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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:
19.09.2002 to 30.04.2004
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: The study was conducted according to the appropriate OECD test guideline, and in compliance with GLP, and is therefore considered to be reliability 1. Read-across of the result is considered to be reliability 2.

Data source

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

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
GLP compliance:
yes (incl. certificate)
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories, France.
- Age at study initiation: Males: 8 weeks; Females: 10 weeks.
- Weight at study initiation: Males: 283-339 g; Females: 213-285 g.
- Fasting period before study: None
- Housing: Individually in suspended wire-mesh cages.
- Diet (e.g. ad libitum): Ad libitum
- Water (e.g. ad libitum): Ad libitum
- Acclimation period: 9-11 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ±2
- Humidity (%): 50 ±20
- Air changes (per hr): 12
- Photoperiod (hrs dark / hrs light): 12/12


IN-LIFE DATES: From: 30.09.2002 To: 9-21.11.2002 for principal and toxicity groups. From: 01.04.2004 to 30.4.2004 for complementary groups.

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
corn oil
Details on exposure:
PREPARATION OF DOSING SOLUTIONS: The test substance was mixed with the required quantity of vehicle at concentrations of 3.33, 16.66 and 33.33 mg/ml. The dosage forms were performed as follows: the required quantity of test substance was weighed into an appropriate container; 75% of the final volume of the vehicle was added and the preparation was homogenised with a magnetic stirrer. Sufficient vehicle was thereafter added to make the solutions up to the required volume. The vehicle for the control group was measured first, followed by preparation of the low and intermediate, then theh high dose forms to avoid contamination. Solutions were kept for up to 9 days.


VEHICLE
- Justification for use and choice of vehicle (if other than water): None given
- Concentration in vehicle: 3.33, 16.66 and 33.33 mg/ml
- Amount of vehicle (if gavage): Various depending on concentration
- Lot/batch no. (if required): 81K2204 and 062K0006
- Purity: No data
Details on mating procedure:
- M/F ratio per cage: 1:1
- Length of cohabitation: Overnight
- Proof of pregnancy: vaginal plug / sperm in vaginal smear referred to as day 0 of pregnancy.
- Each female was placed with the same male until mating occurred or 14 days elapsed.
- Further matings after two unsuccessful attempts: no
- After successful mating each pregnant female was caged (how): No data
Analytical verification of doses or concentrations:
no
Duration of treatment / exposure:
Throughout the pre-mating period (15 days), during the mating and post-mating periods until final sacrifice for the males (at least 4 weeks in total). Throughout pre-mating (15 days) and mating period, during pregnancy and lactation, until day 4 post-partum inclusive (or until sacrifice for un-mated females) for the females.
Three groups of 10 females received the test item and a fourth group received the vehicle under the same experimental conditions as males of the principal groups for at least 4 weeks in total.
Frequency of treatment:
daily
Details on study schedule:
Not applicable to screening study
Doses / concentrations
Remarks:
Doses / Concentrations:
10, 50 and 100 mg/kg bw/day
Basis:
actual ingested
No. of animals per sex per dose:
Ten
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: Based on a seven day range-finding study
- Rationale for animal assignment (if not random): random
Positive control:
None

Examinations

Parental animals: Observations and examinations:
See Section 7.5.1.
Oestrous cyclicity (parental animals):
None
Sperm parameters (parental animals):
Parameters examined: testis weight, epididymis weight, prostate weight. PAS/hematoxylin stained sections from the control animals and those given 100 mg/kg bw/day were examined microscopically. The tailed and round spermatids, spermatocytes, spermatogenia and the different stages of the spermatogenic cycles were evaluated.
Litter observations:
STANDARDISATION OF LITTERS: None - screening study only.


PARAMETERS EXAMINED
The following parameters were examined in 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: no; possible cause of death was not determined for pups born or found dead.
Postmortem examinations (parental animals):
SACRIFICE
- Male animals: All surviving animals either at the end of treatment period, or after the mating period, depending on group.
- Maternal animals: All surviving animals either at the end of the treatment period, or on Day 5 post-partum, depending on group.


