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Toxicological information

Developmental toxicity / teratogenicity

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Administrative data

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
27/09/1974 - 29/10/1974
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
test procedure in accordance with national standard methods with acceptable restrictions
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
In this instance, the substance similarities are as follows:
1. The source and target substances are both inorganic salts of a monovalent cation from Group 1A of the periodic table; sodium and phosphate anion(s).
2. Both substances will ultimately dissociate into the common breakdown products; Na+ cations and PO43- anions. In biological systems, the metaphosphate will undergo hydrolysis (increased in acidic solutions) to form shorter phosphate chains and ultimately phosphate (PO43- anions).
3. Both substances have similar physicochemical and toxicological profiles. The ionic components of both the source and the target compounds are essential micronutrients and their uptake is tightly regulated.

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’.
Cross-referenceopen allclose all
Reason / purpose:
reference to same study
Reference
Endpoint:
developmental toxicity
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
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
In this instance, the substance similarities are as follows:
1. The source and target substances are both inorganic salts of a monovalent cation from Group 1A of the periodic table; sodium and phosphate anion(s).
2. Both substances will ultimately dissociate into the common breakdown products; Na+ cations and PO43- anions. In biological systems, the metaphosphate will undergo hydrolysis (increased in acidic solutions) to form shorter phosphate chains and ultimately phosphate (PO43- anions).
3. Both substances have similar physicochemical and toxicological profiles. The ionic components of both the source and the target compounds are essential micronutrients and their uptake is tightly regulated.

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:
reference to same study
Reason / purpose:
read-across source
Reason / purpose:
read-across: supporting information
Vehicle:
water
Details on maternal toxic effects:
Maternal toxic effects:no effects
Key result
Dose descriptor:
NOAEL
Effect level:
> 370 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: no effects noted
Key result
Abnormalities:
no effects observed
Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:no effects
Key result
Dose descriptor:
NOAEL
Effect level:
> 370 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: no effects noted
Key result
Abnormalities:
no effects observed
Key result
Developmental effects observed:
no

Table 2 Reproduction data

Dose (mg/kg)

Sham

Aspirin

3.7

17.2

79.7

370.0

Pregnancies

 

 

 

 

 

 

Total No.

21

20

22

19

20

22

Died or aborted (before Day 17)

0

0

0

0

0

0

To term (on Day 17)

21

20

22

19

20

22

Corpora Lutea

 

 

 

 

 

 

Total no.

275

233

255

233

251

279

Average/dam mated

11.0

8.63

10.2

9.32

10.0

11.2

Live litters

 

 

 

 

 

 

Total No.*

21

20

22

19

20

22

Implant Sites

 

 

 

 

 

 

Total No.

259

218

240

224

236

255

Average/dam*

12.3

10.9

10.9

11.8

11.8

11.6

Resorptions

 

 

 

 

 

 

Total No*

8

8

5

9

10

13

Dams with 1 or more sites resorbed

8

6

5

4

9

11

Dams with all sites resorbed

--

--

--

--

--

--

Per cent partial resorptions

38.1

30.0

22.7

21.1

45.0

50.0

Per cent complete resorptions

--

--

--

--

--

--

Live foetuses

 

 

 

215

 

 

Total No

248

208

233

11.3

224

240

Average/dam*

11.8

10.4

10.6

1.01

11.2

10.9

Sex ratio (M/F)

1.04

0.84

0.82

 

0.84

1.07

Dead Foetuses

 

 

 

--

 

 

Total No.*

3

2

2

--

2

2

Dams with 1 or more dead

3

1

2

--

2

2

Dams with all dead

--

--

--

--

--

--

Per cent partial dead

14.3

5.00

9.09

--

10.0

9.09

Per cent all dead

--

--

--

--

--

--

Average foetus weight (g)

0.8

0.85

0.85

0.92

0.93

0.86

* Includes only those dams examined at term

** Positive control: 150 mg/kg

 

Table 3 Summary of skeletal findings

Findings

Dose (mg/kg)

Sham

Aspirin

3.7

17.2

79.7

370.0

Live foetuses examined (at term)

173/21

144/20

165/22

148/149

156/20

167/22

Sternebrae

 

 

 

 

 

 

Incomplete oss.

