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Toxicological information

Toxicity to reproduction

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Administrative data

Endpoint:
screening for reproductive / developmental toxicity
Remarks:
based on test type (migrated information)
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Study period:
2012
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Guideline study according to GLP. Read-across justification is given in the read-across document attached in IUCLID Section 13.

Data source

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

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
OECD Guideline 421 (Reproduction / Developmental Toxicity Screening Test)
Deviations:
no
GLP compliance:
yes (incl. certificate)
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Type:
Constituent

Test animals

Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Harlan Laboratories BV
- Age at study initiation: approx. 7 weeks
- Weight at study initiation: 199 - 233 g (males), 133 - 154 g (females)
- Fasting period before study: yes (overnight)
- Housing: in groups of 5 in Makrolon type-4 cages
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: yes

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 +/- 3 °C
- Humidity (%): 30 - 70 %
- Air changes (per hr): 10 - 15 per hour
- Photoperiod (hrs dark / hrs light): 12 hour dark / light cycle

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
water
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:

DIET PREPARATION
- Rate of preparation of diet (frequency): n.a.
- Mixing appropriate amounts with (Type of food): n.a.
- Storage temperature of food: n.a.

VEHICLE
- Justification for use and choice of vehicle (if other than water): purified water
- Concentration in vehicle: 0 - 100 mg/mL
- Amount of vehicle (if gavage): 10 mL (dose volume)
Details on mating procedure:
- M/F ratio per cage: 1:1
- Length of cohabitation: until evidence of copulation (up to 14 days pairing period)
- Proof of pregnancy: vaginal plug / sperm in vaginal smear referred to as day 0 of pregnancy
- After 14 days of unsuccessful pairing replacement of first male by another male with proven fertility.
- Further matings after two unsuccessful attempts: no
- After successful mating each pregnant female was caged: individually
- Any other deviations from standard protocol: no
Analytical verification of doses or concentrations:
yes
Duration of treatment / exposure:
Males: minimum 4 weeks
Females: approximately 7 weeks
Frequency of treatment:
once daily
Doses / concentrationsopen allclose all
Remarks:
Doses / Concentrations:
0 mg/kg body weight
Basis:
actual ingested
Remarks:
Doses / Concentrations:
62.5 mg/kg body weight
Basis:
actual ingested
Remarks:
Doses / Concentrations:
250 mg/kg body weight
Basis:
actual ingested
Remarks:
Doses / Concentrations:
1000 mg/kg body weight
Basis:
actual ingested
No. of animals per sex per dose:
11 per sex per group
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: Based on dose-range-finding study
- Rationale for animal assignment: random

Examinations

Parental animals: Observations and examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: daily

BODY WEIGHT: Yes
- Time schedule for examinations: daily from start of treatment to day of necropsy

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): n.a.


WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): n.a.

Sperm parameters (parental animals):
Parameters examined in [all/P/F1/F2] male parental generations:
No abnormal microscopic findings during sperm staging regarding completeness of stages and maturation of cell populations.
Litter observations:
PARAMETERS EXAMINED
The following parameters were examined in [F1 / F2 / F3] offspring:
number and sex of pups, stillbirths, live births, postnatal mortality, presence of gross anomalies, weight gain, physical or behavioural abnormalities

GROSS EXAMINATION OF DEAD PUPS:
yes, for external and internal abnormalities; possible cause of death was determined for pups born or found dead
Postmortem examinations (parental animals):
SACRIFICE
- Male animals: All surviving animals after treatment for 28 days.
- Maternal animals: All surviving animals on day 21 post coitum (if birth did not occur at that day, the dam was sacrificed on day 25 post coitum).

GROSS NECROPSY
- Gross necropsy consisted of external and internal examinations including the cervical, thoracic, and abdominal viscera.

HISTOPATHOLOGY / ORGAN WEIGHTS
Postmortem examinations (offspring):
SACRIFICE
The F1 offspring were sacrificed at 4 days of age.

GROSS NECROPSY
No test item related findings in any pubs at any dose level observed.

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:
no effects observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Organ weight findings including organ / body weight ratios:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Other effects:
not examined

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:
no effects observed
Reproductive function: sperm measures:
no effects observed
Reproductive performance:
no effects observed

Details on results (P0)

CLINICAL SIGNS AND MORTALITY (PARENTAL ANIMALS):
No mortality occurred. No significant test item-related clinical signs were noted at any dose level.

