Registration Dossier

Diss Factsheets

Administrative data

Key value for chemical safety assessment

Effects on fertility

Description of key information

Data waiving (study scientifically not necessary / other information available): According to column 2 of REACH Annex VIII, the study does not need to be conducted if a pre-natal developmental study is available.

Link to relevant study records
Reference
Endpoint:
screening for reproductive / developmental toxicity
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
the study does not need to be conducted because a pre-natal developmental toxicity study is available
Justification for type of information:
JUSTIFICATION FOR DATA WAIVING
According to column 2 of REACH Annex VIII, the study does not need to be conducted if a pre-natal developmental study is available.
Reason / purpose for cross-reference:
data waiving: supporting information
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

Effects on developmental toxicity

Description of key information

Key study. Read-across from analogue substance. Method according to OECD 414, GLP study. For the analogue substance, the NOAEL (developmental) in rabbits was determined to be greater than 60 mg/kg bw/day; whereas the NOAEL (maternal toxicity) was found to be between 30 and 60 mg/kg bw/day. Based on the available data for the read-across approach, the target substance has a NOAEL (maternal toxicity) ≥ 24.9 mg/kg bw/day and a NOAEL (developmental) ≥ 49.8 mg/kg bw/day in rabbits.

Link to relevant study records
Reference
Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
November 29, 1988 - December 30, 1988
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Version / remarks:
(May 1981)
Deviations:
no
Qualifier:
according to guideline
Guideline:
other: EEC Guidelines No. L 332 (83/571/EEC)
Version / remarks:
(November 1983)
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Limit test:
no
Species:
rabbit
Strain:
Chinchilla
Remarks:
(Kfm: CHIN, hybrids, SPF)
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: KFM, Kleintierfarm Madörin AG, CH 4414 Füllinsdorf, Switzerland; or Dr. K. Thomae GmbH, D-7950 Biberach an der Riss, West Germany.
- Age at study initiation: dose range-finding (DRF): 4 to 6 months old at pairing; main test: 5 to 7 months old.
- Weight at study initiation: DRF: 2.5 - 3.8 kg; main test: 2.62 - 4.06 kg
- Fasting period before study: not specified.
- Housing: Animals were housed individually in stainles steel cages equipped with an automatic cleaning system, under standard laboratory conditions.
- Diet: Pelleted standard Kliba 341 rabbit maintenance diet (Klingentalmuehle AG, CH-4303 Kaiseraugst, Switzerland, Batch nos. 45/89, 46/89), ad libitum.
- Water: tap water, provided by an automatic system, ad libitum.
- Acclimation period: at least 5 days after veterinary examination

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 ± 3
- Humidity (%): 40 - 70
- Air changes (per hr): 10-15
- Photoperiod (hrs dark / hrs light): 12/12
Route of administration:
oral: gavage
Vehicle:
CMC (carboxymethyl cellulose)
Details on exposure:
PREPARATION OF DOSING SOLUTIONS: the mixtures of the test article and vehicle were prepared daily before administration. The test item was weighed into a glass beaker on a tared precision balance and the vehicle was added (w/v). The mixtures were prepared using a homogenizer. During the daily administration period, homogeneity was maintained using a magnetic stirrer.

