3,9-dimethyl-2,4,8,10-tetraoxa-3,9-diphosphaspiro[5.5]undecane 3,9-dioxide

Repeated dose toxicity: oral

Administrative data

Endpoint:

short-term repeated dose toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2018

Report date:

2018

Materials and methods

Test guideline

Test guideline 1

Qualifier:

according to guideline

Guideline:

OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)

Version / remarks:

2015

Deviations:

no

Test guideline 2

Qualifier:

equivalent or similar to guideline

Guideline:

other: EPA OPPTS 870.3650 (2000)*

Version / remarks:

*Note: The study design is similar to OPPTS 870.3650 design, but pups will be kept longer and additional endpoints will
be measured.

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

3,9-dimethyl-2,4,8,10-tetraoxa-3,9-diphosphaspiro[5.5]undecane 3,9-dioxide

EC Number:

221-088-9

EC Name:

3,9-dimethyl-2,4,8,10-tetraoxa-3,9-diphosphaspiro[5.5]undecane 3,9-dioxide

Cas Number:

3001-98-7

Molecular formula:

C7H14O6P2

IUPAC Name:

3,9-dimethyl-2,4,8,10-tetraoxa-3λ⁵,9λ⁵-diphosphaspiro[5.5]undecane-3,9-dione

Test material form:

solid: particulate/powder

Details on test material:

AFLAMMIT® PCO 962

Test animals

Species:

rat

Strain:

Wistar

Details on species / strain selection:

Crl:WI rats

Sex:

male/female

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

water

Analytical verification of doses or concentrations:

yes

Duration of treatment / exposure:

28 days

Frequency of treatment:

7 days a week

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

100 mg/kg bw/day (nominal)

Remarks:

20 mg/mL, dose volume 5 mL/kg bw

Doses / concentrations 2

Dose / conc.:

300 mg/kg bw/day (nominal)

Remarks:

60 mg/mL, dose volume 5 mL/kg bw

Doses / concentrations 3

Dose / conc.:

1 000 mg/kg bw/day (nominal)

Remarks:

200 mg/mL, dose volume 5 mL/kg bw

No. of animals per sex per dose:

15

Control animals:

yes, concurrent vehicle

Positive control:

none

Results and discussion

Results of examinations

Clinical signs:

effects observed, non-treatment-related

Mortality:

no mortality observed

Body weight and weight changes:

effects observed, non-treatment-related

Food consumption and compound intake (if feeding study):

effects observed, non-treatment-related

Food efficiency:

not examined

Water consumption and compound intake (if drinking water study):

not examined

Ophthalmological findings:

not examined

Haematological findings:

effects observed, non-treatment-related

Clinical biochemistry findings:

effects observed, non-treatment-related

Urinalysis findings:

no effects observed

Behaviour (functional findings):

effects observed, non-treatment-related

Immunological findings:

not examined

Organ weight findings including organ / body weight ratios:

no effects observed

Gross pathological findings:

not examined

Neuropathological findings:

not examined

Histopathological findings: non-neoplastic:

effects observed, non-treatment-related

Histopathological findings: neoplastic:

no effects observed

Other effects:

no effects observed

Description (incidence and severity):

No endocrine disruptor effect of test item was observed in the study based on the results of thyroid hormone analysis and thyroid gland weights.

Effect levels

Key result

Dose descriptor:

NOAEL

Effect level:

> 1 000 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

behaviour (functional findings)

body weight and weight gain

clinical biochemistry

clinical signs

dermal irritation

food consumption and compound intake

gross pathology

haematology

immunology

mortality

neuropathology

ophthalmological examination

organ weights and organ / body weight ratios

urinalysis

water consumption and compound intake

Remarks on result:

not determinable due to absence of adverse toxic effects

Target system / organ toxicity

Key result

Critical effects observed:

no

Applicant's summary and conclusion

Conclusions:

Daily administration of the test item by oral gavage to Wistar rats at dose levels of 100, 300 or 1000 mg/kg bw/day (Low, Mid and High dose levels, respectively) during the treatment period under the conditions of this study did not result in test item related mortality, clinical signs, or effects on body weight or body weight gain, food consumption, haematology, coagulation, clinical chemistry or urinalysis parameters.
No test item related effect was detected during neurotoxicity assessment. In case of decreased motor activity results in High dose females, based on the historical control data, shape of the curve, lack of similar results in High dose males and lack of similar indication in the other tests, the observed data were considered as animal variability and not related to the test item treatment.
No test item-related macroscopic findings were recorded in any of the dose groups at necropsy; no microscopic effects were seen at histopathology. There were no test-item related differences among groups in the weights of organs measured when compared to controls.
No test item effect on oestrus cycle of parental females were was noted.
No test item related changes were noted in the reproductive parameters, gestation, parturition and lactation.
There were no adverse effects on the F1 offspring viability, clinical signs, physical or sexual development. No test item related macroscopic finding were was recorded for F1 pups at necropsy.
No endocrine disruptor effect of test item was observed in the study.

In conclusion, under the conditions of this study, the no observed adverse effect level (NOAEL) for the test substance is considered to be 1000 mg/kg bw/day for the female and male parental/adult generation, and also for the F1/pups generation.