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Key value for chemical safety assessment

Effects on fertility

Description of key information

In two subchronic oral feeding studies with a structural analogue, no effects on reproductive organs have been observed.

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

No animal studies were conducted with the test substance to investigate possible substance-related effects on the reproductive performance. For a structural analogue, two subchronic feeding studies are available. Please refer to the Annex of the CSR for the read across justification.

When given to male and female CD rats at 700, 2000, 6000 ppm no findings of pathological significance were noted in testes and epididymis of males as well as in uterus and ovaries of females in comparison with untreated control animals (1979). Similarly, in a subchronic oral feeding study conducted in Beagle dogs after exposure to 200, 600, 2000 ppm no findings of pathological significance were noted in testes and epididymis of males as well as in uterus and ovaries of females in comparison with untreated control animals (1980).

Effects on developmental toxicity

Description of key information

In a prenatal developmental toxicity study with a structurally related compound (1983, OECD 414) 25 pregnant Tif:RAIf (SPF) rats per dose were treated daily by gavage with 400, 1200 and 2400 mg test substance per kg bodyweight from day 6 to 15 of gestation. No adverse effects have been observed. Based on the findings a NOEL of 2400 mg/kg bw (highest dose tested) was deduced for developmental toxicity.

Link to relevant study records
Reference
Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
Nov 1982 - Mar 1983
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions
Remarks:
Guideline study performed under GLP-like quality control. No data on purity were available. Dosing was performed from day 6 to 15 of gestation only.
Qualifier:
according to
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Version / remarks:
12 May 1981
Deviations:
no
GLP compliance:
no
Remarks:
predating GLP, QAU statement included
Limit test:
no
Specific details on test material used for the study:
STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: Room temperature
- Stability under test conditions: Determined by the sponsor
- Solubility and stability of the test substance in the solvent/vehicle: Insoluble in water

FORM AS APPLIED IN THE TEST (if different from that of starting material): Suspension
Species:
rat
Strain:
other: Sprague-Dawley derived Tif:RAIf (SPF) rats
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: closed breeding colony, Ciba-Geigy WST
- Age at study initiation: 2 months
- Weight at study initiation: 180-200 g
- Housing: 5 per cage in Makrolon cages
- Diet: NAFAG No. 890, ad libitum
- Water: ad libitum
- Acclimation period: day 0 to day 6 post coitum

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21+/-2
- Humidity (%): 55+/-10
- Photoperiod: 12 hrs dark / 12 hrs light
Route of administration:
oral: gavage
Vehicle:
CMC (carboxymethyl cellulose)
Remarks:
0.5%
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:
The suspension of the test material was freshly prepared daily by homogenization and stirring (magnetic stirrer), and administered at a rate of 10 ml/kg of body weight.
VEHICLE
- Justification for use and choice of vehicle (if other than water): Insoluble in water
- Amount of vehicle (if gavage): 10 mL/kg bw
Analytical verification of doses or concentrations:
no
Details on mating procedure:
The females were mated overnight with males of proven fertility in the ratio of 1 male / 3 females. The day on which spermatozoa were found in the vaginal smear or a vaginal plug was observed, was designated as day 0 of pregnancy.
Duration of treatment / exposure:
Day 6 to day 15 of pregnancy
Frequency of treatment:
Once daily
Duration of test:
until day 21 of gestation
Dose / conc.:
400 mg/kg bw/day (actual dose received)
Dose / conc.:
1 200 mg/kg bw/day (actual dose received)
Dose / conc.:
2 400 mg/kg bw/day (actual dose received)
No. of animals per sex per dose:
25 pregnant rats
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale:
Doses were based on results of a preliminary study, where 10 rats were dosed with vehicle or 2000 mg/kg bw test substance. The dams of the experimental group (2000 mg/kg bw) reacted to the treatment by some reduction in body-weight gain and food intake in comparison with the vehicle control. Concerning the progeny, no abnormalities were revealed by the external examination; the average weight of the foetuses of the 2000 mg/kg bw dose group was not significantly diminished in comparison with the vehicle control (Student's t test, one-tailed, observed p < 0.01).
Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Daily during treatment period

BODY WEIGHT: Yes
- Time schedule for examinations: Daily during treatment period

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Yes
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes / No / No data
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: Yes / No / No data