VEHICLE
- bi-distilled water with 4% CMC (Fluka AG, CH 9470 Buchs, Switzerland)
- Amount of vehicle (if gavage): standard dose volume of 4 ml/kg
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
The concentration and homogeneity of the test article/vehicle mixtures were determined during the dose range-finding study using a photometric method. The results were considered to be imprecise, so an HPLC method was used to perform the analyses throughout this study. Samples were taken on one occasion during the dosing period for the determination of concentration, homogeneity and stability of the test article/vehicle mixtures. Samples for stability were taken two hours after preparation. Analyses were performed by the Analytical Chemistry Laboratory using the method supplied by the Sponsor.
Details on mating procedure:
- Impregnation procedure: cohoused
- M/F ratio per cage: 1:1
- Length of cohabitation: until copulation had occurred.
- Proof of pregnancy: vaginal plug / sperm in vaginal smear referred to as day 0 of pregnancy
- Any other deviations from standard protocol: none reported
Duration of treatment / exposure:
12 days
Frequency of treatment:
daily
Duration of test:
28 days
Dose / conc.:
0 mg/kg bw/day (nominal)
Remarks:
(vehicle control)
Dose / conc.:
15 mg/kg bw/day (nominal)
Dose / conc.:
30 mg/kg bw/day (nominal)
Dose / conc.:
60 mg/kg bw/day (nominal)
No. of animals per sex per dose:
16 mated females per dose
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: Based on the results of a Dose Range-Finding Study (DRF): 5 mated female rabbits per group were administered the test item at various doses by gavage once daily from day 6 to day 18 postcoitum to assess the effects of the test item on embryonic and fetal development in pregnant rabbits. In the high dose group, one animal died on day 11 postcoitum; there was an initial weight loss followed by severely retarded weight gain over the first seven days of the dosing period; and food consumption was reduced during the first 5 days of the dosing period. In the mid dose group, a slight reduction in food consumption was observed during the first 5 days of treatment. No other effects were observed at any dose tested. Based on this data, the doses selected for the main study were 0 (vehicle control), 15, 30 and 60 mg/kg bw/d.
- Rationale for animal assignment: random
Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: at least twice daily

