Registration Dossier
Registration Dossier
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EC number: 230-785-7 | CAS number: 7320-34-5
Endpoint summary
Administrative data
Key value for chemical safety assessment
Effects on developmental toxicity
Description of key information
A weight of evidence approach based on the use of data from analogous substances has been used to assess the teratogenic potential of tetrapotassium pyrophosphate. A study on disodium dihydrogenpyrophosphate was conducted on mice, rats, hamsters and rabbits (Morgareidge, 1973) and a study on tetrasodium pyrophosphate was conducted in mice and rats (Bailey, 1974 ). These data are considered to be adequate to fulfil this endpoint as part of a weight of evidence approach. Potassium and sodium pyrophosphates are not considered to be developmental toxicants.
Link to relevant study records
- Endpoint:
- developmental toxicity
- Type of information:
- experimental study
- Adequacy of study:
- weight of evidence
- Study period:
- 1/9/74 - 5/10/74
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- study well documented, meets generally accepted scientific principles, acceptable for assessment
- Remarks:
- Meets generally accepted scientific standards with acceptable restrictions. Deficiencies: Food consumption not reported Uterine weights 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, not until day before pregnancy
- Justification for type of information:
- REPORTING FORMAT FOR THE ANALOGUE APPROACH
See read-across justification report under Section 13 ‘Assessment Reports’.
1. HYPOTHESIS FOR THE ANALOGUE APPROACH
In accordance with REACH Annex XI, Section 1.5, of Regulation (EC) No. 1907/2006 (REACH) the standard testing regime may be adapted in cases where a grouping or read-across approach has been applied.
The similarities may be based on:
(1) a common functional group
(2) the common precursors and/or the likelihood of common breakdown products via physical or biological processes, which result in structurally similar chemicals; or
(3) a constant pattern in the changing of the potency of the properties across the category
(1) The source and target substances are both inorganic salts of a monovalent cation from Group 1A of the periodic table, sodium or potassium, and pyrophosphoric acid. Thus, they all share the Na+ or K+ cation and the P2O74- anion as common functional groups.
(2) All members of the group will ultimately dissociate into the common breakdown products of the Na+ or K+ cations and the P2O74-anion.
(3) The pyrophosphate ion is the simplest form of a condensed phosphate group. A condensed phosphate anion has one or several P-O-P bonds. As the group contains only two phosphate groups, both of the phosphorus ions are classified as “terminal phosphorus”. The pyrophosphate can undergo ionisation with loss of H+ from each of the two –OH groups on each P and therefore can occur in the -1, -2 -3 or -4 state. The degree of ionisation is dependent upon the associated cations and the ambient pH (if in solution). Therefore the above substances have a pyrophosphate anion that is likely to behave in a similar way. In addition, the sodium and potassium cations are key elements in various cellular processes their import and export over cell membranes is regulated via pore systems and usually tightly regulated. As such, the presence of varying quantities of such cations is not expected to have an impact on the genotoxicity of the substances therefore as the both ionic components of the substance are common the results of toxicity studies can be reliably read-across within the group.
2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
See read-across justification report under Section 13 ‘Assessment Reports’.
3. ANALOGUE APPROACH JUSTIFICATION
See read-across justification report under Section 13 ‘Assessment Reports’.
4. DATA MATRIX
See read-across justification report under Section 13 ‘Assessment Reports’. - Reason / purpose for cross-reference:
- read-across: supporting information
- Qualifier:
- according to guideline
- Guideline:
- other: no data
- Deviations:
- not specified
- 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 1.3, 6.0, 28.0 and 130.0 mg/kg was carried out daily on Days 6 to 15 of gestation. Observations of body weight, appearence, behaviour, and food consumption were performed. On Day 17 of gestation all dams underwent Caesarean section. Sex, numbers of corporea 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. 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 - 31 g
- Fasting period before study: No data
- Housing: Gang housing in disposable plastic cages
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: No data
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 - 26.67
- Humidity (%): 62 - 76
IN-LIFE DATES: 1/9/74 - 5/10/74 - 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
- No. of animals per sex per dose:
- Table 1 Number of animals dosed
Material Dose (mg/kg) Total
Mated Pregnant
Sham 0.0 30 21
Aspirin 150.0 25 20
FDA 71-3 1.3 24 20
6.0 27 20
28.0 26 18
130.0 29 21 - Control animals:
- yes, sham-exposed
- other: positive control: 150 mg/kg 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: Yes
- 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
- Details on maternal toxic effects:
- Maternal toxic effects:no effects
- Dose descriptor:
- NOAEL
- Effect level:
- > 130 mg/kg bw/day
- Based on:
- test mat.
- Basis for effect level:
- other: no effects observed
- Abnormalities:
- no effects observed
- Details on embryotoxic / teratogenic effects:
- Embryotoxic / teratogenic effects:no effects
- Dose descriptor:
- NOAEL
- Effect level:
- > 130 mg/kg bw/day
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: no effects observed
- Abnormalities:
- no effects observed
- 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 130 mg/kg bw showed no maternal or developmental toxicity. The NOAEL for both maternal and fetotoxicity is > 130 mg/kg bw.
- Endpoint:
- developmental toxicity
- Type of information:
- experimental study
- Adequacy of study:
- weight of evidence
- Study period:
- 3/9/74 - 2/10/74
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- study well documented, meets generally accepted scientific principles, acceptable for assessment
- Remarks:
- Meets generally accepted scientific standards with acceptable restrictions. Deficiencies: Food consumption not reported Uterine weights 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, not until day before pregnancy
- Reason / purpose for cross-reference:
- read-across: supporting information
- Qualifier:
- according to guideline
- Guideline:
- other: no data
- Deviations:
- not specified
- 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 1.38, 6.41, 29.7 and 138.0 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. Sex, 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. 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:
- 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: 215 - 221 g
- Fasting period before study: No data
- Housing: Individual housing in mesh bottom cages
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: No data
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21 - 26.7
- Humidity (%): 62 - 76
IN-LIFE DATES: 3/9/74 - 2/10/74 - 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
- No. of animals per sex per dose:
- Table 1 Number of animals dosed
Material Dose (mg/kg) Total
Mated Pregnant
Sham 0.0 25 20
Aspirin 250.0 25 19
FDA 73-1 1.38 23 21
6.41 24 20
29.7 25 20
138.0 25 19 - Control animals:
- yes, sham-exposed
- other: positive control: 250 mg/kg 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 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: Yes
- 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
- Details on maternal toxic effects:
- Maternal toxic effects:no effects
- Dose descriptor:
- NOAEL
- Effect level:
- > 138 mg/kg bw/day
- Based on:
- test mat.
- Basis for effect level:
- other: no effects observed
- Abnormalities:
- no effects observed
- Details on embryotoxic / teratogenic effects:
- Embryotoxic / teratogenic effects:no effects
- Dose descriptor:
- NOAEL
- Effect level:
- > 138 mg/kg bw/day
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: no effects observed
- Abnormalities:
- not specified
- Developmental effects observed:
- no
- Conclusions:
- Under the conditions of the study, the test material administered to pregnant rats for 10 days up to a dose level of 138 mg/kg bw showed no maternal or developmental toxicity. The NOAEL for both maternal and fetotoxicity is > 138 mg/kg bw.
