Registration Dossier

Administrative data

Key value for chemical safety assessment

Effects on fertility

Description of key information
No further study available.
Link to relevant study records
Reference
Endpoint:
three-generation reproductive toxicity
Remarks:
based on test type (migrated information)
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Study well documented, meets generally accepted scientific principles of GLP, acceptable with restrictions.
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 416 (Two-Generation Reproduction Toxicity Study)
Deviations:
yes
Remarks:
Additional third generation, missing assay parameters: lenght of estrus cycle, vaginal opening, preputial separation, sperm parameters, anogenital distance
Principles of method if other than guideline:
The effects of Caprolactam on reproduction were studied in a three-generation reproduction study in albino rats. The chemical was administered in the diet at levels of 0, 1000, 5000, and 10000 ppm (0, 100, 500 and 1000 mg/kg bw/d, respectively). Criteria used to evaluate for compound effect in the parental animals were mortality, clinical signs, body weight, food consumption, reproduction indices, and gross and microscopic pathology. Criteria evaluated in the offspring were gross appearance, survival, body weight, male pup percentages, gross pathology and kidney weight data.
GLP compliance:
not specified
Limit test:
no
Species:
rat
Strain:
Fischer 344
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Breeding Laboratories, Inc., Wilmington, Massachusetts
- Weight at study initiation: (P) Males: 88-133 g, Females: 67-104 g


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 17-29
- Humidity (%): 31-68
- Photoperiod (hrs dark / hrs light): 12/12
- Housing in non-breeding period: individually in wire-mesh cages
- Housing in breeding period: one male and two females per breeding cage
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: 2 weeks
Route of administration:
oral: feed
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:
- The compound and feed were mixed in a Hobart mixer which at small amounts gave a better blend. Fresh diets were prepared and presented weekly.
- fresh diest were prepared weekly and reserve samples were retained from each mixed batch and sent to the sponsor for analysis.
Details on mating procedure:
Mating phase of first (P1), second (P2) and third (P3) generation:
10 males and 20 females were mated / group.
- M/F ratio per cage: 1/2
- Length of cohabitation: 2 weeks
- each parental generation was subjected to two breeding phases. The second breeding occurred 7-13 days after the sacrifice of the first litter of
offspring.



Analytical verification of doses or concentrations:
yes
Duration of treatment / exposure:
Treatment phase:
10 weeks-premating exposure period (males and females of P1).
Following mating the treatement phase was 10 weeks.
Dosing of test substance continuously in the diet throughout three successive generations.

Frequency of treatment:
daily
Details on study schedule:
- parental animals were 10 males and 20 females per dose group in each generation. They were treated 10 weeks before mating.

- F1-generations:
F1a
(1) gross necropsy on approx. 1/3 of the pups
(2) remaining pups were sacrificed without necropsy
F1b
(1) 10males and 20 females / group were selected for P2 generation
(2) gross necropsy on approx. 1/3 of the pups
(3) remaining pups were sacrificed without necropsy

- F2-generations:
F2a
(1) gross necropsy on approx. 1/2 of the pups
(2) remaining pups were sacrificed without necropsy
F2b
(1) 10males and 20 females / group were selected for P3 generation
(2) gross necropsy on approx. 1/3 of the pups
(3) remaining pups were sacrificed without necropsy

- F3-generations:
F3a
(1) gross necropsy on approx. 1/3 of the pups
(2) remaining pups were sacrificed without necropsy
F3b
(1) gross necropsy on approx. 1/2 of the pups
(2) remaining pups were sacrificed without necropsy

- Each litter was observed and the number of live and dead pups (by sex), individual body weights and any evidence of abnormality were recorded on days 1, 7 and 21 of lactation . At Day 7, litters were culled by random card draw to eight pups (equal number per sex where possible).
- The second (P2) and third (P3) parenteral animals were selected by random card draw from each group of F1b and F2b litters for assignment to the same treatment group as described above.


