Reaction Mass of Didodecyl nonylphenyl phosphite and Dodecyl bis(4-nonylphenyl) phosphite and 4-nonylphenyl ditridecyl phosphite and Bis(4-nonylphenyl) tridecyl

Repeated dose toxicity: oral

Administrative data

Endpoint:

sub-chronic toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

2002

Reliability:

1 (reliable without restriction)

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2002

Report date:

2002

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

other: OECD Test Guideline 421 (1998).

Principles of method if other than guideline:

OECD Test Guideline 421 (1998). This study exceeds the OECD 421 study design as follows: (1) enhanced evaluation of toxicity in the F0 generation, including the evaluation of a recovery group of F0 males; (2) evaluation of developmental landmarks in the F1 generation; and (3) following the F1 offspring to adulthood, with continued exposure and assessments of reproductive structures and functions, including potential effects on sperm.

GLP compliance:

yes

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

tris (4-nonylphenol, branch) phosphorous acid ester

EC Number:

701-028-2

Molecular formula:

C45H69O3P

IUPAC Name:

tris (4-nonylphenol, branch) phosphorous acid ester

Constituent 2

Reference substance name:

Nonylphenol

EC Number:

246-672-0

EC Name:

Nonylphenol

Cas Number:

25154-52-3

IUPAC Name:

2-nonylphenol

Test material form:

liquid

Test animals

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

No data

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

other: Mazola Corn OIl

Details on oral exposure:

Test procedure: Male and female CD® (Sprague-Dawley) rats (the F0 generation) were administered TNPP orally by gavage at 0, 50, 200, or 1000 mg/kg/day at a dose volume of 5 ml/kg/day in Mazola® corn oil, ten/animals/sex/dose, for two weeks of prebreed exposure (males and females) and two weeks of mating (males and females) for F0 parents.

Analytical verification of doses or concentrations:

not specified

Details on analytical verification of doses or concentrations:

No data

Duration of treatment / exposure:

Males = 4 weeks (2 weeks pre-breeding, 2 weeks mating) Females = 10 weeks (2 weeks prebeed, 2 weeks mating, 3 weeks gestation, and 3 weeks lactation) F1 generation dosed until 85 days of age

Frequency of treatment:

daily

Doses / concentrations

Remarks:

Doses / Concentrations:0, 50, 200 and 1000 mg/kg/day Basis:

No. of animals per sex per dose:

No data

Control animals:

yes, concurrent no treatment

Details on study design:

Post-exposure period: 5 F0 males per group from control and 1000 mg/kg/d - dose groups were designated as recovery group and held without dosing for 2 weeks after the F0 male dosing period was completed.

Positive control:

No data

Examinations

Observations and examinations performed and frequency:

DETAILED CLINICAL OBSERVATIONS: Yes- Time schedule: at least once daily for all animals. BODY WEIGHT: Yes- Time schedule for examinations: Body weights for the F0 males and females were recorded at least weekly during the prebreed period for both sexes, for F0 females during gestation and lactation, and F1 offspring from birth through scheduled sacrifice. FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): -Feed consumption for the F0 males and females were recorded at least weekly during the prebreed period for both sexes, for F0 females during gestation and lactation, and F1 offspring from birth through scheduled sacrifice.

Sacrifice and pathology:

No data

Other examinations:

No data

Statistics:

No data

Results and discussion

Results of examinations

Details on results:

CLINICAL SIGNS AND MORTALITYThree of ten pregnant F0 parental females from the 1000 mg/kg/day group were found dead on Day 22 of gestation. These deaths may have been related to dystocia, since the dams appeared to be unable to deliver their normal appearing pups.ORGAN WEIGHTSIn addition, absolute ovarian weights and ovarian weights relative to terminal body or brain weights were reduced in F0 females at 1000 mg/kg/day.

Effect levels

1

Key result

Dose descriptor:

NOAEL

Effect level:

200 mg/kg bw/day (nominal)

Sex:

male/female

Basis for effect level:

other: No adverse effects observed

2

Key result

Dose descriptor:

LOAEL

Effect level:

1 000 mg/kg bw/day (nominal)

Sex:

male/female

Basis for effect level:

other: reduced weight gains, kidney effects

Target system / organ toxicity

Critical effects observed:

not specified

Any other information on results incl. tables

These adverse effects observed in dams and linked with reproduction won't be taken into account in this chapter but in chapter 5.8.3. No other consistent, treatment-related effects were observed.

