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Toxicological information

Developmental toxicity / teratogenicity

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Administrative data

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2016-03-15 - 2016-04-07
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2017
Report date:
2017

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
GLP compliance:
yes (incl. QA statement)
Limit test:
no

Test material

1
Chemical structure
Reference substance name:
Oligomerisation and alkylation reaction products of 2-phenylpropene and phenol
EC Number:
700-960-7
Molecular formula:
not applicable
IUPAC Name:
Oligomerisation and alkylation reaction products of 2-phenylpropene and phenol
Test material form:
liquid: viscous
Details on test material:
- Manufacturers identification: Novares LA 300
- Substance type: organic
- Test material is 'Oligomerisation and alkylation reaction products of 2-phenylpropene and phenol' (OAPP), EC list number 700-960-7 (assigned manually to validated substances from inquiries by ECHA). Originally the substance phenol, methylstyrenated, CAS No. 68512-30-1, EC No. 270-966-8 was submitted for registration. Subsequent to substance validation, the identity of the substance was changed by ECHA.
- for additional information see respective study record
Specific details on test material used for the study:
- Name of test material (as cited in study report): Oligomerisation and alkylation reaction products of 2-phenylpropene and phenol (OAPP)
- Source and lot/batch No.of test material: RÜTGERS Novares GmbH, batch No. 38900
- Expiry date: 2017-02-13
- Composition of test material: composition is specified in IUCLID Sect. 13 - Assessment reports under Certificate of Analysis_Novares LA 300_phenol, methylstyrenated
- Stability under test conditions: found to be stable for 8 days (no longer observation)
- Storage condition of test material: room temperature, exclusion of light

Test animals

Species:
rat
Strain:
Wistar
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories, Research Models and Services, Germany GmbH, D-97633, Sulzfeld, from SPF colony
- Age at study initiation: 11 weeks old at mating
- Weight at study initiation: 186 - 229 g (females)
- Fasting period before study: no
- Housing: Standard laboratory conditions; individual housing
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19.9 - 23.9 °C
- Humidity (%): 40 - 53
- Air changes (per hr): 15 - 20
- Photoperiod (hrs dark / hrs light): 12 / 12

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
corn oil
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
According to CiToxLAB validation study, code 15/094-316AN, the test item is stable in the vehicle in the concentration range of 10 to 250 mg/mL for at least 8 days when stored at room temperature.
Details on mating procedure:
- Impregnation procedure: cohoused
- If cohoused:
- M/F ratio per cage: 1/1
- Length of cohabitation: approx. 2 h each event
- Proof of pregnancy: sperm in vaginal smear referred to as day 0 of pregnancy (GD0)
- Any other deviations from standard protocol:
Duration of treatment / exposure:
from GD6 to GD19
Frequency of treatment:
1x/d
Duration of test:
20 d
Doses / concentrationsopen allclose all
Dose / conc.:
60 mg/kg bw/day
Dose / conc.:
150 mg/kg bw/day
Dose / conc.:
300 mg/kg bw/day
No. of animals per sex per dose:
pregnant rats: 21 (control), 23 (low), 24 (mid), 23 (high)
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: Maternal toxicity at 300 mg/kg bw/day (evident in decreased corrected body-weight gain and decreased food consumption).
- Rationale for animal assignment (if not random): The sperm-positive females were allocated to each experimental group (on each mating day) in such a way that the group averages of the body weight were as similar as possible.
- Dosage: Volume 3 mL/kg bw. The individual volume of the treatment was based on the most recent individual body weight of the animals.

Examinations

Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: 2x/d (working day)
- Cage side observations checked in Appendix 3.1 were included.

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: 1x/d (GD6), then 1x/wk

BODY WEIGHT: Yes
- Time schedule for examinations: on GD 0, 3, 6, 8, 10, 12, 14, 16, 18 and 20

FOOD CONSUMPTION: 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 (gavage)

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 20
- Organs examined: gross pathology

