIONS:
VEHICLE: Water
- Amount of vehicle (if gavage): 1 mL/kg bw at doses equal to or below 250 mg/kg bw and 2 mL/kg at doses up to 500 mg/kg bw - Analytical verification of doses or concentrations:
- not specified
- Details on mating procedure:
- - Impregnation procedure: No data
- Proof of pregnancy: vaginal plug referred to as day 0 of pregnancy - Duration of treatment / exposure:
- 10 days (Day 6 to Day 15 of gestation)
- Frequency of treatment:
- Daily
- Duration of test:
- 20 days
Doses / concentrationsopen allclose all
- Dose / conc.:
- 4.1 mg/kg bw/day (actual dose received)
- Remarks:
- test substance
- Dose / conc.:
- 19.1 mg/kg bw/day (actual dose received)
- Remarks:
- test substance
- Dose / conc.:
- 88.5 mg/kg bw/day (actual dose received)
- Remarks:
- test substance
- Dose / conc.:
- 410 mg/kg bw/day (actual dose received)
- Remarks:
- test substance
- Dose / conc.:
- 250 mg/kg bw/day (actual dose received)
- Remarks:
- Aspirin
- No. of animals per sex per dose:
- Table 1 Number of animals dosed
Material Dose (mg/kg) Total
Mated Pregnant
Sham 0.0 25 21
Aspirin 250.0 25 21
FDA 71-81 4.1 28 22
19.1 29 21
88.5 25 19
410.0 25 22 - Control animals:
- yes, sham-exposed
- other: positive control: 250 mg/kg bw aspirin
Examinations
- Maternal examinations:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Appearence, behaviour, food consumption and weight observed daily.
DETAILED CLINICAL OBSERVATIONS: No
BODY WEIGHT: Yes
- Time schedule for examinations: Body weights recorded on days 0, 6, 11, 15 and 20.
POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 20
- Organs examined: uterus and urogenital tract - Ovaries and uterine content:
- The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: No
- Number of corpora lutea: No
- Number of implantations: Yes
- Number of resorptions: Yes - Fetal examinations:
- - External examinations: Yes: one third per litter
- Soft tissue examinations: Yes: one third per litter
- Skeletal examinations: Yes: two thirds per litter
- Head examinations: Yes: two thirds per litter - Statistics:
- No data
- Indices:
- No data
- Historical control data:
- No
Results and discussion
Results: maternal animals
General toxicity (maternal animals)
- Clinical signs:
- not specified
- Mortality:
- no mortality observed
- Description (incidence):
- No mortality occurred.
- Body weight and weight changes:
- no effects observed
- Food consumption and compound intake (if feeding study):
- not specified
- 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:
- not examined
- Gross pathological findings:
- not specified
- Description (incidence and severity):
- Urogenital tract was observed but no data regarding this point were described in the report.
- Neuropathological findings:
- not examined
- Histopathological findings: non-neoplastic:
- not examined
- Histopathological findings: neoplastic:
- not examined
Maternal developmental toxicity
- Number of abortions:
- no effects observed
- Description (incidence and severity):
- see table 2 below for details
- Pre- and post-implantation loss:
- no effects observed
- Description (incidence and severity):
- see table 2 below
- Total litter losses by resorption:
- no effects observed
- Description (incidence and severity):
- see table 2 below
- Early or late resorptions:
- not examined
- Dead fetuses:
- no effects observed
- Description (incidence and severity):
- see table 2 below
- Changes in pregnancy duration:
- not examined
- Description (incidence and severity):
- Migrated Data from removed field(s)
Field "Effects on pregnancy duration" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsMaternalAnimals.MaternalDevelopmentalToxicity.EffectsOnPregnancyDuration): not examined - Changes in number of pregnant:
- not examined
Effect levels (maternal animals)
open allclose all
- Key result
- Dose descriptor:
- NOAEL
- Remarks:
- systemic toxicity
- Effect level:
- > 410 mg/kg bw/day
- Based on:
- test mat.
- Basis for effect level:
- body weight and weight gain
- mortality
- Key result
- Dose descriptor:
- NOAEL
- Remarks:
- developmental toxicity
- Effect level:
- > 410 mg/kg bw/day
- Based on:
- test mat.
