Dihydroxypyrimidine

Toxicity to reproduction

Administrative data

Endpoint:

two-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)

Rationale for reliability incl. deficiencies:

other: GLP study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2009

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

OECD Guideline 416 (Two-Generation Reproduction Toxicity Study)

GLP compliance:

yes (incl. QA statement)

Limit test:

no

Test material

Reference

Name:

Unnamed

Type:

Constituent

Test animals

Species:

rat

Strain:

Wistar

Sex:

male/female

Administration / exposure

Route of administration:

oral: feed

Results and discussion

Results: P0 (first parental generation)

Effect levels (P0)

1

Dose descriptor:

NOAEL

Effect level:

8.7 mg/kg bw/day (nominal)

Sex:

male

2

Dose descriptor:

NOAEL

Effect level:

10.8 mg/kg bw/day (nominal)

Sex:

female

3

Dose descriptor:

LOAEL

Effect level:

17.8 mg/kg bw/day (nominal)

Sex:

male

4

Dose descriptor:

LOAEL

Effect level:

20.8 mg/kg bw/day (nominal)

Sex:

female

Results: F1 generation

Effect levels (F1)

1

Dose descriptor:

NOAEL

Generation:

F1

Effect level:

11.1 mg/kg bw/day (nominal)

Sex:

male/female

2

Dose descriptor:

LOAEL

Generation:

F1

Effect level:

24.2 mg/kg bw/day (nominal)

Sex:

male/female

Overall reproductive toxicity

Reproductive effects observed:

not specified

Applicant's summary and conclusion

Executive summary:

Effects attributed to exposure to Technical Grade HEC 5725 Dihydroxypyrimidine were as follows: 300 ppm P-generation Adults: An increased incidence of non patent cervices, increased uterine weight (absolute/relative) correlating with increased incidence of “dilatation” of uterus upon microscopic observation. Recovery P-Males: Statistically and/or non-statistically significant organ weight trends (>10%) in the recovery males considered to be test substance-related occurred in the prostate (decreased in absolute and relative) and testes (decreased in absolute and relative). These trends were considered to be a test substance-related response since these changes were enhanced compared to the changes seen in the main 300 ppm dose group at the end of the treatment period. Recovery P-Females: A slight effect on fertility was observed, relative to controls, although more difficult to dicern due to the small sample size of animals in this recovery group. Since it is believed that the fertility effect is due to some insult on the female, the fact that females were taken off the treated feed on Gestation Day 0 demonstrates that the effect likely occurred prior to this time. Statistically and/or non-statistically significant organ weight trends (>10%) in the recovery females considered to be test substance-related occurred in the thymus (increased in absolute and relative) and adrenals (decreased in absolute and relative). These trends were considered to be a test substance-related response since these changes were enhanced compared to the changes seen in the main 300 ppm dose group at the end of the treatment period. F1 -Offspring: Organ weight effects included increased spleen weight (absolute/relative) in both genders and as with the P-generation adult females, the F1-female offspring exhibited an increased uterine weight (absolute/relative). F1-generation Adults:. Decrease in epididymal and testicular weight correlating with decreased counts for both organs noted at sperm analysis. Nonstatistical microscopy observations included a slight to marked hypospermia of the epididymis and a slight to moderate abnormal spermatozoa of the testis, relative to controls. F2-Offspring: No test substance-related findings were observed. Reproductive Performance (P and F1): Low fertility only observed in the P-generation. Increased cycle length (more persistence of estrous, designated by cornified cells) correlating with a decrease in the number of days to insemination in both the P and F1 females.

150 ppm P-generation Adults: No test substance-related findings were observed. F1 -Offspring: No test substance-related findings were observed. F1-generation Adults: No test substance-related findings were observed. F2-Offspring: No test substance-related findings were observed. Reproductive Performance (P and F1): No test substance-related findings were observed.

50 ppm P-generation Adults: No test substance-related findings were observed. F1 -Offspring: No test substance-related findings were observed. F1-generation Adults: No test substance-related findings were observed. F2-Offspring: No test substance-related findings were observed. Reproductive Performance (P and F1): No test substance-related findings were observed.

Test Substance-Related Effects at LOAEL:

Reproductive Males: Decrease epididymal count (F1) Decrease testicular count (F1) Decreased epididymal and testicular weights (F1) Hypospermia of epididymis (F1) Abnormal spermatozoa in testes (F1) Females: Decreased fertility (P) Increased incidence nonpatent cervices (P) Increased uterine weight (P) Increased incidence of “dilatation” of uterus (P) Increased cycle length (persistence of estrous) (P, F1) Decrease in days to insemination (P, F1)

Offspring Increased spleen weight (F1- m,f) Increased uterine weight (F1-f)