Myo-Inositol, hexakis(dihydrogen phosphate), sodium salt

Endpoint summary

Description of key information

Acute Toxicity Oral (read across), rat (Fischer 344/DuCrj) m / f: LD50: 1030 mg/kg bw (male); 1200 mg/kg bw (female)

Acute Toxicity Oral (read across), mice (ICL-ICR) m / f: LD50: 1030 mg/kg bw (male); 2750 mg/kg bw (female)

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Reference

Reference 1

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

weight of evidence

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:

This endpoint study record is part of a Weight of Evidence approach comprising two published studies. The test item of this study was a sodium phytate (grade of neutralisation not specified) and the test item of the second published study (RL1) was an analogue substance ("Myo-Inositol, hexakis(dihydrogen phosphate), dodecasodium salt" (CAS 17211 -15 -3; EC 241 -253 -9)) with a similar structure and similar intrinsic properties (Read-across approach). For the justification of the Read-across approach, please refer to the analogue justification attached to IUCLID section 13.
Both data sources are in accordance with generally accepted scientific standards and were performed on different test animal species (mouse and rat). The derived results from the studies are comparable and are sufficient to fulfil the information requirements of this endpoint as further explained in the provided endpoint summary.

Qualifier:

no guideline followed

Principles of method if other than guideline:

single oral administration

GLP compliance:

no

Remarks:

Study carried out in 1987, before 1 June 2008 (refering to REACH Article 13(4))

Specific details on test material used for the study:

SOURCE OF TEST MATERIAL
- Source and lot/batch No.of test material: Sodium Phytate from NAKARAI CHEMICALS, LTD. (unknown grade of neutralisation)
- Expiration date of the lot/batch: no data
- Purity test date: no data

TREATMENT OF TEST MATERIAL PRIOR TO TESTING
- Treatment of test material prior to testing: Sample was water solution. For information on the applied doses (mg/kg B.W.) refer to Table 3 in section "Illustration (picture/graph)".

Species:

mouse

Strain:

ICL-ICR

Sex:

male/female

Route of administration:

oral: unspecified

Doses:

590 / 880 / 1320 / 1980 / 2970 mg/kg bw

No. of animals per sex per dose:

5

Control animals:

no

Details on study design:

- Duration of observation period following administration: 48 hr
- Frequency of observations and weighing: 7 (no weighing)
- Other examinations performed: clinical signs

Statistics:

Lichtfield Wilcoxon

Key result

Sex:

female

Dose descriptor:

LD50

Effect level:

2 750 mg/kg bw

Based on:

test mat.

95% CL:

>= 1 990 - <= 3 800

Key result

Sex:

male

Dose descriptor:

LD50

Effect level:

1 030 mg/kg bw

Based on:

test mat.

95% CL:

>= 560 - <= 1 910

Mortality:

Male: At 2970 mg/kg bw two animals died in the first hour, one animal in the third and another animal in the fourth hour after dosing. At 1980 mg/kg bw 3 animals died in the first hour and one animal between 24 to 48h. At 1320 mg/kg bw 3 animals died in the first hour.No mortalities occurred at 880 mg/kg bw and lower.

Female: At 2970 mg/kg bw two animals died in the fiirst hour and one animal after 5 hours after dosing. At 1980 mg/kg bw one animal died in the first hour. No mortalities occurred at 1320 mg/kg bw and lower.

Clinical signs:

other: In the substance-treated animals the following clinical signs were observed: - Erosion of the stomach wall - bleeding of the glandular portion of the stomach - hypertrophy of the gallbladder - thinning of the small intestinal wall

		Lichtfield-Wilcoxon
	Dose Range (mg/kg bw)	LD50 (mg/kg bw)	Confidence limit (p = 0.05)
Male	590 - 2970	1030	560 - 1910
Female	590 - 2970	2750	1990 - 3800

Interpretation of results:

Category 4 based on GHS criteria

Conclusions:

The LD50 values for acute toxicity (oral) in mice (ICL-ICR) of the test item were reported to be 2750 mg/kg bw (female) and 1030 mg/kg bw (male).

