Registration Dossier

Toxicological information

Toxicity to reproduction

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Administrative data

Endpoint:
screening for reproductive / developmental toxicity
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
the study does not need to be conducted because a pre-natal developmental toxicity study is available
Cross-reference
Reason / purpose for cross-reference:
data waiving: supporting information
Reference
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
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:
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
Basis for effect level:
other: 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:
no effects observed
Developmental effects observed:
no

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

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 foetal toxicity is > 138 mg/kg bw.
This study is considered to be adequate and reliable for the purpose of registration under REACH (Regulation (EC) No. 1907/2006) and for classification and labelling in accordance with Regulation (EC) No. 1272/2008 (EU CLP) as part of a weight of evidence approach.

Data source

Materials and methods

Results and discussion

Overall reproductive toxicity

Reproductive effects observed:
not specified

Applicant's summary and conclusion