- 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:
- study well documented, meets generally accepted scientific principles, acceptable for assessment
- Remarks:
- Meets generally accepted scientific standards with acceptable restrictions. Deficiencies: 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, not until day before pregnancy
- Justification for type of information:
- REPORTING FORMAT FOR THE ANALOGUE APPROACH
See read-across justification report under Section 13 ‘Assessment Reports’.
1. HYPOTHESIS FOR THE ANALOGUE APPROACH
In accordance with REACH Annex XI, Section 1.5, of Regulation (EC) No. 1907/2006 (REACH) the standard testing regime may be adapted in cases where a grouping or read-across approach has been applied.
The similarities may be based on:
(1) a common functional group
(2) the common precursors and/or the likelihood of common breakdown products via physical or biological processes, which result in structurally similar chemicals; or
(3) a constant pattern in the changing of the potency of the properties across the category
(1) The source and target substances are both inorganic salts of a monovalent cation from Group 1A of the periodic table, sodium or potassium, and pyrophosphoric acid. Thus, they all share the Na+ or K+ cation and the P2O74- anion as common functional groups.
(2) All members of the group will ultimately dissociate into the common breakdown products of the Na+ or K+ cations and the P2O74-anion.
(3) The pyrophosphate ion is the simplest form of a condensed phosphate group. A condensed phosphate anion has one or several P-O-P bonds. As the group contains only two phosphate groups, both of the phosphorus ions are classified as “terminal phosphorus”. The pyrophosphate can undergo ionisation with loss of H+ from each of the two –OH groups on each P and therefore can occur in the -1, -2 -3 or -4 state. The degree of ionisation is dependent upon the associated cations and the ambient pH (if in solution). Therefore the above substances have a pyrophosphate anion that is likely to behave in a similar way. In addition, the sodium and potassium cations are key elements in various cellular processes their import and export over cell membranes is regulated via pore systems and usually tightly regulated. As such, the presence of varying quantities of such cations is not expected to have an impact on the genotoxicity of the substances therefore as the both ionic components of the substance are common the results of toxicity studies can be reliably read-across within the group.
2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
See read-across justification report under Section 13 ‘Assessment Reports’.
3. ANALOGUE APPROACH JUSTIFICATION
See read-across justification report under Section 13 ‘Assessment Reports’.
4. DATA MATRIX
See read-across justification report under Section 13 ‘Assessment Reports’. - Reason / purpose for cross-reference:
- reference to same study
- Reason / purpose for cross-reference:
- reference to same study
- Reason / purpose for cross-reference:
- reference to same study
- Reason / purpose for cross-reference:
- read-across: supporting information
- Qualifier:
- according to guideline
- Guideline:
- other: no data
- Deviations:
- not specified
- 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 1.69, 9.24, 42.95 and 169.0 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
- 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: 214 - 225 g
- Fasting period before study: No data
- Housing: Individual housing in mesh bottom cages
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: No data
ENVIRONMENTAL CONDITIONS
- Temperature (°C): Not recorded
- Humidity (%): Not recorded
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: 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
- No. of animals per sex per dose:
- Table 1 Number of animals dosed
Material Dose (mg/kg) Total
Mated Pregnant
Sham 0.0 25 23
Aspirin 250.0 24 21
FDA 71-61 1.69 25 24
9.24 25 24
42.95 24 24
169.0 25 21 - Control animals:
- yes, sham-exposed
- other: positive control: 250 mg/kg 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 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
- Details on maternal toxic effects:
- Maternal toxic effects:no effects
- Dose descriptor:
- NOAEL
- Effect level:
- > 169 mg/kg bw/day
- Based on:
- test mat.
- Basis for effect level:
- other: no effects observed
- Abnormalities:
- no effects observed
- Details on embryotoxic / teratogenic effects:
- Embryotoxic / teratogenic effects:no effects
- Dose descriptor:
- NOAEL
- Effect level:
- > 169 mg/kg bw/day
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: no effects observed
- Abnormalities:
- no effects observed
- Developmental effects observed:
- no
- Conclusions:
- Under the conditions of the study, the test material administered to pregnant rats for 10 days up to a dose level of 169 mg/kg bw showed no maternal or developmental toxicity. The NOAEL for both maternal and fetotoxicity is > 169 mg/kg bw.
- 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:
- study well documented, meets generally accepted scientific principles, acceptable for assessment
- Remarks:
- Meets generally accepted scientific standards with acceptable restrictions. Deficiencies: Food consumption not reported Uterine weights or copora 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, not until day before pregnancy
- Justification for type of information:
- REPORTING FORMAT FOR THE ANALOGUE APPROACH
See read-across justification report under Section 13 ‘Assessment Reports’.
1. HYPOTHESIS FOR THE ANALOGUE APPROACH
In accordance with REACH Annex XI, Section 1.5, of Regulation (EC) No. 1907/2006 (REACH) the standard testing regime may be adapted in cases where a grouping or read-across approach has been applied.
The similarities may be based on:
(1) a common functional group
(2) the common precursors and/or the likelihood of common breakdown products via physical or biological processes, which result in structurally similar chemicals; or
(3) a constant pattern in the changing of the potency of the properties across the category
(1) The source and target substances are both inorganic salts of a monovalent cation from Group 1A of the periodic table, sodium or potassium, and pyrophosphoric acid. Thus, they all share the Na+ or K+ cation and the P2O74- anion as common functional groups.
(2) All members of the group will ultimately dissociate into the common breakdown products of the Na+ or K+ cations and the P2O74-anion.
(3) The pyrophosphate ion is the simplest form of a condensed phosphate group. A condensed phosphate anion has one or several P-O-P bonds. As the group contains only two phosphate groups, both of the phosphorus ions are classified as “terminal phosphorus”. The pyrophosphate can undergo ionisation with loss of H+ from each of the two –OH groups on each P and therefore can occur in the -1, -2 -3 or -4 state. The degree of ionisation is dependent upon the associated cations and the ambient pH (if in solution). Therefore the above substances have a pyrophosphate anion that is likely to behave in a similar way. In addition, the sodium and potassium cations are key elements in various cellular processes their import and export over cell membranes is regulated via pore systems and usually tightly regulated. As such, the presence of varying quantities of such cations is not expected to have an impact on the genotoxicity of the substances therefore as the both ionic components of the substance are common the results of toxicity studies can be reliably read-across within the group.
2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
See read-across justification report under Section 13 ‘Assessment Reports’.
3. ANALOGUE APPROACH JUSTIFICATION
See read-across justification report under Section 13 ‘Assessment Reports’.