Remarks:
Doses / Concentrations:
1000, 5000 and 10000 ppm
Basis:
nominal in diet
Remarks:
Doses / Concentrations:
100, 500 and 1000 mg/kg bw
Basis:
other: calculated based on a conversion factor of 10 (Derelanko, M.J., The Toxicologist's Pocket Handbook, 2nd Ed., p.29, 2008).
Remarks:
Doses / Concentrations:
79, 355, 726 mg/kg bw/day in females; 86, 422, 878 mg/kg bw/day in males
Basis:
actual ingested
No. of animals per sex per dose:
10 males and 20 females
Control animals:
yes, concurrent vehicle
Parental animals: Observations and examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily
- Cage side observations: any gross signs of toxicity and pharmacologic effects


BODY WEIGHT: Yes
- Time schedule for examinations: initially and at week 4 and 10


FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption for each animal determined: Yes for weeks 4 and 10
Postmortem examinations (parental animals):
P1 animals were sacrificed and complete gross necropsies were performed.
The P2 and P3 animals were sacrificed and discarded without necropsy.
All parental animals that died on study were necropsied and gross observations recorded.
Postmortem examinations (offspring):
Gross necropsy was performed of 1/3 (F1a/b, F2b, F3a/b) or 1/2 (F3b) of the offspring.
The kidneys from each necropsied F3b pup were weighed and kidney/body weight ratios were determined.
Statistics:
Parental body weights and food consumption values, and offspring body weights from each generation of the control group, were compared statistically to data of the treated groups of the same sex by Bartlett's test for homogeneity of variance and the one-way classification analyses of variance (ANOVA).
If there were significant results, a multiple pairwise comparison procedure or Scheffe's multiple pairwise comparison procedure was used to compare the group mean values. Reproduction and viability indices were analyzed using the chi-square method.
The percentage of male pups at each interval was analyzed using Wilcoxon's non-parametric comparison of group means. The individual litter was considered as the experimental unit in all calculations.
The F3b kidney weight data for the control group were compared statistically to the data for the caprolactam treated groups of the same sex by Bartlett's test for homogeneity of variance, and then by a one-way classification analysis of variance (ANOVA) if the variance proved to be homogeneous. If the variances were heterogeneous, a log10 transformation was performed, followed by Bartlett's test. If the log10 transformation could not remove the variance heterogeneity, a loge transformation of the original data, followed by Bartlett's test, was performed. If homogeneity could not be achieved, the ANOVA of the non-transformed data was completed. If the ANOVA of homogeneous data was significant, Scheffe's multiple pairwise comparison
procedure was used to compare the group mean values. If the ANOVA of heterogeneous data was significant, Games and Howell's multiple pairwise
comparison procedure was used to compare the group mean values. All analyses were evaluated at 5% probability (one-tailed) level.
CLINICAL SIGNS AND MORTALITY (PARENTAL ANIMALS): No treatment-related clinical signs were noted within the parental generations. Within the P1 animals, one low- and two high-dose females died during Week 1 of the ten-week growth period. One P2 control male was found dead following the growth period and one P3 male was found dead just prior to the F3b breeding. These deaths were noted randomly by test group, sex and parenteral generation, and were not attributed to the administration of caprolactam.


BODY WEIGHT AND FOOD CONSUMPTION (PARENTAL ANIMALS, see tables 1 and 2):
Significantly (p<=0.05) lower body weights were noted in both the high-dose P2 and P3 males and females at weeks 0, 4, and 10. In addition, generally lower body weights were noted in the mid-dose group of both sexes of the P2 animals, and the male P3 animals at the same intervals, with the mid-dose P2 males at Week 4 being significant.
A similar effect on food consumption was observed although the response in the males appeared to be more pronounced than in the females. Significantly lower food consumption values were noted in the high-dose P1 females at week 10 (17 %), the mid-dose P2 males at weeks 4 and 10 (10-15 %), the high-dose P2 and P3 males at weeks 4 and 10 (9-18%), and the high-dose P2 and P3 females at week 10 (7-10%).
No effects on body weight and food consumption were noted in the rats treated at 1000 ppm.