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 21
- organs


Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: No data
- Number of corpora lutea: No data
- Number of implantations: No data
- Number of resorptions: Yes
- Number of abortions
- Mucosa and contents, including amniotic fluid and placentae
Fetal examinations:
- External examinations: Yes: [all per litter]
- Soft tissue examinations: Yes [One third per litter]
- Skeletal examinations: Yes: [ Two third per litter ]
- Head examinations: No data
- Sex determination
- Weighing
- Uterine horns showing no evident implantation sites were placed into a solution of ammonium sulfide to visualize possible haemorrhagic alterations in such sites.
Statistics:
The numbers of embryonic and/or foetal deaths (resorptions) (Chi*-test, Yates' correction, observed p > 0.01).
The male to female ratios of the foetuses (Chi* -test, Yates' correction, observed p > 0.05).
Historical control data:
Spontaneous data characteristic of the breed of rats used in the present study refer to a series of untreated controls ("historical" or cumulative control) observed over a period of 69 months (listed in the study report).
Clinical signs:
not specified
Dermal irritation (if dermal study):
not examined
Mortality:
mortality observed, non-treatment-related
Description (incidence):
1 female (400 mg/kg bw) died on day 6 in consequence of an intubation error. No spontaneous deaths occured.
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
effects observed, non-treatment-related
Description (incidence and severity):
food consumption was reduced in all exposure groups (from day 6 of pregnancy)
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:
effects observed, non-treatment-related
Description (incidence and severity):
Signs of inflammation of the liver in one female vehicle control
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
not examined
Histopathological findings: neoplastic:
not examined
Number of abortions:
no effects observed
Pre- and post-implantation loss:
not examined
Total litter losses by resorption:
no effects observed
Early or late resorptions:
no effects observed
Dead fetuses:
no effects observed
Changes in pregnancy duration:
no effects observed
Description (incidence and severity):
One female vehicle control and one female exposed to 2400 mg/kg delivered "spontaneously" (i.e. shortly before sacrifice on day 21 p.c.) and were not taken into further consideration of data.
Changes in number of pregnant:
no effects observed
Dose descriptor:
NOAEL
Effect level:
2 400 mg/kg bw/day (actual dose received)
Based on:
test mat.
Basis for effect level:
other: abscence of adverse effects for the tested doses
Fetal body weight changes:
effects observed, non-treatment-related
Description (incidence and severity):
In comparison with the vehicle control, the average body-weight of the live fetuses was not diminished at either dose. A slight but significant
increase was noted for the live fetuses of the intermediate and, at a lower extent, of the high-dose group (Student's t test, onetailed,
observed p < 0.01). This finding, however, is not assumed to be of a biological relevance.
Reduction in number of live offspring:
no effects observed
Changes in sex ratio:
no effects observed
Changes in litter size and weights:
not specified
Changes in postnatal survival:
not examined
External malformations:
effects observed, non-treatment-related
Description (incidence and severity):
One fetus with omphalocele in the high-dose group, mandibular aplasia in one fetus of the intermediate-dose group
Skeletal malformations:
effects observed, non-treatment-related
Description (incidence and severity):
The skeletal assessment revealed instances of irregular sternebral ossification in the dose groups and in the vehicle control
Visceral malformations:
effects observed, non-treatment-related
Description (incidence and severity):
One fetus with anasarca in the vehicle control, two fetuses from one
litter with subpleural haemorrhage in the low-dose group, one fetus displaying partial aplasia of the lungs in the intermediate-dose group
Dose descriptor:
NOAEL
Effect level:
2 400 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: abscence of adverse effects for the tested doses
Abnormalities:
not specified
Developmental effects observed:
not specified

Table 1: Summarized reproduction data of the main study.

Dose group

(mg/kg d)

0

400

1200

2400

Historical control

Spontaneous deaths

0/25

0/24

0/25

0/25

0/842

Body-weight gain (%)

+10.3

+10.3

+13.0

+9.3

 

Females with deciduomata

0/25

0/24

0/25

0/25

1/842

Females with implantations

22/25

22/24

24/25

22/25

784/842

Implantations/female (mean, SD)

15.4±2.0

15.7±2.9

14.5±1.9

15.0±2.7

13.09±2.33

Females with total abortion

0

0

0

0

0/784

Females with partial abortion

0

0

0

0

2/784

Embryonal deaths (resorptions)

3.8

7.0

8.4

8.2

8.74

Foetal deaths (resorptions)

0.3

0.3

0

0.3

0.28

Dead foetuses

0

0

0

0

0.13

Number of live foetuses (males-females)

155-170

166-154

160-158

146-155

4554-4765

Percent males of live foetuses

47.7

51.9

50.3

48.5

48.9

Average weight of live foetuses (g)

