Registration Dossier

Toxicological information

Toxicity to reproduction

Currently viewing:

Administrative data

Endpoint:
one-generation reproductive 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:
14.11.1991 to 26.03.1992
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
The study was conducted according to the appropriate OECD guideline and in compliance with GLP and is therefore considered to be reliability 1. Read-across of the study itself is considered to be reliability 2. Further information on read-across is given in the endpoint summary.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1992
Report Date:
1992

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
OECD Guideline 415 [One-Generation Reproduction Toxicity Study (before 9 October 2017)]
GLP compliance:
yes
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Type:
Constituent
Type:
Constituent

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River (UK) Limited, Manston, Kent.
- Age at study initiation: Males: 37-44 days; Females; 37-43 days
- Weight at study initiation: Males: approximately 194 g; Females: approximately 155 g
- Fasting period before study: No
- Housing: Groups of four in polypropylene cages. During mating period animals were transferred to a similar cage on a 1:1 basis. After mating females were housed individually.
- Diet : Ad libitum
- Water : Ad libitum
- Acclimation period: 16 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19-25
- Humidity (%): 40-70
- Air changes (per hr): at least 15
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: 14.11.1991 To: 26.03.1992

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
arachis oil
Details on exposure:
PREPARATION OF DOSING SOLUTIONS: Prior to preparation, Dynasylan IBTEO was filtered to remove any sediment. Dynasylan was dissolved in dried arachis oil by weighing into suitable containers and subsequently the vehicle was added to make the appropriate final volume. The test substance and vehicle were shaken until an homogenous mixture was observed. From week 12 each dose level was prepared in two batches. Each batch was analysed separately for achieved concentration. Once an acceptable concentration was achieved, both batches of a particular dose level were pooled. The control vehicle was prepared weekly.
Details on mating procedure:
- M/F ratio per cage: 1:1
- Length of cohabitation: Up to 21 days
- Proof of pregnancy: vaginal plug and/or sperm in vaginal smear referred to as day 0 of pregnancy
- Further matings after two unsuccessful attempts: no
- After successful mating each pregnant female was caged (how): Individually
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Prior to the start of the study a procedure was developed to prepare the test substance for dose administration. These preparations were analysed for achieved concentration, stability and homogeneity. During the study, samples of the test substance formulations were taken weekly for analysis of achieved concentration of the preparations.
Duration of treatment / exposure:
The test substance was administered for 74 days prior to mating and then through breeding, gestation and lactation periods.
Frequency of treatment:
Daily
Details on study schedule:
None - One generation study
Doses / concentrations
Remarks:
Doses / Concentrations:
50, 250 and 1000 mg/kg bw/day
Basis:
actual ingested
No. of animals per sex per dose:
32
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: Based on a 14-day range-finding study.

Examinations

Parental animals: Observations and examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: All animals were checked twice daily for morbidity and mortality (once at weekends and bank holidays). All animals were observed daily, immediately before and one hour after dosing, for clinical signs of toxicity.

DETAILED CLINICAL OBSERVATIONS: No

BODY WEIGHT: Yes
- Time schedule for examinations: During the maturation and mating period the parental generation animals were weighed weekly. Following mating, the parental generation males were weighed weekly until termination. Parental generation females showing evidence of mating were weighed on days 1, 4, 7, 14 and 21 post coitum. Parental generation females with a live litter were weighed on days 1, 4, 7, 14 and 21 post partum.

FOOD CONSUMPTION:
During the maturation periods food consumption was recorded weekly for each cage of parental generation adults. Following mating, weekly food consumption was recorded for parental generation males until termination. For parental generation females showing evidence of mating, individual food consumption was recorded for the periods covering days 1 to 7, 7-14 and 14-21 post coitum. For parental generation females with live litters, individual food consumption was recorded for the periods covering days 1-7 and 7-14 post partum.
Oestrous cyclicity (parental animals):
A vaginal smear was prepared for each female and the stage of the estrous cycle or the presence of sperm was recorded. No other tests for cyclicity recorded.
Sperm parameters (parental animals):
Parameters examined in P male parental generations: histopathological examination of estes, epididymides, seminal vesicles, and prostate.
Litter observations:
STANDARDISATION OF LITTERS
- Performed on day 4 postpartum: yes
- If yes, maximum of 8 pups/litter (4/sex/litter as nearly as possible); excess pups were killed and discarded.

PARAMETERS EXAMINED
The following parameters were examined in F1 offspring: number and sex of pups, stillbirths, live births, postnatal mortality, clinical signs of toxicity, presence of gross anomalies, weight gain, physical or behavioural abnormalities. All live offspring were observed for the following landmarks of development: detachment of pinna, tooth eruption and eye opening. They were also assessed for reflexological response to various stimuli as follows: surface righting reflex, mid-air righting reflex, startle reflex and pupil reflex.

GROSS EXAMINATION OF DEAD PUPS: yes, for external and internal abnormalities; possible cause of death was not determined for pups born or found dead.
Postmortem examinations (parental animals):
SACRIFICE
- Male animals: All surviving animals as soon as possible after the last litters were weaned on day 21.
- Maternal animals: All surviving animals on weaning (day 21).

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

HISTOPATHOLOGY
The following tissues were prepared for microscopic examination: ovaries, uterus, cervix, vagina, testes, epididymides, seminal vesicles, prostate, coagulating gland, pituitary gland and significant abnormalities.
Postmortem examinations (offspring):
SACRIFICE
- The F1 offspring not selected to continue to weaning and animals killed on postnatal day 21.
- These animals were subjected to postmortem macroscopic examination only.

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

HISTOPATHOLOGY
Not conducted in offspring.
Statistics:
Data were processed to give litter mean values, group mean values and standard deviations.