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: at least twice daily

BODY WEIGHT: Yes
- Time schedule for examinations: daily

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

WATER CONSUMPTION AND COMPOUND INTAKE: No

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day #28 by cervical dislocation
- Organs examined: gross macroscopic examination of all internal organs, with emphasis on the uterus, uterine contents, position of fetuses in the uterus and number of corpora lutea.
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
Fetal examinations:
- External examinations: Yes: all per litter. The fetuses were removed from the uterus, weighed individually, examined for gross external abnormalities, killed by subcutaneous injection of pentobarbitone sodium and prepared for internal examination.
- Soft tissue examinations: Yes: all per litter
- Skeletal examinations: Yes: all per litter
- Head examinations: Yes: all per litter
Statistics:
The following statistical methods were used to analyse body weights, food consumption, reproduction and skeletal examination data: means and standard deviation; univariate one-way analysis of variance was used to assess the significance of intergroup differences if the variables could be assumed to follow a normal distribution; the Dunnett many-one t-test, based on a pooled variance estimate, was used for intergroup comparisons; the steel test (many-one rank test) was applied when the data could not be assumed to follow a normal distribution; Fisher's Exact test for 2x2 tables was applied if the variables could be dichotomized without loss of information.
Clinical signs:
no effects observed
Description (incidence and severity):
No treatment-related clinical signs were observed at any dose tested.
Dermal irritation (if dermal study):
not examined
Mortality:
mortality observed, non-treatment-related
Description (incidence):
In the high dose group, 2 deaths occurred (gestation D10 and D18). Both animals lost weight from the start of the dosing period, and one female also showed reduced food consumption from the start of the dosing period. No obvious treatment-related macroscopic changes were observed at necropsy.
Body weight and weight changes:
effects observed, non-treatment-related
Description (incidence and severity):
In the high dose group, there was a mean body weight loss over the first 3 days of treatment and subsequent increased weight gain compared to the control. Differences from the control attained statistical significance (p < 0.05) for the lower percentage mean body weight gain on D8 and D9 only.
In the mid and low dose groups, body weight gain compared favourably with that of the control throughout the study. Differences attained statistical significance for the increased percentage mean body weight gain on D16-17 in the low dose group and on D2 in the mid dose group. There was no indication of an effect of treatment in the values for overall weight gain corrected for the uterus weight.
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
In the high dose group, food consumption was reduced during the first 5 days (D6 - 11) of treatment. In the mid dose group, a slight reduction in food consumption was observed during the first 5 days of the dosing period as well. Differences from the control value attained statistical significance at the highest dose only (p < 0.05). Food consumption was similar in all groups during the rest of the study.
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 specified
Gross pathological findings:
effects observed, treatment-related
Description (incidence and severity):
In the high dose group, there was an increased incidence of dams with macroscopic changes to the mucosal surface of the stomach indicative of gastric irritation compared to the other groups (1/16 in the control, 1/16 in the low dose, 0/16 in the mid dose, 5/14 in the high dose group). No other treatment-related macroscopic changes were observed.
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
not specified
Histopathological findings: neoplastic:
not specified
Other effects:
no effects observed
Description (incidence and severity):
Maternal reproduction parameters, as assessed by the pregnancy rate, the no. of implantations, pre- and post-implantation loss and no. of live fetuses, were not affected by the treatment at any dose tested.
Number of abortions:
no effects observed
Description (incidence and severity):
No abortions were observed.
Pre- and post-implantation loss:
effects observed, non-treatment-related
Description (incidence and severity):
There was an increased incidence of post-implantation loss (both embryonic and fetal resorptions at 30 mg/kg (mid dose), whereas no indication of increased post-implantation loss was noted at the highest dose tested. In the mid group, the post-implantation losses for 2 females contributed 46% of loss in this group and, in particular, one female showed an unusually high post-implantation loss (1 embryonic and 6 fetal resorptions). It was noted that this female had been extremely nervous and that her overall weight gain was negligible (6 g). When these 2 females are exclueded from the calculations, post-implantation loss at this dose level was similar to the control. Therefore, the apparent effect was considered not to be treatment-related.
Total litter losses by resorption:
no effects observed
Description (incidence and severity):
There were no dams with total resorption.
Early or late resorptions:
effects observed, non-treatment-related
Dead fetuses:
no effects observed
Changes in pregnancy duration:
no effects observed
Changes in number of pregnant:
no effects observed
Description (incidence and severity):
All except 2 control females were pregnant.
Other effects:
no effects observed
Details on maternal toxic effects:
Maternal parameters were not affected by the treatment with the test item at 30 mg/kg bw/day test item or lower.
Key result
Dose descriptor:
NOAEL
Effect level:
>= 30 - <= 60 mg/kg bw/day (nominal)
Based on:
test mat.
Basis for effect level:
gross pathology
Key result
Abnormalities:
no effects observed
Fetal body weight changes:
no effects observed
Reduction in number of live offspring:
no effects observed
Changes in sex ratio:
no effects observed
Changes in litter size and weights:
no effects observed
Description (incidence and severity):
At external examination of the fetuses, there were 4 runts (weight < 19.0 g) – two, in separate litters, in the control group; and one each at 30 and 60 mg/kg. All runts occurred in larger-than-average litters (with 11 - 14 live fetuses). The variations in mean fetal body weights generally reflected the variations in live litter size. None of the differences from control values were statistically significant (p > 0.05) and no effect of the treatment was observed.
Changes in postnatal survival:
no effects observed
External malformations:
no effects observed
Description (incidence and severity):
One fetus with hydrocephaly was observed during examination of the fixed fetal heads in the high dose group. No effect of the treatment was indicated.
Skeletal malformations:
effects observed, non-treatment-related
Description (incidence and severity):
The incidences of fetuses with abnormal skeletal findings were as follows: 1/138 fetuses in 1/14 litters in the control; 3/132 fetuses in 3/16 litters in the low dose group; 6/129 fetuses in 5/16 litters in the mid dose group; and 1/122 fetuses in 1/14 litters in the high dose group. The abnormal findings note consisted of incompletely ossified, hemicentric or missing thoracic vertebral centra, some with associated missing vertebral arches and fuesd or missing ribs or fetuses with 4 variant sternebrae. Neither the type nor the distribution of these findings indicated an association with the treatment.
Occasional statistically significant differences from the control were observed for the incidences of fetuses with incompletely or non-ossified sternebrae or phalangeal bones and non-ossified, shortened or flying ribs were considered to be within the normal range of variation for rabbits of this strain and were not considered to be treatment-related.
Visceral malformations:
no effects observed
Description (incidence and severity):
During the fresh visceral examination, two fetuses with hemidiaphragm were observed, one each at 15 and 60 mg/kg. Neither the types nor the incidences of fetuses with abnormal findings indicated an association with the treatment.
Other effects:
no effects observed
Details on embryotoxic / teratogenic effects:
Fetal parameters were not affected by the treatment with the test item at any dose tested.
Key result
Dose descriptor:
NOAEL
Effect level:
>= 60 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Remarks on result:
not determinable due to absence of adverse toxic effects
Key result
Abnormalities:
no effects observed
Key result
Developmental effects observed:
no

