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Toxicological information

Developmental toxicity / teratogenicity

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Administrative data

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2016
Report date:
2017

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
1,4-diazabicyclooctane
EC Number:
205-999-9
EC Name:
1,4-diazabicyclooctane
Cas Number:
280-57-9
Molecular formula:
C6H12N2
IUPAC Name:
1,4-diazabicyclooctane
Details on test material:
- Name of test material (as cited in study report): 1,4 - diazabicyclooctane- Common name: TEDA
Specific details on test material used for the study:
Test item: TEDA (1,4-Diazabicyclo[2.2.2]octane
Supplier: Chemical Marketing Concepts
200 Pickett District Road
New Milford, Connecticut 06766
Description: White crystalline solid
Storage conditions: Cool (8 to 15°C from receipt to GD 8 Set 1; GD 6 Set 2; 8 to
25°C thereafter)
Lot number: 2090462
Purity: 99.97%
Expiration date: 10 January 2018

Test animals

Species:
rat
Strain:
Crj: CD(SD)
Details on test animals or test system and environmental conditions:
Animal model Albino Rats (Outbred) VAF/Plus
CD (Sprague-Dawley derived) [Crl:CD (SD)BR]
Supplier Charles River Laboratories
Raleigh, North Carolina 27610
Number of animals
received/placed on test
80 time-mated females
The female rats selected for breeding were nulliparous and
previously virgin and not mated with male siblings.
Age of the animals at
receipt
Approximately 10 to 12 weeks on GD 0, where GD 0 was the
day of detection of a copulatory plug in situ and/or sperm in a
vaginal smear.

Currently acceptable practices of good animal husbandry were followed

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
water
Details on exposure:
Will be provided when final study report is available
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Analysis of preliminary mixes confirmed that the preparation procedure used for this study
produced homogeneous mixtures. Analyses conducted during the exposure period confirmed
that dose formulations of appropriate concentration were administered.
Duration of treatment / exposure:
From GD 6 to 19, inclusive, where GD 0 is the day of detection of mating (copulatory plug in situ and/or sperm in a vaginal smear).
Frequency of treatment:
The test and control (vehicle) items were administered once daily, 7 days per week, from GD 6 to 19, inclusive, where GD 0
is the day of detection of mating (copulatory plug in situ and/or sperm in a vaginal smear).
Duration of test:
All surviving animals were euthanized on GD 20
Doses / concentrationsopen allclose all
Dose / conc.:
100 mg/kg bw/day (nominal)
Dose / conc.:
300 mg/kg bw/day (nominal)
Dose / conc.:
1 000 mg/kg bw/day (nominal)
No. of animals per sex per dose:
20 femaled per group
Control animals:
yes

Examinations

Maternal examinations:
- clinical signs
- body weight
- food consumtions
- clinical chemistry
- macroscopic examination
- organ weights
- histopathology

Clinical chemistry
Aspartate aminotransferase (AST) (Kinetic - Modified Bergmeyer)
Alanine aminotransferase (ALT) (Kinetic - Modified Bergmeyer)
Alkaline phosphatase (ALKP) (Kinetic – Tietz AMP Buffer)
Blood urea nitrogen (BUN) (Enzymatic – Roch-Ramek with Urease)
Creatinine (CREAT) (Jaffe Picric Acid in Alkaline Medium)
Glucose (GLU) (Glucose Hexokinase II Method)
Cholesterol (CHOL) (Enzymatic esterase/oxidase – Trinder Endpoint)
Triglycerides (TRIG) (Fossati Three Step Enzymatic – Trinder Endpoint)
Total protein (TP) (Biuret Technique)
Albumin (ALB) (Bromocresol Green Method)
Total bilirubin (TBILI) (Oxidation with Vandate)
Sodium (NA+) (Ion Selective Electrode)
Potassium (K+) (Ion Selective Electrode)
Chloride (Cl-) (Ion Selective Electrode)
Calcium (Ca++) (Michaylova & Ilkova, Arsenazo III)
Inorganic phosphorus (PHOS) (Phosphomolybdate – UV Method)
Fetal examinations:
- External Examinations
- Soft Tissue (Visceral) Examinations
- Skeletal Examinations
Statistics:
Unrounded individual animal data were used to calculate the reported mean and standard deviation values. Therefore, use of the reported individual values to reproduce means, standard deviations and/or to perform any subsequent calculations may produce minor discrepancies between the calculated values and those presented in this report. Group means and standard deviations for calculated data points (i.e. body weight change) were derived from individual animal values.

