Diisotridecyl phosphonate

Endpoint summary

Description of key information

• Repeat dose oral (OECD 422, read-across): No signs of systemic toxicity or reproductive or developmental effects at any dose level up to, and including, 1000 mg/kg/day.

• Repeat dose dermal: No studies are available

• Repeat dose inhalation: No studies are available

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Reference

Endpoint:

short-term repeated dose toxicity: oral

Remarks:

combined repeated dose and reproduction / developmental screening

Type of information:

experimental study

Adequacy of study:

key study

Study period:

2005

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Reason / purpose for cross-reference:

reference to same study

Qualifier:

equivalent or similar to guideline

Guideline:

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

Deviations:

yes

Remarks:

This protocol exceeded the OECD 422 study design by following the F1 offspring to adulthood, with continued exposure and assessments of neurologic, immunologic and reproductive structures and functions. The protocol also assessed F0 recovery males, 28-day

Principles of method if other than guideline:

Method: Modified

GLP compliance:

yes

Limit test:

no

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Route of administration:

oral: gavage

Vehicle:

corn oil

Details on oral exposure:

Male and female CD (Sprague-Dawley(SD)) F0 rats were administered TDP orally by gavage at 0, 50, 250 and 1000 mg/kg/day at a dose volume of 5 ml/kg/day in Mazola® corn oil, 10 animals/sex/dose, for 2 weeks of prebreed exposure (males and females), 2 weeks of mating (males and females) and 3 weeks of gestation and lactation each (F0 females).

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Homogeneity and stability studies were run on TDP in corn oil at concentrations of 10, 50, and 200 mg/mL (TDP in corn oil). The 50 and 200 mg/mL concentrations were prepared weekly as they were found to be stable. The 10 mg/mL concentration was prepared daily due to stability concerns.

Duration of treatment / exposure:

8 weeks

Frequency of treatment:

once per day

Remarks:

Doses / Concentrations:
0, 50, 250 and 1000 mg/kg/day
Basis:
actual ingested

No. of animals per sex per dose:

10

Control animals:

yes

Details on study design:

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: at least once daily for F0 males and females until necropsy.

BODY WEIGHT: Yes
- Time schedule for examinations: F0 males and females weekly during the prebreed period for both sexes and for F0 females during gestation and lactation.

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Yes
- F0 males and females weekly during the prebreed period for both sexes and for F0 females during gestation and lactation.

Clinical signs:

no effects observed

Mortality:

no mortality observed

Body weight and weight changes:

no effects observed

Food efficiency:

no effects observed

Haematological findings:

no effects observed

Clinical biochemistry findings:

no effects observed

Urinalysis findings:

no effects observed

Behaviour (functional findings):

no effects observed

Organ weight findings including organ / body weight ratios:

no effects observed

Gross pathological findings:

no effects observed

Histopathological findings: non-neoplastic:

no effects observed

Key result

Dose descriptor:

NOAEL

Effect level:

>= 1 000 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Remarks on result:

not determinable due to absence of adverse toxic effects

Critical effects observed:

not specified

Conclusions:

TDP administered by gavage once daily at 0, 50, 250 and 1000 mg/kg/day to parental F0 CD (SD) rats, 10/sex/group through prebreed, mating, gestation and F1 lactation resulted in essentially no treatment or dose related adult F0 parental toxicity at any dose at any time. Reproductive toxicity was not present in F0 males or females. There was also no F1offspring toxicity observed postnatally through the weanling necropsy. Therefore, the F0 male and female systemic no observable adverse effect level (NOAEL) was at or above 1000mg/kg/day for males and females. The NOAELs for F0 reproductive toxicity were observed at or above 1000 mg/kg/day for males and females. The NOAELs for F1 offspring toxicity during lactation were also at or above 1000 mg/kg/day for males and females. (Author)

Executive summary:

TDP administered by gavage once daily at 0, 50, 250 and 1000 mg/kg/day to parental F0 CD (SD) rats, 10/sex/group through prebreed, mating, gestation and F1 lactation resulted in essentially no treatment or dose related adult F0 parental toxicity at any dose at any time. Reproductive toxicity was not present in F0 males or females. There was also no F1offspring toxicity observed postnatally through the weanling necropsy. Therefore, the F0 male and female systemic no observable adverse effect level (NOAEL) was at or above 1000mg/kg/day for males and females. The NOAELs for F0 reproductive toxicity were observed at or above 1000 mg/kg/day for males and females. The NOAELs for F1 offspring toxicity during lactation were also at or above 1000 mg/kg/day for males and females.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

1 000 mg/kg bw/day

Study duration:

subchronic

Species:

rat

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Dose descriptor:

NOAEL

5 000 mg/kg bw/day

Study duration:

subchronic

Species:

rat

Additional information

Use of data on a closely related analog, triisodecyl phosphite (TDP), has been selected to represent the repeat-dose toxicity of TiTDP. Based on similar toxicity on other mammalian endpoints it appears appropriate to use TDP repeat-dose toxicity data to read-across to TiTDP. In addition, the OECD- accepted category approach for the C10 and C13 isoalkyl alcohols, hydrolysis products of TDP and TiTDP, respectively, further supports this read-across approach. See justification document in Section 13.  

 

An enhanced combined repeat-dose and reproductive and developmental effects study was performed on TDP. This study was conducted in rats via oral gavage and included evaluations of systemic toxicity and neurotoxicity in both the F0 and F1 generations in addition to evaluations of reproductive performance and developmental effects.

 

TDP administered by gavage once daily at 0, 50, 250 and 1000 mg/kg/day to parental F0 CD (SD) rats, 10/sex/group through prebreed, mating, gestation and F1 lactation resulted in essentially no treatment or dose related adult F0 parental toxicity at any dose at any time. Reproductive toxicity was not present in F0 males or females. There was also no F1offspring toxicity observed postnatally through the weanling necropsy. Therefore, the F0 male and female systemic no observable adverse effect level (NOAEL) was at or above 1000mg/kg/day for males and females. The NOAELs for F0 reproductive toxicity were observed at or above 1000 mg/kg/day for males and females. The NOAELs for F1 offspring toxicity during lactation were also at or above 1000 mg/kg/day for males and females.

 

The inhalation and dermal NOAELs were extrapolated from the oral study using standard route-to-route extrapolations and assuming 50% oral and inhalation absorption and 10% dermal absorption.

The following information is taken into account for any hazard / risk assessment:

In a study on an analog substance, triisodecyl phosphite (TDP), there were no signs of systemic toxicity or reproductive or developmental effects at any dose level up to, and including, 1000 mg/kg/day.

Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:

The repeat dose toxicity of TiTDP via the oral route has been read-across from a study conducted with the closely related analogue TDP. The study was conducted according to OECD Guideline 422 and to GLP and is adequately reported. Justification for read across to TDP is provided in Section 13.

Justification for selection of repeated dose toxicity dermal - systemic effects endpoint:

Extrapolation from oral repeat-dose study.

Justification for classification or non-classification

The repeated dose toxicity of TiTDP via the oral route has been read-across from the closely related analogue TDP based on the following study: No systemic toxicological findings were detected in rats after repeated administration of TDP by the oral route at dose levels up to 1000 mg/kg bw/day. Therefore, classification of the TDP as STOT RE is not justified under the conditions of this test. As such, it can be considered that classification of TITDP is also not justified according to the criteria described in Regulation (EC) No 1272/2008.Justification for read across to TDP is provided in Section 13.