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Key value for chemical safety assessment

Effects on fertility

Description of key information

In a 90-day repeated dose study according to OECD 408 the gonads of male and female animals were examined for abnormalities. No macroscopical or microscopical changes have been observed in the gonads of the animals. Overall, the test substance had no apparent effect on reproductive organs of either sex.

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

The test article was given orally in feed to groups of rats for a total of 90 days at dose levels of up to 624 mg/kg body weight (see chapter 7.5.1). Treatment-related adverse effects on reproductive organs were not observed in this study. All major organs were examined grossly and microscopically. A slight decrease of testes weight was noted in treated male group 4 (10,000 ppm). The statistical significance of this weight loss, however, is mainly triggered by one individual animal which displayed a reduced testes weight of -65% compared to controls. In addition, there were no histopathological effects noted for the testes in any dose group. Therefore, this weight loss is considered of no toxicological relevance. Overall, the test substance had no apparent effect on reproductive organs of either sex. The pathological and microscopic/ macroscopic examination was carried out on testes, prostate, uterus, fallopian tubes and ovaries along with other organs. No outstanding differences were noted between control and test groups. Thus, based on the parameters examined in a 90-day feeding study, the test substance does not possess potential for toxicity to reproduction.

Effects on developmental toxicity

Description of key information

A prenatal developmental toxicity study in Sprague-Dawley Tif: RAIf (SPF) is available (OECD TG 414).  NOAEL, maternal toxicity, rat, oral gavage: 3000 mg/kg bw. NOAEL, developmental toxicity, rat, oral gavage: 3000 mg/kg bw.

Link to relevant study records
Reference
Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
January 1983 - August 1983
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
guideline study with acceptable restrictions
Qualifier:
according to guideline
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Version / remarks:
(1981)
Deviations:
no
GLP compliance:
no
Remarks:
QAU statement available, no GLP compliance statement available
Limit test:
no
Species:
rat
Strain:
other: Sprague-Dawley Tif: RAIf (SPF)
Details on test animals or test system 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: 4 per cage throughout the experiment
- Diet: standard cube diet, NAFAG No. 890, ad libitum
- Water: tap water, ad libitum
- Acclimation period: 6 days (between allocation to the corresponding group on day 0 and the first treatment on day 6 post coitum)

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21+/-2
- Humidity (%): 55+/-10
- Photoperiod: 12 hrs dark /12 hrs light (Light: 6 am-6 pm)
Route of administration:
oral: gavage
Vehicle:
other: water:polyethylene glycol400 (1:1)
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.
Analytical verification of doses or concentrations:
no
Details on mating procedure:
- Impregnation procedure: cohoused
- M/F ratio per cage: 1:3
- Length of cohabitation: overnight
- Proof of pregnancy: vaginal plug or sperm in vaginal smear referred to as day 0 of pregnancy
Duration of treatment / exposure:
day 6-15 p.c.
Frequency of treatment:
once daily
Duration of test:
day 0- 21 p.c.
Dose / conc.:
500 mg/kg bw/day (actual dose received)
Dose / conc.:
1 500 mg/kg bw/day (actual dose received)
Dose / conc.:
3 000 mg/kg bw/day (actual dose received)
No. of animals per sex per dose:
24 females
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale:
A preliminary experiment was carried out on 15 fertilized rats each for the vehicle control and the dose group (3000 mg/kg d). The test material was suspended in a mixture of distilled water and polyethylene glycol 400 (1:1) and administered orally by intubation from day 6 until day 15 of pregnancy, inclusive. Treatment at this 3000 mg/kg dose level caused no depression in either food consumption or body-weight gain of the mother animals. Apart from a reduced body weight no adverse effects were recorded for the progeny at sacrifice shortly before term in comparison with the vehicle control. On the basis of the foregoing results the doses for the main stpdy were selected at 0, 500, 1500 and 3000 mg/kg of body weight
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:
- On day 6, 11, 16, 21.