Table 1. Summary of performance of parent animals (F0).

Group

Dose (mg/kg)

1

(0)

2

(15)

3

(30)

4

(60)

No. of mated females

16

16

16

16

Female nos.

1 – 16

17 – 32

33 – 48

49 – 64

No. of mortalities

0

0

0

2 (a)

No. of non-pregnant females

2 (b)

0

0

0

No. of females with live fetuses at termination

14

16

16

14

(a): Female no. 56 died on D10, female no. 60 died on D18; (b): Female nos. 6 and 13 were not pregnant. Only dams with live fetuses at termination on D28 were included in the calculations of food consumption, body weight gain, corrected body weight gain and reproduction data.

Table 2. Differences in food consumption of dams, mean (g/animal/day)

Group

(mg/kg)

Days (Post-coitum), g(%)*

Treatment period, g (%)

Post-treatment period, g (%)

0 – 6

6 – 11

11 – 15

15 – 19

19 – 24

24 – 28

6 – 19

19 – 28

1 (0)

216

220

167

169

167

154

188

161

2 (10)

210

211

200

191

166

142

201

155

(-2.8)

(-4.1)

(+19.8)

(+13.0)

(-0.6)

(-7.8)

(+6.9)

(-3.7)

3 (20)

207

191

184

201

172

143

192

159

(-4.2)

(-13.2)

(+10.2)

(+18.9)

(+3.0)

(-7.1)

(+2.1)

(-1.2)

4 (40)

194

119

152

189

189

152

151

173

(-10.2)

(-45.9)

(-9.0)

(+11.8)

(+13.2)

(-1.3)

(-19.7)

(+7.5)

*Percentage values refer to the values of group 1. The calculations of food consumption and body weight gain during the treatment period started on day 6 post coitum (immediately prior to first administration) and ended on day 19 (approximately 24h after the last administration).

 

Table 3. Differences body weight gain of dams, mean

Group

(mg/kg)

Days (Post-coitum), g(%)*

Treatment period, g (%)

Post-treatment period, g (%)

Corrected body weight gain %

0 – 6

6 – 11

11 – 15

15 – 19

19 – 24

24 – 28

6 – 19

6 – 28

1 (0)

142

29

40

34

61

69

103

233

-7.2

(+4.1)

(+0.8)

(+1.1)

(+0.9)

(+1.6)

(+1.8)

(+2.9)

(+6.5)

2 (10)

179

50

50

47

55

78

147

280

-4.6

(+5.5)

(+1.5)

(+1.4)

(+1.3)

(+1.3)

(+2.2)

(+4.3)

(+7.6)

3 (20)

186

15

41

95

45

90

151

286

-4.3

(+5.7)

(+0.4)

(+1.2)

(+2.7)

(+1.3)

(+2.5)

(+4.4)

(+8.3)

4 (40)

163

-104

71

55

136

91

22

249

-6.4

(+5.2)

(-3.1)

(+2.2)

(+1.7)

(+9.5)

(+2.6)

(+0.7)

(+7.5)

Differences from control values attained statistical significance (p < 0.05, Dunnett’s test) for: the increased mean body weight gain (%) at 15 mg/kg on D16 and D17, and at 30 mg/kg on D2; and for the lower mean body weight gain (%) at 60 mg/kg on D8 and D9.

 

Table 4. Reproduction data summary. Dams with live fetuses.

