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Toxicological information

Toxicity to reproduction

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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: guideline study under GLP
Cross-reference
Reason / purpose for cross-reference:
reference to same study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2010

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
OECD Guideline 416 (Two-Generation Reproduction Toxicity Study)
GLP compliance:
yes
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
A mixture of: 2,2,6,6-tetramethylpiperidin-4-yl-hexadecanoate; 2,2,6,6-tetramethylpiperidin-4-yl-octadecanoate
EC Number:
415-430-8
EC Name:
A mixture of: 2,2,6,6-tetramethylpiperidin-4-yl-hexadecanoate; 2,2,6,6-tetramethylpiperidin-4-yl-octadecanoate
Cas Number:
86403-32-9
Molecular formula:
C25H49NO2 and C27H53NO2
IUPAC Name:
Reaction mass of 2,2,6,6-tetramethylpiperidin-4-yl hexadecanoate and 2,2,6,6-tetramethylpiperidin-4-yl octadecanoate

Test animals

Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Velaz Praha, Czech Republic
- Age at study initiation: (P) x wks; (F1) x wks
- Mean Weight at study initiation: (P) Males: 216.46g; Females: 218.75 g; (F1) Males: 56.25 g; Females: 49.58 g
- Fasting period before study:
- Housing: 4 animals per cage, mating: 1 male and 2 females; 1 pregnant female individually, 1 female and offspring individually
- Diet : ad libitum
- Water: ad libitum
- Acclimation period: > 6d

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 +/- 2°C
- Humidity (%): 45-65%
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
olive oil
Details on exposure:
0.5 ml/100 g body weight
Lot-no of the vehicle: L 809182
Details on mating procedure:
- M/F ratio per cage: 1/2
- Length of cohabitation: max. 21 days
- Proof of pregnancy: vaginal plug / sperm in vaginal smear referred to as day 0 of pregnancy
- After 16 days of unsuccessful pairing replacement of first male by another male with proven fertility (in sum 6 males were replaced).
- After successful mating each pregnant female was caged: individually
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
2 controls of analysis of sampleas were performed with 3 concentrations, recovery rate was nearly 100%.
Duration of treatment / exposure:
Parental males were dosed for 70 days before mating. Parental females were dosed 14 days prior to mating, no more than 21 days during the mating process, 22-24 days during gestation, and 21-28 days during lactation up until the weaning of F1 pups. F1 males and F1 females were dosed according to the this same schedule.
Frequency of treatment:
7 days per week.
Doses / concentrationsopen allclose all
Remarks:
Doses / Concentrations:
25 mg/kg bw/d
Basis:
actual ingested
0.5 ml/100 g body weight
Remarks:
Doses / Concentrations:
125 mg/kg bw/d
Basis:
actual ingested
0.5 ml/100 g body weight
Remarks:
Doses / Concentrations:
250 mg/kg bw/d
Basis:
actual ingested
0.5 ml/100 g body weight
No. of animals per sex per dose:
12 males, 24 females
Control animals:
yes, concurrent vehicle
Details on study design:
P and F1 adults were weighed weekly. Pups of F1 and F2 generation were weighed 24 hours after birth, and on days 4,7,14 and 21 post-parturition. For mating, F1 offspring were selected litters of the same dose level at weaning to produce F2 generation. Age difference between selected pups was about one week. Since F! pups were too small in day 21 post-partum, they were weaned in day 28 post-parturition. All animals were monitored for the signs of toxicity during the application of the test substance.

Examinations

Parental animals: Observations and examinations:
During the study, clinical observations and food consumption were recorded. Gross and histological examinations on selected organs were undertaken after termination of the study.
Oestrous cyclicity (parental animals):
not examined
Sperm parameters (parental animals):
not examined
Postmortem examinations (parental animals):
At the end of the study, all animals were sacrificed and underwent histological evaluationo of uterus, ovaries, mammary gland, testes, epididymis, prostate, glandula coagulations, liver, kidney and duodenum.
Postmortem examinations (offspring):
At the end of the study, all animals were sacrificed and underwent histological evaluationo of uterus, ovaries, mammary gland, testes, epididymis, prostate, glandula coagulations, liver, kidney and duodenum.
Statistics:
separately for P and F1 males, females and litters;
Test for homogeneity of the groups: Barlett´s test
in the way of homogeneity: one way analysis with consecutive Multiple Rangers test
no homogeneity: Kruskal-Wallis one way Analysis by ranks
Reproductive indices:
copulation index, fertility index, gestation index, delivery index
Offspring viability indices:
Live birth index, viability (Survival) index

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:
effects observed, non-treatment-related
Description (incidence and severity):
No important visible signs of intoxication were noted. Alopecia and smooth stool in P0 generation were registered, with no dose-response relationship.
Mortality:
mortality observed, non-treatment-related
Description (incidence):
One animal died due to a gavage accident.
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
Food intake in P females at 250 mg/kg bw/d after the first and second week, and in dose group 125 mg/kg bw/d after the second week pre-mating period was decreased compared to controls.
Food efficiency:
no effects observed
Water consumption and compound intake (if drinking water study):
no effects observed
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
no effects observed
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: 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
Description (incidence and severity):
Length of pregnancy 22-24 days. Body weights, number of offspring and sex distribution in F1 and F2 were largely stable. The number of live pups of F1 females in dose groups 25 and 250 mg/kg bw/d were decreased compared to contols. Health condition of