REPRODUCTIVE PERFORMANCE (PARENTAL ANIMALS, see tables 3-5):
The pregnancy and fertility indices were comparable between the treated and control groups for each filial generation, and no dose-related trends were apparent.


GROSS PATHOLOGY (PARENTAL ANIMALS): no treatment related effects were observed


HISTOPATHOLOGY (PARENTAL ANIMALS): Compound-related histopathologic findings noted in the high-dose P1 animals consisted of a slight increase in the severity of spontaneous nephropathies.
This nephropathy was characterized by the presence of regenerative tubule epithelium, mononuclear inflammatory cells and occasional dilated tubules
containing proteinaceous casts. In addition, dilated tubules containing granular casts were noted in three of the rats. Kidney sections from rats in the control group as well as the low- and mid-dose treated groups revealed slightly less severe nephropathy and were essentially comparable in appearance between the control and treated rats.

Key result
Dose descriptor:
NOAEL
Effect level:
500 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: body weight, spontaneous nephropathies
Remarks on result:
other: P-generation
Key result
Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: highest dose tested
Remarks on result:
other: Generation: Fertility (migrated information)
VIABILITY (OFFSPRING, see tables 3-5): The live birth, neonatal survival and weaning survival indices were generally comparable between the treated and control groups for each filial generation, and no dose-related trends were noted.

CLINICAL SIGNS (OFFSPRING): No treatment-related clinical observations were noted in any of the three filial generations.

BODY WEIGHT (OFFSPRING, see tables 3-5): Lower mean body weights were observed in male and female pups at the two highest dose levels in all filial generations. The response was dose-related, with significant differences (P ≤ 0.05) noted more frequently in the pups receiving a dose of 10000 ppm.

SEX (OFFSPRING): No treatment-related effects were noted in evaluation of the percentage of male pups.

ORGAN WEIGHTS (OFFSPRING): No significant differences were noted in the mean relative kidney weights (Table 6).

GROSS PATHOLOGY (OFFSPRING): no treatment related effects were observed
Dose descriptor:
NOAEL
Generation:
F1
Effect level:
100 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
body weight and weight gain
Reproductive effects observed:
not specified

Table 1. Summary of maternal reproduction indeces, offspring survival, and growth from the first generation.  

 

F1a

F1b

Dose [ppm]

0

1000

5000

10000

0

1000

5000

10000

Parental reproduction indeces

#females

20

19

20

18

20

19

20

18

#pregnant females

19

15

19

14

19

17

18

16

Pregnancy rate [%]

95

79

95

77

95

89.5

90

88.9

Male fertility rate [%]

100

100

100

100

100

90

100

100

Offspring indeces

Day 1 #pups/litter

9.8 +/-2.2

8.7 +/-2.5

9.1 +/-2.0

9.2 +/-2.5

10.6 +/-4.2

8.8 +/-3.1

10.3 +/-2.8

9.7 +/-3.3

Day 1 live birth index [%]

98.7

100

100

93.8

99.5

100

99.1

100

Day 7 survival index [%]

100

96.2

100

93.9

99

98.6

98.6

97.9

Day 21 survival index [%]