OTHER: Gravid uterine weight
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:
Fetal examinations:
- External examinations: yes; all per litter
- Soft tissue examinations: yes; half per litter
- Skeletal examinations: yes; half per litter
- Head examinations: yes; half per litter
Statistics:
The statistical evaluation of data* was performed with the program package SPSS PC+4.0 (SPSS Hungary Kft, Budapest) or SAS 9.2 in the case of Provantis 9, by an appropriate statistical method (Bartlett, ANOVA and Duncan, Kruskal-Wallis and Mann-Whitney U tests, Chi2) using the litter as the unit for data analysis. The homogeneity of variance between groups was checked by Bartlett`s homogeneity of variance test. Where no significant heterogeneity was detected a one-way analysis of variance (ANOVA) was made. If the obtained result was significant Duncan’s Multiple Range test was used to assess the significance of inter-group differences. Significant results with inter-group comparisons were further compared using Kruskal-Wallis, and Mann-Whitney U-tests.
Indices:
Maternal: Preimplantation loss: %, group mean / Postimplantation loss: %, group mean
Foetal: Sex distribution: %, group mean; External abnormalities/litter: %, group mean; Visceral abnormalities/litter: %, group mean; Skeletal abnormalities/litter: %, group mean
Historical control data:
availabe for litter and external foetal data, as well as for visceral and skeletal malformations, provided in combination with respective results tables.
Total available HC data have been compiled in Appendix 6 of the results report.

Results and discussion

Results: maternal animals

General toxicity (maternal animals)

Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
There was no statistically significant difference in the development of total body weight across all groups (Report, Fig. 1). However, bw gain during the treatment period from GD6 - GD20 revealed some significance in the mid- and high-dose groups (decrease ~11 to ~12% vs. control, p<0.05). This trend became more prominent after correction for the uterus content: decrease in bw gain from GD6 - GD20 = ~50% and ~40%, respectively (p<0.01) (Report, Tab. 1 and Fig. 2).
See also: "Any other information on results" below, and Attached Document
---------------------------------------------------------------------------------------------------------------------------------
Table 1: Body weight changes during the study
---------------------------------------------------------------------------------------------------------------------------------
Dose (mg/kg bw/day) 0 60 150 300
Number of litters 21 23 24 23
--------------------------------------------------------------------------------------------------------------------------------
Body weight gain GD6-20
(g) Mean 77.9 74.5 68.5* 69.3* DN
SD 12.64 11.77 11.08 13.52
% - -4.3 -12.1 -11.0
............................................................................................................................................................................
Body weight gain GD0-20
(g) Mean 97.2 93.6 87.8 90.0 NS
SD 13.71 14.68 13.33 13.44
% - -3.8 -9.8 -7.4
.............................................................................................................................................................................
Corrected net body weight gain
GD6-20
(g) Mean 20.62 18.83 10.25** 12.35* U
SD 8.40 6.10 11.00 10.64
% - -8.7 -50.3 -40.1
............................................................................................................................................................................
Corrected body weight gain
GD0-20
(g) Mean 40.00 37.87 29.54 33.13 NS
SD 10.07 6.61 12.56 10.44
% - -5.3 -26.1 -17.2
------------------------------------------------------------------------------------------------------------------------------------
*= p<0.05, **= p<0.015,
NS=Not Significant, DN=Duncan’s multiple range test, U = Mann-Whitney U-test
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
The reduction in the food intake in the mid- and high-dose groups - though overall small and without clear dose-response - became more marked from the time of dosing on GD6 and thus is consistent with the concomittant decreases in the corrected body-weight gains (comp. Report, Fig. 3 and 4). Therefore, these effects on food intake are ascribed to treatment (see Attached document).
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:
no effects observed
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
not examined
Histopathological findings: neoplastic:
not examined
Other effects:
not specified

Maternal developmental toxicity

Number of abortions:
no effects observed
Description (incidence and severity):
See "Any other information", Table 2
Pre- and post-implantation loss:
no effects observed
Description (incidence and severity):
See "Any other information", Table 2
Total litter losses by resorption:
no effects observed
Description (incidence and severity):
See "Any other information", Table 2
Early or late resorptions:
no effects observed
Description (incidence and severity):
See "Any other information", Table 2
Dead fetuses:
no effects observed
Description (incidence and severity):
See "Any other information", Table 2
Changes in pregnancy duration:
not examined
Description (incidence and severity):
Pregnancy was terminated on GD19.
Changes in number of pregnant:
effects observed, non-treatment-related
Description (incidence and severity):
Number of non-pregnant females: 2/24 (control); 1/24 (low); 0/24 (mid), and 1/24 (high)
Other effects:
not specified
Details on maternal toxic effects:
Significant treatment-related decreases in food consumption and in body-weight gain (without uterine weight) after dosage of 150 and 300 mg/kg bw/d from GD6 to GD19, considered adverse but without toxic manifestation.

