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Toxicological information

Toxicity to reproduction

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Administrative data

Endpoint:
one-generation reproductive toxicity
Remarks:
based on test type (migrated information)
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2002

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 421 (Reproduction / Developmental Toxicity Screening Test)
Principles of method if other than guideline:
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

Reference
Name:
Unnamed
Type:
Constituent
Type:
Constituent
Test material form:
liquid

Test animals

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

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
corn oil
Details on 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)
Analytical verification of doses or concentrations:
yes
Duration of treatment / exposure:
Duration of test: F1 Generation dosed until Post natal day 85
Frequency of treatment:
Daily
Doses / concentrations
Remarks:
Doses / Concentrations:0, 50, 200, and 1000 mg/kg/day Basis:actual ingested
No. of animals per sex per dose:
10 animals per sex per dose.
Control animals:
yes, concurrent vehicle
Details on study design:
See discussion on materials and methods.

Results and discussion

Results: P0 (first parental animals)

Effect levels (P0)

Key result
Dose descriptor:
NOAEL
Effect level:
200 mg/kg bw/day
Sex:
male/female
Basis for effect level:
other: No adverse effects observed

Results: F1 generation

Effect levels (F1)

Key result
Dose descriptor:
NOAEL
Generation:
F1
Effect level:
200 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No adverse effects observed

Overall reproductive toxicity

Reproductive effects observed:
not specified

Any other information on results incl. tables

Three 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. In addition, absolute ovarian weights and ovarian weights relative to terminal body or brain weights were reduced in F0 females at 1000 mg/kg/day. No other consistent, treatment-related effects were observed. There was no evidence of F0 reproductive toxicity in males. The only evidences of F1 offspring toxicity pre- or postnatally were observed at 1000 mg/kg and were a reduced litter size on pnd 0 and 4, renal histopathology in F1 adult males and a significantly decreased paired epididymides weight, relative to terminal body weights in Fi male rats. This last 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. No effects were seen on the developmental landmarks, including the time to vaginal opening or preputial separation, or estrous cycle normality or length. Therefore, under the conditions of this study in rats, the no observable adverse effect levels (NOAELs) for systemic parental toxicity and for reproductive and offspring toxicity were 200 mg/kg/day.

F0 Parental Reproductive Toxicity: Table 5.8.3.3 (attached to Chapter 1.11) presents a summary of F0 adult reproductive toxicity.

      Trisnonylphenyl Phosphite      (mg/kg/day)

F0

0

50

200

1000

FEMALES

 

 

 

 

Precoital interval, days

3.1

2.5

2.3

2.2

Indices:   Mating

--

--

--

--

           Fertility

--

--

--

--

           Gestational

--

--

--

--

Gestational length, days

22.2

22.4

22.1

22.3

Death due to dystocia on gd 22

0

0

0

3

No. implant sites/litter

15.80

14.67

16.90

13.50

% postimplantation loss/litter

5.58

15.48

5.68

9.04

No. total pups/litter, pnd 0

15.1

13.8

16.3

12.1

No. live pups/litter, pnd 0

14.9

12.8

15.9

12.0

No. dead pups/litter, pnd 0

0.2

1.0

0.4

0.1

No. females pregnant

10

9

10

10

No. litters on pnd 0

10

8

10

7

No. litters on pnd 21

10

7

10

6

 

 

 

 

 

MALES

 

 

 

 

Indices:   Mating

--

--

--

--

           Fertility

--

--

--

--

           Gestational

--

--

--

--

a   Indicated parameters were assessed in control and high dose animals only

­b  Presence of renal corticomedullary mineralization in two F1 males at 1000 mg/kg/day versus 0 at 0 mg/kg/day. F1 females exhibited the same findings with the same incidence and severity at both 0 and 1000 mg/kg/day.

---=No statistically significant difference

* =Statistically significantly different from control group value at p<0.05

Applicant's summary and conclusion

Conclusions:
NOAEL for systemic and reproductive toxicity from this study was 200 mg/kg/day.
Executive summary:

NOAEL for systemic and reproductive toxicity from this study was 200 mg/kg/day.