Based on the renal lesions in F0 and F1 males and on the abnormal rooting behaviour (males and females) observed at the dose level of 1000 mg/kg/day, the NOAEL derived from this study for repeated dose toxicity was 200 mg/kg/day.

F0 Males: There were no treatment-related deaths for the F0 males. For parental males, minor systemic toxicity was present at 1000 mg/kg/day, expressed as a trend toward decreased body weights and reduced body weight gains. Feed consumption was significantly increased at 1000 mg/kg/day during mating. This finding was considered most likely because of the excessive rooting behavior observed during the dosing period. Paired kidney weights, both absolute and relative to terminal body and brain weight, were significantly increased at 1000 mg/kg/day. There were no treatment-related effects for the gross necropsy findings. However, histological findings included minimal corticomedullary junction mineralization in the kidneys in three of ten males (with no males exhibiting this finding at 0 mg/kg) at 1000 mg/kg/day, which correlated with the increased kidney weights, both absolute and relative to body and brain weight, at this dose. In recovery males, there was a trend toward increasing body weights in the high dose group, so that at the end of the two-week recovery period, the body weights were similar to the control group values. There was no effect on kidney weights in the recovery group.

F0 Females: One F0 female at 50 mg/kg/day and four F0 females at 1000 mg/kg/day were found dead. The unscheduled deaths of the low dose F0 female during gestation and one of the high dose F0 female during lactation were attributed to dosing errors and were not considered treatment related. Of the three remaining unscheduled F0 females deaths, all were found on gestation day 22, possibly attributable to dystocia. Dystocia was evident due to the inability of the dams to deliver their pups. Examination of the pups at maternal necropsy indicated that they were full term and normal in external appearance. F0 parental females did not exhibit any other overt adult systemic toxicity at any dose, as evidenced by a lack of statistically significantly different body weights or weight changes during prebreed, gestation or lactation, changes in feed consumption, or gross necropsy findings. However, trends toward increased feed consumption in females from the high-dose group (except during lactation) were noted. As with the males, because of the clinical signs, particularly of rooting behavior following dosing, the feed consumption differences were considered likely related to this observation. Paired ovary weights (absolute and relative to terminal body and brain weights) were significantly decreased at 1000 mg/kg/day. Gross necropsy and histological findings of F0 parental females exhibited no treatment- or dose-related pattern of incidence or severity at scheduled sacrifice.

F1 Males: There were no unscheduled deaths for the adult F1 males. There were no significant differences in body weight or weight gain for the F1 males during the postweaning period (from pnd 22 to 85) at any dose. Increased feed consumption as g/day and g/kg/day at 1000 mg/kg/day, considered related to increased rooting behavior, was observed. Paired epididymides weights, relative to terminal body weights, were significantly decreased at 1000 mg/kg/day. This finding is of uncertain toxicological significance, since there were no changes in epididymal weight in the F0 generation or in absolute organ weight in the F1 generation. There were no treatment-related effects for gross necropsy findings. Histological findings included corticomedullary junction mineralization in the kidneys of two of ten males (with no males exhibiting this finding at 0 mg/kg/day) at 1000 mg/kg/day and were considered treatment related.

F1 Females: There were no treatment-related deaths for the adult F1 females. There were no significant differences in body weight or weight gain for the F1 females during the postweaning period (from pnd 22 to 85). Feed consumption values (as g/kg/day), presumably associated with excessive rooting behavior, were increased at 1000 mg/kg/day. Also, there were no significant differences in the F1 female estrous cycles across all groups. There were no treatment-related effects for the gross necropsy or histopathological findings.

Applicant's summary and conclusion

Conclusions:

Exposure once daily to TNPP at 0, 50, 200, or 1000 mg/kg/day resulted in mild systemic toxicity in F0 parental males at 1000 mg/kg/day, expressed as reduced weight gains, increased kidney weights, and renal histopathologic findings in F0 and F1 males (renal corticomedullary junction mineralization).

Executive summary:

Exposure once daily to TNPP at 0, 50, 200, or 1000 mg/kg/day resulted in mild systemic toxicity in F0 parental males at 1000 mg/kg/day, expressed as reduced weight gains, increased kidney weights, and renal histopathologic findings in F0 and F1 males (renal corticomedullary junction mineralization).