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Toxicological information

Toxicity to reproduction

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Administrative data

Endpoint:
screening for reproductive / developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Justification for type of information:
May, 2017. Because of in the NDA 01-04-1385-00 carried out by Germany was not requested to indicate the endpoint study record, considering the data inserted in the course of the assessment to be correct and exhaustive the proper “Adequacy of study” has been selected.

Data source

Reference
Reference Type:
other: Body responsible for the test
Title:
Unnamed
Year:
2000
Report date:
2000

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
OECD Guideline 421 (Reproduction / Developmental Toxicity Screening Test)
GLP compliance:
yes

Test material

Constituent 1
Chemical structure
Reference substance name:
-
EC Number:
438-670-5
EC Name:
-
Cas Number:
87199-17-5
Molecular formula:
Hill formula: C7H7BO3 CAS formula: C7H7BO3
IUPAC Name:
(4-formylphenyl)boronic acid
Test material form:
solid

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
other: 0,5 % CMC
Details on mating procedure:
A few days prior to the initiation of mating, the males were separated into individual cages. Pairing was on a one male to one female basis, each female being transferred to the cage of a co-group male, where it remained until mating had been detected.
A vaginal lavage from each female was examined early each morning and the day of detection of a copulatory plug in situ and/or sperm in the lavage was designated Day 0 of gestation.
Each female remained with its first designated male for a maximum of 7 consecutive neghts. If non positive mating sign was detected in that time, a rest period of 2 nights was allowed before the female was placed with another suitable co-group male that had already demonstrated successful mating, for an additional period of a maximum of 7 nights. Daily vaginal lavages continued to be taken throuhghout and assessed for stage of oestrus
Duration of treatment / exposure:
The males were dosed from 2 weeks prior to mating until termination.
The females were dosed once daily from 2 weeks prior to mating until at least Day 4 of lactation
Frequency of treatment:
Dosing regime (males): 7 days/week
Dosing regime (females): 7 days/week
Details on study schedule:
Number of litters per dose/conc.: 0 at mg/kg or mg/l
No. of animals per sex per dose:
Male: 10 animals at 0 mg/kg or mg/l
Male: 10 animals at 50 mg/kg or mg/l
Male: 10 animals at 250 mg/kg or mg/l
Male: 10 animals at 1000 mg/kg or mg/l
Female: 10 animals at 0 mg/kg or mg/l
Female: 10 animals at 50 mg/kg or mg/l
Female: 10 animals at 250 mg/kg or mg/l
Female: 10 animals at 1000 mg/kg or mg/l
Control animals:
yes

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
At 1000 mg.kg-1.day-1, transient clinical signs, including findings such as salivation, stained and unkempt coats were noted in all animals. At 250 mg.kg-1.day-1, salivation and/or coat staining was evident in 3 males and 5 females
Dermal irritation (if dermal study):
not specified
Mortality:
mortality observed, treatment-related
Description (incidence):
At 1000 mg.kg-1.day-1 4 females were killed. 3 were sacrificed primarily due to their extended gestation length (23 days or longer) and also their clinical signs which included hunched posture, respiration, difficulties subdued behavior and unkempt coats. Necroscopy findings were inconclusive. Animals 80 were sacrificed on Day 11 of dosing due to gasping respiration, necropsy reveled no abnormal findings so cause of death was uncertain
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Males treated at 1000 mg.kg-1.day-1, showed a decrease in weight gain over the first 2 weeks of treatment. Thereafter weight gain was essentially similar to that of the Controls, although overall weight gain remained marginally lower. Males treated at 250 mg.kg-1.day-1, showed a slight decrease in bodyweight gain over the first 2 weeks of treatment, but by the end of the study mean weight was again similar to the Control. Weight gain of males treated at 50 mg.kg-1.day-1, was similar to Control.
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not specified
Haematological findings:
not specified
Clinical biochemistry findings:
not specified
Urinalysis findings:
not specified
Behaviour (functional findings):
not specified
Immunological findings:
not specified
Organ weight findings including organ / body weight ratios:
not specified
Histopathological findings: non-neoplastic:
not specified
Histopathological findings: neoplastic:
not specified
Other effects:
effects observed, treatment-related
Description (incidence and severity):
Pregnancy performance:
At 1000 mg.kg-1.day-1, there was an obvious effect of treatment on the mean duration of gestation, with only one animal littering on Day 22 and the remaining animals littering on Days 23 or 24 of gestation. In addition, 3 out of 8 pregnant females were sacrificed due to their increased gestation length. At 250 mg.kg-1.day-1, the mean duration of gestation was greater than that of the Controls with no animals giving birth on Day 21 of gestation, and 3 animals giving birth on Day 23 of gestation. Duration of gestation at 50 mg.kg-1.day-1 was similar to Control

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)

Mating performance and fertility were not obviously affected by treatment.