Effect levels (maternal animals)

open allclose all
Key result
Dose descriptor:
NOEL
Effect level:
60 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: based on absence of any test item-related effect
Key result
Dose descriptor:
LOAEL
Effect level:
150 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
body weight and weight gain
food consumption and compound intake

Maternal abnormalities

Key result
Abnormalities:
effects observed, treatment-related
Localisation:
not specified
Description (incidence and severity):
reduced body-weight gain associated with suppressed food intake

Results (fetuses)

Fetal body weight changes:
no effects observed
Description (incidence and severity):
The weight of viable foetuses per litter in the Low-, Mid- and High-dose groups (60, 150 and 300 mg/kg bw/day, respectively) did not differ significantly from the control mean value. In any dose-group, the total number of retarded foetuses (with a weight of < the concurrent control mean minus 2 S.D.) as well as the number of affected litters was not significantly higher than the untreated control (see "Any other information", Table 3).
Reduction in number of live offspring:
no effects observed
Description (incidence and severity):
The mean number of viable foetuses was comparable with the control mean (see "Any other information", Table 2 and 3).
Changes in sex ratio:
no effects observed
Description (incidence and severity):
There was no toxicologically significant difference in the sex distribution of foetuses between the control and treatment groups (see "Any other information", Table 3).
Changes in litter size and weights:
no effects observed
Description (incidence and severity):
See "Any other information", Table 3
Changes in postnatal survival:
not examined
External malformations:
no effects observed
Description (incidence and severity):
No statistically significant differences were observed in these examined parameters of any test item-treated groups when compared to the negative (vehicle) control (see "Any other information on results", Table 4).
Skeletal malformations:
no effects observed
Description (incidence and severity):
All of the skeletal findings correspond to the current historical control (HC) or the concurrent study control data, or were considered to be spontaneous events unrelated to treatment (see "Any other information on results", Table 5).
Visceral malformations:
no effects observed
Description (incidence and severity):
All abnormalities observed at visceral examination in this study were considered incidental findings, consistent with the concurrent study control data and with historical control (HC) data, spontaneous events unrelated to treatment (see "Any other information on results", Table 6).

Other effects:
not specified
Details on embryotoxic / teratogenic effects:
no treatment-related effects observed (see under "Any other inormation on results").

Effect levels (fetuses)

Key result
Dose descriptor:
NOAEL
Effect level:
300 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: absence of any adverse effect
Remarks on result:
other: highest dose tested

Fetal abnormalities

Key result
Abnormalities:
no effects observed

Overall developmental toxicity

Key result
Developmental effects observed:
no

Any other information on results incl. tables

Table 1 (Report Table 1): Body weight changes during the study

Concentration
(mg/kg bw/day

Dose (mg/kg bw/day)

0

60

150

300

Number of animals

21

23

24

23

Body weight gain D06-20 (g)

Mean

77.9

74.5

68.5* (DN)

69.3* (DN)

SD

12.64

11.77

11.08

13.52

%

-

-4.3

-12.1

-11.0

Body weight gain D0-20 (g)

Mean

97.2

93.6

87.8

90.0

SD

13.71

14.68

13.33

13.44

%

-

-3.8

-9.8

-7.4

Corrected body weight gain
D06-20 (g)

Mean

20.62

18.83

10.25** (U)

12.35* (U)

SD

8.4

6.1

11

10.64

%

-

-8.7

-50.3

-40.1

Corrected body weight gain
D0-20 (g)

Mean

40

37.87

29.54

33.13

SD

10.07

6.61

12.56

10.44

%

-

-5.3

-26.1

-17.2

*= p<0.05, **= p<0.01, NS=Not Significant, DN=Duncan’s multiple range test, U = Mann-Whitney U-test.

Table 2 (Report Table 3): Summary of the intrauterine evaluation

Parameters

Dose (mg/kg bw/day)

0

60

150

300

Number of evaluated dams

21

23

24

23

Mean number of corpora lutea

11.29

10.83

11.29

11.30

Mean number of implantations

10.48

10.04

10.63

10.65

Preimplantation loss, mean

0.81

0.78

0.67

0.65

Preimplantation loss (%), mean

6.43

6.96

5.83

5.83

Early embryonic loss, mean

0.24

0.39

0.08

0.43

Early embryonic loss (%), mean

2.43

4.17

1.00

4.43

Late embryonic loss, mean

0.00

0.04

0.00

0.09

Late embryonic loss (%), mean

0.00

0.48

0.00

0.70

Dead foetuses, mean

0.00

0.00

0.04

0.00

Dead foetuses (%), mean

0.00

0.00

0.30

0.00

Postimplantation loss, mean

0.24

0.43

0.13

0.52

Postimplantation loss (%), mean

2.43

4.65

1.29

5.13

Total intrauterine mortality, mean

1.05

1.22

0.79

1.13

Total intrauterine mortality (%), mean

8.71

11.39

7.04

10.17

Viable foetuses, mean

10.24

9.61

10.50

10.13

Notes:

1.     No statistically significant differences were observed in these examined parameters of any test item-treated groups when compared to the negative (vehicle) control.