Details on results (P0)

One unscheduled death of an animal occurred, a female in dose group 125 mg/kg bw/d, of the P generation, on day 19 immediately after application of the test article. Gross necropsy was not informative about the death. All animals gained weight. Food intake in P females at 250 mg/kg bw/d after the first and second week, and in dose group 125 mg/kg bw/d after the second week pre-mating period was decreased compared to controls. Length of pregnancy was 22-24 days. The index of Live Births in the F1 females of 25 mg/kg bw/d group was slightly decreased against the control group. The number of corpora lutea and implantation sites in P females could not be established, as they were not visible when assessed after 28 days of parturition. The number of corpora lutea and implantation sites in F1 females were stable. While there were no significant changes histologically in the P generation, it was noted that there was an increased relative liver weight in females of the 250 mg/kg bw/d group, compared to controls.

Effect levels (P0)

open allclose all
Key result
Dose descriptor:
NOAEL
Effect level:
125 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
female
Basis for effect level:
other: based on increased relative liver weights in females of the 250 mg/kg bw/d group. No adverse effects in fertility parameters were observed at the highest dose tested.
Key result
Dose descriptor:
NOAEL
Effect level:
250 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male
Basis for effect level:
clinical signs

Results: P1 (second parental generation)

General toxicity (P1)

Clinical signs:
effects observed, non-treatment-related
Description (incidence and severity):
No important visible signs of intoxication were noted. Alopecia and smooth stool in P1 generation were registered, with no dose-response relationship.
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
no effects observed
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
no effects observed

Reproductive function / performance (P1)

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

Effect levels (P1)

Key result
Dose descriptor:
NOAEL
Effect level:
250 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No effects observed

Results: F1 generation

General toxicity (F1)

Clinical signs:
no effects observed
Mortality / viability:
mortality observed, non-treatment-related
Description (incidence and severity):
Control: 12/153 (dead/alive), 25 mg/kg bw: 7/199 (dead/alive), 125 mg/kg bw: 9/185 (dead/alive), 250 mg/kg bw: 11/184 (dead/alive)
Body weight and weight changes:
effects observed, non-treatment-related
Description (incidence and severity):
Mean body growth of F1 pups in the mid dose group was slightly decreased compared to controls.
Food consumption and compound intake (if feeding study):
not examined
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Sexual maturation:
no effects observed
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Histopathological findings:
no effects observed
Description (incidence and severity):
Histopathology examinations of male and females of the control and high dose groups of both generations showed no changes related to the test material.

Developmental neurotoxicity (F1)

Behaviour (functional findings):
not examined

Developmental immunotoxicity (F1)

Developmental immunotoxicity:
not examined

Details on results (F1)

Body weights, number of offspring and sex distribution in F1 and F2 were largely stable. The number of live pups of F1 females in dose groups 25 and 250 mg/kg bw/d were decreased compared to controls. Health condition of all pups was standard. One incidence of hydrocephalus occurred in the offspring of a F1 female in the 25 mg/kg bw/d group. Mean body growth of F1 pups in the mid dose group was slightly decreased compared to controls; it was stable in all F2 pups. Histopathology examinations of male and females of the control and high dose groups of both generations showed no changes related to the test material.

Effect levels (F1)

Key result
Dose descriptor:
NOAEL
Generation:
F1
Effect level:
250 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: NOAEL > 250 mg/kg bw/day. No adverse effects in fertility parameters were observed at the highest dose tested.

Results: F2 generation

General toxicity (F2)

Clinical signs:
no effects observed
Mortality / viability:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
not examined
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Sexual maturation:
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
no effects observed
Histopathological findings:
not examined

Developmental neurotoxicity (F2)

Behaviour (functional findings):
not examined

Developmental immunotoxicity (F2)

Developmental immunotoxicity:
not examined

Overall reproductive toxicity

Key result
Reproductive effects observed:
no

Any other information on results incl. tables

The results of a two-generation reproductive toxicity study in rats show that Dastib 845, at doses of 25, 125 and 250 mg/kg bw/d, caused no test article-related changes based on the evaluation of the survival, clinical signs, body weight, production parameters, and organ weights. The exception was that P females of the 250 mg/kg bw/d group showed increased relative liver weight. The LOAEL for the P generation is 250 mg/kg bw/d, and the NOAEL is 125 mg/kg bw/d based on these effects. The LOAEL for the P generation males and F1 generation is greater than 250 mg/kg bw/d.

Applicant's summary and conclusion

Conclusions:
A two-generation reproductive toxicity study in Wistar rats on Dastib 845, at doses of 25, 125 and 250 mg/kg bw/d, was undertaken according to OECD guideline 416. Results indicate there was no test article-related changes based on the evaluation of the survival, clinical signs, body weight, production parameters, and organ weights, except for elevated relative liver weights in P females. The NOAEL for the P generation males and F1 generation is greater than 250 mg/kg bw/d; for P females is 125 mg/kg bw/d based on systemic toxicity.