Registration Dossier

Administrative data

Endpoint:
toxicity to reproduction
Remarks:
other: subacute
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: GLP - Guideline study according to OECD 407 for repeated dose including reproductive parameters
Cross-reference
Reason / purpose:
reference to same study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2012
Report Date:
2012

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to
Guideline:
other: OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity in Rodents) including reproductive parameters
Qualifier:
according to
Guideline:
other: EU Method B.7 (Repeated Dose (28 Days) Toxicity (Oral)) including reproductive parameters
GLP compliance:
yes (incl. certificate)
Remarks:
BASF SE Experimental Toxicology and Ecology 67056 Ludwigshafen, Germany
Limit test:
no

Test material

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

Test animals

Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals and environmental conditions:
for details see Chapter 7.5.1

Administration / exposure

Route of administration:
oral: gavage
Type of inhalation exposure (if applicable):
other: not applicable
Vehicle:
corn oil
Details on exposure:
for details see Chapter 7.5.1
Details on mating procedure:
No mating performed
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
for details see Chapter 7.5.1
Duration of treatment / exposure:
4 weeks
Frequency of treatment:
daily
Details on study schedule:
for details see Chapter 7.5.1
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 100, 300, 1000 mg/kg bw/day
Basis:
actual ingested
No. of animals per sex per dose:
5
Control animals:
yes, concurrent vehicle
Positive control:
not applicable

Examinations

Parental animals: Observations and examinations:
for details see Chapter 7.5.1
Oestrous cyclicity (parental animals):
Vaginal smears for cycle determination were be prepared in the morning and evaluated for at least 2 weeks.
Sperm parameters (parental animals):
Parameters examined in [P] male parental generations:
sperm motility, sperm morphology, sperm head count (cauda epididymis), sperm head count (testis)
Litter observations:
not examined
Postmortem examinations (parental animals):
for details see Chapter 7.5.1
Postmortem examinations (offspring):
not examined
Statistics:
for details see Chapter 7.5.1
Reproductive indices:
not examined
Offspring viability indices:
not examined

Results and discussion

Results: P0 (first parental generation)

Details on results (P0)

REPRODUCTIVE FUNCTION: ESTROUS CYCLE (PARENTAL ANIMALS)
No test substance-related effects on estrous cycle length and the number of cycles were obtained.

REPRODUCTIVE FUNCTION: SPERM MEASURES (PARENTAL ANIMALS)
In males of test groups 2 and 3 (300 and 1000 mg/kg bw/d), sperm motility and total sperm head counts in the right cauda epididymidis were decreased, whereas the incidence of abnormal sperms in the right cauda epididymidis was increased.


ORGAN WEIGHTS (PARENTAL ANIMALS)
Significant weight increase (relative +26%, absolute +33%) of the epididymides of males of test group 3 (1000 mg/kg bw/d) was observed.
All other weight parameters concerning primary and secondary reproductive organs did not show test substance related changes, i.e. Adrenal glands, Ovaries, Prostate, Seminal vesicles with coagulating glands, Testes, Thyroid glands, Uterus with cervix

GROSS PATHOLOGY (PARENTAL ANIMALS)
All findings occurred individually. They were considered to be incidental in nature and not related to treatment.

HISTOPATHOLOGY (PARENTAL ANIMALS)
- Epididymis, left
Test group 3: 1000 mg/kg bw/d
o Immature ducts in all males (slight to severe)
o Interstitial edema in all males (minimal to slight)
o Intraductal granulocytic infiltration in 2 of 5 males (minimal)

Test group 2: 300 mg/kg bw/d
o Immature ducts in all males (minimal to slight)
o Interstitial edema in 1 of 5 males (minimal)

Test group 1: 100 mg/kg bw/d
No histopathological changes were found.

- Testis, left
No histopathological changes were found in the left testes.

No test substance related changes were observed in other primary or secondary reproductive organs, i.e. Adrenal glands, Ovaries, Pituitary gland, Prostate, Seminal vesicles, Thyroid glands, Uterus, Vagina

For further information, see Chapter 7.5.1.

Effect levels (P0)

open allclose all
Dose descriptor:
NOAEL
Effect level:
100 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male
Basis for effect level:
other: spermatotoxicity, pathology epididymis
Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
female
Basis for effect level:
other: Reprod. organs, estrous cycling

Results: F1 generation

Details on results (F1)

no data

Effect levels (F1)

Remarks on result:
other: Effects on parameters addressing reproductive toxicity in F0 males, indicative of adverse effects on F1 offspring.

Overall reproductive toxicity

Reproductive effects observed:
not specified

Any other information on results incl. tables

In mid/ high dose males sperm function and morphology in the cauda epididymidis were adversely affected.

Histopathology revealed in the left epididymis the presence of immature ducts in the distal corpus and/or cauda epididymis in all mid/ high dose males. Immature ducts increased in severity dose dependently. With increasing severity the immature ducts were accompanied by increasing interstitial edema, which correlated with the significant weight increase found in the high dose group. In only two of five high dose males, additional intraductal granulocytic infiltration was observed in single distended ducts of the cauda with apparent sperm stasis. All of these findings were attributed to treatment and were regarded as adverse.

 

Applicant's summary and conclusion