2.     For calculation of the relative values (shown as %), the relative (%) value was calculated for each litter, then the mean value of those individual values was taken.

3.     Data were rounded off to two decimal places.

Table 3 (Report Table 4): Examination of viable foetuses

Parameters

Dose (mg/kg bw/day)

0

60

150

300

Number of examined litters

21

23

24

24

Viable foetuses, mean

10.24

9.61

10.50

10.13

Male foetuses, mean

4.90

4.26

4.79

4.70

Female foetuses, mean

5.33

5.35

5.71

5.43

Total number of foetuses

215

221

252

233

Total number of male foetuses

103

98

115

108

Total number of female foetuses

112

123

137

125

Mean foetal weight / litter (g)

3.373

3.442

3.329

3.433

Number of foetuses with retarded body weight

8

1*CH

11

9

Number of affected litters

6

1*CH

7

7

*statistically significant at p<0.05, CH = Chi square test

 

Table 4 (Report Table 5): Summary table of the external abnormalities

Parameter

Control

Dose (mg/kg bw/day)

HC data

60

150

300

Total number of examined litters

21

23

24

23

485

Total number of examined foetuses

215

221

252

233

4955

Total number of intact (normal) foetuses

215

221

251

233

--

Total number of foetuses / litters
with malformation

0 / 0

0 / 0

0 / 0

0 / 0

--

Total number of foetuses / litters
with variation

0 / 0

0 / 0

1 / 1

0 / 0

--

External malformations

No external variations were recorded

External variations

Foetus, pale

Litter
incidence

n

0

0

1

0

1

%

0.0

0.0

4.2

0.0

0.2

Foetal
incidence

n

0

0

1

0

1

%

0.000

0.000

0.396

0.000

0.020

Notes:     Numbers represent the number (n) or ratio (%) of abnormalities.Notes: Numbers represent the number (n) or ratio (%) of abnormalities.

HC: historical control

No statistically significant differences were observed in these examined parameters of any test item-treated groups when compared to the negative (vehicle) control.

Table 5 (Report Table 7): Summary table of the skeletal abnormalities

Parameter

Control

Dose (mg/kg bw/day)

HC data

60

150

300

Total number of examined litters

21

23

24

23

485

Total number of examined foetuses

107

111

127

116

2467

Total number of intact (normal) foetuses

99

97

117

111

--

Total number of foetuses / litters
with malformation

1 / 1

1 / 1

0 / 0

1 / 1

--

Total number of foetuses / litters
with variation

7 / 7

13 / 11

10 / 7

4 / 4

--

Skeletal malformations

Pelvic girdle, mal-positioned#

Litter
incidence

n

1

0

0

1

2

%

4.8

0.0

0.0

4.3

0.4

Foetal
incidence

n

1

0

0

1

2

%

0.935

0.000

0.000

0.862

0.081

Malformed vertebrae, (Hemivertebrae)

Litter
incidence

n

0

1

0

0

0

%

0.0

4.3

0.0

0.0

0.0

Foetal
incidence

n

0

1

0

0

0

%

0.000

0.901

0.000

0.000

0.000

Skeletal variations

Skull, 2 or more bones incomplete ossification

Litter
incidence

n

3

2

1

2

326

%

14.3

8.7

4.2

8.7

67.2

Foetal
incidence

n

4

2

3

2

474

%

3.738

1.802

2.362

1.724

19.214

Ossified sternebra (3 or less)

Litter
incidence

n

1

1

1

0

37

%

4.8

4.3

4.2

0.0

7.6

Foetal
incidence

n

1

1

1

0

46

%

0.935

0.901

0.787

0.000

1.865

Xiphoid cartilage, hole

Litter
incidence

n

1

1

0

1

11

%

4.8

4.3

0.0

4.3

2.3

Foetal
incidence

n

1

1

0

1

14

%

0.935

0.901

0.000

0.862

0.567

Fontanelle, large

Litter
incidence

n

0

0

1

0

2

%

0.0

0.0

4.2

0.0

0.4

Foetal
incidence

n

0

0

1

0

2

%

0.000

0.000

0.787

0.000

0.081

Rib, wavy, marked

Litter
incidence

n

1

0

0

0

149

%

4.8

0.0

0.0

0.0

30.7

Foetal
incidence

n

1

0

0

0

243

%

0.935

0.000

0.000

0.000

9.850

Vertebra, dumbbell or asymmetric ossification (2 or more)

Litter
incidence

n

1

6

4

1

73

%

4.8

26.1

16.7

4.3

15.1

Foetal
incidence

n

1

7*CH

4

1

79

%

0.935

6.306

3.150

0.862

3.202

Notes: Numbers represent the number (n) or ratio (%) of abnormalities.