100

99.2

100

91.1

100

100

99.3

100

% males day 1

44.9

46.9

50.9

55.7

51.8

50

46.5

52.9

Mean offspring body weights

Males day 1

5.91 +/-0.89

5.87 +/-0.71

6.07 +/-0.77

4.86 +/-0.36**

5.49 +/-0.73

5.77 +/-1.05

5.22 +/-0.52

5.25 +/-0.66

females day 1

5.56 +/-0.73

5.61 +/-0.68

5.59 +/-0.75

4.53 +/-1.56

5.4 +/-0.71

5.36 +/-0.58

4.79 +/-0.35**

4.86 +/-0.66

Males day 7

10.77 +/-1.28

11.49 +/-2.22

10.78 +/-1.4

8.76 +/-1.69**

11.02 +/-1.17

11.68 +/-1.96

9.94 +/-1.28

9.03 +/-1.55**

females day 7

10.25 +/-1.40

11.11 +/-2.06

10.31 +/-1.09

8.9 +/-1.06**

10.62 +/-1.23

11.09 +/-1.68

9.28 +/-1.17

8.75 +/-1.45**

Males day 21

29.65 +/-2.66

30.46 +/-4.4

27.65 +/-2.98

22.79 +/-1.28**

31.58 +/-2.46

31.48 +/-4.09

27.97 +/-3.8**

25.03 +/-3.35**

females day 21

28.08 +/-2.3

29.11 +/-3.56

26.62 +/-3.05

22.22 +/-1.69**

29.82 +/-2.68

30.08 +/-3.64

25.79 +/-2.26**

24.63 +/-3.28**

**p≤0.05

Table 2. Summary of maternal reproduction indeces, offspring survival, and growth from the second generation.  

 

F2a

F2b

Dose [ppm]

0

1000

5000

10000

0

1000

5000

10000

Parental reproduction indeces

#females

20

20

20

20

20

20

20

20

#pregnant females

16

19

15

17

15

20

18

17

Pregnancy rate [%]

80

95

75

85

75

100

90

85

Male fertility rate [%]

100

100

100

100

100

100

100

100

Offspring indeces

Day 1 #pups/litter

10 +/-2.7

9.2 +/-3.6

9.5 +/-2.8

8.4 +/-2.2

10.3 +/-2.7

10.7 +/-3.2

8.6 +/-3.4

7.8 +/-3.4

Day 1 live birth index [%]

100

98.2

98.1

100

100

99.6

100

98.2

Day 7 survival index [%]

100

100

99.3

100

99.1

99.2

99.2

91.1

Day 21 survival index [%]

100

99.3

100

99.3

100

100

99.3

93.4

% males day 1

54.7

52.6

50.3

53.4

49.3

52.1

47.9

46.6

Mean offspring body weights

Males day 1

5.54 +/-0.7

5.6 +/-0.65

5.46 +/-0.627

4.99 +/-0.94

5.56 +/-0.49

5.48 +/-0.57

5.5 +/-0.59

5.12 +/-0.7

females day 1

5.35 +/-0.61

5.18 +/-0.4

5.09 +/-0.6

4.67 +/-0.78**

5.32 +/-0.47

5.15 +/-0.41

5.16 +/-0.6

4.74 +/-0.63**

Males day 7

11.48 +/-1.85

10.79 +/-1.16

10.7 +/-1.23

9.33 +/-0.82**

10.83 +/-1.37

10.67 +/-1.65

10.24 +/-1.47

9.29 +/-1.79

females day 7

10.87 +/-1.46

10.24 +/-1.03

10.27 +/-1.18

8.75 +/-0.99**

10.26 +/-1.25

9.84 +/-1.84

9.75 +/-1.41

8.76 +/-1.76

Males day 21

31.95 +/-3.46

31.07 +/-2.94

29.69 +/-2.86

24.36 +/-3.26**

31.89 +/-2.39

32.1 +/-3.2

29.47 +/-2.51**

25.03 +/-4.94**

females day 21

30.14 +/-2.99

29.47 +/-2.02

27.73 +/-2.12

22.97 +/-2.51**

30.46 +/-1.97

29.43 +/-3.28

28.32 +/-2.74

23.49 +/-4.43**

**p≤0.05

Table 3. Summary of maternal reproduction indeces, offspring survival, and growth from the third generation.  

 

F3a

F3b

Dose [ppm]

0

1000

5000

10000

0

1000

5000

10000

Parental reproduction indeces

#females

20

20

20

20

20

20

20

20

#pregnant females

14

15

17

16

17

17

15

15

Pregnancy rate [%]

70

75

85

80

85

85

75

83.3

Male fertility rate [%]

90

100

100

100

100

100

100

100

Offspring indeces

Day 1 #pups/litter

9.4 +/-2.6

9.8 +/-3.6

10.8 +/-2.8

9.5 +/-1.6

9 +/-4.5

9.9 +/-4.3

9.1 +/-3.1

7.7 +/-1.9

Day 1 live birth index [%]

99.5

100

100

100

99.5

100

98

96.2

Day 7 survival index [%]

