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Effects on fertility

Effect on fertility: via oral route
Endpoint conclusion:
no study available
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

Short description of key information:
One reliable study is supplied for the endpoint ‘8.7.1 Screening for reproductive / developmental toxicity’. This study has been conducted according to an appropriate method (OECD guideline 422) and under the conditions of GLP. However as the study is only a 28-day study and in accordance with Annex XI, Section 3.2 (a. ii) of Regulation (EC) N0. 1907/2006 (REACH) the data are not considered to be suitable for derivation of a DNEL as subchronic data are available. Furthermore, full access to the data has not been granted to all registrants.
No further laboratory studies for reproductive toxicity are available. The Justifications for the deviations from the standard testing requirements are detailed in the data adaptation record.

Justification for selection of Effect on fertility via oral route:
An adaptation is submitted.

Effects on developmental toxicity

Description of key information
One reliable study is supplied for the endpoint ‘8.7.1 Screening for reproductive / developmental toxicity’. This study has been conducted according to an appropriate method (OECD guideline 422) and under the conditions of GLP. However as the study is only a 28-day study and in accordance with Annex XI, Section 3.2 (a.ii) of Regulation (EC) N0. 1907/2006 (REACH) the data are not considered to be suitable for derivation of a DNEL as subchronic data are available. Furthermore, full access to the data has not been granted to all registrants.
In addition a key study is available for the endpoint '8.7.2. Developmental toxicity study'. The study is performed on an analogous substance. This study assesses the teratogenic potential of sodium dihydrogenorthophosphate (Bailey, 1975) in rats and mice. This study is considered to be adequate to fulfil this endpoint. In addition, supporting data on the analogous substance monopotassium phosphate is also provided to support the lack of developmental toxicity potential of sodium and potassium orthophosphates as a group of chemicals. Studies on additional test species are not considered to be scientifically necessary due to the lack of toxicity of the substance to be registered.
Link to relevant study records
Reference
Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
06/10/1974 - 02/11/1974
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
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

The source substance and the target substance are considered to be similar enough to facilitate read-across for the following reasons:
1. Both substances show low systemic toxicity in in vivo studies. A number of studies are provided to show that monovalent potassium and/or sodium inorganic orthophosphates exhibit low systemic toxicity via the oral route for both acute exposure and repeated dose exposure.
2. Substance similarities: Both salts are monovalent inorganic phosphates, composed of a phosphate anion and a sodium cation. Differences arise in their local effects profile due to the increasing or decreasing acidity of the substances. This has been shown not to have an effect on the systemic toxicity profile of the substances, thus suggesting that they are metabolized via similar metabolic pathways and to similar breakdown products.

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: supporting information
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 3.7, 17.2, 79.7 or 370.0 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 17 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:
mouse
Strain:
other: albino CD-1
Details on test animals 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): ave 21 - 26
- Humidity (%): 42 - 74%

IN-LIFE DATES: From: 06/10/1974 To: 02/11/1974
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:
Test material and vehicle control: 25 females / dose level
Positive control: 27 females
Table 1 Number of animals dosed
Material Dose (mg/kg) Total
Mated Pregnant
Sham 0.0 25 21
Aspirin 150.0 27 20
FDA 73-2 3.7 25 22
17.2 25 19
79.7 25 20
370.0 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: 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:
> 370 mg/kg bw/day
Basis for effect level:
other: No effects noted at top dose
Abnormalities:
no effects observed
Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:no effects
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 at top dose
Abnormalities:
no effects observed
Developmental effects observed:
not specified

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 fetotoxicity is > 370 mg/kg bw.

This study is considered to be of adequate reliability and relevance to be submitted as the key study for this endpoint.
Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
370 mg/kg bw/day
Study duration:
subacute
Species:
mouse
Quality of whole database:
One key study on a similar substance exists - both mice and rats are investigated. In addition, supporting evidence on an analogous substance is also submitted. Both studies are Klimisch reliability 2.
Effect on developmental toxicity: via inhalation route
Endpoint conclusion:
no study available
Effect on developmental toxicity: via dermal route
Endpoint conclusion:
no study available
Additional information

Justification for read-across

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

The following substances are considered to be similar enough to facilitate read across for systemic toxicity endpoints:

Sodium dihydrogenorthophosphate, CAS: 7558-80-7

Disodium hydrogenorthophosphate, CAS: 7558-79-4

Trisodium orthophosphate, CAS: 7601-54-9

Potassium dihydrogenorthophosphate, CAS: 7778-77-0

Dipotassium hydrogenorthophosphate, CAS: 7758-11-4

Tripotassium orthophosphate, CAS: 7778-53-2

Potassium pentahydrogen bis(phosphate), CAS: 14887-42-4

The source chemicals and the target chemical have the following similar properties:

1. All members of the group are structurally similar ionic inorganic compounds with the anion only changing by the number of hydrogen atoms to account for changes in charge due to increase in cation numbers.

Progression through the group sees an increase in cation number from one to three followed by a change in cation from sodium to potassium and again an increase in number from one to three. Both cations are group 1 alkali metals with the same ionic charge, similar chemical behaviour and both sodium and potassium are essential biological elements. Both the Na+ and the K+ cation have a similar biological function and therefore orthophosphate salts of these types are not considered to differ in their systemic toxicity profile.

2. All members of the group will ultimately dissociate into the common breakdown products of the Na+ or K+ cations and the PO43- anion.

3. All substances have been shown to have a similar systemic toxicological profile and predictable physicochemical nature.

No members of the group are classified for acute toxicity and generally exhibited no mortalities at the classification limit. Two members of the group are classified for local effects only (i.e. skin/eye irritation) which will not have an impact on the systemic toxicity of the compounds. Irritation effects are considered to be predictable based on structural similarities. All are highly water soluble.


Justification for selection of Effect on developmental toxicity: via oral route:
One key study on an analogous substance exists. Selection is made on the basis that the mouse study had a slightly lower NOAEL (although this was still a greater than value).

Justification for classification or non-classification

Under the conditions of the study on sodium dihydrogenorthophosphate, 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 fetotoxicity in mice is > 370 mg/kg bw. When the test material was administered to pregnant rats for 10 days up to a dose level of 410 mg/kg bw no maternal toxicity or developmental toxicity was observed. The NOAEL for both maternal and fetotoxicity is > 410 mg/kg bw.

It is not considered to be scientifically justified to further investigate the effects of trisodium orthophosphate on developmental or maternal toxicity and as such no classification is proposed for this endpoint and no further studies are deemed necessary.