2,5-dihydroxy-3,6-dimethyl-3,6-bis(dihydroxyphosphinyl)-1,4,2,5-dioxadiphosphorane-2,5-dioxide, hexasodium salt

Endpoint summary

Description of key information

- Acute oral toxicity: In accordance with column 2 of REACH Annex VII, the acute oral toxicity study does not need to be conducted as the available information indicates that the criteria for classification as corrosive to the skin are met. Indeed as the pH for 1% solution (1% ADPA Dimer Na Salt) is 10.7, ADPA Na Dimer Na Salt is classified as corrosive to skin (Skin Corr. 1A, H314). However, ACD/Percepta predicted for ADPA an acute oral LD50 to mouse equal to 1000 mg/kg and an acute oral LD50 to rat equal to 750 mg/kg. 
- Acute inhalation toxicity: no data available
- Acute dermal toxicity: no data available

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Reference

Endpoint:

acute toxicity: oral

Type of information:

(Q)SAR

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Justification for type of information:

QSAR prediction: migrated from IUCLID 5.6

Qualifier:

according to guideline

Guideline:

other: REACH guidance on QSARs R.6, May/July 2008.

Principles of method if other than guideline:

ACD labs/Percepta (Release 2014) - Acute Toxicity Prediction Module The ACD/Labs Acute Toxicity predictor (LD50 module) provides predictions of LD50 values for rats and mice according to various routes of administration Advanced Chemistry Development, Inc. (ACD/Labs).

Test type:

other: QSARs prediction

Sex:

not specified

Dose descriptor:

LD50

Effect level:

750 mg/kg bw

Based on:

other: QSAR Prediction

Remarks on result:

other: based on acidic form

Sex:

not specified

Dose descriptor:

LD50

Effect level:

1 013 mg/kg bw

Remarks on result:

other: recalculated for sodium salt form

ACD/Percepta predicted for ADPA an acute oral LD50 to rat equal to 750 mg/kg. The prediction is considered of moderate reliability (RI in range 0.5 - 0.75).

- Applicability domain (OECD principle 3):

Domains: ACD/Percepta provides an estimation of the reliability of the prediction, by a reliability index (RI). This index provides values in a range from 0 to 1 and gives an evaluation of whether a submitted compound falls within the model applicability domain. In particular: RI < 0.3 (Not Reliable), RI in range 0.3-0.5 (Borderline Reliability), RI in range 0.5-0.75 (Moderate Reliability), RI >= 0.75 (High Reliability). Estimation of the RI takes into account the following two aspects: similarity of the tested compound to the training set and the consistency of experimental values for similar compounds. In this case the prediction is considered as moderately reliable since RI is equal to 0.66.

i. descriptor domain: not applicable.

ii. structural fragment domain: not applicable.

iii. mechanism domain: not applicable.

iv. metabolic domain, if relevant: not applicable.

- Structural analogues:

Five training set compounds found to be mostly similar to ADPA:

Etidronic acid LD50 = 1300 mg/kg (Similarity: 0.83)

Alendronate LD50 = 550 mg/kg (Similarity: 0.81)

Phosphonic acid, (nitrilotris(methylene))tri- LD50 = 2100 mg/kg (Similarity: 0.72)

Glycine, N,N-bis(phosphonomethyl)- LD50 = 3900 mg/kg (Similarity: 0.68)

Phosphonic acid, ethyl-, monoethyl ester LD50 = 2100 mg/kg (Similarity: 0.62)

The uncertainty of the prediction (OECD principle 4):

The uncertainty of the prediction is evaluated by ACD/Percepta by means of the reliability index (RI). This index provides values in a range from 0 to 1 and gives an evaluation of whether a submitted compound falls within the model applicability domain. In particular: RI < 0.3 (Not Reliable), RI in range 0.3 -0.5 (Bordeline Reliability), RI in range 0.5 -0.75 (Moderate Reliability), RI >= 0.75 (High Reliability). Estimation of the RI takes into account the following two aspects: similarity of the tested compound to the training set and the consistency of experimental values for similar compounds. In this case the prediction is considered as moderately reliable since RI is equal to 0.66.

Interpretation of results:

Toxicity Category IV

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

ACD/Percepta predicted for ADPA (acidic form) an acute oral LD50 to rat equal to 750 mg/kg ( corresponding to 1013 mg/kg bw for sodium salt form). The prediction is considered of moderate reliability (RI in range 0.5 - 0.75). Based on these data, ADPA Dimer Na Salt is considered as harmful if swallowed.

Executive summary:

The acute oral toxicity on rat was estimated by using ACD/Percepta predictor. The reliability of ACD/Percepta prediction is estimated with the reliability index (RI), which takes into account the similarity of the tested compound with the training set compounds and the consistency of experimental values for similar compounds. It ranges from 0 to 1, in particular:RI in range 0.3-0.5 (Borderline Reliability), RI in range 0.5-0.75 (Moderate Reliability), RI >= 0.75 (High Reliability).

For ADPA, ACD/Percepta provided a prediction of LD50 equal to 750 mg/kg, corresponding to 1013 mg/kg bw for salt form. The prediction is of moderate reliability being the reliability index equal to 0.66. Together with the prediction, ACD/Percepta displays up to 5 most structurally similar structures from the training set along with experimental results. The information on the structurally similar compounds in the training set is used to further assess the reliability of the prediction, since it illustrates how the test compound, i.e. ADPA, is represented in the training set. The five mostly similar compounds from the training set exhibit moderate to high similarity with respect to ADPA (similarity index ranging from 0.62 to 0.83), and experimental LD50 (rat oral) values ranging from 550 to 3900 mg/kg.

Based on ACD/Percepta acute oral toxicity on rat, moderately reliable LD50 predictions were obtained for ADPA: LD50 equal to 750 mg/kg, corresponding to 1013 mg/kg bw for salt form.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LD50

Value:

750 mg/kg bw

Quality of whole database:

Two ACD/Percepta prediction are available (WoE, Kr. 2).The prediction is considered of moderate reliability.

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

ACD/Percepta predicted for ADPA an acute oral LD50 to rat equal to 750 mg/kg. The prediction is considered of moderate reliability (RI in range 0.5 - 0.75). ACD/Percepta predicted for ADPA an acute oral LD50 to mouse equal to 1000 mg/kg. The prediction is considered of moderate reliability. Based on these data, ADPA is considered as harmful if swallowed.

Justification for selection of acute toxicity – oral endpoint
The lowest LD50 predicted for ADPA was 750 mg/kg bw in rat.

Justification for classification or non-classification

No study is available for acute oral toxicity, therefore testing should be envisaged but since ADPA Dimer Na Salt is classified as corrosive to skin by worst case considerations (pH for 1% solution is 10.7), in-vivo acute toxicity study, oral testing does not need to be conducted in accordance with section 8.5.1, column 2, Annex VII of regulation (EC) 1907/2006.

However, two QSAR calculations using ACD/Percepta, predicted for ADPA an acute oral LD50 to mouse equal to 1000 mg/kg and an acute oral LD50 to rat equal to 750 mg/kg. Based on these data, ADPA is considered as harmful if swallowed and classified into Category. 4 (H302) according to CLP Regulation (1272/2008) criteria.