4. DATA MATRIX
See read-across justification report under Section 13 ‘Assessment Reports’. - Reason / purpose for cross-reference:
- reference to same study
- Reason / purpose for cross-reference:
- reference to same study
- Reason / purpose for cross-reference:
- reference to same study
- Reason / purpose for cross-reference:
- read-across: supporting information
- Qualifier:
- according to guideline
- Guideline:
- other: no data
- Deviations:
- not specified
- Principles of method if other than guideline:
- Adult female golden hamsters were mated with mature males (1:1). Observation of motile sperm in the vaginal smear 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 1.66, 7.71, 35.8 and 166.0 mg/kg was carried out daily on Days 6 to 10 of gestation. Observations of body weight, appearence, behaviour, and food consumption were performed. On Day 14 of gestation all dams underwent Caesarean section. Implantation sites, resorption sites and live/dead foetuses recorded. Body weights of live pups recorded. Genital 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:
- hamster
- Strain:
- other: Golden
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Outbred
- Age at study initiation: No data
- Weight at study initiation: 122.2 - 133.4 g
- Fasting period before study: No data
- Housing: Individually housed in mesh-bottomed cages
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: No data
ENVIRONMENTAL CONDITIONS
- Temperature (°C): No data
- Humidity (%): No data
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: 1:1 mating
- Proof of pregnancy: appearence of motile sperm in vaginal smear - Duration of treatment / exposure:
- 5 days (Day 6 to Day 10 of gestation)
- Frequency of treatment:
- Daily
- Duration of test:
- 14 days
- No. of animals per sex per dose:
- Table 1 Number of animals dosed
Material Dose (mg/kg) Total
Mated Pregnant
Sham 0.0 22 20
Aspirin 250 22 21
FDA 71-81 1.66 22 20
7.71 24 20
35.8 22 21
166.0 22 22 - Control animals:
- yes, sham-exposed
- other: positive control: 250 mg/kg 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, 8, 10 and 14.
POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 14
- Organs examined: uterus and genital 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
- Soft tissue examinations: Yes
- Skeletal examinations: Yes
- Head examinations: Yes - Statistics:
- No data
- Indices:
- No data
- Historical control data:
- No
- Details on maternal toxic effects:
- Maternal toxic effects:no effects
- Dose descriptor:
- NOAEL
- Effect level:
- > 166 mg/kg bw/day
- Based on:
- test mat.
- Basis for effect level:
- other: no effects observed
- Abnormalities:
- no effects observed
- Details on embryotoxic / teratogenic effects:
- Embryotoxic / teratogenic effects:no effects
- Dose descriptor:
- NOAEL
- Effect level:
- > 166 mg/kg bw/day
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: no effects observed
- Abnormalities:
- no effects observed
- Developmental effects observed:
- no
- Conclusions:
- Under the conditions of the study, the test material administered to pregnant hamsters for 5 days up to a dose level of 166 mg/kg bw showed no maternal or developmental toxicity. The NOAEL for both maternal and fetotoxicity is > 166 mg/kg bw.
- 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:
- study well documented, meets generally accepted scientific principles, acceptable for assessment
- Remarks:
- Meets generally accepted scientific standards with acceptable restrictions. Deficiencies: 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, not until day before pregnancy
- Justification for type of information:
- REPORTING FORMAT FOR THE ANALOGUE APPROACH
See read-across justification report under Section 13 ‘Assessment Reports’.
1. HYPOTHESIS FOR THE ANALOGUE APPROACH
In accordance with REACH Annex XI, Section 1.5, of Regulation (EC) No. 1907/2006 (REACH) the standard testing regime may be adapted in cases where a grouping or read-across approach has been applied.
The similarities may be based on:
(1) a common functional group
(2) the common precursors and/or the likelihood of common breakdown products via physical or biological processes, which result in structurally similar chemicals; or
(3) a constant pattern in the changing of the potency of the properties across the category
(1) The source and target substances are both inorganic salts of a monovalent cation from Group 1A of the periodic table, sodium or potassium, and pyrophosphoric acid. Thus, they all share the Na+ or K+ cation and the P2O74- anion as common functional groups.
(2) All members of the group will ultimately dissociate into the common breakdown products of the Na+ or K+ cations and the P2O74-anion.
(3) The pyrophosphate ion is the simplest form of a condensed phosphate group. A condensed phosphate anion has one or several P-O-P bonds. As the group contains only two phosphate groups, both of the phosphorus ions are classified as “terminal phosphorus”. The pyrophosphate can undergo ionisation with loss of H+ from each of the two –OH groups on each P and therefore can occur in the -1, -2 -3 or -4 state. The degree of ionisation is dependent upon the associated cations and the ambient pH (if in solution). Therefore the above substances have a pyrophosphate anion that is likely to behave in a similar way. In addition, the sodium and potassium cations are key elements in various cellular processes their import and export over cell membranes is regulated via pore systems and usually tightly regulated. As such, the presence of varying quantities of such cations is not expected to have an impact on the genotoxicity of the substances therefore as the both ionic components of the substance are common the results of toxicity studies can be reliably read-across within the group.
2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
See read-across justification report under Section 13 ‘Assessment Reports’.
3. ANALOGUE APPROACH JUSTIFICATION
See read-across justification report under Section 13 ‘Assessment Reports’.
4. DATA MATRIX
See read-across justification report under Section 13 ‘Assessment Reports’. - Reason / purpose for cross-reference:
- reference to same study
- Reason / purpose for cross-reference:
- reference to same study
- Reason / purpose for cross-reference:
- reference to same study
- Reason / purpose for cross-reference:
- read-across: supporting information
- Qualifier:
- according to guideline
- Guideline:
- other: no data
- Deviations:
- not specified
- 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 3.35, 15.6, 72.3 and 335.0 mg/kg was carried out daily on Days 6 to 15 of gestation. Observations of body weight, appearence, behaviour, and food consumption were performed. 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: 26.3 - 29.3 g
- Fasting period before study: No data
- Housing: Gang housing in disposable plastic cages
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: No data
ENVIRONMENTAL CONDITIONS
- Temperature (°C): No data
- Humidity (%): No data
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
- No. of animals per sex per dose:
- Table 1 Number of animals dosed
Material Dose (mg/kg) Total
Mated Pregnant
Sham 0.0 25 25
Aspirin 150.0 24 21
FDA 71-61 3.35 25 23
15.6 25 23
72.3 24 23
335.0 25 22 - Control animals:
- yes, sham-exposed
- other: positive control: 150 mg/kg 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
- Details on maternal toxic effects:
- Maternal toxic effects:no effects
- Dose descriptor:
- NOAEL
- Effect level:
- > 335 mg/kg bw/day
- Based on:
- test mat.
- Basis for effect level:
- other: no effects observed
- Abnormalities:
- no effects observed
- Details on embryotoxic / teratogenic effects:
- Embryotoxic / teratogenic effects:no effects
- Dose descriptor:
- NOAEL
- Effect level:
- > 335 mg/kg bw/day
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: no effects observed
- Abnormalities:
- no effects observed
- 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 335 mg/kg bw showed no maternal or developmental toxicity. The NOAEL for both maternal and fetotoxicity is > 335 mg/kg bw.
- 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:
- study well documented, meets generally accepted scientific principles, acceptable for assessment
- Remarks:
- Meets generally accepted scientific standards with acceptable restrictions. Deficiencies: 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
- Justification for type of information:
- REPORTING FORMAT FOR THE ANALOGUE APPROACH
See read-across justification report under Section 13 ‘Assessment Reports’.
1. HYPOTHESIS FOR THE ANALOGUE APPROACH
In accordance with REACH Annex XI, Section 1.5, of Regulation (EC) No. 1907/2006 (REACH) the standard testing regime may be adapted in cases where a grouping or read-across approach has been applied.
The similarities may be based on:
(1) a common functional group
(2) the common precursors and/or the likelihood of common breakdown products via physical or biological processes, which result in structurally similar chemicals; or
(3) a constant pattern in the changing of the potency of the properties across the category
(1) The source and target substances are both inorganic salts of a monovalent cation from Group 1A of the periodic table, sodium or potassium, and pyrophosphoric acid. Thus, they all share the Na+ or K+ cation and the P2O74- anion as common functional groups.
