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Diss Factsheets

Toxicological information

Developmental toxicity / teratogenicity

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Administrative data

Endpoint:
developmental toxicity
Remarks:
in rodents: rats
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: GLP status not known, near guideline study, published in peer reviewed literature, minor restrictions in design and/or reporting but otherwise adequate for assessment.
Justification for type of information:
The purpose of this assessment is the presentation of a cohesive rationale for using data from proximate metabolites in the metabolic pathway for 3-methoxybutanol (i.e.3-methoxy acetate (Butoxyl) and 1,3-butanediol) to fill data gaps on sensitization, in vivo genotoxicity, repeated dose toxicity, reproductive and developmenatl toxicity for 3-methoxybutanol as required for REACH registration.
Cross-reference
Reason / purpose for cross-reference:
reference to same study

Data source

Reference
Reference Type:
publication
Title:
Unnamed
Year:
1981

Materials and methods

Test guideline
Qualifier:
equivalent or similar to guideline
Guideline:
other: OECD Guideline 414 (Developmental Toxicity in rats)
Version / remarks:
OECD 414
Deviations:
yes
Remarks:
Basic design is FDA multigeneration with 2 matings per generation (5 generations) and additional phases including teratogenicity assessment of 3/4 of the dams from the F3B generation
Principles of method if other than guideline:
According the the US FDA operating protocols
GLP compliance:
not specified

Test material

Constituent 1
Chemical structure
Reference substance name:
Butane-1,3-diol
EC Number:
203-529-7
EC Name:
Butane-1,3-diol
Cas Number:
107-88-0
Molecular formula:
C4H10O2
IUPAC Name:
butane-1,3-diol
Details on test material:
- Name of test material (as cited in study report): 1,3-butanediol
- Supplied by: Celanese Chemical Company, New York, USA
- No further details
Specific details on test material used for the study:
Name: 1,3-butanediol
Manufacturer: Celanese Chemical Company
Detalles an test material: purity bot reported

Test animals

Species:
rat
Strain:
Wistar
Remarks:
FDRL-stock
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Age at study initiation: 14-15 weeks
- Housing: Individually except during mating
- Diet: Semi-purified diet ad libitum (20% casein, 8% refined corn oil, 4% salt mix, 1% vitamin mix, 33.5% corn starch, 33.5% dextrose)
- Water: tap water ad libitum

ENVIRONMENTAL CONDITIONS
- Temperature: 22±2°C
- Photoperiod: 12 hrs dark / 12 hrs light

Administration / exposure

Route of administration:
oral: feed
Vehicle:
other: diet (by replacing equal amounts of corn starch and dextrose with 1,3-butanediol)
Details on exposure:
DIET PREPARATION: Test diets were prepared by replacing equal amounts by weight of corn starch and dextrose with 1,3-butanediol.
Analytical verification of doses or concentrations:
not specified
Details on analytical verification of doses or concentrations:
not available
Details on mating procedure:
- M/F ratio per cage: 1:1
- Length of cohabitation: 7 days
- Proof of pregnancy: vaginal plug, referred to as day 0 of pregnancy
- After 7 days of unsuccessful pairing replacement of first male by another male with proven fertility.
- Further matings after two unsuccessful attempts: no
Duration of treatment / exposure:
F0 generation fed test diets for 4 weeks and then mated to produce F1A litters. One to two weeks after weaning, each F0 female was mated with a different male to produce the F1B litters. Pregnant F0 rats fed test diet throughout mating, gestation and lactation. After 11 weeks of feeding test diets, 25/sex/group from the F1A generation were selected and mated to produce F2 generation. On day 19 of pregnancy, 75% of the F2A dams in each group were given a caesarean section. The numbers of implantations, resorptions, viable and nonviable foetuses, gross abnormalities, weight and gender of foetuses were recorded. Of these F3B foetuses a third were used for soft tissue examination following Bouin’s fixation and the rest were used for skeletal examination following staining with alizarin red.
Frequency of treatment:
continuous (day 0-19 of gestation)
Duration of test:
dams killed on day 19 of gestation
Doses / concentrationsopen allclose all
Dose / conc.:
0 other: % of the diet by weight
Dose / conc.:
5 other: % of the diet by weight
Dose / conc.:
10 other: % of the diet by weight
Dose / conc.:
24 other: % of tthe diet by weight
No. of animals per sex per dose:
On day 19 of pregnancy, three quater of the F2A dams per group (0, 5, 10, 24% or 15, 15, 14, 14 number of pregnant females, respectively) were sacrificed and one third of F3B fetuses were examined
Control animals:
yes, concurrent vehicle