BODY WEIGHT AND FOOD CONSUMPTION (PARENTAL ANIMALS):
A reduction of food consumption at the dose level of 1000 mg/kg body weight per day was noted in males and females. A related but not statistically significant reduction in body weights was noted only in male animals but not in females.

REPRODUCTIVE FUNCTION:
No effects observed.

REPRODUCTIVE FUNCTION: SPERM MEASURES (PARENTAL ANIMALS)
No abnormal lesions noted during microscopic staging regarding completeness of stages and maturation of cell populations.

REPRODUCTIVE PERFORMANCE (PARENTAL ANIMALS):
No effects on mating performance or fertility was observed at any dose level.

ORGAN WEIGHTS (PARENTAL ANIMALS):
No changes in organ weights considered to be test item-related were noted at any dose level.

GROSS PATHOLOGY (PARENTAL ANIMALS):
Individual findings in male animals were within the range of the normal background of animals from this strain. No test item-related findings were noted in females at any dose level.

HISTOPATHOLOGY (PARENTAL ANIMALS):
No histopathological findings attributable to the treatment with the test item could be observed. No test item related findings related to ovaries, testes and epididymides could be detected.

Effect levels (P0)

Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: overall effects

Results: F1 generation

General toxicity (F1)

Clinical signs:
no effects observed
Mortality / viability:
mortality observed, treatment-related
Body weight and weight changes:
no effects observed
Sexual maturation:
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
no effects observed
Histopathological findings:
not examined

Details on results (F1)

VIABILITY (OFFSPRING):
Mean value of living pubs per dam at first litter check was in the range of historical controls.

CLINICAL SIGNS (OFFSPRING):
No test item-related observations were noted in pubs during the first litter check or during lactation at any dose level.

BODY WEIGHT (OFFSPRING):
No effects on pub body weights were noted at any dose level.

GROSS PATHOLOGY (OFFSPRING):
No test item-related findings were found in pubs at any dose level.

Effect levels (F1)

Dose descriptor:
NOAEL
Generation:
F1
Effect level:
250 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: see 'Remark'

Overall reproductive toxicity

Reproductive effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
Based on the results, the NOAEL of Hostapon SG for general toxicity in male and female parental animals is considered to be 1000 mg/kg body weight per day. A test item related influence on the offspring with regard to an increased post-implantation and postnatal loss observed in this study cannot be excluded. However, these effects are most probably attributable to the high sodium chloride content of the test item and thus are not considered to reflect substance specific toxicity.
Executive summary:

Hostapon SG Dried was administered in highly purified water as vehicle at dosages of 62.5, 250, and 1000 mg/kg body weight/day, and controls received the vehicle only. Hostapon SG Dried was administered to male rats for 28 days and to female rats for 14 days prior to pairing, through the pairing and gestation periods until the F1 generation reached day 4 post partum. Test item-related effects were observed at the dose level of 1000 mg/kg bw/day, no of them was considered to be adverse.

Treatment with the test item at the high-dose level caused also a reduction in food consumption of males and females. In males, reduction in food consumption was accompanied by a reduction in body weights observed during the entire study period and a reduction in body weight gain which was significant during the pre-pairing but recovered during the pairing period. In females no effects on body weights or body weight gain were noted. The effects on food consumption, body weights and body weight gain at the high dose level were considered not to be adverse.

During necropsy and following histopathological examination no significant test item-related findings were noted in males and females at any dose level. There were no microscopic abnormal lesions encountered during sperm staging regarding completeness of stages and maturation of cell populations. There were no findings noted that could be attributed to treatment with the test item, Hostapon SG. The findings observed were within the range of normal background lesions which may be recorded in animals of this strain and age.

No effects on mating performance, fertility, corpora lutea count or duration of gestation were observed at any dose level. At the dose level of 1000 mg/kg bw/day, higher incidences of post-implantation loss and higher postnatal loss as well as lower litter size at first litter check and on day 4 post partum were noted.

No test item-related findings were noted at first litter check and during lactation in pups at any dose level.

Based on the results, the NOAEL of Hostapon SG for general toxicity in male and female parental animals is considered to be 1000 mg/kg body weight per day. A test item related influence on the offspring with regard to an increased post-implantation and postnatal loss observed in this study cannot be excluded. However, these effects are most probably attributable to the high sodium chloride content of the test item and thus are not considered to reflect substance specific toxicity.