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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:
key study
Study period:
not stated
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Read across from dodecanol. Comparable to guideline study (draft guideline) with acceptable restrictions.
Cross-reference
Reason / purpose:
reference to same study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1992

Materials and methods

Test guideline
Qualifier:
no guideline available
Principles of method if other than guideline:
Draft OECD 422 Combined Repeat dose and Reproductive/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): 1-Dodecanol
- Substance type: no data
- Physical state: no data
- Analytical purity: 99%
- Impurities (identity and concentrations): no data
- Composition of test material, percentage of components: no data
- Isomers composition: no data
- Purity test date: no data
- Lot/batch No.: no data
- Expiration date of the lot/batch: no data
- Stability under test conditions: no data
- Storage condition of test material: no data

Test animals

Species:
rat
Strain:
Wistar
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Moellegard breeding centre
- Age at study initiation: F 8 weeks, M 7 weeks
- Weight at study initiation: no data
- Fasting period before study: no data
- Housing: 2/cage, steel wire cages type 3 (for males and for females up to day 20 of gestation); macrolon cages type 3 (for females from day 20 of gestation)
- Diet (e.g. ad libitum): IT chow 101, presumably ad libitum
- Water (e.g. ad libitum): acidified tapwater, ad libitum
- Acclimation period: 8 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 +- 2
- Humidity (%): 55 +- 10
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): 12 / 12

IN-LIFE DATES: no data

Administration / exposure

Route of administration:
oral: feed
Vehicle:
unchanged (no vehicle)
Details on exposure:
DIET PREPARATION
- Rate of preparation of diet (frequency): no data
- Mixing appropriate amounts with (Type of food): IT chow 101
- Storage temperature of food: no data
- Preparation procedure: Diet preparation involved first mixing an aqueous dodecanol solution with the barley component, which varied for each dose level. The other components of the diet were then added.
Analytical verification of doses or concentrations:
no
Details on mating procedure:
- Impregnation procedure: cohoused with treated males
- If cohoused:
- M/F ratio per cage: 1:1
- Length of cohabitation: 14 days
- After 14 days of unsuccessful pairing replacement of first treated male by another treated male for up to 8 days
- Further matings after two unsuccessful attempts: no
- Verification of same strain and source of both sexes: yes
- Proof of pregnancy: vaginal plug recorded during the morning referred to as day 1 of pregnancy; vaginal plug recorded at lunch time or during the afternoon referred to as day 0 of pregnancy
- Any other deviations from standard protocol: none
Duration of treatment / exposure:
Females: up to 54 days (premating, mating and gestation until post natal day 5)
Males: 41-44 days (including 14 premating)
Frequency of treatment:
continuous in diet
Duration of test:
pups examined on postnatal day 5, following continuous treatment of male and female parents from 14 days prior to mating
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 1500, 7500 & 30,000 ppm (approx 100, 500, 2000 mg/kg bw/day)
Basis:
nominal in diet
No. of animals per sex per dose:
12 male and 12 female parental animals per dose
Control animals:
yes, plain diet
Details on study design:
- Dose selection rationale: preliminary test apparently via a dermal route
- Rationale for animal assignment (if not random): 2 days prior to the start of dosing, animals randomised into four groups with same mean body weight

Examinations

Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily
- Cage side observations included: mortality

DETAILED CLINICAL OBSERVATIONS: No data

BODY WEIGHT: Yes
- Time schedule for examinations: females - premating once per week

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption in g body weight gain/kg food per week calculated from the consumption and body weight gain data: Yes

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on postnatal day (parental females): 5
- Organs examined (parental females): organ weights of liver, kidneys, thymus; organs fixed in formalin - liver, kidneys, adrenals, brain, heart, spleen, ovaries, thymus, other organs with observed pathological changes; histopathology - control and top dose group, all fixed organs except thymus
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
- Number of late resorptions: No
- Other:
- Total number of resorptions: Yes
Fetal examinations:
- On postnatal day 5, the pups were weighed and examined macroscopically for external malformations then sexed and examined for internal malformations, including:
- External examinations: Yes: all per litter
- Head examinations: Yes: all per litter
- Soft tissue examinations: No
- Skeletal examinations: No
Statistics:
Using the SAS-stat program; analysis of variance; all statistically significant findings further evaluated by Dunnett's t-test; chi-squared test for pregancy rate
Indices:
numbers of corpora lutea, implantations, resorptions and pups at birth and on days 4 and 5
Historical control data:
no data

Results and discussion

Results: maternal animals

Maternal developmental toxicity

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

Details on maternal toxic effects:
- no mortality
- no statistically significant effects on body weight
- no statistically significant effects on organ weights or pathology

Effect levels (maternal animals)

open allclose all
Dose descriptor:
NOAEL
Effect level:
2 000 mg/kg bw/day (nominal)
Basis for effect level:
other: maternal toxicity
Dose descriptor:
NOAEL
Effect level:
2 000 mg/kg bw/day (nominal)
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 statistically significant effects on numbers of corpora lutea, implantations, resorptions or pups at birth; no statistically significant abnormalities in pups (see table 1)

Fetal abnormalities

Abnormalities:
not specified

Overall developmental toxicity

Developmental effects observed:
not specified

Any other information on results incl. tables

Table 1: Developmental toxicity data

Observation

Dose (mg/kg bw/day) (nominal via diet)

0

100

500

2000

Pregnancy rate (%)

92

83

83

75

Number of litters

12

11

10

9

Mean (±SD) number of corpora lutea

14±1.7

14±0.9

14±1.5

14±1.6

Mean (±SD) number of implantations

13±2.4

14±1.4

14±1.9

14±1.1

Total number of resorptions

0

0

0

0

Total number of pups (day 1)

159

146

132

120

Mean number of pups per litter (day 1)b

13.25

13.27

13.20

13.33

Mean (±SD) litter weight (day 1) (g)

75±12.9

75±7.3

71±8.9

77±5.5

Total number of pups (day 4)

156

143a

125

118

Total number of pup deaths (days 1-4)

3

3

7

2

Mean (±SD) litter weight (day 4) (g)

106±14.9

107±9.9

101±12.9

104±9.8

Mean (±SD) litter weight gain (day 4) (g)

31±8.5

32±4.5

30±6.3

27±7.8

Total number of pups (day 5)

number of males

number of females

156

70

86

144a

55

89

125

61

63

118

62

56

Sex Ratio (% Male)b

45

38

49

53

Mean (±SD) male pup body weight (day 5) (g)

9±0.7

9±0.5

9±1.2

9±1.1

Mean (±SD) female pup body weight (day 5) (g)

10±0.9

10±0.7

10±1.2

9±1.1

Postmortem findings - pups (day 5)

hydronephrosis (1 female), unilateral dil. renal pelvis (1 male), yellow spots on liver (1 male)

bilateral dil. renal pelvis (2 females), unilateral dil. renal pelvis (1 female)

 

aplasia testisuni. (1 male)


aAs reported in study report

bCalculated for this table

Applicant's summary and conclusion

Conclusions:
Read across from dodecanol. In a reliable study conducted to the draft OECD guideline 422, the NOAEL for maternal and developmental toxicity was 2000 mg/kg bw/day, the highest dose tested. The study was performed in compliance with GLP.