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Toxicological information

Toxicity to reproduction

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Administrative data

Endpoint:
screening for reproductive / developmental toxicity
Remarks:
based on test type (migrated information)
Type of information:
migrated information: read-across based on grouping of substances (category approach)
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
GLP - Guideline study. According to the ECHA guidance document "Practical guide 6: How to report read-across and categories (March 2010)", the reliability was changed from RL1 to RL2 to reflect the fact that this study was conducted on a read-across substance.

Data source

Referenceopen allclose all

Reference Type:
study report
Title:
Unnamed
Year:
1996
Reference Type:
secondary source
Title:
Dibutyl adipate CAS N°: 105-99-7
Author:
OECD
Year:
1996
Bibliographic source:
SIDS Initial Assessment Report for SIAM 4; Tokyo, Japan, 20-22 May 1996

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
OECD Guideline 421 (Reproduction / Developmental Toxicity Screening Test)
Deviations:
no
GLP compliance:
yes
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
Dibutyl adipate
EC Number:
203-350-4
EC Name:
Dibutyl adipate
Cas Number:
105-99-7
Molecular formula:
C14H26O4
IUPAC Name:
dibutyl adipate

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories Japan, Inc., Yokohama, Japan
- Age at study initiation: 8 wks;
- Weight at study initiation: males: 270.6 - 326.5 g; females: 199.5 - 243.4 g
- Fasting period before study: No
- Diet: CA-1 by CLEA Japan, Meguro, Japan, ad libitum
- Water: tap water, ad libitum
- Acclimation period: 7 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 24 ± 1
- Humidity (%): 55 ± 5
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
corn oil
Details on exposure:
VEHICLE
- Justification for use and choice of vehicle: due to the lipophilic properties of the test material, corn oil was selected as the appropriate vehicle
- Amount of vehicle: 5 mL/kg
Details on mating procedure:
- M/F ratio per cage: 1/1
- Length of cohabitation: up to 14 days
- Proof of pregnancy: vaginal plug and sperm in vaginal smear referred to as Day 0 of pregnancy
- After successful mating each pregnant female was caged: Individually
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Detailed method was not described. The measured concentration was between 98.3 and 104% of nominal concentration.
Duration of treatment / exposure:
Males: 14 days before mating and for 28 days thereafter
Females: total of 42-53 days beginning 14 days before mating to day 3 of lactation

Frequency of treatment:
7 days /week
Details on study schedule:
- Age at mating of the mated animals in the study: 10 weeks
Doses / concentrations
Remarks:
Doses / Concentrations:
100, 300, 1000 mg/kg bw/day
Basis:
actual ingested
No. of animals per sex per dose:
13
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: A dose finding study was performed. Test solutions of 0, 500 and 1000 mg/kg bw/day were administered for 14 days to female rats. Slight salivation was observed during treatment but no mortality occured. No difference in body weight and food consumption was observed and necropsy revealed no abnormalities.No change in organ weight compared with control group was observed.

Examinations

Parental animals: Observations and examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily, before and after administration

BODY WEIGHT: Yes
- Time schedule for examinations: Males on Days 1, 8, 15, 22, 29, 36 and 43, females on Days 1, 8 and 15 of treatment, Days 0, 7, 14 and 20 of gestation and Days 0 and 4 of lactation

FOOD CONSUMPTION: not examined
Oestrous cyclicity (parental animals):
Observed
Sperm parameters (parental animals):
Parameters examined in parental animals:
testis weight, epididymis weight, other: histopathology
Litter observations:
PARAMETERS EXAMINED
The following parameters were examined in F1 offspring:
number and sex of pups, stillbirths, live births, postnatal mortality, presence of gross anomalies, weight gain, physical or behavioural abnormalities

GROSS EXAMINATION OF DEAD PUPS:
yes, for external and internal abnormalities
Postmortem examinations (parental animals):
SACRIFICE
- Male animals: All surviving animals on Day 43
- Maternal animals: All surviving animals on Day 4 of lacation

GROSS NECROPSY
- Gross necropsy consisted of external and internal examinations including the cervical, thoracic, and abdominal viscera.

HISTOPATHOLOGY / ORGAN WEIGHTS
Organ weight: kidneys and spleen of both sexes and testes and epididymides of males.
Microscopic observation: testes and epididymides of males; ovary and uterus of females
Postmortem examinations (offspring):
SACRIFICE
- The F1 offspring were sacrificed at 4 days of age.