94.1

90.9

98.2

99.3

96.8

94.8

90.5

99.3

Day 21 survival index [%]

96.5

99.1

96.3

99.3

99.3

93.4

98.1

100

% males day 1

47.1

47.3

45.9

56.7

53.3

52.8

57.8

51.9

Mean offspring body weights

Males day 1

5.9 +/-0.51

5.43 +/-0.45

5.27 +/-0.72**

5.17 +/-0.62**

5.79 +/-1.01

5.47 +/-0.92

5.59 +/-1.01

4.93 +/-0.68

females day 1

5.44 +/-0.35

5.15 +/-0.4

4.91 +/-0.78

4.73 +/-0.57**

5.36 +/-0.71

5.04 +/-0.67

5.35 +/-0.95

4.62 +/-0.42

Males day 7

10.29 +/-1.64

10.49 +/-1.7

9.85 +/-1.78

9.09 +/-1.74

10.85 +/-2.22

10.36 +/-2.95

10. 4 +/-2.31

8.86 +/-1.46

females day 7

9.81 +/-1.5

9.89 +/-1.85

9.63 +/-1.79

8.75 +/-1.79

10.28 +/-1.68

9.77 +/-2.47

9.96 +/-2.35

8.11 +/-1.28**

Males day 21

29.96 +/-3.07

30.28 +/-4.35

27.18 +/-2.65**

23.03 +/-3.82**

31.22 +/-3.63

30.46 +/-5.67

28.3 +/-5.08

23.77 +/-4.32**

females day 21

27.61 +/-2.56

28.01 +/-3.36

26.21 +/-2.44

22.49 +/-3.56**

29.22 +/-2.71

28.75 +/-4.41

27.41 +/-4.42

21.96 +/-3.33**

**p≤0.05

Table 4. Mean terminal body weights, kidney weights and kidney/body weight ratiosa, of selected F3b, pups from a three-generation reproduction study of Caprolactam in rats.

Dose (ppm)

No. examined

Terminal body weight (g)

Kidney weight (g)

Kidney/body weight ratio

Males

0

25

30.80±3.571

0.456±0.1163

1.481±0.3432

1000

31

28.84±40.50

0.448±0.1402

1.545±0.4001

5000

26

27.62**±3.060

0.402±0.1045

1.453±0.3094

10000

25

22.32**±2.174

0.318**±0.0378

1.426±0.1416

Females

0

21

27.95±2.397

0.424±0.1248

1.513±0.3946

1000

20

29.40±4.604

0.419±0.0710

1.428±0.1492

5000

20

27.35±4.030

0.427±0.1126

1.555±0.3029

10000

26

21.31±2.739

0.310**±0.476

1.455±0.1083

aEach value shown is the mean± the standard deviation

** p<0.05 vs control

Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

There is no reproductive toxicity study available for N-Vinylcaprolactam. The available data for ε-caprolactam (CAS 105-60-2) were considered in a read across approach:

In a three-generation study F344 rats were continuously fed with caprolactam (CAP) at dose levels of ca. 100, 500, 1000 mg/kg bw throughout three successive generations (Serota et al., 1981). Following the 10 weeks premating exposure periods, no treatment-related clinical signs of toxicity, changes in reproductive performance or gross-pathological findings were noted within the parental generations. Compound-related findings were mainly related to body weight loss (significant in the high-dose group only). Histopathologic findings noted in the high-dose P1 animals consisted of a slight increase in the severity of spontaneous nephropathies, occasionally accompanied by granular casts in 3 of 10 male animals. Based on these findings, the NOAEL for the parental P1-P3 generations was identified as 500 mg/kg bw.

Pregnancy and fertility indices were comparable between treated and control groups for each filial generation and no dose-related trends were apparent, thus the NOAEL for fertility was 1000 mg/kg bw.

The offspring data revealed no treatment-related effects with respect to gross appearance, gross pathology, survival, number of pups, and percentage of male pups or kidney weight. The only effect observed in offspring were lower mean body weights in male and female pups at the two highest dose levels in all filial generations, the NOAEL of F1-F3 offspring was 1000 ppm (100 mg/kg bw). Summarized no adverse effect on reproductive organs or function were found in this 3-generation study with rats.