(2) All members of the group will ultimately dissociate into the common breakdown products of the Na+ or K+ cations and the P2O74-anion.
(3) The pyrophosphate ion is the simplest form of a condensed phosphate group. A condensed phosphate anion has one or several P-O-P bonds. As the group contains only two phosphate groups, both of the phosphorus ions are classified as “terminal phosphorus”. The pyrophosphate can undergo ionisation with loss of H+ from each of the two –OH groups on each P and therefore can occur in the -1, -2 -3 or -4 state. The degree of ionisation is dependent upon the associated cations and the ambient pH (if in solution). Therefore the above substances have a pyrophosphate anion that is likely to behave in a similar way. In addition, the sodium and potassium cations are key elements in various cellular processes their import and export over cell membranes is regulated via pore systems and usually tightly regulated. As such, the presence of varying quantities of such cations is not expected to have an impact on the genotoxicity of the substances therefore as the both ionic components of the substance are common the results of toxicity studies can be reliably read-across within the group.
2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
See read-across justification report under Section 13 ‘Assessment Reports’.
3. ANALOGUE APPROACH JUSTIFICATION
See read-across justification report under Section 13 ‘Assessment Reports’.
4. DATA MATRIX
See read-across justification report under Section 13 ‘Assessment Reports’. - Reason / purpose for cross-reference:
- reference to same study
- Reason / purpose for cross-reference:
- reference to same study
- Reason / purpose for cross-reference:
- reference to same study
- Reason / purpose for cross-reference:
- read-across: supporting information
- Qualifier:
- according to guideline
- Guideline:
- other: no data
- Deviations:
- not specified
- 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 20 x 10E06 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 at 1.28, 5.95, 27.6 and 128.0 mg/kg was carried out daily on Days 6 to 18 of gestation. The positive control 6-aminonicotinamide at 2.5 mg/kg 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: 2.17 - 2.51 kg
- Fasting period before study: No data
- Housing: Individually housed in mesh-bottomed cages
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: No data
ENVIRONMENTAL CONDITIONS
- Temperature (°C): No data
- Humidity (%): No data
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
- No. of animals per sex per dose:
- Table 1 Number of animals dosed
Material Dose (mg/kg) Total
Mated Pregnant
Sham 0.0 17 11
6-AN 2.5 15 10
FDA 71-61 1.28 15 12
5.95 16 12
27.6 20 9
128.0 15 11 - 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
- Details on maternal toxic effects:
- Maternal toxic effects:no effects
- Dose descriptor:
- NOAEL
- Effect level:
- > 128 mg/kg bw/day
- Based on:
- test mat.
- Basis for effect level:
- other: no effects observed
- Abnormalities:
- no effects observed
- Details on embryotoxic / teratogenic effects:
- Embryotoxic / teratogenic effects:no effects
Details on embryotoxic / teratogenic effects:
No dose related response observed. - Dose descriptor:
- NOAEL
- Effect level:
- > 128 mg/kg bw/day
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: no effects observed
- Abnormalities:
- no effects observed
- 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 128 mg/kg bw showed no maternal or developmental toxicity. The NOAEL for both maternal and fetotoxicity is > 128 mg/kg bw.
Referenceopen allclose all
Table 2 Reproduction data
Dose (mg/kg) |
Sham |
Aspirin |
1.3 |
6.0 |
28.0 |
130.0 |
Pregnancies |
|
|
|
|
|
|
Total No. |
21 |
20 |
20 |
20 |
18 |
21 |
Died or aborted (before Day 17) |
0 |
0 |
0 |
0 |
0 |
0 |
To term (on Day 17) |
21 |
20 |
20 |
20 |
18 |
21 |
Corpora Lutea |
|
|
|
|
|
|
Total no. |
277 |
253 |
239 |
254 |
224 |
261 |
Average/dam mated |
9.23 |
10.1 |
10.4 |
9.41 |
8.62 |
9.32 |
Live litters |
|
|
|
|
|
|
Total No.* |
21 |
20 |
20 |
20 |
18 |
20 |
Implant Sites |
|
|
|
|
|
|
Total No. |
250 |
220 |
231 |
237 |
209 |
243 |
Average/dam* |
11.9 |
11.0 |
11.6 |
11.9 |
11.6 |
11.6 |
Resorptions |
|
|
|
|
|
|
Total No* |
9 |
11 |
11 |
13 |
17 |
18 |
Dams with 1 or more sites resorbed |
6 |
8 |
7 |
9 |
10 |
9 |
Dams with all sites resorbed |
-- |
-- |
-- |
-- |
-- |
1 |
Per cent partial resorptions |
28.6 |
40.0 |
35.0 |
45.0 |
55.6 |
42.9 |
Per cent complete resorptions |
-- |
-- |
-- |
-- |
-- |
4.76 |
Live foetuses |
|
|
|
|
|
|
Total No |
240 |
209 |
219 |
223 |
191 |
223 |
Average/dam* |
11.4 |
10.5 |
11.0 |
11.2 |
10.6 |
10.6 |
Sex ratio (M/F) |
0.86 |
0.99 |
0.92 |
1.14 |
1.01 |
1.05 |
