Phosphorous acid, tri-C12-14-alkyl esters

Repeated dose toxicity: oral

Administrative data

Endpoint:

sub-chronic toxicity: oral

Remarks:

combined repeated dose and reproduction / developmental screening

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 1

Reference Type:

review article or handbook

Title:

U.S. HIGH PRODUCTION VOLUME (HPV) CHEMICAL CHALLENGE PROGRAM ROBUST SUMMARY Phosphorous acid, triisodecyl ester (CAS# 25448-25-3)

Author:

General Electric Company on behalf of the Phosphite Producers HPV Consortium and Phosphite Manufacturers Consortium

Year:

2001

Bibliographic source:

US Environmental Protection Agency, HPV Information System

Reference 2

Reference Type:

secondary source

Title:

Unnamed

Report date:

2005

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

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

Version / remarks:

Version: 1996
See: Principles of method

Deviations:

yes

Remarks:

exceeded OECD 422 by following the F1 offspring to weaning

Principles of method if other than guideline:

The study exceeded the OECD 422 guideline design by extending dosing of F0 females through Day 21 of lactation. The original study design included evaluation of 28 day exposure in females (to correlate with 28 day exposure in males), male and female recovery groups, and extended post weaning evaluation (70 days) in F1 offspring. The final study report contains all sections required by the OECD 422 guideline (1996), including data collected on the FO parental animals and on the Fl offspring to their weaning on pnd 21 (an extension beyond the specified termination on pnd 4 in the OECD 422 [1996] testing guideline). The data collected on the 28-day females, the recovery males and females, and on the F1 offspring animals after weaning were collected as initially specified in the protocol but were not included in the study report. The data not reported (and wet tissues, blocks and slides not processed or examined) were retained in the study records and archived with the study upon the submission of the final report.

GLP compliance:

yes

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Phosphorous acid, triisodecyl ester (25448-25-3)

IUPAC Name:

Phosphorous acid, triisodecyl ester (25448-25-3)

Test material form:

other: liquid

Details on test material:

Doverphos 6, Batch 162T041801
Purity: > 99%

Test animals

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

Male and female CD (Sprague-Dawley(SD)) F0 rats, no other detail given

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

corn oil

Details on oral exposure:

Rats were administered Triisodecyl phosphite (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:

not specified

Duration of treatment / exposure:

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).
Therefore:
F0 males were exposed 28 days
F0 females were exposed until 10 weeks (14 days prebreed, mating, gestation, lactation through pnd 21).

Frequency of treatment:

daily

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

0 mg/kg bw/day (actual dose received)

Remarks:

Basis: actual ingested

Doses / concentrations 2

Dose / conc.:

50 mg/kg bw/day (actual dose received)

Remarks:

Basis: actual ingested

Doses / concentrations 3

Dose / conc.:

250 mg/kg bw/day (actual dose received)

Remarks:

basis: actual ingested

Doses / concentrations 4

Dose / conc.:

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

Remarks:

basis: actual ingested

No. of animals per sex per dose:

10 per sex per dose

Examinations

Observations and examinations performed and frequency:

Body weights and feed consumption for the F0 males and females were recorded weekly during the prebreed period for both sexes and for F0 females during gestation and lactation.
Clinical signs were recorded at least once daily for F0 males and females until necropsy.
Functional Observational Battery (FOB) including home cage observations, handling observations, open field observations, sensory and neuromuscular observations and physiological observations, was performed on all initial animals once during quarantine and at least once per week for F0 animals during prebreed, mating (both sexes), gestation and lactation (F0 females).
After the 2-week prebreed exposure period, animals were randomly mated within treatment groups for a 2-week mating period to produce the F1 generation, with continuing exposure.
Five F0 males and five F0 females per dose group were evaluated for auditory function, motor activity, and assessment of grip strength prior to necropsy.

Sacrifice and pathology:

All F0 parental animals were necropsied with complete histologic evaluation of 5 selected males and females in the 0 and 1000 mg/kg/day groups.
The culled F1 pups were weighed, euthanized, and necropsied with complete external and visceral examinations.

Other examinations:

On the day of birth (postnatal day [pnd] 0), anogenital distance was measured and body weights recorded for all live F1 pups in all litters. F1 litters were culled on pnd 4 to yield as nearly as possible 5 males and 5 females per litter. For the remaining F1 pups, survival indices were calculated at least weekly through weaning (pnd 21). In addition, hematology, clinical biochemistry and urinalysis assays were performed at necropsy for 5 randomly selected F0 males. Clinical biochemistry was also assessed for the 28-day females.

Results and discussion

Results of examinations

Clinical signs:

no effects observed

Mortality:

no mortality observed

Body weight and weight changes:

no effects observed

Food consumption and compound intake (if feeding study):

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

Gross pathological findings:

no effects observed

Histopathological findings: non-neoplastic:

no effects observed

Histopathological findings: neoplastic:

no effects observed

Details on results:

No systemic toxicity was shown at any dose at any time.

Effect levels

Dose descriptor:

NOAEL

Effect level:

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

Based on:

test mat.

Sex:

male/female

Basis for effect level:

body weight and weight gain

clinical biochemistry

clinical signs

food consumption and compound intake

gross pathology

histopathology: non-neoplastic

mortality

organ weights and organ / body weight ratios

urinalysis

other: Functional Observational Battery (FOB)

Target system / organ toxicity

Critical effects observed:

not specified

Applicant's summary and conclusion

Conclusions:

Under the test conditions, the F0 male and female systemic no observable adverse effect level (NOAEL) was at or above 1000mg/kg/day for males and females.

Executive summary:

Triisodecyl phosphite (TDP) was tested for repeated toxicity according to the OECD 422 test guideline

Triisodecyl phosphite (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 F1 offspring toxicity observed postnatally through the weanling necropsy. Therefore, the F0 male (28 days) and female (8 - 9 weeks) systemic no observable adverse effect level (NOAEL), including neurotoxicity, was at or above 1000 mg/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.