Short description of key information:
There is no reproductive toxicity study available for N-Vinylcaprolactam. The available data for ε-caprolactam (CAS 105-60-2; read across) revealed no effects on reproductive performance and fertility.

Justification for selection of Effect on fertility via oral route:
Acceptable for assessment

Effects on developmental toxicity

Description of key information
There is no developmental toxicity study available for N-Vinylcaprolactam. The available data for ε-caprolactam (CAS 105-60-2; read across) revealed no developmental/teratogenic effects.
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
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Well documented study, meets generally accepted scientific principles of GLP, acceptable with restrictions
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Deviations:
yes
Principles of method if other than guideline:
This study was designed to evaluate the developmental toxicity potential of Caprolactam in rats.
The test material was administered by oral intubation on days 6 through 15 of gestation to each of three groups of twenty pregnant female rats of the Fischer 344 strain at levels of 100, 500, and 1000 mg/kg bw, respectively. A fourth group of twenty pregnant rats received only the vehicle (distilled water) and served as the control group. Criteria evaluated for evidence of compound effect were maternal body weight and body weight changes, food consumption, clinical observations, survival, gross pathology, implantation and resorption efficiencies, and offspring viability and development.
GLP compliance:
not specified
Limit test:
no
Species:
rat
Strain:
Fischer 344
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Microbiological Associates, Walkerville, Maryland
- Weight at study initiation: 149-205 g
- Diet (e.g. ad libitum): Purina Laboratory Chow
- Water (e.g. ad libitum): Tap water
- Acclimation period: 20 days

Route of administration:
oral: gavage
Vehicle:
water
Details on exposure:
PREPARATION OF DOSING SOLUTIONS: Appropriate amounts of the test material were dissolved in distilled water on a weight-per-volume basis and administered by oral intubation (amount based on individual body weight, dosing factor 10 ml/kg bw) from day 6 through day 15 of gestation.
Details on mating procedure:
- Impregnation procedure: cohoused
- If cohoused:
- M/F ratio per cage: 1/2
- Proof of pregnancy: sperm in vaginal smear referred to as day 0 of pregnancy
Duration of treatment / exposure:
day 6-15 of gestation
Frequency of treatment:
daily
Duration of test:
day 20 of gestation
Remarks:
Doses / Concentrations:
0, 100, 500 and 1000 mg/kg
Basis:
actual ingested
No. of animals per sex per dose:
20
Control animals:
yes, concurrent no treatment
Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily


DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: during day 6-20 of gestation


BODY WEIGHT: Yes
- Time schedule for examinations: on days 0, 6, 11, 15, and 20 of gestation


FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Yes
- Food consumption for each animal determined: Yes on days 6, 11, 15, and 20 of gestation


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

Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes
Fetal examinations:
- External examinations: Yes
- Soft tissue examinations: Yes
- Skeletal examinations: Yes
Details on maternal toxic effects:
Details on maternal toxic effects:
- The maternal survival rate was statistically significantly lower in the high-dose group when compared with the control. Nine high-dose females (six pregnant, three not pregnant) were found dead during the treatment phase of this study.

- Clinical observations made during the treatment and post treatment periods that were noted in the treated groups: urine stains, a rough hair coat, a red discharge from the vagina, a bloody crust on or about the eyes, mouth, and/or nose, a thin and/or hunched appearance, and/or depression.

- The mean body weight values of the high dose group on day 15 and 20 of gestation and the mean body weight changes of the mid- and high dose groups for the days 6-11 and 6-15 were statistically significantly (p<0.05) lower than the control values at these intervals (Table 1). The percent body weight change in the mid dose group during the treatment period 6-11 and 6-15 were -0.8 and 5.2, respectively, in comparison to 6.2 and 13.4 in control group. Similarly in the high dose group, the percent body weight change were -2.7 and 2.3, respectively.

- The mean food consumption was significantly lower (p<0.05) in the mid- and high-dose groups.