Executive summary:

A single oral administration to mice (ICL-ICR)with5 different doses between 590 - 2970 mg/kg body weight were conducted. Most of the deaths in male and female mice occured within 1h after administration.In male animals dosed at 2970 mg/kg body weight mortality occurred in 4 of 5 males in the first 4 hours after administration. At a dose of 1980 mg/kg bw 3 of 5 male mice died in the first hour and one animal between 24 to 48h after administration. At a dose of 1320 mg/kg bw 3 of 5 male animals died in the first hour. No mortalities occurred at a dose of 880 mg/kg bw and lower. In female mice at 2970 mg/kg bw mortality occured for 2 of 5 animals in the first hour and for one animal after 5 hours. At a dose of 1980 mg/kg bw 1 of 5 female mice died in the first hour. No mortalities among female mice occurred at a dose of 1320 mg/kg bw and lower. In the substance-treated animals erosion of the stomach wall, bleeding of the glandular portion of the stomach, hypertrophy of the gallbladder, and thinning of the intestinal wall were reported.

The oral LD50 values of this test item in mice (ICL-ICR) were reported to be 1030 (males) and 2750 (females) mg/kg body weight.

Reference 2

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: test procedure in accordance with generally accepted scientific standards and described in sufficient detail

Remarks:

Due to READ-ACROSS: RL2

Justification for type of information:

This endpoint study record is part of a Weight of Evidence approach comprising two published scientific studies. The test item of this study was an analogue substance ("Myo-Inositol, hexakis(dihydrogen phosphate), dodecasodium salt" (CAS 17211 -15 -3; EC 241 -253 -9)) with a similar structure and similar intrinsic properties (Read-across approach). The test item of the second study (RL2) was a sodium phytate with an unknown grade of neutralisation. For the justification of the Read-across approach, please refer to the analogue justification attached to IUCLID section 13.

Both data sources are in accordance with generally accepted scientific standards and were performed on different test animal species (mouse and rat). The derived results from the studies are similar and are sufficient to fulfil the information requirements of this endpoint as further explained in the provided endpoint summary.

Qualifier:

no guideline followed

Principles of method if other than guideline:

single oral administration

GLP compliance:

no

Remarks:

Study conducted in 1987, before 1 June 2008 (refering to REACH Article 13(4))

Specific details on test material used for the study:

SOURCE OF TEST MATERIAL
- Source and lot/batch No.of test material:: Sodium Phytate from NAKARAI CHEMICALS, LTD. (Reagent first grade, Lot No. M6H 2435, C6H6(PO3Na2)6 x H2O, Water content 11%)

TREATMENT OF TEST MATERIAL PRIOR TO TESTING
- Treatment of test material prior to testing: Sample was diluted or dissolved with purified water. For details on volumes (ml/kg bw) & doses (g/kg bw) refer to Table in section "Any other information on materials and methods incl. tables".

Species:

rat

Strain:

Fischer 344/DuCrj

Sex:

male/female

Vehicle:

water

Doses:

Experiment 3: 0.61 / 0.91 / 1.35 / 2.03 / 3.04 g/kg bw (Volume 0.8 ml/kg bw)
Experiment 4: 0.94 / 1.03 / 1.14 / 1.25 / 1.38 / 1.51 g/kg bw (Volume 0.5 ml/kg bw)

No. of animals per sex per dose:

5

Control animals:

no

Statistics:

Experiment 3: Moving Avergae method
Experiment 4: Lichtfield-Wilcoxon

Sex:

male

Dose descriptor:

LD50

Effect level:

1.13 other: g/kg bw

Based on:

test mat.

95% CL:

>= 0.935 - <= 1.365

Remarks on result:

other: Experiment 3

Sex:

female

Dose descriptor:

LD50

Effect level:

1.672 other: g/kg bw

Based on:

test mat.

Remarks on result:

other: Experiment 3

Remarks:

by Moving Avergae method

Key result

Sex:

male

Dose descriptor:

LD50

Effect level:

1.03 other: g/kg bw

Based on:

test mat.

95% CL:

>= 0.95 - <= 1.117

Remarks on result:

other: Experiment 4

Key result

Sex:

female

Dose descriptor:

LD50

Effect level:

1.2 other: g/kg bw

Based on:

test mat.