5.3±0.5

5.3±0.4

5.4±0.4

5.4±0.4

5.34±0.45

 

Conclusions:
Based on the results and under the condition chosen, the test article is considered to be not teratogenic.
Executive summary:

In a prenatal developmental toxicity study following OECD guideline 414, 25 pregnant Tif:RAIf (SPF) rats per dose group were treated daily with the test article by gavage at 400, 1200, 2400 mg/kg body weight from day 6 to 15 of gestation. Dams were killed on day 21 and fetuses removed by Caesarian section. Body-weight gain was comparable for the dams of all groups. Food consumption of the experimental groups, however, showed some reduction during the treatment period (from day 6 of pregnancy) in comparison with the vehicle control. One female of the low dose group died due to an intubation error. Females No. 4 (vehicle control) and No. 78 (2400 mg/kg) delivered "spontaneously" (i.e. shortly before sacrifice on day 21 p.c.) and were not taken into further consideration of data.

The rates of implantation sites per female were comparable for all groups. The numbers of embryonic and/or fetal deaths (resorptions) were not increased at either dose. The male to female ratios of the fetuses were also comparable for all groups. In comparison with the vehicle control, the average body-weight of the live fetuses was not diminished at either dose. A slight but significant increase was noted for the live fetuses of the intermediate and, at a lower extent, of the high-dose group. This finding, however, is not assumed to be of a biological relevance. The gross and/or visceral examination of the live fetuses revealed one fetus with anasarca in the vehicle control, two fetuses from one litter with subpleural haemorrhage in the low-dose group, one fetus each displaying mandibular aplasia and partial aplasia of the lungs, respectively, in the intermediate dose and one fetus showing omphalocele in the high-dose group. The skeletal assessment revealed instances of irregular sternebral ossification in the dose groups and in the vehicle control. Concerning the status of skeletal maturation of the fetuses shortly before term, no delay of ossification could be found for the experimental groups in comparison with the vehicle control. Based on the findings a NOAEL of 2400 mg/kg body weight (highest dose tested) was derived for maternal and developmental toxicity.

Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
2 400 mg/kg bw/day
Species:
rat
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

No data for the test article are available. Therefore, data obtained with a structurally related compound is used to assess developmental toxicity. Please refer to the Annex of the CSR for the read across justification.

In a prenatal developmental toxicity study following OECD guideline 414, 25 pregnant Sprague-Dawley derived Tif:RAIf (SPF) rats per dose group were treated daily with the test article by gavage at 400, 1200, 2400 mg/kg body weight from day 6 to 15 of gestation. Dams were killed on day 21 and fetuses removed by Caesarian section. Body-weight gain was comparable for the dams of all groups. Food consumption of the experimental groups, however, showed some reduction during the treatment period (from day 6 of pregnancy) in comparison with the vehicle control. One female of the low dose group died due to an intubation error. The rates of implantation sites per female were comparable for all groups. No differences between control and test groups were reported regarding fetal death (resorption), male to female ratio of fetuses and average fetal body weight. A slight but significant increase was noted for the live fetuses of the intermediate and, at a lower extent, of the high-dose group. This finding, however, is not assumed to be of a biological relevance. Some instances of anomalies and/or malformations were recorded for the dose groups as well as for the vehicle control: two fetuses from one litter of the low dose displayed subpleural hemorrhage; mandibular aplasia and partial aplasia of the lungs, respectively, were found in one fetus each of the intermediate dose, omphalocele occurred in one fetus of the high dose and anasarca in one fetus of the vehicle control group. These findings are considered to be of a spontaneous origin and not related to the treatment. The incidences of mandibular aplasia, omphalocele and anasarca were found to be 0.05%, 0.04% and 0.12%, respectively, in the historical control population of the breed of rats used for the present experiment. Likewise, the occurrence of sternebral anomalies in all groups was not assumed to be of an experimental significance, the overall incidence of sternebral anomalies being 0.37% in the historical control. Concerning the status of skeletal maturation of the fetuses, no delay of ossification could be found for the experimental groups in comparison with the vehicle control. Based on the findings a NOAEL of 2400 mg/kg body weight (highest dose tested) was derived for maternal and developmental toxicity.

Justification for classification or non-classification

Classification, Labelling, and Packaging Regulation (EC) No 1272/2008

The available experimental test data are reliable and suitable for classification purposes under Regulation 1272/2008 (CLP). As a result the substance is not classified for reproduction toxicity under Regulation (EC) No 1272/2008.