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 21
- Organs examined: ovaries and uterus (mucosa and contents, including amniotic fluid and placentae as well as abortions and resorption sites)
Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: No
- Number of corpora lutea: No
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes
Fetal examinations:
- External examinations: Yes: all per litter
- Soft tissue examinations: Yes: 1/3 per litter
- Skeletal examinations: Yes: 2/3 per litter
- Head examinations: No data
Statistics:
Average weight: Student's t test, one-tailed
Records of reproduction data:
The numbers of embryonic and/or foetal deaths (resorptions): Chi-Square-test, Yates' correction
Historical control data:
Historical cumulative control (1977-1983) of reproduction data and anomalies and malformations provided.
Historical cumulative control of visceral examination provided.
Details on maternal toxic effects:
With regard to the vehicle control and in accordance with the results of the preliminary experiment, neither food consumption nor body-weight gain was altered in the experimental groups.
Female No. 78 (3000 mg/kg d) died spontaneously on day 7 p.c. (i.e. after one application) likely in consequence of an intubation error.
Dose descriptor:
NOAEL
Effect level:
3 000 mg/kg bw/day (actual dose received)
Based on:
test mat.
Basis for effect level:
other: No adverse effects recorded
Details on embryotoxic / teratogenic effects:
The pregnancy rates expressed as average number ot implantation sites per female were comparable for all groups in the present experiment. The numbers of embryonic and/or foetal deaths (resorptions) were not increased at either dose.
The male to female ratios of the foetuses were also comparable for all groups. In comparison with the vehicle control, the average body-weight of the live foetuses was not diminished at either dose. Fusion of placentas, the implantation sites consisting of a embryonic resorption and a poorly developed male foetus, respectively, was noted for one female (No. 48) of the 500 mg/kg group.
The gross inspection of the live foetuses revealed one foetus with omphalocele in the low-dose group. Carrying out the slicing technique for "visceral" examination, dilatation of the renal pelvis (unilateral) was found in one foetus of the vehicle control. These instances are considered to be of a spontaneous origin and not related to the treatment.
The skeletal assessment revealed instances of irregular sternebral ossification in the dose groups and in the vehicle control; abnormal "wide suture" was found in one foetus of the high-dose group, in addition. Concerning the status of skeletal maturation of the foetuses shortly before term, a slight delay in ossification of the phalangeal nuclei of the hind-limbs was recorded for the high-dose group in comparison with the vehicle control; this finding, however, is not assumed to be of experimental significance.
Dose descriptor:
NOAEL
Effect level:
3 000 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No adverse effects recorded
Abnormalities:
not specified
Developmental effects observed:
not specified

Table 1: Summarized reproduction data of the main study.

Dose group

(mg/kg d)

0

500

1500

3000

Historical control data (range)

Spontaneous deaths

0/24

0/24

0/24

1/24

0/858

Body-weight gain (%)

+14.6

+13.3

+16.7

+13.9

 

Females with deciduomata

0/24

0/24

0/24

0/23

1/858

Females with implantations

22/24

22/24

23/24

20/23

800/858

Implantations/female (mean, SD)

15.9±2.5

16.3±1.5

15.4±1.9

16.1±1.8

13.14±2.36

Females with total abortion

0

0

0

0

0/800

Females with partial abortion

0

0

0

0

2/800

Embryonal deaths (resorptions)

6.3

4.2

6.5

8.4

8.71

Foetal deaths (resorptions)

0

0.3

0

0

0.28

Dead foetuses

0

0

0

0

0.12

Number of live foetuses (males-females)

163-165

158-185

164-167

150-144

4662- 4888

Percent males of live foetuses

49.7

46.1

49.5

51.0

48.8

Average weight of live foetuses

5.4±0.4

5.3±0.5

5.4±0.5

5.4±0.5

5.34±0.45

 


Table 2: Summarized data of skeletal assessment of the foetuses (in percent).