95% CL:

>= 0.668 - <= 2.156

Remarks on result:

other: Experiment 4

Mortality:

Experiment 4:
- Most of deaths occurred ≤24 h after administration
- male: onset after 3h / peak after 7h / last after 24h
- female: onset after 3h / peak after 5h / last after 46h

Clinical signs:

other: Marked expansion of the stomach and bleeding of the glandular portion of the stomach were seen. The color of liver and spleen was turned dark red. The color of the duodenum, ileum and jejunum was turned dark or black due to bleeding or bodily fluid contai

Table: LD50 of sodium phytate in rats

Material	Exp. No.	Sex	Death Time (hr.)	Slope Function (Confidence Interval at p = 0.05)	LD50 (g/kg) (Confidence Interval at p = 0.05)
Sodium phytate (C6H6(PO3Na2)6* xH2O)	3	M		1.241 (0.874 ~ 1.763)	1.13 (0.935 ~ 1.365)
		F			1.672 (-)
	4	M	3 (onset)  7 (peak) 24 (last)	1.119 (1.018 ~ 1.230)	1.03 (0.950 ~ 1.117)
		F	3 (onset) 5 (peak) 46 (last)	1.180 (0.594 ~ 2.346)	1.20 (0.668 ~ 2.156)

Interpretation of results:

Category 4 based on GHS criteria

Conclusions:

The LD50 values for acute toxicity (oral) in rats (Fischer 344/DuCrj) of the test item were reported to be 1200 mg/kg bw (female) and 1030 mg/kg bw (male). [Exp. 4]

Executive summary:

A single oral administration to rats (Fischer 344/DuCrj) was followed by a 7 -day observation period. Rats were dosed between 940 - 1510 mg/kg body weight with in total 6 different doses (Experiment 4). Most of the deaths in male and female rats occured ≤ 24 h after administration in the treated animals. For male rats the onset was after 3 h, the peak of deaths was reached after 7 h and the last death occured after 24 h. For female rats the onset was also after 3h, the peak of deaths was already reached after 5 h and the last death occured after 46 h. Observed clinical signs of treated animals comprised marked expansion of the stomach and bleeding of the glandular portion of the stomach.

The oral LD50 values of the test item in rats were reported to be 1030 (males) and 1200 (females) mg/kg body weight.

The study was performed on the analogue substance "Myo-Inositol, hexakis(dihydrogen phosphate), dodecasodium salt" (CAS 17211 -15 -3; EC 241 -253 -9).

This read-across is in accordance with Regulation (EC) No. 1907/2006 Annex XI, 1.5. For the justification of the Read-across approach, please refer to the analogue justification attached to IUCLID section 13.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LD50

Value:

1 030 mg/kg bw

Quality of whole database:

The available information comprises two adequate, reliable (with restrictions; RL2) and consistent studies (published data) from a reference substance with a similar structure and similar intrinsic properties and from an unspecified sodium phytate (undefined grade of neutralisation). The test procedure of the two published studies are in accordance with generally accepted scientific standards and are described in sufficient detail. Both studies are non-GLP because they were published, before 1 June 2008, in 1987.
The Target substance and the reference substance (test item) are both sodium salts of fytic acid. The Target Substance is the half neutralized sodium salt of thepolyprotic fytic acid and the reference subsance is the fully neutralied sodium salt. The Read-across is justified based on the common functional groups and common breakdown products of hydrolysis and the consistent trends in environmental fate, ecotoxicological and toxicological profile. For the justification of the Read-across approach, please refer to the analogue justification attached to IUCLID section 13.
The selected studies are thus sufficient to fulfill the standard information requirements set out in Annex VII, 8.5, in accordance with Annex XI, 1.5, of Regulation (EC) No 1907/2006.

