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Toxicological information

Repeated dose toxicity: oral

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Administrative data

Endpoint:
repeated dose toxicity: oral
Remarks:
combined repeated dose and carcinogenicity
Type of information:
migrated information: read-across based on grouping of substances (category approach)
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1985
Report date:
1985

Materials and methods

Principles of method if other than guideline:
Similar to OECD 451
GLP compliance:
yes
Limit test:
no

Test material

Constituent 1
Reference substance name:
[ethylenebis[nitrilobis(methylene)]]tetrakisphosphonic acid, sodium salt
EC Number:
244-742-5
EC Name:
[ethylenebis[nitrilobis(methylene)]]tetrakisphosphonic acid, sodium salt
Cas Number:
22036-77-7
IUPAC Name:
22036-77-7
Details on test material:
Name of test material (as cited in study report): Ethylenediamine tetra (Methylene Phosphonic Acid)
- Physical state: Solid, but dissolved in water and neutralised with NaOH prior to dosing.
- Analytical purity: 96-97%
- Impurities (identity and concentrations): None identified.
- Composition of test material, percentage of components: No details on composition.
- Isomers composition:- Purity test date: No information.
- Lot/batch No.:Sample 81-0640 was used for weeks 1-68 of dosing and sample 82-0220 was used for weeks 69-107 of dosing

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
unchanged (no vehicle)
Duration of treatment / exposure:
94 - 107 weeks (Note,dosage was increased to 333 mg/kg (bw) on day 329 of study)
Frequency of treatment:
Daily

Results and discussion

Effect levels

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Dose descriptor:
NOAEL
Effect level:
15 mg/kg bw/day (nominal)
Based on:
act. ingr.
Sex:
female
Basis for effect level:
other: metaphyseal osteosclerosis
Dose descriptor:
NOAEL
Effect level:
50 mg/kg bw/day (nominal)
Based on:
act. ingr.
Sex:
male
Basis for effect level:
other: metaphyseal osteosclerosis

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables

Organ weights - No statistically significant differences in absolute or relative organ weights were present between the control or any treatment group for either sex throughout the study.

Opthalmology - No treatment related effects were observed.

Body Weights - Group mean body weights in high dose males significantly decreased from week 55 until termination. No other statistically significant effects were noted in other dosage groups.

Haematology - No significant treatment related effects were observed.

Clinical chemistry – no significant treatment related effects were observed in any of the groups.

Urine analysis - No significant treatment related effects were observed.

Pathology - A significantly increased incidence of metophyseal osteosclerosis in femur, rub & sternum in high dose males and mid/high dose females.

Osteosarcomas involving primarily the long bones in both sexes incidence as follows,

Control           – Males and females  0/60 respectively

15 mg/kg (bw) - Males (0/60, females 0/60)

50 mg/kg (bw) - Males (1/60, females 0/60)

150/333 mg/kg (bw) - Males (28/60, females 4/60)

Note, the first palpable bone tumour evident after 35 weeks of treatment, prior to the increase of the high dose level.

Due to the rarity of this type of tumour in rats, the finding one one tumour in the mid dose male group and four such females at the high dose was considered biologically significant, together with the high dose males. The highest incidence of osteoarcoma as found in the tibia. Metastasis sites of these tumours were the lungs, liver, regional lymph nodes, adrenals, kidneys and heart.

Metaphyseal osteoscherosis was significantly increased in the femur, rib and sternum of males at the high dose level and in the females at the mid and high dose levels.

Applicant's summary and conclusion

Executive summary:

In a well conducted study male and female SD rats were administered EDTMP under (by gavage) resulted in neoplastic (osteosarcomas) and non neoplastic (metaphyseal osteosclerosis) effects which were related to the administration of the test substance.

The non neoplastic effects (metaphyseal osteosclerosis) that were considered to be treatment related at the mid and high dose female group and high dose male group. NOAEL (female) = 15 mg/kg (bw), NOAEL (male) = 50 mg/kg (bw)

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