Group

(mg/kg)

1

(0)

2

(15)

3

(30)

4

(60)

No. of dams

16

16

16

16

Corpora lutea

149

142

156

132

 

Mean

10.6

8.9

9.8

9.4

 

SD

2.1

2.1

1.8

1.9

Pre-implantation loss

0

6

3

2

 

% of corp. lutea

 

4.2

1.9

1.5

 

mean

 

0.4

0.2

0.1

 

SD

 

0.9

0.8

0.5

 

No. of dams affected (#)

 

3

1

1

Implantation sites

149

136

153

130

 

% of corp. lutea

100.0

95.8

98.1

98.5

 

mean

10.6

8.5

9.6

9.3

 

SD

2.1

2.3

2.1

2.3

Post-implantation loss

11

4

24

8

 

% of impl. sites

7.4

2.9

15.7

6.2

 

Mean

0.8

0.3

1.5

0.6

 

SD

1.3

0.4

1.9

0.9

 

No. of dams affected (#)

5

4

9

5

Implantation site scars

0

0

0

0

Embryonic deaths: total

11

4

24

8

-         Embryonic resorptions

2

2

8

1

 

% of impl. sites

1.3

1.3

5.2

0.8

 

Mean

0.1

0.1

0.5

0.1

 

SD

0.1

0.3

1.0

0.3

 

No. of dams affected (#)

2

2

4

1

-         Fetal resorptions

9

2

16

7

 

% of impl. sites

6.0

1.5

10.5

5.4

 

Mean

0.6

0.1

1.0

0.5

 

SD

1.0

0.3

1.8

0.8

 

No. of dams affected (#)

3

2

6

5

Fetuses

 

 

 

 

Total fetuses

138

132

129

122

 

% of impl. sites

92.6

97.1

84.3

93.8

 

Mean

9.9

8.3

8.1

8.7

 

SD

1.8

2.3

2.4

2.1

Live fetuses

138

132

129

122

Dead Fetuses

0

0

0

0

Abnormal fetuses

2

1

1

2

 

% of fetuses

1.4

0.8

0.8

1.6

 

Mean

0.1

0.1

0.1

0.1

 

SD

0.4

0.3

0.3

0.4

 

No. of dams affected (#)

2

1

1

2

 

Abnormal live fetuses

2

1

1

2

 

Abnormal dead fetuses

0

0

0

0

Sex of fetuses

 

 

 

 

-         Total males (#)

68

65

61

57

 

% of fetuses

49.3

49.2

47.3

46.7

 

Mean

4.9

4.1

3.8

4.1

 

SD

1.6

1.5

1.3

1.2

-         Total females (#)

70

67

68

65

 

% of fetuses

50.7

50.8

52.7

53.3

 

Mean

5.0

4.2

4.3

4.6

 

SD

1.0

1.6

2.0

1.5

Weights of live fetuses (litter basis)

 

 

 

 

-         M and F

 

 

 

 

 

N (litters)

14

16

16

14

 

Mean

31.8

35.3

34.1

33.3

 

SD

3.5

4.0

5.4

3.5

-         Males

 

 

 

 

 

N (litters)

14

16

16

14

 

Mean

32.4

35.5

33.8

33.5

 

SD

3.8

4.4

6.0

3.3

-         Females

 

 

 

 

 

N (litters)

14

16

15

14

 

Mean

31.4

34.7

34.0

32.6

 

SD

3.7

3.7

5.1

4.1

Weights of live fetuses (individual basis)

 

 

 

 

-         M and F

 

 

 

 

 

N (fetuses)

138

132

129

122

 

Mean

31.6

34.3

33.2

33.0

 

SD

5.1

4.8

6.2

5.1

-         Males

 

 

 

 

 

N (fetuses)

68

65

61

57

 

Mean

31.8

34.6

33.4

33.1

 

SD

4.8

5.2

6.5

4.9

-         Females

 

 

 

 

 

N (fetuses)

70

67

68

65

 

Mean

31.3

34.1

33.1

33.0

 

SD

5.4

4.5

6.0

5.2

Dunnett test based on pooled variance significant at level 5% (*) or 1% (**); Fisher’s exact test significant at level 5% (#) or 1% (##); Steel test significant at level 5% (+) or 1% (++).