GROSS NECROPSY
- Gross necropsy consisted of external and internal examinations.

Statistics:
Barlett's test, Dunett's test, Scheffe's test, Kruskal-Wallis test
Reproductive indices:
copulation index (no. of copulated rats/no. of mated rats x 100),
fertility index (no. of pregnant females/no. of females with successful copulation x 100),
gestation index (no. of females with live pups/no. of pregnant females x 100),
implantation index (no. of implantation sites/no. of corpora lutea x 100),
delivery index (no. of pups born/no. of implantation sited x 100)
Offspring viability indices:
birth index (no. of live pups on day 0/no. of implantation sites x 100),
live birth index (no. of live pups on Day 0/no. of pups born x 100),
viability index (no. of pups alive on Day 4 of lactation/no. of pups born x 100)

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
Dose-dependent increase in number of rats with salivation after dose administration in both sexes.
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Histopathological findings: non-neoplastic:
no effects observed
Other effects:
no effects observed

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:
no effects observed
Reproductive function: sperm measures:
no effects observed
Reproductive performance:
no effects observed

Details on results (P0)

CLINICAL SIGNS AND MORTALITY (PARENTAL ANIMALS)
Slight salivation was observed in treatment group with dose-responsibility (see Table 1). This change was not regarded as neurological effect but caused by stimulation by the administration of the test compound.

BODY WEIGHT AND FOOD CONSUMPTION (PARENTAL ANIMALS)
Light suppression of body weight gain was observed in males in 1000 mg/kg group but there was no significant difference.

ORGAN WEIGHTS (PARENTAL ANIMALS)
An increase in relative weight of kidney was observed in both sexes of 1000 mg/kg bw group. An increase in relative weight of spleen in males of 100 and 1000 mg/kg bw, increase in absolute weight of spleen in females of 100 mg/kg was observed ( see Table 2).

HISTOPATHOLOGY (PARENTAL ANIMALS)
Infiltration of lymphocyte in testis was observed in control and 1000 mg/kg group. This change was not related to the test compound.

OTHER FINDINGS (PARENTAL ANIMALS)
A dam in 300 mg/kg bw group didn't retrieve pups and all pups were dead until on PND 2. But this change was not regarded as compound-related effect.

Effect levels (P0)

open allclose all
Dose descriptor:
NOAEL
Remarks:
systemic
Effect level:
300 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: organ weights: kidney weights increased
Dose descriptor:
NOAEL
Remarks:
reproduction
Effect level:
>= 1 000 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: NOAEL for reproductive parameters is corresponding to the highest dose tested

Results: F1 generation

General toxicity (F1)

Clinical signs:
no effects observed
Mortality / viability:
mortality observed, treatment-related
Description (incidence and severity):
1000 mg/kg: Pup viability on PND 4 was decreased.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
1000 mg/kg bw: pup weight on PND 0 and 4 was slightly decreased (without reaching statistical significance)
Sexual maturation:
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
no effects observed
Histopathological findings:
no effects observed

Details on results (F1)

VIABILITY (OFFSPRING)
1000 mg/kg: Pup viability on PND 4 was statistically significantly decreased (see Table 3).

CLINICAL SIGNS (OFFSPRING)
No effects were observed.

BODY WEIGHT (OFFSPRING)
1000 mg/kg bw: pup weight on PND 0 and 4 was slightly decreased (without reaching statistical significance (see Table 3).

GROSS PATHOLOGY (OFFSPRING)
No effects were observed.

Effect levels (F1)

Dose descriptor:
NOAEL
Generation:
F1
Effect level:
300 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: pup weight; viability index

Overall reproductive toxicity

Reproductive effects observed:
not specified

Any other information on results incl. tables

Table 1: Number of animals showing salivation upon treatment [male/female]

 

Dose [mg/kg bw/day]

Days of treatment

0

100

300

1000

1-7

-

-

-

12/9

18-14

-

-/1

4/4

13/13

15-21

-

3/2

7/9

13/13

22-28

-

-

2/1

12/13

29-35

-

-

6/4

13/13

36-42

-

-

6/3

13/12

43

-

-

-

-

Total

-

3/3

11/9

13/13

 