Dead Foetuses |
|
|
|
|
|
|
Total No.* |
1 |
-- |
1 |
1 |
1 |
2 |
Dams with 1 or more dead |
1 |
-- |
1 |
1 |
1 |
2 |
Dams with all dead |
-- |
-- |
-- |
-- |
-- |
-- |
Per cent partial dead |
4.76 |
-- |
5.00 |
5.00 |
5.56 |
9.52 |
Per cent all dead |
-- |
-- |
-- |
-- |
-- |
-- |
Average foetus weight (g) |
0.90 |
0.91 |
0.91 |
0.90 |
0.91 |
0.88 |
* Includes only those dams examined at term
** Positive control: 150 mg/kg
Table 3 Summary of skeletal findings
Findings |
Dose (mg/kg) |
|||||
Sham |
Aspirin |
1.3 |
6.0 |
28.0 |
130.0 |
|
Live foetuses examined (at term) |
165/21 |
146/20 |
150/20 |
157/20 |
134/18 |
157/20 |
Sternebrae |
|
|
|
|
|
|
Incomplete oss. |
28/9 |
66/18 |
12/7 |
61/18 |
14/10 |
19/9 |
Scrambled |
|
|
|
|
|
|
Bipartite |
1/1 |
3/3 |
|
|
|
|
Fused |
|
|
|
|
|
|
Extra |
|
|
|
|
|
|
Missing |
17/7 |
21/10 |
9/6 |
17/8 |
13/7 |
10/7 |
Other |
|
|
|
|
|
|
Ribs |
|
|
|
|
|
|
Incomplete oss. |
|
|
|
|
|
|
Fused/split |
|
|
|
|
|
|
Wavy |
|
|
1/1 |
|
|
|
Less than 12 |
|
|
|
|
|
|
More than 13 |
25/13 |
32/12 |
31/16 |
21/11 |
29/13 |
38/13 |
Other |
|
|
|
|
|
|
Vertebrae |
|
|
|
|
|
|
Incomplete oss. |
7/6 |
4/4 |
4/3 |
2/1 |
5/4 |
6/4 |
Scrambled |
|
|
|
|
|
|
Fused |
|
|
|
|
|
|
Extra ctrs. oss. |
|
|
|
|
|
|
Scoliosis |
|
|
|
|
|
|
Tail defects |
|
|
|
|
|
|
Other |
|
|
|
|
|
|
Skull |
|
|
|
|
|
|
Incomplete closure |
|
|
|
|
|
2/1 |
Missing |
|
|
|
|
|
|
Craniostosis |
|
|
|
|
|
|
Other |
|
|
|
|
|
|
Extremities |
|
|
|
|
|
|
Incomplete oss. |
4/2 |
5/4 |
2/2 |
3/2 |
1/1 |
5/4 |
Missing |
|
|
|
|
|
|
Extra |
|
|
|
|
|
|
Miscellaneous |
|
|
|
|
|
|
Hyoid; missing |
32/11 |
33/14 |
26/12 |
40/15 |
37/12 |
31/14 |
Hyoid; reduced |
13/8 |
23/11 |
11/8 |
21/11 |
13/8 |
20/13 |
* 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 |
23629 |
1 |
Cleft palate |
FD 73-1 |
6.0 |
23700 |
1 |
Exophthalmos; encephalomeningocele |
Table 2 Reproduction data
Dose (mg/kg) |
Sham |
Aspirin |
1.38 |
6.41 |
29.7 |
138.0 |
Pregnancies |
|
|
|
|
|
|
Total No. |
20 |
19 |
21 |
20 |
20 |
19 |
Died or aborted (before Day 20) |
0 |
0 |
0 |
0 |
0 |
0 |
To term (on Day 20) |
20 |
19 |
21 |
20 |
20 |
19 |
Corpora Lutea |
|
|
|
|
|
|
Total no. |
244 |
258 |
267 |
263 |
249 |
248 |
Average/dam mated |
9.76 |
10.3 |
11.6 |
11.0 |
9.96 |
9.92 |
Live litters |
|
|
|
|
|
|
Total No.* |
20 |
19 |
21 |
20 |
20 |
19 |
Implant Sites |
|
|
|
|
|
|
Total No. |
228 |
225 |
240 |
249 |
237 |
232 |
Average/dam* |
11.4 |
11.8 |
11.4 |
12.5 |
11.9 |
12.2 |
Resorptions |
|
|
|
|
|
|
Total No* |
4 |
17 |
1 |
5 |
8 |
1 |
Dams with 1 or more sites resorbed |
2 |
8 |
1 |
4 |
6 |
1 |
Dams with all sites resorbed |
-- |
-- |
-- |
-- |
-- |
-- |
Per cent partial resorptions |
10.0 |
42.1 |
4.76 |
20.0 |
30.0 |
5.26 |
Per cent complete resorptions |
-- |
-- |
-- |
-- |
-- |
-- |
Live foetuses |
|
|
|
|
|
|
Total No |
224 |
208 |
239 |
244 |
229 |
231 |
Average/dam* |
11.2 |
11.0 |
11.4 |
12.2 |
11.5 |
12.2 |
Sex ratio (M/F) |
0.96 |
1.04 |
0.98 |
0.95 |
1.14 |
0.94 |
Dead Foetuses |
|
|
|
|
|
|
Total No.* |
-- |
-- |
-- |
-- |
-- |
-- |
Dams with 1 or more dead |
-- |
-- |
-- |
-- |
-- |
-- |
Dams with all dead |
-- |
-- |
-- |
-- |
-- |
-- |
Per cent partial dead |
-- |
-- |
-- |
-- |
-- |
-- |
Per cent all dead |
-- |
-- |
-- |
-- |
-- |
-- |
Average foetus weight (g) |
3.90 |
2.97 |
4.01 |
4.01 |
3.95 |
4.09 |
* 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 |
19.0 |
88.3 |
410.0 |
|
Live foetuses examined (at term) |
156/20 |
145/19 |
165/21 |
169/20 |
163/20 |
160/19 |
Sternebrae |
|
|
|
|
|
|
Incomplete oss. |
20/12 |
86/18 |
36/14 |
19/11 |
46/15 |
7/5 |
Scrambled |
|
|
|
|
|
|
Bipartite |
|
3/2 |
1/1 |
|
|
|
Fused |
|
|
|
|
|
|
Extra |
|
|
|
|
|
|
Missing |
2/2 |
117/19 |
9/7 |
4/3 |
15/9 |
|
Other |
|
|
|
|
|
|
Ribs |
|
|
|
|
|
|
Incomplete oss. |
3/2 |
|
|
2/1 |
|
|
Fused/split |
|
1/1 |
|
|
|
|
Wavy |
21/9 |
55/16 |
25/11 |
23/8 |
24/13 |
13/9 |
Less than 12 |
1/1 |
|
|
|
|
|
More than 13 |
|
110/17 |
5/1 |
|
1/1 |
1/1 |
Other |
|
|
|
|
|
|
Vertebrae |
|
|
|
|
|
|
Incomplete oss. |
6/4 |
64/17 |
4/2 |
3/2 |
2/2 |
|
Scrambled |
|
|
|
|
|
|
Fused |
|
|
|
|
|
|
Extra ctrs. oss. |
|
|
|
|
|
|
Scoliosis |
|
|
|
|
|
|
Tail defects |
|
|
|
|
|
|
Other |
|
|
|
|
|
|
Skull |
|
|
|
|
|
|
Incomplete closure |
32/12 |
48/14 |
19/12 |
27/11 |
17/7 |
18/9 |
Missing |
|
|
|
|
|
|
Craniostosis |
|
|
|
|
|
|
Other |
|
|
|
|
|
|
Extremities |
|
|
|
|
|
|
Incomplete oss. |
1/1 |
4/3 |
|
|
|
|
Missing |
|
|
|
|
|
|
Extra |
|
|
|
|
|
|
Miscellaneous |
|
|
|
|
|
|
Hyoid; missing |
16/8 |
45/15 |
10/8 |
17/9 |
17/7 |
10/9 |
Hyoid; reduced |
29/14 |
9/6 |
19/10 |
19/9 |
13/7 |
28/10 |
* 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 |
43634 |
1 |
Encephalomeningocele; encephalomyelocele |