- The pregnancy rates were slightly higher in the low- and mid-dose groups (80 and 75%) than in the control (60%). The mean implantation efficiencies were slightly lower in the low-and high-dose groups than in the control (Table 2). The mean incidence of resorptions was statistically significantly (p<0.05) higher than the control value in the high-dose group (Table 2).
Dose descriptor:
NOAEL
Effect level:
100 mg/kg bw/day (actual dose received)
Basis for effect level:
other: maternal toxicity
Details on embryotoxic / teratogenic effects:
Details on embryotoxic / teratogenic effects:
- The mean incidence of fetal death was comparable for all groups, and the mean incidence of fetal viability was lower in the high-dose group than in the control group.
- The mean body weight of the male fetuses in the treated groups was slightly lower than that of the control group, and the mean body weight of the female fetuses in the mid-and high-dose groups was slightly lower than that of the control group. The difference in the mean body weight was remarkable only in the high dose males (10% low) and females (15% low), however the difference was not statistically significant.
- The mean fetal lengths were slightly lower (below 10 %) in the high dose-group than in the controls.
- No treatment-related visceral or skeletal anomalies were observed. Skeletal variants were observed in each group with the mid- and high dose groups having a higher incidence of skeletal variants than the control group. In the control group the variants included incomplete ossification of the skull (supraoccipital or interparietal), a nonfused vertebral column (centra), and/or extra ribs. The variants observed in the treated groups included incomplete ossification of the skull (supraoccipital and/or interparietal), incomplete and/or malfused sternebrae, extra ribs, and/or nonfused and/or incomplete ossification of the vertebral column (centra). No statistically significant differences were noted in these data.
Dose descriptor:
NOAEL
Effect level:
500 mg/kg bw/day (actual dose received)
Basis for effect level:
other: fetotoxicity
Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day (actual dose received)
Basis for effect level:
other: teratogenicity
Abnormalities:
not specified
Developmental effects observed:
not specified

Table 1. Mean maternal body weights and body weight changesa

Body weights

Days

Dose level (mg/kg bw)

0

100

500

1000

 

 

Mean weight (g)

0

167.2

174.4

170.8

168.0

6

176.7

184.4

180.7

176.8

11

187.6

192.9

179.3

172.0

15

200.3

204.4

190.1

180.8s-

20

234.6

233.9

225.3

208.8s-

Mean change (g)

Pre-treatment period

0-6

9.5

10.5

9.9

8.8

Treatment period

6-11

10.9

8.0

-1.4s-

-4.8s-

Treatment period

11-15

12.7

11.5

10.8

8.8

Total Treatment period

6-15

23.6

19.5

9.4s-

4.0s-

Post-treatment period

15-20

34.3

29.5

35.2

28.0

Total study period

0-20

67.4

59.5

54.5

40.8

Percent change (%)

Pre-treatment period

0-6

5.7

6.0

5.8

5.2

Treatment period

6-11

6.2

4.3

-0.8

-2.7

Treatment period

11-15

6.8

6.0

6.0

5.1

Total Treatment period

6-15

13.4

10.5

5.2

2.3

Post-treatment period

15-20

17.1

14.4

18.5

15.5

Total study period

0-20

40.3

34.1

31.9

24.3

aOnly data from pregnant rats surviving to Day 20 of gestation were included in calculations of the mean values

S-:Statistically significantly (p<0.05) lower than the control value.

Table 2. Summary of the Ovarian, Uterine, and Litter Dataa

Parameters

Dose level (mg/kg bw)

0

100

500

1000

Number of females mated

20

20

20

20

Number of rats pregnant

12

16

15

11

Pregnancy rate (%)

30.0

80.0

75.0

55.0

Number of pregnant rats surving to day 20

12

16

15

5

Maternal survival rate (%)

100.0

100.0

100.0

45.5

Mean number of:

Corpora lutea

11.8

12.9

11.7

12.8

Implantations

9.6

8.5

9.6

8.6

Resorptions

0.4

0.5

0.3

3.2

Fetuses- Dead

0.0

0.0

0.0

0.0

Fetuses- Live

9.2

8.6

9.3

5.4

Indices calculated on aper litter per group basis:

Mean implantation efficiency (%)

81.78

70.56

81.11

67.92

Mean incidence of resorption (efficiency) (%)

4.64

5.24

3.27

41.34

Mean incidence of fetal death (%)

0.00

0.00

0.00

0.00

Mean incidence of fetal viability (%)

95.36

94.76

96.39

58.66

aOnly data from pregnant rats surviving to Day 20 of gestation were included in calculations of the mean values

S-:Statistically significantly (p<0.05) lower than the control value.