Table 2: Organ weights

Males after 42 days of treatment

Dose [mg/kg bw/day]

Kidney

 

0

100

300

1000

absolute weight [g]

mean

2.96

3.12

3.04

3.08

 

SD

0.39

0.34

0.32

0.35

relative weight [% of mean body weight]

mean

0.6

0.61

0.63

0.65*

 

SD

0.05

0.04

0.06

0.06

Spleen

absolute weight [g]

mean

0.79

0.95

0.84

0.9

 

SD

0.14

0.19

0.11

0.2

relative weight [% of mean body weight]

mean

0.16

0.18*

0.17

0.19**

 

SD

0.02

0.03

0.02

0.03

Females at Day 4 of lactation

Kidney

absolute weight [g]

mean

1.95

1.97

2.1

2.11

 

SD

0.15

0.19

0.22

0.17

relative weight [% of mean body weight]

mean

0.6

0.58

0.62

0.65

 

SD

0.04

0.03

0.05

0.07

Spleen

absolute weight (in g)

mean

0.59

0.74*

0.65

0.68

 

SD

0.08

0.16

0.13

0.09

relative weight (% of mean body weight)

mean

0.18

0.22

0.19

0.21

 

SD

0.03

0.04

0.03

0.03

 

Table 3: Reproductive parameters

Dose [mg/kg bw/day]

 

0

100

300

1000

No.of female animals:

 

13

13

13

13

No. of mated pairs:

 

13

13

13

13

No. of copulated pairs:

 

13

13

13

13

Copulation index [%]

 

100

100

100

100

No. of pregnant females

 

12

12

12

12

Fertility index [%]

 

92.3

92.3

92.3

92.3

Pairing day until copulation

 

 

mean

4.1

2.6

3

2.7

 

SD

3.3

0.8

2.3

1

Frequency of vaginal estrus

 

 

mean

1.1

1

1.2

1

 

SD

0.3

0

0.6

0

No. of pregnant females with pups alive:

 

12

12

12

12

Gestation index (%)

 

100

100

100

100

Gestation length (days)

 

 

mean

22.3

22.1

22.2

22.2

 

SD

0.5

0.3

0.4

0.4

No. of corpora lutea

 

 

mean

15.7

15.6

17

16.9

 

SD

2

1.6

1.9

1.7

No.of implantation site

 

 

mean

14.8

14.7

15.8

15.5

 

SD

2.6

2.1

3.1

2.1

Implantation index [%]

 

 

mean

94.2

94

92.2

91.5

 

SD

7.8

8.4

14.1

7.5

Day 0 of lactation

 

No.of pups born

 

 

mean

13.6

14.2

15

14.6

 

SD

2.4

1.9

2.9

2.3

Delivery index [%]

 

 

mean

91.8

96.7

95.5

93.9

 

SD

6.5

3.4

5.7

5.9

No.of pups alive

 

 

mean

13.3

13.9

14.3

13.7

 

SD

2.4

1.9

2.6

3.3

Birth index (%)

 

 

mean

90.1

95.2

91.8

88.2

 

SD

6.1

6

8.8

16.8

Live birth index (%)

 

 

 

 

 

 

mean

98.2

98.4

96.2

93.6

 

SD

4.6

4.1

8.4

15.2

Pups weight [g]

 

Male

mean

6.5

6.4

6.2

6.1

 

SD

0.7

0.6

0.8

0.7

Female

mean

6.1

6

5.8

5.8

 

SD

0.6

0.6

0.7

0.5

Sex ratio on day 0 of lactation [no. of male pups/total no. of pups]

 

 

mean

47.6

41.4

49.4

48.6

 

SD

13

7.7

12.7

11.9

Day 4 of lactation

 

No.of pups alive

 

 

mean

13.3

13.8

13.1

13.3

 

SD

2.4

1.7

4.8

3.5

Viability index [%]

 

 

mean

100

99.5

90.6

96.1*

 

SD

0

1.7

28.6

5.3

Pups weight [g] on day 4 of lactation

 

Male

mean

10.6

10.8

10.2

9.9

 

SD

1.8

1.2

1.7

1.9

Female

mean

10.1

10.1

9.7

9.3

 

SD

1.7

1.2

1.6

1.4

SD standard deviation

* significant difference from control, p<0.05

** significant difference from control, p<0.01

Applicant's summary and conclusion

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