60/19

65/19

32/14

51/16

13/5

81/19

Scrambled

 

 

 

 

 

 

Bipartite

 

1/1

 

3/2

 

3/2

Fused

 

 

 

 

 

 

Extra

 

 

 

 

 

 

Missing

39/12

36/11

19/9

13/7

2/2

20/12

Other

 

 

 

 

 

 

Ribs

 

 

 

 

 

 

Incomplete oss.

 

 

 

 

 

 

Fused/split

 

 

 

1/1

 

 

Wavy

 

 

 

 

 

 

Less than 12

 

 

 

 

 

 

More than 13

23/10

32/14

23/12

25/10

30/16

25/15

Other

 

 

 

 

 

 

Vertebrae

 

 

 

 

 

 

Incomplete oss.

4/2

11/5

4/3

1/1

 

 

Scrambled

 

 

 

 

 

 

Fused

 

 

 

 

 

 

Extra ctrs. oss.

 

 

 

 

 

 

Scoliosis

 

 

 

 

 

 

Tail defects

 

 

 

 

 

 

Other

 

 

 

 

 

 

Skull

 

 

 

 

 

 

Incomplete closure

2/2

 

 

 

 

 

Missing

 

 

 

 

 

 

Craniostosis

 

 

 

 

 

 

Other

 

 

 

 

 

 

Extremities

 

 

 

 

 

 

Incomplete oss.

6/4

15/5

2/2

1/1

 

1/1

Missing

 

 

 

 

 

 

Extra

 

 

 

 

 

 

Miscellaneous

 

 

 

 

 

 

Hyoid; missing

30/12

60/16

24/12

26/11

27/11

43/15

Hyoid; reduced

26/12

18/13

22/13

26/16

19/10

22/14

* Numerator = Number of foetuses affected; Denominator = Number of litters affected

** Positive control: 150 mg/kg

Summary of soft tissue abnormalities: 1 pup from a litter where the dam was dosed with 3.7 mg/kg test material showed exophthalmos and encephalmeningocele.

Conclusions:
Under the conditions of the study, the test material administered to pregnant mice for 10 days up to a dose level of 370 mg/kg bw showed no maternal or developmental toxicity. The NOAEL for both maternal and fetoxicity is > 370 mg/kg bw.


Reason / purpose:
read-across: supporting information

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1975
Report Date:
1975

Materials and methods

Test guideline
Qualifier:
according to
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 4.1, 19.0, 88.3 or 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 and humidity were 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

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
solid: particulate/powder
Remarks:
migrated information: powder
Details on test material:
- Name of test material (as cited in study report): FDA 73-2 (Monosodium phosphate, anhydrous)
- Physical state: Fine white powdered material

Test animals

Species:
rat
Strain:
Wistar
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Outbred
- Age at study initiation: No data
- Weight at study initiation: 223 - 237 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): 20 - 28
- Humidity (%): 42 - 74%

IN-LIFE DATES: From: 27/09/1974 To: 29/10/1974

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
No. of animals per sex per dose:
Test material and vehicle control: 20 females / dose level
Control animals:
yes, sham-exposed
other: positive control: 250 mg/kg 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: 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

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:
Maternal toxic effects:no effects

Effect levels (maternal animals)

Dose descriptor:
NOAEL
Effect level:
> 410 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: no effects noted

Maternal abnormalities

Abnormalities:
no effects observed

Results (fetuses)

Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:no effects

Effect levels (fetuses)

Dose descriptor:
NOAEL
Effect level:
> 410 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: no effects noted

Fetal abnormalities

Abnormalities:
no effects observed

Overall developmental toxicity

Developmental effects observed:
no

Any other information on results incl. tables

Table 1 Reproduction data

Dose (mg/kg)

Sham

Aspirin

4.1

19.0

88.3

410.0

Pregnancies

 

 

 

 

 

 

Total No.