Dose group

(mg/kg d)

0

500

1500

3000

Historical control data (range)

Number of skeletons examined

219

229

222

195

6180

Phalangeal nuclei (a):

Fore-limb

14.6

21.0

10.4

9.2

0-10.7

Phalangeal nuclei (a):

Hind-limb

45.2

50.2

50.5

55.4

4.5-65.6

Calcaneus

89.5

86.9

91.0

93.8

6.8-90.3

5thsternebra (c)

15.1

14.4

20.3

9.7

3.0-88.3

Vertebrae (d)

1.4

1.7

3.2

3.6

0-6.9

Vertebrae (e)

0.0

0.4

1.4

0.5

0.23

Skeletal anomalies

0.9

2.2

1.4

1.5

0.52

(a) Ossification still absent in proximal phalanges, digit 5

(b) Ossification still absent

(c) Still incompletely ossified

(d) Some thoracic vertebral centres still dumbbell-shaped

(e) Some thoracic vertebral centres bipartite

 

Conclusions:
The test substance was devoid of an enbryotoxic potential and did not reveal teratogenic potency in the rat under the present experimental conditions.
Executive summary:

A developmental toxicity/teratogenicity study according OECD TG 414 was performed (Ciba-Geigy, 1983). 24 female rats were mated, and treated with 500, 1500, and 3000 mg test substance/kg body weight once daily on day 6 -15 p.c. On gestation day 21 the animals were sacrificed. Dams were observed for clinical signs, behavior, body weight and food consumption. After sacrifice ovaries and uterus (mucosa and contents, including amniotic fluid and placentae as well as abortions and resorption sites) were examined. In the fetuses external examinations, soft tissue examinations, and skeletal examinations were conducted. Neither food consumption nor body-weight gain was altered in the experimental groups. The pregnancy rates expressed as average number of implantation sites per female were comparable for all groups in the present experiment. 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. The gross inspection of the live fetuses revealed one fetus with omphalocele in the low-dose group. Dilatation of the renal pelvis (unilateral) was found in one fetus of the vehicle control. The skeletal assessment revealed instances of irregular sternebral ossification in the dose groups and in the vehicle control; abnormal" wide suture" was found in one fetus of the high-dose group, in addition. Concerning the status of skeletal maturation of the fetuses shortly before term, a slight delay in ossification of the phalangeal nuclei of the hind-limbs was recorded for the high-dose group in comparison with the vehicle control; this finding, however, is not assumed to be of experimental significance.

In summary, the test article was devoid of an embryotoxic activity and did not reveal teratogenic potency in the rat under the present experimental conditions.

Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
3 000 mg/kg bw/day
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

A developmental toxicity/teratogenicity study was performed according to OECD TG 414. Groups of pregnant rats were treated with the test article by gavage at dose levels of 0, 500, 1500 and 3000 mg/kg body weight from days 6 - 15 of pregnancy. Neither dams nor progeny of the experimental groups were affected by the treatment in comparison with the vehicle control. Occasional anomalies and/or malformations were found in all dose groups and in the controls (vehicle and historical). One fetus of the low-dose group displayed omphalocele. Renipelvic dilatation (unilateral) was noted for one fetus of the vehicle control. These instances are considered to be of a spontaneous origin and not related to the treatment, the incidences for omphalocele and dilatation of renal pelvis being 0.04% and 0.03%, 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 and the one fetus of the high-dose showing abnormal "wide suture" were not assumed to be of an experimental significance. The overall incidence of sternebral anomalies was recorded to be 0.37% in the historical control. A slight delay in ossification of the phalangeal nuclei of the hind-limbs was recorded for the high-dose group in comparison with the vehicle control; this finding, however, is not assumed to be of experimental significance. To summarize, the test article was devoid of an embryotoxic activity and did not reveal teratogenic potency in the rat under the present experimental conditions. Based on the results of this study, the NOAEL for developmental toxicity can be set at 3000 mg/kg body weight.

Justification for classification or non-classification

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

The available experimental test data are reliable and suitable for the purpose of classification under Regulation (EC) No.1272/2008. Based on the data, classification for reproduction toxicity is not warranted under Regulation (EC) No.1272/2008.

Additional information