S+:Statistically significantly (p<0.05) higher than the control value.

Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
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

There is no developmental toxicity study available for N-Vinylcaprolactam. The available data for ε-caprolactam (CAS 105-60-2) were considered in a read across approach:

In a developmental toxicity study performed according to the current OECD guideline 414, 20 F344 rats/group were gavaged with dose levels of 100, 500 and 1000 mg/kg/d bw on days 6-15 of gestation. The maternal survival rate was statistically lower in the high-dose group when compared with the control. Nine high-doses females were found dead during the treatment phase of this study. Clinical observations such as urine stains, rough hair coat, red discharge from the vagina, bloody crust on eyes, mouth and nose, and thin and/or hunched appearance were observed in dose dependent manner in all treated groups.

The mean body weight values of the high dose group were significantly (p<0.05) lower than in controls on days 15 (10%) and 20 (11%) of gestation. Furthermore, the mean body weight changes of the mid- and high-dose groups for the days 6-11 and 6-15 were significantly (p<0.05) lower than the control values at these intervals. These effects on body weights were accompanied by significantly lower values of mean food consumption in the mid- and high-dose groups. In these maternally toxic doses, a slight reduction in fetal body weight was observed. The mean number of corpora lutea and implantations per group were not affected by treatment, but the mean implantation efficiencies were slightly reduced in the high-dose group. No treatment-related visceral or skeletal anomalies were observed.

Based on these results in rats, the NOAEL for maternal toxicity was identified as 100 mg/kg bw/d, for embryotoxicity as 500 mg/kg bw/d and for teratogenicity as 1000 mg/kg bw/d.

 

In an analogous developmental toxicity study (Bio-Research, 1983) with New Zealand White Rabbits, 25 animals/group were gavaged with dose levels of 50, 150 and 250 mg/kg bw on days 6-28 of gestation. In the high dose group 4 rabbits died during the treatment period. Also exclusively in the high dose group, adverse clinical findings were observed. The absolute weight gain between day 6 and 29 was decreased in the high dose group, whereas the corrected body weight gain (body weight gain day 6-29 minus weight of gravid uterus) was significantly decreased in mid dose animals.

Fetotoxicity was evidenced by lower fetal weights at the mid and high dose groups, and an increased incidence of thirteenth ribs was observed in the high dose group. Neither embryotoxicity nor teratogenicity occurred. Based on these findings in rabbits, the NOAEL for maternal toxicity and fetotoxicity was identified as 50 mg/kg bw. No teratogenicty was observed with the highest dose tested (NOAELtera 250 mg/kg bw/day).

 

In a BASF study (1978), no signs of maternal toxicity and fetotoxicity were observed in rats after dosing 166 mg/kg bw by oral-gavage. Thus, the NOAEL for maternal, fetal and developmental toxicity was above 166 mg/kg bw/d. 

 

Combining all data, no teratogenic effects from the oral application of epsilon-caprolactam were observed in rats or rabbits. Fetotoxic effects were only observed in rats and rabbits at doses that also produced maternal toxicity.


Justification for selection of Effect on developmental toxicity: via oral route:
Acceptable for assessment

Justification for classification or non-classification

ε-Caprolactam (CAS 105-60-2; read across) showed no effect on reproductive performance and fertility. The available data for ε-caprolactam revealed also no developmental/teratogenic effects. The available repeated dose toxicity studies performed with N-Vinylcaprolactam revealed no effects on reproductive organs. Therefore, classification for reproductive toxicity is not warranted according to EU Directive 67/548 EEC and EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No 1272/2008.