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


HISTOPATHOLOGY / ORGAN WEIGHTS: See Table 2 in Section 7.5.1.
Postmortem examinations (offspring):
None
Statistics:
Yes, to assess statistical significance of findings in treatment group compared with control group.
Reproductive indices:
Mating index: No. of mated animals/No. of paired animals x100.
Fertility index: No. of pregnant female partners/No. mated pairs x100.
Gestation index: No. of females with live born pups/No. of pregnant females x100.
Offspring viability indices:
Live birth index: No.live born pups/No. of pups delivered x100.
Viability index (on day 4 post-partum): No. surviving pups on day 4 post-partum/No. live born pups x 100.

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:
effects observed, treatment-related
Other effects:
not examined

Reproductive function / performance (P0)

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

Details on results (P0)

CLINICAL SIGNS AND MORTALITY, BODY WEIGHT AND FOOD CONSUMPTION, ORGAN WEIGHTS, GROSS PATHOLOGY, AND HISTOPATHOLOGY (PARENTAL ANIMALS): See secrion 7.5.1.

REPRODUCTIVE FUNCTION: SPERM MEASURES (PARENTAL ANIMALS): In 1/10 treated males, severe degeneration of seminiferous tubules was noted. This finding correlated with a reduced size of testes. Taking into consideration the low incidence of this finding and that such a finding can occur spontaneously in untreated rats, the reported incidence was considered to be without relationship to the treatment. There were no such findings in any other animal, and the spermatogenic cycle was undisturbed in all other animals. Degenerated/necrotic spermatocytes sloughed in the centre of the seminiferous tubules, multinucleated giant cells, spermatid retention and occasional seminiferous tubules lined by Sertoli cells onlywere found, with minimal severity, in few individuals from the control and treated groups. These findings, with such severity, are commonly recorded spontaneous changes in the rat of this strain and age and were considered to be of no toxicological importance.

REPRODUCTIVE PERFORMANCE (PARENTAL ANIMALS): No adverse treatment-related effects on the mating index, pre-coital time, the fertility index was 100% in all groups, duration of gestation, delivery data, implantation sites, or post-implantation losses.

Effect levels (P0)

open allclose all
Dose descriptor:
NOAEL
Effect level:
50 mg/kg bw/day (actual dose received)
Sex:
female
Basis for effect level:
other: Based on tubular nephropathy at 100 mg/kg bw/day in toxicity group females.
Dose descriptor:
NOAEL
Effect level:
10 mg/kg bw/day (actual dose received)
Sex:
male
Basis for effect level:
other: Based on tubular nephropathy observed at 50 and 100 mg/kg bw/day.

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:
not examined
Histopathological findings:
not examined

Details on results (F1)

VIABILITY (OFFSPRING): Post-natal mortality was similar between groups.


CLINICAL SIGNS (OFFSPRING): No notable clinical signs.


BODY WEIGHT (OFFSPRING): All groups were similar.

Effect levels (F1)

Dose descriptor:
NOAEL
Generation:
F1
Effect level:
>= 100 mg/kg bw/day (actual dose received)
Sex:
male/female

Overall reproductive toxicity

Reproductive effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
In a good quality OECD 422 study conducted to GLP (reliability score 1) there were no treatment-related effects on reproduction evident up to 100 mg/kg bw/day tetraethylorthosilicate in rats. The NOAELs for parental toxicity were 10 and 50 mg/kg bw/day for males and females, respectively.
Executive summary:

In a good quality OECD 422 study conducted to GLP (reliability score 1) there were no treatment-related effects on reproduction evident up to 100 mg/kg bw/day tetraethylorthosilicate in rats. The NOAELs for parental toxicity were 10 and 50 mg/kg bw/day for males and females, respectively.