Examinations

Maternal examinations:
CLINICAL OBSERVATIONS: No data

BODY WEIGHT: No

FOOD CONSUMPTION: No

WATER CONSUMPTION: No

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 19
- Organs examined: Uterus

Ovaries and uterine content:
The uterine content was examined after termination: Yes
Examinations included:
- Mean number of viable pups per litter: Yes
- Mean number of non-viable pups per litter: Yes
- Gravid uterus weight: No
- Number of corpora lutea: No
- Number of implantations: Yes
- Number of resorptions: Yes
Fetal examinations:
- Mean foetal weight: Yes
- Sex: Yes
- External examinations: Yes: all per litter
- Soft tissue examinations: Yes: one third of each litter
- Skeletal examinations: Yes: two thirds of each litter
- Head examinations: No
Statistics:
chi-square test

Results and discussion

Results: maternal animals

General toxicity (maternal animals)

Clinical signs:
no effects observed
Description (incidence and severity):
no effects associated with the tst substance
Dermal irritation (if dermal study):
not examined
Description (incidence and severity):
Not applicable
Mortality:
no mortality observed
Description (incidence):
no effects observed with the test substance
Body weight and weight changes:
effects observed, non-treatment-related
Description (incidence and severity):
males bwg in all generations were slightly decreased but not statistically significantly different
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
no effects observed with the test substance
Food efficiency:
no effects observed
Description (incidence and severity):
no effects associated with the test substance
Water consumption and compound intake (if drinking water study):
no effects observed
Description (incidence and severity):
no effects observed with the test substance
Ophthalmological findings:
not specified
Description (incidence and severity):
not specified
Haematological findings:
no effects observed
Description (incidence and severity):
no effects observed with the test substance
Clinical biochemistry findings:
no effects observed
Description (incidence and severity):
no effects observed with the test substance
Urinalysis findings:
no effects observed
Description (incidence and severity):
no effects observed with the test substance
Behaviour (functional findings):
no effects observed
Description (incidence and severity):
no effects observed with the test substance
Immunological findings:
not specified
Description (incidence and severity):
not specified
Organ weight findings including organ / body weight ratios:
not specified
Description (incidence and severity):
not specified
Gross pathological findings:
no effects observed
Description (incidence and severity):
no effects observed with the test substance
Neuropathological findings:
not specified
Description (incidence and severity):
not specied
Histopathological findings: non-neoplastic:
not specified
Description (incidence and severity):
not specified
Histopathological findings: neoplastic:
not specified
Description (incidence and severity):
not speficed

Maternal developmental toxicity

Number of abortions:
no effects observed
Description (incidence and severity):
no effects observed with the test substance
Pre- and post-implantation loss:
no effects observed
Description (incidence and severity):
no effects observed with the test substance
Total litter losses by resorption:
no effects observed
Description (incidence and severity):
no effects observed with the test substance
Early or late resorptions:
no effects observed
Description (incidence and severity):
no effects observed with the test substance
Dead fetuses:
no effects observed
Description (incidence and severity):
no effects observed with the test substance
Changes in pregnancy duration:
no effects observed
Description (incidence and severity):
no effects observed with the test substance
Migrated Data from removed field(s)
Field "Effects on pregnancy duration" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsMaternalAnimals.MaternalDevelopmentalToxicity.EffectsOnPregnancyDuration): no effects observed
Field "Description (incidence and severity)" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsMaternalAnimals.MaternalDevelopmentalToxicity.DescriptionIncidenceAndSeverityEffectsOnPregnancyDuration): no effects observed with the test substance
Changes in number of pregnant:
no effects observed
Description (incidence and severity):
no effects observed with the test substance
Details on maternal toxic effects:
Maternal toxic effects:no effects observed with the test substance

Effect levels (maternal animals)