- Basis for effect level:
- dead fetuses
- number of abortions
- pre and post implantation loss
- total litter losses by resorption
Maternal abnormalities
- Key result
- Abnormalities:
- no effects observed
Results (fetuses)
- Fetal body weight changes:
- not examined
- Description (incidence and severity):
- Fetal body weights after Caesarean section were determined. The average body weights of fetuses were similar in all groups except the group with aspirin which showed decreased body weights (see table 2 below).
Migrated Data from removed field(s)
Field "Fetal/pup body weight changes" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.FetalPupBodyWeightChanges): not examined - Reduction in number of live offspring:
- no effects observed
- Description (incidence and severity):
- for details see table 2 below
- Changes in sex ratio:
- no effects observed
- Description (incidence and severity):
- for details see table 2 below
- Changes in litter size and weights:
- not examined
- Changes in postnatal survival:
- not examined
- External malformations:
- no effects observed
- Skeletal malformations:
- effects observed, non-treatment-related
- Description (incidence and severity):
- The results indicate that the number of wavey ribs (47 foetuses affected/ 12 litters) observed at the highest dose level in the study (410.0 mg/kg) might be significant in relation to the sham control. However, the same result is not observed in either of the other two species tested (mice and rabbit) so can be discounted. For details see table 3 below.
- Visceral malformations:
- no effects observed
- Description (incidence and severity):
- one pup in the lowest dose group (4.1 mg/kg bw) had a hydrocephalus which was considered to be a spontanous effects since it was not observed in any other dose group or in the other two tested species mice and rabbits.
Effect levels (fetuses)
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- >= 410 mg/kg bw/day
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- reduction in number of live offspring
- changes in sex ratio
- skeletal malformations
- visceral malformations
Fetal abnormalities
- Key result
- Abnormalities:
- effects observed, non-treatment-related
- Localisation:
- skeletal: rib
- Description (incidence and severity):
- increased wavy ribs only in the highest dose group
Overall developmental toxicity
- Key result
- Developmental effects observed:
- no
Any other information on results incl. tables
Table 2 Reproduction data
Dose (mg/kg) |
Sham |
Aspirin |
4.1 |
19.1 |
88.5 |
410.0 |
Pregnancies |
|
|
|
|
|
|
Total No. |
21 |
21 |
22 |
22 |
19 |
22 |
Died or aborted (before Day 20) |
0 |
0 |
0 |
0 |
0 |
0 |
To term (on Day 20) |
21 |
21 |
22 |
22 |
19 |
22 |
Live litters |
|
|
|
|
|
|
Total No.* |
21 |
19 |
22 |
22 |
19 |
22 |
Implant Sites |
|
|
|
|
|
|
Total No. |
235 |
235 |
257 |
257 |
196 |
244 |
Average/dam* |
11.2 |
11.2 |
11.7 |
11.7 |
10.3 |
11.1 |
Resorptions |
|
|
|
|
|
|
Total No* |
2 |
63 |
3 |
3 |
3 |
2 |
Dams with 1 or more sites resorbed |
2 |
13 |
3 |
3 |
2 |
1 |
Dams with all sites resorbed |
-- |
2 |
-- |
-- |
-- |
-- |
Per cent partial resorptions |
9.52 |
61.9 |
13.6 |
13.6 |
10.5 |
4.55 |
Per cent complete resorptions |
-- |
9.52 |
-- |
-- |
-- |
-- |