Acute toxicity: via inhalation route

Endpoint conclusion

Endpoint conclusion:

no study available

Acute toxicity: via dermal route

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Read-across justification

The acute oral toxicity of the substance was evaluated in rats by considering data on Similar Substance 02, due to the absence of data on the substance itself. Justification for Read Across is given in Section 13 of IUCLID. The assessment of acute oral toxicity was therefore based on two scientific studies, one conducted on a reference substance (Similar Substance 02) as part of a read across approach and another one on a soidum phytate with an unknown grade of neutralisation. The Read-across to Similar Substance 02 is in accordance with Regulation (EC) No. 1907/2006, Annex XI, 1.5. A detailed justification for the read-across approach is provided in the technical dossier (see IUCLID Section 13).

Acute oral toxicity

The acute oral toxicity of the test item was investigated in two published scientific studies:

Study 1:

A single oral administration to rats (Fischer 344/DuCrj) was followed by a 7-day observation period. Rats were dosed between 940 - 1510 mg/kg body weight with in total 6 different doses. Most of the deaths in male and female rats occured ≤ 24 h after administration in the treated animals. For male rats the onset was after 3 h, the peak of deaths was reached after 7 h and the last death occured after 24 h. For female rats the onset was also after 3h, the peak of deaths was already reached after 5 h and the last death occured after 46 h. Observed clinical signs of treated animals comprised marked expansion of the stomach and bleeding of the glandular portion of the stomach.

Result study 1: LD50 (rat, oral): 1030 mg/kg bw (male); 1200 mg/kg bw (female)

Study 2:

A single oral administration to mice (ICL-ICR) with 5 different doses between 590 - 2970 mg/kg body weight were conducted. Most of the deaths in male and female mice occured within 1h after administration. In male animals dosed at 2970 mg/kg body weight mortality occurred in 4 of 5 males in the first 4 hours after administration. At a dose of 1980 mg/kg bw 3 of 5 male mice died in the first hour and one animal between 24 to 48h after administration. At a dose of 1320 mg/kg bw 3 of 5 male animals died in the first hour. No mortalities occurred at a dose of 880 mg/kg bw and lower. In female mice at 2970 mg/kg bw mortality occured for 2 of 5 animals in the first hour and for one animal after 5 hours. At a dose of 1980 mg/kg bw 1 of 5 female mice died in the first hour. No mortalities among female mice occurred at a dose of 1320 mg/kg bw and lower. In the substance-treated animals erosion of the stomach wall, bleeding of the glandular portion of the stomach, hypertrophy of the gallbladder, and thinning of the intestinal wall were reported.

Results Study 2: LD50 (mice, oral): 1030 mg/kg bw (male); 2750 mg/kg bw (female)

Overall conclusion for acute oral toxicity and weigth of evidence justification:

The two data sources available for the test item (Similar Substance 02) and a generic sodium phytate (undefined grade of neutralisation) indicate a LD50 value of > 1000 mg/kg bw for acute oral toxicity.

The tests performed do not contradict each other and are consistent in their results:

- Both studies result in LD50 values lower than the limit of 2000 mg/kg bw for male animals (C&L limit) and would result in a classification (Cat.4) of the substance.

- In both studies male animals were more sensitive than female animals.

- In both studies clinical signs after administration were comparable within the expected variability of different test animals (mice vs. rats). In both studies damages to the gastrointestinal tract were reported.

In conclusion, the weight of evidence approach is valid. The acute oral toxiticity of the target substance is considered to match the worst-case result from the more common rat model system.

LD50: 1030 mg/kg bw (male); 1200 mg/kg bw (female)

Acute inhalation toxicity

Not evaluated, because information not required (Regulation (EC) No. 1907/2006, Annex XII).

Acute dermal toxicity

Not evaluated, because information not required (Regulation (EC) No. 1907/2006, Annex XII).

Justification for classification or non-classification

According to the CLP Regulation (EC) No.1272/2008 Annex I: 3.1.2.1.: "Substances can be allocated to one of four hazard categories based on acute toxicity by the oral, dermal or inhalation route according to the numeric criteria shown in Table 3.1.1. Acute toxicity values are expressed as (approximate) LD50 (oral, dermal) or LC50 (inhalation) values or as acute toxicity estimates (ATE)."

The LD50 values obtained in the acute oral toxicity studies is between > 300 - 2000 mg/kg bw and for this reason the substance is classified in Category 4 (H302) according to the CLP classification criteria.