Effect levels (P0)

Dose descriptor:
LOAEL
Effect level:
ca. 250 mg/kg bw/day
Based on:
not specified
Sex:
female
Basis for effect level:
other: Gestation length

Results: P1 (second parental generation)

General toxicity (P1)

Clinical signs:
not examined
Dermal irritation (if dermal study):
not examined
Mortality:
not examined
Body weight and weight changes:
not examined
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
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
not examined
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
not examined
Histopathological findings: neoplastic:
not examined
Other effects:
not examined

Reproductive function / performance (P1)

Reproductive function: oestrous cycle:
not examined
Reproductive function: sperm measures:
not specified
Reproductive performance:
not examined

Effect levels (P1)

Remarks on result:
not measured/tested

Results: F1 generation

General toxicity (F1)

Clinical signs:
not specified
Dermal irritation (if dermal study):
not specified
Mortality / viability:
mortality observed, treatment-related
Description (incidence and severity):
Effects on F1 generation:
Slight intergroup differences in the numbers of implants were considered to be incidental, in the absence of any effect at 1000 mg.kg-1.day-1. At 1000 mg.kg-1.day-1, there was a notable reduction in the birth, live birth and viability indices when compared with the Controls. There findings were primarily linked to the performance of Animal 77 which gave birth on Day 24 of gestation, and where all pups subsequently died. Among the four litters that survived to Day 4, litter size and survival were not obviously affected. The live birth and viability indices were also reduced for animals treated at 250 mg.kg-1.day-1. The mean litter size at birth was not obviously affected by treatment; the apparently smaller litter size reflected Animal 62, which had a very small litter. At 50 mg.kg-1.day-1, there were no obvious effects of treatment on pup survival. The slightly lower mean litter size was considered to reflect the incidentally lower number of implants at this level.
Body weight and weight changes:
effects observed, non-treatment-related
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 specified
Haematological findings:
not specified
Clinical biochemistry findings:
not specified
Urinalysis findings:
not specified
Sexual maturation:
not specified
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
not specified
Histopathological findings:
not specified
Other effects:
not specified

Developmental neurotoxicity (F1)

Behaviour (functional findings):
not specified

Developmental immunotoxicity (F1)

Developmental immunotoxicity:
not specified

Details on results (F1)

Effects on F1 generation:
At 1000 mg.kg-1.day-1, there was a notable reduction in the birth, live birth and viability indices when compared with the Controls. There findings were primarily linked to the performance of Animal 77 which gave birth on Day 24 of gestation, and where all pups subsequently died. Among the four litters that survived to Day 4, litter size and survival were not obviously affected. The live birth and viability indices were also reduced for animals treated at 250 mg.kg-1.day-1. The mean litter size at birth was not obviously affected by treatment

Effect levels (F1)

Dose descriptor:
LOAEL
Generation:
F1
Effect level:
250 mg/kg bw/day
Based on:
test mat.
Sex:
not specified
Basis for effect level:
viability
mortality

Results: F2 generation

General toxicity (F2)

Clinical signs:
not examined
Dermal irritation (if dermal study):
not examined
Mortality / viability:
not examined
Body weight and weight changes:
not examined
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:
not examined
Histopathological findings:
not examined
Other effects:
not examined

Developmental neurotoxicity (F2)

Behaviour (functional findings):
not examined

Developmental immunotoxicity (F2)

Developmental immunotoxicity:
not examined

Effect levels (F2)

Remarks on result:
not measured/tested

Overall reproductive toxicity

Reproductive effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
There were no fertility-influencing effects
detected.

Effects on F1 generation:
The live birth and viability indices were reduced for animals treated at 250 mg.kg-1.day-1. The developmental toxicity effects were in association with maternal toxicity

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