The following data types were analyzed at each timepoint separately:
maternal body weight
maternal interval body weight change
food consumption
fetal weights per litter
placental weights per litter
litter size
count of corpora lutea
count of implantation sites
percent pre-implantation loss
percent post-implantation loss (resorptions and early/fetal deaths)
sex ratio per litter

Results and discussion

Results: maternal animals

General toxicity (maternal animals)

Clinical signs:
no effects observed
Description (incidence and severity):
There were no test item-related clinical observations during the study.
Dermal irritation (if dermal study):
not examined
Mortality:
mortality observed, non-treatment-related
Description (incidence):
Two unscheduled deaths occurred in the 1000 mg/kg/day group. The cause of death and relationship of mortality to the test item could not be determined in either animal. Animal
No. 4564 was found dead on GD 13 and had no ante mortem clinical findings or macroscopic abnormalities at necropsy. Animal No. 4565 was found dead on GD 18. It exhibited moist rales
on GD’s 10 and 11 and had a moderately enlarged liver at necropsy which was not examined microscopically.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
The 100 and 300 mg/kg/day groups had gestation body weight and body weight gain values which were comparable to control values.
There were test item-related effects on gestation body weights and body weight gains at 1000 mg/kg/day. Statistically significant, test item-related decreases in absolute body weights and body weight loss/decreased body weight gain were noted in females at 1000 mg/kg/day throughout the dosing and one-day recovery periods. Despite the slight decreased absolute body weight pretest (GD 3 and 6), decreases in absolute body weight ranged from -10% to -14% as compared with mean control values, with the greatest decrease (loss) from GDs 6 to 9. Weights increased slightly
thereafter, but body weight gains were still reduced by 34% when compared with mean control values for the entire study (GDs 6 to 20).
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
The 100 and 300 mg/kg/day groups had food consumption values which were comparable to control values.
Statistically significant, test item-related decreases in food consumption were observed in females at 1000 mg/kg/day, occurring throughout the dosing and one-day recovery periods. The greatest decreases occurred from GDs 6 to 9 (-55% as compared to mean control values) and increased slightly thereafter, but were still reduced by 32% when compared with mean control values for the entire study (GDs 6 to 20).
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
effects observed, treatment-related
Description (incidence and severity):
The 100 and 300 mg/kg/day exposure groups had clinical chemistry values which were comparable to control values.
Test item-related clinical chemistry changes at 1000 mg/kg/day included increases in alkaline phosphatase activity (1.33× control) and decreases in total protein (0.87× control), albumin
(0.86× control), and globulins (0.88× control). These changes are considered non-adverse due to their relatively small magnitude and are likely due to decreases in food consumption identified at
1000 mg/kg/day.
Urinalysis findings:
not examined
Behaviour (functional findings):
no effects observed
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Description (incidence and severity):
There were no test item-related organ weight changes in the liver or kidneys. The absolute weights of the liver and kidneys were reduced in the 1000 mg/kg/day group, however the relative organ weights (as a percentage of body weight) of the liver and kidneys were comparable with the control group values. These changes are considered non-adverse due to their relatively small magnitude and are likely due to decreases in body weight and food consumption identified at 1000 mg/kg/day.
Gross pathological findings:
no effects observed
Description (incidence and severity):
Macroscopic
There were no test item-related macroscopic findings.
All macroscopic findings occurred sporadically or at similar incidence and severity in the control and test item-treated groups and were considered incidental and due to biological variability.
Microscopic
TEDA-related microscopic findings were present in the kidneys at 1000 mg/kg/day and urinary bladder at ≥300 mg/kg/day.
Kidneys
Minimal to slight acute/subacute inflammation was present within the renal pelvis or medullary interstitium of the kidneys in 2 of 18 (terminal necropsy) animals at 1000 mg/kg/day. Both
animals had minimal to slight urothelial hyperplasia and acute hemorrhage (minimal to slight) within the renal pelvis.
Urinary Bladder
Minimal to slight urothelial hyperplasia was present within the urinary bladder of 1 animal each at a 300 and 1000 mg/kg/day and exhibited a dose related increase in severity. Hyperplasia in
the 300 mg/kg/day animal was associated with slight acute/subacute mucosal inflammation. Urothelial hyperplasia in the 1000 mg/kg/day animal was not associated with inflammation
within the urinary bladder, but occurred in an animal (Animal No. 4578) with inflammation and urothelial hyperplasia in the renal pelvis. Inflammatory and/or proliferative lesions in the
kidneys and/or urinary bladder have been described rats given TEDA at 1000 mg/kg/day and the findings were considered to be test item-related (Air Products and Chemicals Inc., 2013).
All other microscopic findings occurred sporadically or at a similar incidence and severity in control and test item-treated groups and were considered incidental and due to biological
variability.
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
not examined
Histopathological findings: neoplastic:
not examined
Other effects:
not examined