Key result
Dose descriptor:
NOEL
Effect level:
24 other: % of the diet by weight
Based on:
test mat.
Basis for effect level:
other: maternal toxicity
Remarks on result:
other:
Remarks:
effect level not specified

Results (fetuses)

Fetal body weight changes:
no effects observed
Description (incidence and severity):
no effects observed with the test substance
Migrated Data from removed field(s)
Field "Fetal/pup body weight changes" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.FetalPupBodyWeightChanges): no effects observed
Field "Description (incidence and severity)" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.DescriptionIncidenceAndSeverityFetalPupBodyWeightChanges): no effects observed with the test substance
Reduction in number of live offspring:
no effects observed
Description (incidence and severity):
no effects observed with the test substance
Changes in sex ratio:
no effects observed
Description (incidence and severity):
no effects observed with the test substance
Changes in litter size and weights:
no effects observed
Description (incidence and severity):
no effects observed with the test substance
Changes in postnatal survival:
not specified
Description (incidence and severity):
no specified
External malformations:
no effects observed
Description (incidence and severity):
no effects observed with the test substance
Skeletal malformations:
effects observed, treatment-related
Description (incidence and severity):
Skeletal tissue examination showed a statistically significant increase of incomplete ossification of sternebrae for the middle and high level fetuses (40 and 63%, respectively). Akso, missing sternebrae was statisticaly significant increase in the high dose group. Other abnormalities seen either in skeletal or soft tissue of the fetuses were not significantly different when compared to control.
Visceral malformations:
not specified
Description (incidence and severity):
not specified
Other effects:
effects observed, non-treatment-related
Description (incidence and severity):
no effects observed with the test substance
Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:yes

Details on embryotoxic / teratogenic effects:
No treatment-related effects on pup viability, numbers of implantation sites, resorption sites and mean foetal weights. There was a statistically significant increase in incomplete ossification of sternebrae at 10 and 24% dose levels (40 and 63% respectively compared to controls of 25%) plus stat sig increase of missing sternebrae at 24% dose level (36% compared to 8% for controls). No other treatment-related effects on skeletal or soft tissues.

Effect levels (fetuses)

Key result
Dose descriptor:
NOEL
Effect level:
5 other: % diet (by weight)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: teratogenicity

Fetal abnormalities

Key result
Abnormalities:
effects observed, treatment-related
Localisation:
skeletal: sternum
Description (incidence and severity):
"skeletal tissue examinaition revealed a statisitically significant increase of incomplete ossification of sternebrae for the middle and high level fetuses (40 and 63%, respectively) as compare with the control fetuses (25%)".

Overall developmental toxicity

Key result
Developmental effects observed:
yes
Lowest effective dose / conc.:
5 other: % of the diet by weight
Treatment related:
yes
Relation to maternal toxicity:
developmental effects in the absence of maternal toxicity effects
Dose response relationship:
yes
Relevant for humans:
no

Any other information on results incl. tables

Incidence of selected foetal skeletal abnormalities

 

Concentration of 1,3-butanediol (%)

0

5

10

24

Incomplete ossification of sternebrae

31/124

31/103

48/120*

65/103*

Bipatite strernebrae

1/124

1/103

0/120

3/103

Missing sternebrae

10/124

3/103

13/120

31/103*

a significantly different from control, p=0.025

 

Applicant's summary and conclusion

Conclusions:
Based on the data, the NOAEL for developmental toxicity is estimated to be 5% of 1,3-butanediol of the diet by weight over 5 consecutive generations is (approximately equivalent to 50000 mg/kg/day) and the NOAEL for maternal toxicity was not determined.
Executive summary:

In a 5-generation reproductive toxicity study also a teratogenicity evaluation was conducted with 1,3-butanediol. Animals were fed continuously to groups of 25 rats/sex/group in the diet at dose levels of 0 (control), 5, 10 or 24 % by weight. There were no definitive dose-related teratological findings in soft or skeletal tissue. Skeletal findings indicative of slightly delayed foetal growth were seen in the 10 and 24% groups (incomplete ossification of sternebrae at 10 and 24%, missing sternebrae at 24%. It is considered that the developmental delays (reduced ossification) are a direct result of altered nutrient supply and not a direct effect of the test substance) and because only limited foetotoxicity was seen at extremely high dose levels, 1,3 -butanediol is considered not to be a developmental toxicant.