HC: historical control

*statistically significant at p<0.05, CH = Chi square test

Table 6 (Report Table 6): Summary table of the visceral abnormalities

Parameter

Control

Dose (mg/kg bw/day)

HC data

60

150

300

Total number of examined litters

21

23

24

23

485

Total number of examined foetuses

108

110

125

117

2484

Total number of intact (normal) foetuses

104

108

121

115

--

Total number of foetuses / litters
with malformation

1 / 1

0 / 0

1 / 1

0 / 0

--

Total number of foetuses / litters
with variation

3 / 3

2 / 2

3 / 3

2 / 2

--

Visceral malformations

A-V septum, defect

Litter
incidence

n

1

0

0

0

0

%

4.8

0.0

0.0

0.0

0.0

Foetal
incidence

n

1

0

0

0

0

%

0.926

0.000

0.000

0.000

0.000

Great arteries, transposition

Litter
incidence

n

0

0

1

0

0

%

0.0

0.0

4.2

0.0

0.0

Foetal
incidence

n

0

0

1

0

0

%

0.000

0.000

0.800

0.000

0.000

Visceral variations

Thymic cord

Litter
incidence

n

2

0

0

1

55

%

9.5

0.0

0.0

4.3

11.3

Foetal
incidence

n

2

0

0

1

66

%

1.852

0.000

0.000

0.855

2.657

Renal papilla, small

Litter
incidence

n

0

0

2

1

16

%

0.0

0.0

8.3

4.3

3.3

Foetal
incidence

n

0

0

2

1

18

%

0.000

0.000

1.653

0.855

0.725

Brachiocephalic trunk, short

Litter
incidence

n

1

1

1

0

35

%

4.8

4.3

4.2

0.0

7.2

Foetal
incidence

n

1

1

1

0

43

%

0.926

0.909

0.800

0.000

1.731

Ureter convoluted

Litter
incidence

n

0

1

0

0

3

%

0.0

4.3

0.0

0.0

0.6

Foetal
incidence

n

0

1

0

0

3

%

0.000

0.909

0.000

0.000

0.121

Notes: Numbers represent the number (n) or ratio (%) of abnormalities.

HC: historical control

No statistically significant differences were observed in these examined parameters of any test item-treated groups when compared to the negative (vehicle) control

#:Lumbar VI.- Sacral I. transverse processes, fused

Applicant's summary and conclusion

Conclusions:
Doses of ≥ 150 mg/kg bw/day of OAPP produced mild but significant maternal toxicity in pregnant Wistar rats. However, this was limited to a reduction in body-weight gain corrected for the uterine mass. Maternal growth retardation correlated with reduced food intake during the exposure period (GD6 through GD19). Prenatal adverse effects that could have been ascribed to the test-item were not observed at any dose level.
The maternal NOEL (No-observed-effect level) and LOAEL were 60 and 150 mg/kg bw/day, respectively, while the NOAEL for embryo- and foetotoxicity was 300 mg/kg bw/day, the highest dose tested, which proved to be maternally toxic.
Executive summary:

In a GLP-conform guideline study on prenatal development according to OECD 414, oligomerisation and alkylation reaction products of 2-phenylpropene and phenol (OAPP) [EC-no. 700 -960 -7], administered daily by oral gavage to pregnant Hannover Wistar rats from gestation days GD6 to GD19, was associated with the following findings: In the Mid- and High-dose group (150 and 300 mg/kg bw/day), there was a reduction in maternal body-weight gain and corrected body-weight gain, as well as in food intake during Gestation Day 6 – 20. The differences were considered to be relatively mild signs of maternal toxicity. There was no evidence of any adverse maternal effects in the Low-dose group at 60 mg/kgbw/day.

There were no toxicologically significant differences or test item related-changes in the reproductive parameters examined up to and including 300 mg/kg bw/day. No foetal effects were seen at exteral, visceral and/or skeletal examination of foetuses in the study which could be related to the test-item administration.

In this study, from the observations made in the dams and their foetuses, the following no-observed-adverse-effect (NOAEL), low-observed-adverse effect (LOAEL) or no-observed-effect (NOEL) levels were derived:

LOAELmaternal toxicity:                  150 mg/kg bw/day

NOELmaternal toxicity:                     60 mg/kg bw/day

NOAELembryotoxicity:                    300 mg/kg bw/day

NOAELfoetotoxicity:                        300 mg/kg bw/day

NOAELteratogenecity:                     300 mg/kg bw/day.