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Toxicological information

Developmental toxicity / teratogenicity

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Administrative data

Endpoint:
developmental toxicity
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
GLP - Guideline study, tested with the source substance methyl laurate (CAS 111-82-0). 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.
Cross-reference
Reason / purpose:
reference to same study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2000

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
other: OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
GLP compliance:
yes
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): Methyl dodecanoate
- CAS-No. of test material (as cited in study report): 111-82-0
- Purity: 99.2 %
- Physical state: colorless liquid
- Lot/batch No.: GD01
- Stability under test conditions: verified
- Storage condition of test material: sealed at room temperature

Test animals

Species:
rat
Strain:
other: Sprague-Dawley(Crj:CD(SD)
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories Japan, Inc., Atsugi, Japan
- Age at study initiation: 10 weeks
- Weight at study initiation: males: 354 - 386 g, femalrs: 216 - 241 g
- Housing: stainless steel cage
- Diet (e.g. ad libitum): NMF from Oriental Yeast Co., Ltd
- Water (e.g. ad libitum): tap water
- Acclimation period: 15 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 24 ± 2 °C
- Humidity (%): 55 ± 10%
- Air changes (per hr): 15 times/hour
- Photoperiod (hrs dark / hrs light): 12/12 (light intensity 150 - 300 lux)

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
corn oil
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:
test substance was dsolved in corn oil. Dosing solutions ware prepared once or more a week, kept under seal, cool and dark until use and used within 7 days after preparation. 5 (w/v)% was confirmed to be stable for at least 8 days under cool and dark condition.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Analysis of the concentration was conducted using a sample by random-choice from each batch. Since 98.6 - 104% was shown as a result, it was confirmed that given amount of dodecanoic acid methyl ester was included.
Details on mating procedure:
- Impregnation procedure: cohoused
- If cohoused:
- M/F ratio per cage: 1/1
- Length of cohabitation: max. 2 weeks
- Further matings after two unsuccessful attempts: no
- Proof of pregnancy: vaginal plug and sperm in vaginal smear referred to as day 0 of pregnancy
- Any other deviations from standard protocol: no
Duration of treatment / exposure:
Females: 14 days before mating until day 3 of lactation (41 - 55 days)
Males: 45 days
Frequency of treatment:
Daily
Duration of test:
Females: 41 - 55 days
Males: 45 days
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 250, 500 and 1000 mg/kg bw/day
Basis:
actual ingested
No. of animals per sex per dose:
12
Control animals:
yes, concurrent vehicle
Details on study design:
- The animals were mated.
- Terminal kill was on day 45 for males and on day 4 of lactation for females.
- Dose selection rationale: A preliminary test was performed to determin dose. Dose group were 0, 250, 500, 750 and 1000 mg / kg for 14 consecutive days in males and females, and the general condition showed no effect relevant to test substance, deaths were also not observed. No change were observed in weight, food consumption, autopsy findings, organ weights, blood chemistry test and hematology test.

Examinations

Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: daily

BODY WEIGHT: Yes
- Time schedule for examinations: days 1, 8 and 15 before mating, on days 0, 7, 14 and 21 of gestation and on days 0 and 4 of Lactation

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: No
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: No
- Time schedule: days 1-8, 8-15 before mating, days 0-7, 7-14 and 14-21 of gestation and during days 0-4 of lactation

FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: No

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 4
- Organs examined: Thymus, Liver, Kidneys, ovaries, lung

ORGAN WEIGHTS: Yes, absolute and relative weights
- How many animals: 10- 12 animals per dose
- Organs: Thymus, Liver, Kidneys, ovaries, lung
Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: No
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: No data
- Number of late resorptions: No data
Fetal examinations:
See any other information on results including tables for more detail.
Statistics:
Barlett test, One-way ANOVA, Kruskal-Wallis test, Dunnett test, Scheffe test, chi-square test
Indices:
copulation index, fertility index, gestation index, implantation index, delivery index

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:
Maternal toxic effects:no effects

Effect levels (maternal animals)

Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day (actual dose received)
Based on:
test mat.
Basis for effect level:
other: developmental toxicity

Results (fetuses)

Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:no effects

Details on embryotoxic / teratogenic effects:
No effects attributable to the test substance were revealed in terms of the number of pups born, number of live pups on Day 0 to 4 of lactation, number of dead pups, live birth index, sex ratio, viability index and body weights of live pups of both sexes in any treated group.

Fetal abnormalities

Abnormalities:
not specified

Overall developmental toxicity

Developmental effects observed:
not specified

Any other information on results incl. tables

Table 1. External observations on live pups (F1) from rats.

Dose level (mg/kg)

0

250

500

100

No. of litters

12

10

12

12

No. of live pups examined

159

144

152

163

No.of live pups with external anomalies (%, Mean ±S.D.)

3

5.2±14.3

1

0.6±1.9

1

0.6±1.9

0

-

Type and incidence of external anomalies (%)1

 

 

 

 

Hypodermic heorrhage

2 (1.3)

0 (0)

0 (0)

0 (0)

Imperforate anus

1 (0.6)

0 (0)

0 (0)

0 (0)

Short tail

0 (0)

0 (0)

1 (0.7)

0 (0)

Rudiment tail

1 90.6)

0 (0)

0 (0)

0 (0)

Nanooffspring

0 (0)

1 (0.7)

0 (0)

0 (0)

1(No. Of live pups with external anomalies/ no. Of live pups examined) x 100

 

Table 2. Body weight change of pups (F1) from rats.

 

Dose level (mg/kg)

0

250

500

1000

No. Of litters

12

Mean ±S.D (N)

10

Mean ±S.D (N)

12

Mean ±S.D (N)

12

Mean ±S.D (N)

Male

 

 

 

 

Days after birth: 0

6.1±0.6 (12)

6.2±0.5 (10)

6.7±0.7 (12)

6.5±0.6 (12)

Days after birth: 4

8.8±1.4 (10)

7.9±1.4 (10)

9.4±1.4 (12)

9.2±1.3 (12)

Female

 

 

 

 

Days after birth: 0

5.8±0.6 (12)

5.8±0.6 (10)

6.2±0.5 (11)

6.1±0.6 (12)

Days after birth: 4

8.5±1.3 (10)

7.6±1.3 (10)

8.8±1.2 (11)

8.8±1.3 (12)

Applicant's summary and conclusion

Conclusions:
In the Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test an oral NOAEL of 1000 mg/kg bw/day was found for male and female rats.