Adult male and female bodyweight, female bodyweight during gestation and lactation, adult male food consumption, female food consumption during gestation and lactation. Offspring litter size, group mean pre-coital length were evaluated as follows: group values were analysed by F-max test to establish homogeneity of group variances followed by one way analysis of variance. Except where significant differences between control and any treated groups were observed, no further pairwise evaluations were performed.

Adult female food consumption, gestation food consumption, litter weight and individual offspring bodyweights: Group values were analysed by the F-max test to establish homogeneity of group variance followed by one way analysis of variance. Where significant differences were observed, pairwise comparison of control group individual values against each of the treated groups was performed using the Student's 't' Test.

Gestation length, offspring sex ratios, landmarks of offspring physical development and offspring reflexological responses: individual values were compared using the Kruskall Wallis nonparametric rank sum test. As there were no significant differences between control and treated groups, no pairwise evaluations were performed.

Mating, pregnancy and parturition indices: probability values were established using the Fisher Exact Probability Test.

Offspring viability indices: probability values were established using Chi-squared analysis.
Reproductive indices:
The following parameters were calculated: pre-coital interval, fertility indices (mating index, pregnancy index), gestation length, parturition index, live birth index.
Offspring viability indices:
Viability index (post natal days 1, 1-4, 4-7, 7-14, 14-21, sex ratio, physical development.

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:
effects observed, treatment-related
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:
not examined
Histopathological findings: non-neoplastic:
no effects observed
Other effects:
not examined

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:
not examined
Reproductive function: sperm measures:
not examined
Reproductive performance:
no effects observed

Details on results (P0)

CLINICAL SIGNS AND MORTALITY (PARENTAL ANIMALS): At 1000 mg/kg bw/day there were three deaths during the maturation period and one female was found dead during the lactation period. Three of the four deaths were found within one hour after dosing. The principle postmortem macroscopic findings were wetness/salivation around the nose and or mouth for 3/4 animals and inflated/spongy appearance of the lungs with a frothy exudate for 4/4 animals. Histopathology of the lungs of the interim deaths showed congestion and minimal peribronchiolar and perivascular lymphoid aggregates. The marked salivation response frequently observed at this dose level pre- and post- dosing, was considered a contributary factor in the death of these animals. One non-fertile female was killed for humane reasons as a result of the condition of a subcutaneous mass on the ventral abdomen. Microscopic examination showed the mass to be a dermal haemangiosarcoma (an incidental finding). There were no mortalities in the mid and low dose groups. One control female had to be killed due to gross enlargement of one mammary gland, due to severe mastitis and mammary gland hyperplasia.

At 1000 mg/kg bw/day all animals showed signs of immediate post dosing salivation with recovery within one hour. This observation was intermittent for all animals and was initially observed at approximately 3-4 weeks after the start of the dosing period, continuing until termination. Salivation before dosing and fur wetness/staining were also observed but at a lower incidence and frequency. All other clinical signs were incidental and not related to treatment. In the mid dose group 3/32 males and 0/32 females showed signs of immediate post dosing salivation. There were no treatment-related clinical signs observed in the low dose group.

BODY WEIGHT AND FOOD CONSUMPTION (PARENTAL ANIMALS): No treatment-related effects.

REPRODUCTIVE PERFORMANCE (PARENTAL ANIMALS): At 1000 mg/kg bw/day a reduction in the total number of pregnancies was observed but without statistically significant differences in the mating and pregnancy indices. This finding was considered not to be a treatment-related effect upon fertility. The precoital intervals were comparable for all groups with the majority of matings occuring within four days of pairing. The pregnancy and mating indices for all groups were within acceptable limits.

The gestation length was comparable with no statistically significant differences between treated groups and controls.

GROSS PATHOLOGY (PARENTAL ANIMALS): No adverse findings.

HISTOPATHOLOGY (PARENTAL ANIMALS): No adverse findings.

Effect levels (P0)

Dose descriptor:
NOAEL
Effect level:
>= 1 000 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No treatment-related adverse effects observed at any dose.

Results: F1 generation

General toxicity (F1)

Clinical signs:
no effects observed
Mortality / viability:
no mortality observed
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): Live birth index and live litter size, before and after litter standardisation were comparable for all groups throughout lactation up to weaning. There were no effects upon litter sex ratios. Statistical evaluation showed no significant differences for the treated groups compared to controls.

CLINICAL SIGNS (OFFSPRING): All clinical observations were considered incidental and not related to treatment.

BODY WEIGHT (OFFSPRING): At 1000 mg/kg bw/day there was a slight but statistically significant difference in group mean litter weights (p<0.05) and individual offspring bodyweight (p<0.05) in day seven postpartum. The difference in group mean litter weights and individual offspring bodyweight remained statistically significant (litter weights p>0.05, individual weights p>0.01) on day 14 and 21 post partum but the increase in weight gain, relative to the group starting weight for each period of measurement, was comparable for each group. Therefore this was not considered to be toxicologically significant.

There were no differences in the time of appearance of the landmarks of offspring development at any dose. Nor were there any effects observed in the reflexology tests.

GROSS PATHOLOGY (OFFSPRING): No adverse effects.

Effect levels (F1)

Dose descriptor:
NOAEL
Generation:
F1
Effect level:
>= 1 000 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No adverse effects on reproductive parameters at any dose.

Overall reproductive toxicity

Reproductive effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
In a rat oral one-generation reproductive toxicity study conducted to OECD 415 and to GLP (reliability score 1) the NOAEL for parental general toxicity and for reproductive toxicity for the structural analogue substance triethoxy(isobutyl)silane (CAS: 17980-47-1) was at least 1000 mg/kg bw/day, as no adverse effects were observed at any dose.