Live foetuses |
|
|
|
|
|
|
Total No |
233 |
170 |
253 |
253 |
192 |
242 |
Average/dam* |
11.1 |
8.10 |
11.5 |
11.5 |
10.1 |
11.0 |
Sex ratio (M/F) |
1.33 |
1.07 |
0.92 |
0.92 |
0.92 |
0.87 |
Dead Foetuses |
|
|
|
|
|
|
Total No.* |
-- |
2 |
1 |
1 |
1 |
-- |
Dams with 1 or more dead |
-- |
2 |
1 |
1 |
1 |
-- |
Dams with all dead |
-- |
-- |
-- |
-- |
-- |
-- |
Per cent partial dead |
-- |
9.52 |
4.55 |
4.55 |
5.26 |
-- |
Per cent all dead |
-- |
-- |
-- |
-- |
-- |
-- |
Average foetus weight (g) |
3.62 |
2.43 |
3.85 |
3.85 |
3.56 |
3.65 |
* Includes only those dams examined at term
** Positive control: 250 mg/kg
Table 3 Summary of skeletal findings
Findings |
Dose (mg/kg) |
|||||
Sham |
Aspirin |
4.1 |
19.1 |
88.5 |
410.0 |
|
Live foetuses examined (at term) |
165/21 |
124/19 |
174/22 |
162/21 |
133/19 |
168/22 |
Sternebrae |
|
|
|
|
|
|
Incomplete oss. |
45/18 |
49/16 |
31/12 |
36/16 |
42/15 |
45/15 |
Scrambled |
|
1/1 |
|
|
|
|
Bipartite |
1/1 |
13/7 |
|
|
|
1/1 |
Fused |
|
1/1 |
|
|
|
|
Extra |
|
|
|
|
|
|
Missing |
27/12 |
92/18 |
6/4 |
5/4 |
22/10 |
16/7 |
Other |
|
|
|
|
|
|
Ribs |
|
|
|
|
|
|
Incomplete oss. |
|
1/1 |
|
|
|
9/3 |
Fused/split |
|
8/4 |
|
|
|
|
Wavy |
17/10 |
51/14 |
16/9 |
15/7 |
11/8 |
47/12 |
Less than 12 |
|
1/1 |
|
|
|
|
More than 13 |
5/5 |
71/17 |
2/2 |
1/1 |
2/2 |
4/3 |
Other |
|
|
|
|
|
|
Vertebrae |
|
|
|
|
|
|
Incomplete oss. |
26/14 |
92/19 |
10/6 |
6/5 |
22/11 |
29/10 |
Scrambled |
|
|
|
|
|
|
Fused |
|
|
|
|
|
|
Extra ctrs. oss. |
|
|
|
|
|
|
Scoliosis |
|
|
|
|
|
|
Tail defects |
|
|
|
|
|
|
Other |
|
|
|
|
|
|
Skull |
|
|
|
|
|
|
Incomplete closure |
29/12 |
38/12 |
25/11 |
12/6 |
14/10 |
28/10 |
Missing |
|
1/1 |
|
|
|
|
Craniostosis |
|
|
|
|
|
|
Other; facial bones, inc |
|
9/6 |
|
|
|
|
Extremities |
|
|
|
|
|
|
Incomplete oss. |
|
6/3 |
|
|
|
|
Missing |
|
|
|
|
|
|
Extra |
|
|
|
|
|
|
Miscellaneous |
|
|
|
|
|
|
Hyoid; missing |
15/8 |
51/16 |
13/7 |
14/9 |
8/6 |
22/12 |
Hyoid; reduced |
22/11 |
11/7 |
24/10 |
12/7 |
9/8 |
30/14 |
* Numerator = Number of foetuses affected; Denominator = Number of litters affected
** Positive control: 250 mg/kg
Table 4 Summary of soft tissue abnormalities
Material |
Dose level (mg/kg) |
Dam |
Number of pups |
Description |
Aspirin |
250.0 |
A 7065 |
1 |
Encephalomyelocele |
|
|
A 7066 |
1 |
Gastroschisis |
|
|
A 7070 |
1 |
Meningoencephalocele |
|
|
A 7076 |
2 |
Meningoencephalocele |
FDA 71-81 |
4.1 |
H 6028 |
1 |
Hydrocephalus |
Applicant's summary and conclusion
- Conclusions:
- Under the conditions of the study, the test material administered to pregnant rats for 10 days up to a dose level of 410 mg/kg bw showed no maternal or developmental toxicity. The NOAEL for both maternal and developmental toxicity is > 410 mg/kg bw.
Information on Registered Substances comes from registration dossiers which have been assigned a registration number. The assignment of a registration number does however not guarantee that the information in the dossier is correct or that the dossier is compliant with Regulation (EC) No 1907/2006 (the REACH Regulation). This information has not been reviewed or verified by the Agency or any other authority. The content is subject to change without prior notice.
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