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Key value for chemical safety assessment

Effects on fertility

Link to relevant study records
Reference
Endpoint:
two-generation reproductive toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1997-03-26 - 1998-05-11
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Justification for type of information:
Study owner prepared study while seeking authorisation of the substance as active incredient for medical treatment.
Reference:
Composition 0
Qualifier:
according to
Guideline:
other: ICH S5, 4.1.2
Version / remarks:
ICH 4.1.2
GLP compliance:
yes
Test material information:
Composition 1
Species:
rat
Strain:
Sprague-Dawley
Sex:
female
Details on test animals and environmental conditions:
Adaption period: at least 6 days
Age: 7 weeks
B.w. (day 0 of gestation, day of conception): 189 - 236 g
Route of administration:
oral: gavage
Vehicle:
propylene glycol
Remarks:
2.15 ml/kg b.w.
Details on exposure:
from implantation (6th day of gestation) until the end of lactation (dams of the F0-genaration only)
Details on mating procedure:
One male and one female of each group are raised to maturity and mated at the age of 13 weeks. Inbreeding was not carried out. Males were scrificed after the mating period
Duration of treatment / exposure:
from implantation until the end (22nd day) of lactation.
Frequency of treatment:
daily
Dose / conc.:
0 mg/kg bw/day (nominal)
Remarks:
Group 1: Control (2.15 ml/kg b.w. propylene glycol)
Dose / conc.:
14.7 mg/kg bw/day (nominal)
Remarks:
Group 2: low dose
Dose / conc.:
31.6 mg/kg bw/day (nominal)
Remarks:
Group 3: intermediate dose
Dose / conc.:
68.1 mg/kg bw/day (nominal)
Remarks:
Group 4: high dose
No. of animals per sex per dose:
96 females: 20 per group + 16 spare animals
Control animals:
yes
yes, concurrent vehicle
Parental animals: Observations and examinations:
Clinical signs, viability, b.w., food consumption
Litter observations:
b.w., sex, number of live and dead pups
Statistics:
Bartlett chi-square test
Dunnett test (p <= 0.01)
Student's t-test (p <= 0.01)
Reproductive indices:
gestation, index, birth index, Live birth index, viability index, lactation index, overall survival
Clinical signs:
no effects observed
Dermal irritation (if dermal study):
not examined
Mortality:
mortality observed, non-treatment-related
Description (incidence):
one high dosed animal died on day 21 of gestation
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
decreased b.w. in high dosed females.
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
-10 to -14 % (compared to control, not significent at p <= 0.01) in intermediate-dose group
-7 to -15 % (compared to control, significent at p <= 0.01) in high-dose group
Food efficiency:
not specified
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:
not examined
Gross pathological findings:
no effects observed
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
not examined
Histopathological findings: neoplastic:
not examined
Other effects:
not examined
Reproductive function: estrous cycle:
not examined
Reproductive function: sperm measures:
not examined
Reproductive performance:
effects observed, treatment-related
Description (incidence and severity):
1 stillbirth at low dosage (2 in control group)
Lactaion index marginally and significantly (at p <= 0.05) decreased at the high dose.
One of the pups from a high-dosed dam was malformed, it showed haematomas in the head region. This malformation was considered as spontaneous ans not substance-related.
Key result
Dose descriptor:
NOEL
Effect level:
ca. 14.7 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
female
Basis for effect level:
food consumption and compound intake
reproductive performance
Clinical signs:
no effects observed
Dermal irritation (if dermal study):
not examined
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
not specified
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
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:
not examined
Gross pathological findings:
no effects observed
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
not examined
Histopathological findings: neoplastic:
not examined
Other effects:
not examined
Reproductive function: estrous cycle:
not specified
Reproductive function: sperm measures:
not specified
Reproductive performance:
no effects observed
Key result
Dose descriptor:
NOEL
Effect level:
ca. 31.6 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other:
Remarks on result:
not determinable due to absence of adverse toxic effects
Clinical signs:
no effects observed
Dermal irritation (if dermal study):
not examined
Mortality / viability:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
not specified
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
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:
not examined
Gross pathological findings:
no effects observed
Histopathological findings:
not examined
Other effects:
not examined
Behaviour (functional findings):
no effects observed
Developmental immunotoxicity:
not examined
Key result
Dose descriptor:
NOEL
Generation:
F1
Effect level:
ca. 31.6 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other:
Remarks on result:
not determinable due to absence of adverse toxic effects
Clinical signs:
no effects observed
Dermal irritation (if dermal study):
not examined
Mortality / viability:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
not specified
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
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:
not examined
Gross pathological findings:
not examined
Histopathological findings:
not examined
Other effects:
not examined
Behaviour (functional findings):
no effects observed
Developmental immunotoxicity:
not examined
Key result
Dose descriptor:
NOEL
Generation:
F2
Effect level:
ca. 68.1 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other:
Remarks on result:
not determinable due to absence of adverse toxic effects
Key result
Reproductive effects observed:
no
Conclusions:
Under the Present test conditions the following no-effect dose levels were observed:
Effects in the F0-dams during gestation and lactation
NOEL: 14.7 mg/kg b.w./day p.o.
Effects on dewelopment of the conceptus and the offspring (F1-generation) trough sexual maturity
NOEL: 31.6 mg/kg b.w./day p.o.
F2-generation
NOEL: > 68.1 mg/kg b.w./day p.o
Hence, under the present test conditions, the marginally reduced lactation index occured an a dose level that also caused maternal toxicity, and hence, was related to it.
No effect was observed at doses below the maternal toxicity.
Executive summary:

F0 -dams

Mortlity:

None of the low- and intermediate-dosed female animals died prematurely.

One high-dosed female died prematurely on the 21st day of gestation following a rupture of the cardiac artrium. All circumstance connected with the exitus indicate that this death was spontaneous.

Clinical signs:

No substance-related effects were observed on behaviour, external appearance and faeces ind teh dams of the low and intermediate testes dose levels. 7 of 21 pregnant high-dosed animals showed a slightly reduced motility during the first 3 days of treatment.

Body weight:

No substance-related difference in b.w. between treated and control female animals was noted at the low- and intermediate-dose level.

The high dose caused a very marginal - though still detectable - decrease in b.w. during the gestation period (between 2 % and 4 % compared to the controls, significant at p <= 0.01 on gestation days 10, 13, 15, 16) and during the lactation period (between 7 % and 8 % compared to the controls, significant at p <= 0.01 on gestation days 7, 14).

Food consumption:

The relative food consumption was not influenced at the low dose level.

A mild transient decrease in the relative food consumption was noted in the intermediate dose between the 18th and 21st gestation day. The difference fron the controls was minus 10 % to minus 14 % (not significant at p <= 0.01).

A mild decrease in the relative food consumption was also noted at the high dose (on 10th and between 13th and 21st gestation day, minus 7 % to minus 15 %, significant at p <= 0.01 on the 13th, 14th and 19th gestation day).

Reproduction:

The low, intermediate and high dose did not influence the reproduction parameters of the rats. The duration of pregnancy was within the normal range, the parturition not inflienced.

Birth index, live birth index, viability index, lactation and overall survival index were similar to those of the control group at the low and the intermediate dose. However, the lactation index was marginally and significantly (at p <= 0.05) decreased at the high dose.

The number of pups born was not affecte, the pups developed normally. B.w. of pups at birth did not differ between the control and substance-treated groups.

1 stillbirth was observed at the low dose (control: 2 stillbirths). This finding is within the normal range of background data and was not attributed to the administration of the test compound.

One of the pups from a high dosed dam was malformed, it showed haematoms in the head region. This malformation was considered as spontaneous and not substance related.

Macroscopic post mortem findings:

Macroscopic inspection revealed no systemic changes connected with the treatment. the number of implants according to SALEWSKI was similar in the control and substance treated groups. A spontaneous rupture of the atrium was noted in the heart of 1 prematurely deceased high-dosed dam (the one where prematurely death was reported).

F1 -generation (until weaning)

Sex distribution: not influenced

B.w. during pre and post weaning: All values are within normal range at the low. intermediate and high dose.

External examination: Except for 1 malformation (see above) no abnormalities were observed.

Morphological landmarks, functional tests, open-field test:

The time-points for pinna detachment, upper incisor eruption, ear and eye opening, cleavage of the balanopreputilal gland and vagianl opening of the pups fren the low-, intermediate- and high-dosed dams were not influenced.

All functional tests and the open-field test revealed no subtance-related influence for the animals of low, the intermediate and the high dose.

Macroscopic post mortem findings: No substance related pathological changes were observed.

F1-dams and male F1-partners

Mortality: None of the rats died prematurely.

Clinical Signs: None of the F1-parent animals showed any changes of behaviour, external appearance and faeces.

B.w.: All values of the groups 2, 3, 4 were within the normal range

Reproduction:

All reproduction parameters were within the range of the controls. Duration of pregnancy and the parturition were not delayed. Birth index, live birth indedex, viability index, lactation and overall survival index were similar in all groups. No influence was noted on the number of pups born, their birth weight and their development.

One malformed pup in group 4 (a tailless pup) is considered as spontaneous.

Macroscopic post mortem findings: No changes were observed.

F2-generation (until weaning)

Sex distruibution: The sex distribution was not infuenced.

Body weight during pre- and post weaning: All values were within the normal range.

External examination: abnormalities were observed.

Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed

Effects on developmental toxicity

Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed

Justification for classification or non-classification

According to the GHS regulation alpha-Lipoic acid is not classified as toxic to development and fertility.

No effect was observed at doses below the maternal toxicity.