|
|
43639 |
1 |
Gastroschisis |
|
|
43645 |
1 |
Hydrocephalus |
|
|
43654 |
4 |
Encephalomyelocele |
|
|
43655 |
1 |
Encephalomyelocele |
FDA 73-1 |
6.41 |
43707 |
1 |
Hydrocephalus; cleft palate |
Table 2 Reproduction data
Dose (mg/kg) |
Sham |
Aspirin |
1.69 |
9.24 |
42.95 |
169.0 |
Pregnancies |
|
|
|
|
|
|
Total No. |
23 |
21 |
24 |
24 |
24 |
21 |
Died or aborted (before Day 20) |
0 |
1 |
0 |
0 |
0 |
0 |
To term (on Day 20) |
23 |
20 |
24 |
24 |
24 |
21 |
Live litters |
|
|
|
|
|
|
Total No.* |
23 |
18 |
24 |
24 |
24 |
21 |
Implant Sites |
|
|
293 |
|
|
|
Total No. |
283 |
234 |
12.2 |
284 |
287 |
254 |
Average/dam* |
12.3 |
11.7 |
|
11.8 |
12.0 |
12.1 |
Resorptions |
|
|
|
|
|
|
Total No* |
4 |
35 |
4 |
4 |
4 |
-- |
Dams with 1 or more sites resorbed |
2 |
5 |
4 |
4 |
3 |
-- |
Dams with all sites resorbed |
-- |
2 |
-- |
-- |
-- |
-- |
Per cent partial resorptions |
8.70 |
25.0 |
16.7 |
16.7 |
12.5 |
-- |
Per cent complete resorptions |
-- |
10.0 |
-- |
-- |
-- |
-- |
Live foetuses |
|
|
|
|
|
|
Total No |
279 |
197 |
288 |
280 |
283 |
254 |
Average/dam* |
12.1 |
9.85 |
12.0 |
11.7 |
11.8 |
12.1 |
Sex ratio (M/F) |
1.08 |
0.80 |
1.27 |
1.00 |
0.98 |
1.03 |
Dead Foetuses |
|
|
|
|
|
|
Total No.* |
-- |
2 |
1 |
-- |
-- |
-- |
Dams with 1 or more dead |
-- |
2 |
1 |
-- |
-- |
-- |
Dams with all dead |
-- |
-- |
-- |
-- |
-- |
-- |
Per cent partial dead |
-- |
10.0 |
4.17 |
-- |
-- |
-- |
Per cent all dead |
-- |
-- |
-- |
-- |
-- |
-- |
Average foetus weight (g) |
3.65 |
2.41 |
3.71 |
3.78 |
3.78 |
3.75 |
* Includes only those dams examined at term
** Positive control: 250 mg/kg
Table 3 Summary of skeletal findings
Findings |
Dose (mg/kg) |
|||||
Sham |
Aspirin |
1.69 |
9.24 |
42.95 |
169.0 |
|
Live foetuses examined (at term) |
191/23 |
137/18 |
198/24 |
193/24 |
196/24 |
176/21 |
Sternebrae |
|
|
|
|
|
|
Incomplete oss. |
71/20 |
86/16 |
83/19 |
54/19 |
61/16 |
47/17 |
Scrambled |
|
|
|
|
|
|
Bipartite |
|
7/5 |
|
|
2/2 |
4/3 |
Fused |
|
|
|
|
|
|
Extra |
|
|
|
|
|
|
Missing |
7/6 |
117/7 |
9/7 |
15/8 |
1/1 |
5/4 |
Other |
|
|
|
|
|
|
Ribs |
|
|
|
|
|
|
Incomplete oss. |
1/1 |
3/2 |
3/2 |
|
|
1/1 |
Fused/split |
|
14/4 |
|
|
|
|
Wavy |
14/8 |
54/14 |
34/9 |
12/7 |
15/8 |
13/8 |
Less than 12 |
|
|
|
|
|
|
More than 13 |
1/1 |
89/15 |
6/5 |
3/3 |
|
6/5 |
Other |
|
|
|
|
|
|
Vertebrae |
|
|
|
|
|
|
Incomplete oss. |
6/5 |
120/17 |
12/4 |
21/11 |
5/4 |
10/8 |
Scrambled |
|
1/1 |
|
|
|
|
Fused |
|
|
1/1 |
|
|
|
Extra ctrs. oss. |
|
|
|
|
|
|
Scoliosis |
|
3/3 |
|
|
|
|
Tail defects |
|
1/1 |
|
|
|
|
Other |
|
|
|
|
|
|
Skull |
|
|
|
|
|
|
Incomplete closure |
23/10 |
60/13 |
50/16 |
31/12 |
25/13 |
20/11 |
Missing |
|
9/4 |
|
|
|
|
Craniostosis |
|
|
|
|
|
|
Other |
|
1/1 |
|
|
|
|
Extremities |
|
|
|
|
|
|
Incomplete oss. |
|
4/3 |
|
|
|
|
Missing |
|
|
|
|
|
|
Extra |
|
|
|
|
|
|
Miscellaneous |
|
|
|
|
|
|
Hyoid; missing |
19/11 |
69/17 |
37/15 |
14/9 |
26/13 |
7/6 |
Hyoid; reduced |
7/5 |
20/8 |
38/14 |
27/12 |
35/16 |
28/12 |
* 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 4910 |
1 |
Encepalomyelocele |
|
|
A 4913 |
1 |
Exencephaly; exophthalmos |
|
|
A 4917 |
1 |
Renal agenesis |
|
|
A 4921 |
1 |
Encephalomyelocele; gastroschisis |
|
|
A 4923 |
3 |
Encephalomyelocele |
|
|
|
1 |
Exophthalmos; gastroschisis |
|
|
A 4925 |
2 |
Encepalomyelocele |
FDA 71-61 |
42.95 |
M 4076 |
1 |
Gastroschisis |
Table 2 Reproduction data
Dose (mg/kg) |
Sham |
Aspirin |
1.66 |
7.71 |
35.8 |
166.0 |
Pregnancies |
|
|
|
|
|
|
Total No. |
20 |
21 |
20 |
20 |
21 |
22 |
Died or aborted (before Day 14) |
0 |
0 |
0 |
0 |
1 |
1 |
To term (on Day 14) |
20 |
21 |
20 |
20 |
20 |
21 |
Live litters |
|
|
|
|
|
|
Total No.* |
20 |
21 |
20 |
20 |
20 |
21 |
Implant Sites |
|
|
|
|
|
|
Total No. |
298 |
311 |
292 |
289 |
290 |
300 |
Average/dam* |
14.9 |
14.8 |
14.6 |
14.5 |
14.5 |
14.3 |
Resorptions |
|
|
|
|
|
|
Total No* |
1 |
8 |
1 |
1 |
1 |
8 |
Dams with 1 or more sites resorbed |
1 |
6 |
1 |
1 |
1 |
5 |
Dams with all sites resorbed |
-- |
-- |
-- |
-- |
-- |
-- |
Per cent partial resorptions |
5.00 |
28.6 |
5.00 |
5.00 |
5.00 |
23.8 |
Per cent complete resorptions |
-- |
-- |
-- |
-- |
-- |
-- |
Live foetuses |
|
|
|
|
|
|
Total No |
295 |
303 |
291 |
288 |
289 |
292 |
Average/dam* |
14.8 |
14.4 |
14.6 |
14.4 |
14.5 |
13.9 |
Sex ratio (M/F) |
0.89 |
0.94 |
0.81 |
0.78 |
0.75 |
0.75 |
Dead Foetuses |
|
|
|
|
|
|
Total No.* |
2 |
-- |
-- |
-- |
-- |
-- |
Dams with 1 or more dead |
2 |
-- |
-- |
-- |
-- |
-- |
Dams with all dead |
-- |
-- |
-- |
-- |
-- |
-- |
Per cent partial dead |
10.0 |
-- |
-- |
-- |
-- |
-- |
Per cent all dead |
-- |
-- |
-- |
-- |
-- |
-- |
Average foetus weight (g) |
1.70 |
1.72 |
1.72 |
1.82 |
1.82 |
1.75 |
* Includes only those dams examined at term