 

Table 6. Fetal examination

Group

(mg/kg)

No. of fetuses

examined

Findings

External and visceral examination

Heads, incl. brain

Skeletal examination

1 (0)

138

Runt (< 19.0 g) [2]

-

2ndand 4th-6thsternebrae incompletely ossified [1]

2 (10)

132

Hemidiaphragm [1]

-

Sternebrae 2, 4, and 6 incompletely ossified, sternebrae 5 non-ossified [1];

12thand 13thright ribs fused at origin [1];

8ththoracic vertebral centrum incompletely ossified [1]

3 (20)

129

Runt (< 19.0 g) [1]

Hydrocephaly [1]

11ththoracic vertebral centrum missing; 11thand 12thleft thoracic vertebral arches fused, and corresponding ribs fused at origin [1];

Sternebrae 2, 4, and 6 incompletely ossified, sternebrae 5 non-ossified [1];

13thright thoracic vertebral arch vestigial and 13ththoracic vertebral centrum out of alignment resulting in slight scoliosis, 13 left and 12 right ribs [1];

11ththoracic vertebral centrum hemicentric, left side missing, right side fused with 12ththoracic vertebral centrum; 11thleft vertebral arch and corresponding rib missing [1];

2nd– 5thsternebrae asymmetric [1];

10ththoracic vertebral centrum, right vertebral arch and associated rib missing; 13 left and 12 right ribs [1]

4 (40)

122

Runt (< 19.0 g) [1]

Hemidiaphragm [1]

-

One pre-sacral vertebra missing – vertebral configuration: cervical 7, thoracic 12, lumbar 6 instead of normal C7, T12, L7 or C7, T13, L6

 

Conclusions:
The NOAEL (developmental) in rabbits was determined to be greater than 60 mg/kg bw/day; whereas the NOAEL (maternal toxicity) was found to be between 30 and 60 mg/kg bw/day.
Executive summary:

A prenatal developmental toxicity test was conducted according to OECD 414, under GLP contidions. The test item was administered daily by oral gavage to 16 pregnant female chinchilla rabbits per group at doses of 0 (vehicle control), 15, 30, or 60 mg/kg bw/day in bi-distilled water with 4% CMC from the 6th day to the 18th of pregnancy. The animls were observed daily for sings of toxicity from day 0 to day 28th of gestation, when they were sacrificed and the fetuses were removed from the uterus, weighed individually, examined for gross external abnormalities, sacrificed, and prepared for internal examination. This included external, visceral and skeletal examinations. Gross macroscopic examination of maternal animals was performed on all internal organs, with emphasis on the uterus, uterine contents, position of fetuses in the uterus and number of corpora lutea. Regarding maternal toxicity, the administration of the test item was associated with the death of 2 animals, body weight loss on the initiation of dosing and an increased incidence of macroscopic changes indicative of gastric irritation at 60 mg/kg bw/day and with reduced food consumption during the first 5 days of dosing at 30 and 60 mg/kg bw/day. Regarding developmental toxicity, there was no indication of an adverse effect of treatment with the test item on any of the maternal reproduction parameters or any of the fetal parameters up to and including the highest dose examined. The NOAEL (developmental) in rabbits was determined to be greater than 60 mg/kg bw/day; whereas the NOAEL (maternal toxicity) was found to be between 30 and 60 mg/kg bw/day.

Effect on developmental toxicity: via oral route
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
49.8 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
Read-across from a high quality study on analogue substance (Klimisch score = 1).
Effect on developmental toxicity: via inhalation route
Endpoint conclusion:
no study available
Effect on developmental toxicity: via dermal route
Endpoint conclusion:
no study available

Justification for classification or non-classification

Based on available data, the substance is not classified for reproductive toxicity according to the CLP Regulation (EC) No. 1272/2008.

Additional information

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