20

20

20

20

20

20

Died or aborted (before Day 20)

0

0

0

0

0

0

To term (on Day 20)

20

20

20

20

20

20

Corpora Lutea

 

 

 

 

 

 

Total no.

267

263

263

252

264

267

Average/dam mated

12.7

12.5

12.5

12.0

12.6

13.4

Live litters

 

 

 

 

 

 

Total No.*

20

19

20

20

20

20

Implant Sites

 

 

 

 

 

 

Total No.

262

238

240

251

239

244

Average/dam*

13.1

11.9

12.0

12.6

12.0

12.2

Resorptions

 

 

 

 

 

 

Total No*

--

35

1

5

1

2

Dams with 1 or more sites resorbed

--

7

1

3

1

1

Dams with all sites resorbed

--

1

--

--

--

--

Per cent partial resorptions

--

35.0

5.00

15.0

5.00

5.00

Per cent complete resorptions

--

5.00

--

--

--

--

Live foetuses

 

 

 

 

 

 

Total No

262

203

239

246

238

242

Average/dam*

13.1

10.2

12.0

12.3

11.9

12.1

Sex ratio (M/F)

1.06

0.92

1.03

0.95

1.00

1.12

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)

3.93

2.92

3.84

3.91

4.00

3.85

* Includes only those dams examined at term

** Positive control: 250 mg/kg

 

Table 2 Summary of skeletal findings

Findings

Dose (mg/kg)

Sham

Aspirin

4.1

19.0

88.3

410.0

Live foetuses examined (at term)

179/20

143/19

166/20

171/20

168/20

170/20

Sternebrae

 

 

 

 

 

 

Incomplete oss.

37/16

89/19

42/17

82/18

49/15

45/11

Scrambled

 

8/6

1/1

 

 

1/1

Bipartite

 

 

 

 

 

 

Fused

 

 

 

 

 

 

Extra

 

 

 

 

 

 

Missing

3/3

70/15

4/3

10/7

 

7/6

Other

 

 

 

 

 

 

Ribs

 

 

 

 

 

 

Incomplete oss.

2/2

15/8

7/2

 

 

1/1

Fused/split

 

5/2

 

 

 

 

Wavy

23/8

60/17

19/8

23/11

11/6

13/5

Less than 12

 

 

 

 

 

 

More than 13

2/2

59/15

 

4/4

 

1/1

Other

 

 

 

 

 

 

Vertebrae

 

 

 

 

 

 

Incomplete oss.

4/4

68/18

2/1

1/1

9/6

10/4

Scrambled

 

 

 

 

 

 

Fused

 

 

 

 

 

 

Extra ctrs. oss.

 

1/1

 

 

 

 

Scoliosis

 

 

 

 

 

 

Tail defects

 

 

 

 

 

 

Other

 

 

 

 

 

 

Skull

 

 

 

 

 

 

Incomplete closure

38/13

88/19

33/14

30/12

37/11

40/11

Missing

 

 

 

 

 

 

Craniostosis

 

 

 

 

 

 

Other

 

 

 

 

 

 

Extremities

 

 

 

 

 

 

Incomplete oss.

 

3/3

 

 

 

 

Missing

 

 

 

 

 

 

Extra

 

 

 

 

 

 

Miscellaneous

 

 

 

 

 

 

Hyoid; missing

21/10

54/16

21/12

19/10

12/8

20/11

Hyoid; reduced

26/13

21/10

33/14

28/11

41/14

47/14

* Numerator = Number of foetuses affected; Denominator = Number of litters affected

** Positive control: 250 mg/kg

 

Table 3 Summary of soft tissue abnormalities

Material

Dose level (mg/kg)

Dam

Number of pups

Description

Aspirin

250.0

44235

1

Hydrocephalus

 

 

44240

1

Hydrocephalus; Encephalomeningocele

 

 

44246

2

Hydrocephalus

 

 

44252

1

Spina bifida; Encephalomeningocele

 

 

44255

1

Hydrocephalus

FDA 73-2

88.3

44337

1

Umbilical hernia

 

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 fetoxicity is > 410 mg/kg bw.