** Positive control: 250 mg/kg
Table 3 Summary of skeletal findings
Findings |
Dose (mg/kg) |
|||||
Sham |
Aspirin |
1.66 |
7.71 |
35.8 |
166.0 |
|
Live foetuses examined (at term) |
204/20 |
209/21 |
200/20 |
199/20 |
202/20 |
202/21 |
Sternebrae |
|
|
|
|
|
|
Incomplete oss. |
131/20 |
85/20 |
124/20 |
69/17 |
88/18 |
80/20 |
Scrambled |
|
|
|
|
|
|
Bipartite |
18/9 |
16/11 |
22/14 |
20/11 |
15/9 |
25/13 |
Fused |
|
|
|
|
|
|
Extra |
8/2 |
|
1/1 |
6/3 |
5/3 |
|
Missing |
53/14 |
48/13 |
49/12 |
39/10 |
33/10 |
51/14 |
Other |
|
|
|
|
|
|
Ribs |
|
|
|
|
|
|
Incomplete oss. |
|
|
|
|
|
|
Fused/split |
|
|
|
|
|
2/1 |
Wavy |
|
|
|
|
|
|
Less than 12 |
|
|
|
|
|
|
More than 13 |
62/17 |
56/13 |
46/16 |
69/17 |
38/13 |
60/16 |
Other |
|
|
|
|
|
|
Vertebrae |
|
|
|
|
|
|
Incomplete oss. |
2/2 |
15/5 |
|
1/1 |
|
8/2 |
Scrambled |
|
|
|
|
|
|
Fused |
|
|
|
|
|
|
Extra ctrs. oss. |
|
|
|
|
|
|
Scoliosis |
|
|
|
|
|
|
Tail defects |
|
|
|
|
|
|
Other |
|
|
|
|
|
|
Skull |
|
|
|
|
|
|
Incomplete closure |
|
|
|
|
|
|
Missing |
|
|
|
|
|
|
Craniostosis |
|
|
|
|
|
|
Other |
|
|
|
|
|
|
Extremities |
|
|
|
|
|
|
Incomplete oss. |
4/4 |
17/6 |
|
6/4 |
|
13/3 |
Missing |
|
|
|
|
|
|
Extra |
|
|
|
|
|
|
Miscellaneous |
|
|
|
|
|
|
Hyoid; missing |
6/6 |
14/6 |
5/4 |
4/2 |
2/1 |
13/3 |
Hyoid; reduced |
7/7 |
6/5 |
9/7 |
7/3 |
6/5 |
8/6 |
* 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 |
Sham |
0.0 |
S 5908 |
1 |
Meningoencephalocele |
|
|
S 5914 |
1 |
Hydrocephalus |
Aspirin |
250.0 |
A 5912 |
1 |
Hepatomegaly |
FDA 71-61 |
1.66 |
M 5013 |
1 |
Hydrocephalus |
FDA 71-61 |
166.0 |
M 5092 |
4 |
Hydrocephalus |
|
|
|
2 |
Hydromyelia |
Table 2 Reproduction data
Dose (mg/kg) |
Sham |
Aspirin** |
3.35 |
15.6 |
72.3 |
335.0 |
Pregnancies |
|
|
|
|
|
|
Total No. |
25 |
21 |
23 |
23 |
23 |
22 |
Died or aborted (before Day 17) |
0 |
0 |
0 |
0 |
0 |
0 |
To term (on Day 17) |
25 |
21 |
23 |
23 |
23 |
22 |
Live litters |
|
|
|
|
|
|
Total No.* |
25 |
20 |
23 |
23 |
23 |
21 |
Implant Sites |
|
|
|
|
|
|
Total No. |
286 |
254 |
280 |
279 |
265 |
256 |
Average/dam* |
11.4 |
12.1 |
12.2 |
12.1 |
11.5 |
11.6 |
Resorptions |
|
|
|
|
|
|
Total No* |
17 |
37 |
8 |
3 |
10 |
24 |
Dams with 1 or more sites resorbed |
10 |
13 |
6 |
2 |
9 |
9 |
Dams with all sites resorbed |
0 |
1 |
0 |
0 |
0 |
1 |
Per cent partial resorptions |
40.0 |
61.9 |
26.1 |
8.70 |
39.1 |
40.9 |
Per cent complete resorptions |
-- |
4.76 |
-- |
-- |
-- |
4.55 |
Live foetuses |
|
|
|
|
|
|
Total No |
264 |
217 |
271 |
274 |
255 |
229 |
Average/dam* |
10.6 |
10.3 |
11.8 |
11.9 |
11.5 |
10.4 |
Sex ratio (M/F) |
0.96 |
0.75 |
0.75 |
0.73 |
0.82 |
0.84 |
Dead Foetuses |
|
|
|
|
|
|
Total No.* |
5 |
0 |
1 |
2 |
0 |
3 |
Dams with 1 or more dead |
4 |
-- |
1 |
2 |
-- |
3 |
Dams with all dead |
0 |
-- |
0 |
0 |
-- |
0 |
Per cent partial dead |
16.0 |
-- |
4.35 |
8.70 |
-- |
13.6 |
Per cent all dead |
-- |
-- |
-- |
-- |
-- |
-- |
Average foetus weight (g) |
0.88 |
0.84 |
0.84 |
0.89 |
0.86 |
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** |
3.35 |
15.6 |
72.3 |
335.0 |
|
Live foetuses examined (at term) |
183/25 |
154/20 |
188/23 |
190/23 |
176/23 |
159/21 |
Sternebrae |
|
|
|
|
|
|
Incomplete oss. |
23/10 |
34/13 |
19/11 |
45/13 |
33/13 |
29/9 |
Scrambled |
|
|
|
|
|
|
Bipartite |
5/4 |
6/5 |
9/7 |
10/9 |
5/3 |
9/6 |
Fused |
|
|
|
|
|
|
Extra |
|
1/1 |
|
|
|
1/1 |
Missing |
35/14 |
26/11 |
27/11 |
39/8 |
30/10 |
14/6 |
Other |
|
|
|
|
|
|
Ribs |
|
|
|
|
|
|
Incomplete oss. |
|
|
3/1 |
|
2/1 |
|
Fused/split |
|
1/1 |
|
|
|
|
Wavy |
|
|
|
|
|
|
Less than 12 |
|
|
|
|
|
|
More than 13 |
12/7 |
37/15 |
34/15 |
32/14 |
38/11 |
31/15 |
Other |
|
|
|
|
|
|
Vertebrae |
|
|
|
|
|
|
Incomplete oss. |
4/3 |
9/5 |
12/4 |
8/3 |
4/2 |
4/2 |
Scrambled |
|
|
|
|
|
|
Fused |
|
|
|
|
|
|
Extra ctrs. oss. |
|
|
|
|
|
|
Scoliosis |
|
|
|
|
|
|
Tail defects |
|
|
|
|
|
|
Other |
|
|
|
|
|
|
Skull |
|
|
|
|
|
|
Incomplete closure |
|
|
1/1 |
|
|
|
Missing |
|
|
1/1 |
|
|
|
Craniostosis |
|
|
|
|
|
|
Other; facial bones, inc |
|
|
|
1/1 |
|
|
Extremities |
|
|
|
|
|
|
Incomplete oss. |
4/3 |
6/4 |
12/6 |
7/3 |
7/3 |
4/2 |
Missing |
|
|
|
|
|
|
Extra |
|
|
|
|
|
|
Miscellaneous |
|
|
|
|
|
|
Hyoid; missing |
29/12 |
35/15 |
39/15 |
52/16 |
46/15 |
33/13 |
Hyoid; reduced |
17/13 |
23/13 |
24/12 |
18/10 |
17/13 |
23/10 |
* 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 3911 |
1 |
Microblepharia Gastroschisis |
FDA 71-61 |
3.35 |
M 3010 |
1 |
Umbilical hernia |
FDA 71-61 |
15.6 |
M3033 |
1 |
Umbilical hernia |
|
|
M 3053 |
1 |
Hydrocephalus |
FDA 71-61 |
72.3 |
M3078 |
1 |
Hydrocephalus |
Table 2 Reproduction data
Dose (mg/kg) |
Sham |
6-AN |
1.28 |
5.95 |
27.6 |
128.0 |
Pregnancies |
|
|
|
|
|
|
Total No. |
11 |
10 |
12 |
12 |
9 |
11 |
