Registration Dossier

Toxicological information

Endpoint summary

Currently viewing:

Administrative data

Key value for chemical safety assessment

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. Furthermore, a testing proposal has been submitted for analogous substance. It is anticipated that this data, once generated, will be sufficient to fulfil the Annex IX requirements for this endpoint.

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:
27/09/1974 - 29/10/1974
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:
JUSTIFICATION FOR READ ACROSS; sodium and potassium orthophosphates. The following substances are considered to be similar enough to facilitate read across for systemic toxicity endpoints:
Sodium dihydrogenphosphate, 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

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 calcium 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. 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 and all are highly water soluble.
Reason / purpose:
reference to same study
Reason / purpose:
read-across: supporting information
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
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
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
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:
> 410 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: no effects noted
Abnormalities:
no effects observed
Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:no effects
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
Abnormalities:
no effects observed
Developmental effects observed:
no

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

 

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 fetotoxicity is > 410 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 disodium hydrogenorthophosphate on developmental or maternal toxicity and as such no classification is proposed for this endpoint and no further studies are deemed necessary.