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Administrative data

Key value for chemical safety assessment

Effects on fertility

Effect on fertility: via oral route
Endpoint conclusion:
no study available
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information
Short description of key information:
No data have been located concerning toxicity to reproduction.

Effects on developmental toxicity

Description of key information
In a developmental toxicity study (Leuschner/LPT 1993) according to OECD TG 414, the following effect levels were determined:
NOAEL maternal: 100 mg/kg bw/day; NOEL embryotoxicity: 625 mg/kg bw/day (highest dose tested);
NOEL foetotoxicity: 625 mg/kg bw/day (highest dose tested); NOEL teratogenicity: 625 mg/kg bw/day (highest dose tested).
Link to relevant study records
Reference
Endpoint:
developmental toxicity
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Study period:
21 Jul. - 29 Oct. 1992
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP-Guideline study
Qualifier:
according to
Guideline:
EU Method B.31 (Prenatal Developmental Toxicity Study)
Version / remarks:
; cited as Directive 87/302/EEC, part B, p. 24
Deviations:
no
GLP compliance:
yes (incl. certificate)
Limit test:
no
Species:
rat
Strain:
Sprague-Dawley
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: SD Lippische Versuchstierzucht HAGEMANN GmbH, Extertal, Germany
- Age at study initiation: approx. 59 d
- Weight at study initiation: 204 - 294 g
- Fasting period before study: no
- Housing: individual in Macrolon cage
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: 7 d


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 +- 2
- Humidity (%): 50 +-15
- Photoperiod (hrs dark / hrs light): 12 / 12

Route of administration:
oral: gavage
Vehicle:
other: sesame oil
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:

VEHICLE
- Justification for use and choice of vehicle (if other than water): forms stable suspension with DIPN
- Amount of vehicle (if gavage): 5 mL/kg bw
- Purity: DAB 10
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
GC, Column: Chrompack 50 m x 0.25 mm, Coating CP-Wax-52 CB, 250 °C (FID), external standard calibration (Report, p. 219):
Recoveries of DIPN concentrations in test suspension were 90 - 107 %, independent of storage time during study duration.
Details on mating procedure:
- Impregnation procedure: cohoused
- If cohoused:
- M/F ratio per cage: 1 / 1
- Length of cohabitation: overnight
- Further matings repeated if unsuccessful
- Proof of pregnancy: sperm in vaginal smear, referred to as day 0 of pregnancy
Duration of treatment / exposure:
day 6 to 15 of gestation
Frequency of treatment:
1x/d
Duration of test:
20 d
No. of animals per sex per dose:
20
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: Doses for the main study were selected based on results of a range finding study using 2 pregnant rats dosed at 100, 350, 750, and 1000 mg/(kg bw*d)
Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily


DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: daily

BODY WEIGHT: Yes
- Time schedule for examinations: daily

FOOD CONSUMPTION): Yes, daily
- Time schedule for examinations: daily

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): Yes
- Time schedule for examinations: daily

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 20
- Organs examined: gross pathology/necropsy (not specified)

Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: Yes
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes
- Other: sex, viability
Fetal examinations:
- External examinations: Yes: all per litter
- Soft tissue examinations: Yes: half per litter
- Skeletal examinations: Yes: half per litter
- Head examinations: Yes
Statistics:
Analysis of variance: Homogeneity of variance for mean values using the Bartlett chi-square test, one-way analysis if appropriate, Dunnett test was used in cases of significant differences among groups. In case of heterogeneity, Student´s test was carried out. for comparison of malformations, retardation- and variation rates, the Fisher Exact test or chi-square test were employed.
Indices:
Corpera lutea per dam; implantations per dam; number of fetuses (alive and dead) per dam; resorptions per dam (early and late); pre- and post-implantation loss; runts per dam; malformations, variations per dam
Historical control data:
Average in-house data summarised for SD rats from 1988 - 1991 (Report, p. 214-217)
Details on maternal toxic effects:
Maternal toxic effects:yes