Died or aborted (before Day 29) |
1 |
0 |
0 |
2 |
0 |
0 |
To term (on Day 29) |
10 |
10 |
12 |
10 |
9 |
11 |
Corpora Lutea |
|
|
|
|
|
|
Total no. |
175 |
132 |
146 |
191 |
140 |
159 |
Average/dam mated |
14.6 |
12.0 |
12.2 |
13.6 |
9.33 |
12.2 |
Live litters |
|
|
|
|
|
|
Total No.* |
10 |
6 |
12 |
9 |
9 |
11 |
Implant Sites |
|
|
|
|
|
|
Total No. |
53 |
42 |
70 |
64 |
44 |
80 |
Average/dam* |
5.30 |
4.20 |
5.83 |
6.40 |
4.89 |
7.27 |
Resorptions |
|
|
|
|
|
|
Total No* |
-- |
18 |
3 |
9 |
1 |
7 |
Dams with 1 or more sites resorbed |
-- |
6 |
2 |
3 |
1 |
5 |
Dams with all sites resorbed |
-- |
4 |
-- |
1 |
-- |
-- |
Per cent partial resorptions |
-- |
60.0 |
16.7 |
30.0 |
11.1 |
45.5 |
Per cent complete resorptions |
-- |
40.0 |
-- |
10.0 |
-- |
-- |
Live foetuses |
|
|
|
|
|
|
Total No |
52 |
19 |
67 |
55 |
43 |
73 |
Average/dam* |
5.20 |
1.90 |
5.58 |
5.50 |
4.78 |
6.64 |
Sex ratio (M/F) |
0.73 |
5.00 |
0.63 |
1.04 |
1.26 |
0.92 |
Dead Foetuses |
|
|
|
|
|
|
Total No.* |
1 |
5 |
-- |
-- |
-- |
73 |
Dams with 1 or more dead |
1 |
2 |
-- |
-- |
-- |
-- |
Dams with all dead |
-- |
-- |
- |
-- |
-- |
-- |
Per cent partial dead |
10.0 |
20.0 |
-- |
-- |
-- |
-- |
Per cent all dead |
-- |
-- |
-- |
-- |
-- |
-- |
Average foetus weight (g) |
42.2 |
29.7 |
37.0 |
36.0 |
40.0 |
35.8 |
* 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 |
1.28 |
5.95 |
27.6 |
128.0 |
|
Live foetuses examined (at term) |
52/10 |
19/6 |
67/12 |
55/9 |
43/9 |
72/11a |
Sternebrae |
|
|
|
|
|
|
Incomplete oss. |
2/2 |
1/1 |
|
1/1 |
2/2 |
|
Scrambled |
|
|
|
|
|
|
Bipartite |
|
1/1 |
|
1/1 |
|
1/1 |
Fused |
|
3/2 |
|
|
|
|
Extra |
|
1/1 |
2/1 |
|
|
6/4 |
Missing |
|
2/2 |
|
|
|
|
Other |
|
|
|
|
|
|
Ribs |
|
|
|
|
|
|
Incomplete oss. |
|
|
|
|
|
|
Fused/split |
|
5/2 |
|
|
3/1 |
|
Wavy |
|
|
|
|
|
|
Less than 12 |
|
|
|
|
|
|
More than 13 |
|
|
|
|
|
|
Other |
|
|
|
|
|
|
Vertebrae |
|
|
|
|
|
|
Incomplete oss. |
|
|
|
|
|
|
Scrambled |
|
4/2 |
|
|
|
|
Fused |
|
|
|
|
|
|
Extra ctrs. oss. |
|
|
|
|
|
|
Scoliosis |
|
4/3 |
|
|
|
|
Tail defects |
|
13/4 |
|
|
1/1 |
1/1 |
Other |
|
|
|
|
|
|
Skull |
|
|
|
|
|
|
Incomplete closure |
|
1/1 |
|
|
|
|
Missing |
|
|
|
|
|
|
Craniostosis |
|
|
|
|
|
|
Other; facial bones, inc |
|
1/1 |
|
|
|
|
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
a One pup lost in processing
Table 4 Summary of soft tissue abnormalities
Material |
Dose level (mg/kg) |
Dam |
Number of pups |
Description |
6-AN |
2.5 |
Z 6479 |
1 |
Medial rotation of hind limbs |
|
|
Z 6488 |
1 |
Medial rotation of hind limbs |
|
|
Z 6489 |
1 |
Siamese pups (combined stomach and head) |
|
|
Z 6490 |
3 |
Anopia, Medial rotation of hind limbs |
|
|
|
2 |
Anopia |
FDA 71-61 |
27.6 |
M 6051 |
2 |
Anopia |
Effect on developmental toxicity: via oral route
- Endpoint conclusion:
- no adverse effect observed
Justification for classification or non-classification
The following results were reported on the analogous substances:
Under the conditions of the study on tetrasodium pyrophosphate administered to pregnant mice for 10 days up to a dose level of 130 mg/kg bw showed no maternal or developmental toxicity. The NOAEL for both maternal and fetotoxicity was > 130 mg/kg bw.
Tetrasodium pyrophosphate administered to pregnant rats for 10 days up to a dose level of 138 mg/kg bw showed no maternal or developmental toxicity. The NOAEL for both maternal and fetotoxicity is > 138 mg/kg bw.
Under the conditions of the study on disodium dihydrogenpyrophosphate, the test material administered to pregnant mice for 10 days up to a dose level of 335 mg/kg bw showed no maternal or developmental toxicity. The NOAEL for both maternal and fetotoxicity in mice is > 335 mg/kg bw. When the test material was administered to pregnant rats for 10 days up to a dose level of 169 mg/kg bw no maternal toxicity or developmental toxicity was observed. The NOAEL for both maternal and fetotoxicity is > 169 mg/kg bw.
When the test material was administered to pregnant hamsters for 10 days up to a dose level of 166 mg/kg bw no maternal toxicity or developmental toxicity was observed. The NOAEL for both maternal and fetotoxicity is > 166 mg/kg bw.
When the test material was administered to pregnant rabbits for 10 days up to a dose level of 128 mg/kg bw no maternal toxicity or developmental toxicity was observed. The NOAEL for both maternal and fetotoxicity is > 128 mg/kg bw.
It is not considered to be scientifically justified to further investigate the effects of tetrapotassium pyrophosphate on reprotoxicity, developmental or maternal toxicity and as such no classification is proposed for this endpoint and no further studies are deemed necessary.
Additional information
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