Details on maternal toxic effects:
In dams, there was no substance-related mortality. No significant clinical or toxic symptoms were observed, except an disproportionate reduction in feed consumption in the mean and high-dose group, with approx. -15 % and -34 %, respectively, from gd 6 to gd 9 (p<0.01) [Report, Tab. 5, Fig. 2].
Body-weight and body-weight gain were within the normal range at all dose-groups, but a transient decline in body-weight gain after dosing (gd 6 - 9) at 250 and 625 mg/(kg*d) was observed (-26 % and -70% in the 250- and 625-mg group, respectively) [Report Tab. 3].
This transient body-weight loss paralleled the transient decrease in food uptake and was overcompensated by a disproportionate increase in body-weight gain during gd 12 - 15 as compared to the control and low dose treatment group.
Drinking-water consumption was not influenced by the treatment.
No remarkable findings on necropsy.
Dose descriptor:
NOAEL
Effect level:
100 mg/kg bw/day (nominal)
Basis for effect level:
other: maternal toxicity
Dose descriptor:
LOAEC
Effect level:
250 mg/kg bw/day (nominal)
Basis for effect level:
other: maternal toxicity
Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:no effects

Details on embryotoxic / teratogenic effects:
No adverse effects were observed even at the highest dose tested with incipient maternal toxicity.
Dose descriptor:
NOEL
Remarks:
(highest dose tested)
Effect level:
625 mg/kg bw/day (nominal)
Basis for effect level:
other: embryotoxicity
Dose descriptor:
NOEL
Remarks:
(highest dose tested)
Effect level:
625 mg/kg bw/day (nominal)
Basis for effect level:
other: fetotoxicity
Dose descriptor:
NOEL
Remarks:
(highest dose tested)
Effect level:
625 mg/kg bw/day (nominal)
Basis for effect level:
other: teratogenicity
Abnormalities:
not specified
Developmental effects observed:
not specified

Range finding study

 

Dose selection was based on the range-finding study using 2 pregnant rats dosed at 100, 350, 750 and 1000 mg/(kg bw*d). 100 and 350 mg/(kg bw*d) were well tolerated, while 750 mg/(kg bw*d) was within the incipient maternal and fetotoxic range.

 

Main study

 

No developmental toxicity was observed at the highest dose tested with incipient maternal toxicity.

 

Reproduction data:

Fertility rate: 95.5 % (control and 250-mg group)

                     100 % (100- and 625-mg group)

No significant differences from the control were noted in all reproductive parameters.

 

Resorption rates/post-implantation losses:

Controls:              11.9 %

100-mg group:       5.8 %

250-mg group:     10.1 % *

625-mg group:       9.4 %

  * including one dead fetus

No particular developmental adverse effects on the fetuses of any treatment group were observed, comprising physiological (body weight and body length) as well as morphological parameters (malformations and variations).

 

Autopsy findings: none

There were no fetal deaths but one in the 250-mg group.

Conclusions:
The treatment of pregnant rats produced no pathologically relevant effects, neither in the dams nor in the offspring. The authors´ conclusion (p. 13 and 29) of a very slight trend towards an increased incidence of skeletal retardation at the mid and high dose level is not evident from the results tables.

Transient significant reduction in feed consumption and body weight gain were observed during maternal development.

With respect to the maternal body-weight effect, the NOAEL for maternal toxicity is assumed to be 100 mg/(kg*d). Due to the absence of embryotoxic effects, the highest dose, 625 mg/(kg*d), corresponds to a NOEL for developmental effects (embryo-/fetotoxicity and teratogenicity).
Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
625 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
acceptable for assessment, based on SAR
Effect on developmental toxicity: via inhalation route
Endpoint conclusion:
no study available
Effect on developmental toxicity: via dermal route
Endpoint conclusion:
no study available
Additional information

Leuschner/LPT 1993

Pregnant rats were treated by gavage with DIPN in sesame oil at dose levels of 0, 125, 250, and 625 mg/kg bw/day from day 6 to day 15 of gestation.

The treatment of pregnant rats produced no pathologically relevant effects either in the dams or in the offspring. The authors´ conclusion of a very slight trend towards an increased incidence of skeletal retardation at the mid and high dose level is not evident from the results tables.

Transient significant reduction in feed consumption and body weight gain were observed during maternal development.

With respect to the maternal body-weight effect, the NOAEL for maternal toxicity is assumed to be 100 mg/(kg*d). Due to the absence of embryotoxic effects, the highest dose, 625 mg/(kg*d), corresponds to a NOEL for developmental effects (embryo-/foetotoxicity and teratogenicity).

Justification for classification or non-classification

Based on results for developmental toxicity / teratogenicity, classification is not indicated.