Maternal developmental toxicity

Number of abortions:
no effects observed
Pre- and post-implantation loss:
no effects observed
Total litter losses by resorption:
no effects observed
Early or late resorptions:
no effects observed
Dead fetuses:
no effects observed
Changes in pregnancy duration:
no effects observed
Description (incidence and severity):
Migrated Data from removed field(s)
Field "Effects on pregnancy duration" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsMaternalAnimals.MaternalDevelopmentalToxicity.EffectsOnPregnancyDuration): no effects observed
Changes in number of pregnant:
no effects observed
Details on maternal toxic effects:
There were no test item-related effects on pregnancy or cesarean section parameters. There were 19, 20, 20 and 20 pregnant females in the 0, 100, 300 and 1000 mg/kg/day groups, respectively.
Control group female Animal No. 1516 was not pregnant. All pregnant females had viable fetuses. Cesarean section parameters (number of corpora lutea, implantations, resorptions, dead fetuses, live fetuses, sex ratio, percent pre-implantation loss and percent postimplantation loss) were comparable to mean control values.

Effect levels (maternal animals)

open allclose all
Dose descriptor:
NOAEL
Effect level:
> 1 000 mg/kg bw/day (nominal)
Based on:
test mat.
Basis for effect level:
changes in number of pregnant
changes in pregnancy duration
dead fetuses
early or late resorptions
effects on pregnancy duration
maternal abnormalities
necropsy findings
number of abortions
pre and post implantation loss
total litter losses by resorption
Dose descriptor:
NOAEL
Effect level:
> 100 mg/kg bw/day (nominal)
Based on:
test mat.
Basis for effect level:
body weight and weight gain
food consumption and compound intake
gross pathology

Results (fetuses)

Fetal body weight changes:
no effects observed
Description (incidence and severity):
There were no test item effects on gravid uterine, placental or fetal weights. Adjusted body weights on GD 20 and the adjusted body weight changes on GD 6 to 20 were
reduced in the 1000 mg/kg/day females; however the gravid uterine weight in this group was comparable with the control group values and therefore this effect was considered related to the
decreased body weight gain during the study.
Any changes in placental or fetal weights were small in magnitude, not statistically significant, and/or were generally within the concurrent control range.
Migrated Data from removed field(s)
Field "Fetal/pup body weight changes" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.FetalPupBodyWeightChanges): no effects observed
Reduction in number of live offspring:
no effects observed
Changes in sex ratio:
no effects observed
Changes in litter size and weights:
no effects observed
Changes in postnatal survival:
not examined
External malformations:
no effects observed
Description (incidence and severity):
There were no test item-related external findings.
Any findings, including all variations and malformations (i.e. cleft palate), were not present in a dose-related manner, were low in incidence, and are common in this strain of laboratory animal
and/or were generally within current published HCD.
Skeletal malformations:
no effects observed
Description (incidence and severity):
There were no test item-related skeletal findings.
Any findings, including all variations and malformations (i.e. misshapen/fused cervical vertebral arches, partially-fused exoccipital, lumbar vertebral centrum fused to arch, fused ribs, and
cleft/split sternebra) were not considered to be test item-related as they occurred in low incidence per litter and group, were not present in a dose-related manner or were present in the control
group, common in this strain of laboratory animal and/or were generally within current published HCD.
Visceral malformations:
no effects observed
Description (incidence and severity):
There were no test item-related visceral findings.
Any findings, including all variations and malformations (i.e. absent bladder, cleft palate, heart malrotated, membranous intraventricular septal defect, lungs thickened/unexpanded, aortic arch
interrupted, and right-sided aortic arch) were not considered to be test item-related as they occurred in low incidence per litter and group, were not present in a dose-related manner or were
present in the control group, common in this strain of laboratory animal and/or were generally within current published HCD.
Other effects:
not examined

Effect levels (fetuses)

Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
reduction in number of live offspring
changes in sex ratio
fetal/pup body weight changes
changes in litter size and weights
external malformations
skeletal malformations
visceral malformations

Overall developmental toxicity

Developmental effects observed:
no
Treatment related:
no

Applicant's summary and conclusion

Conclusions:
Prenatal Developmental Toxicity Study via Oral Gavage in Rats was performed with 1,4-diazabicyclooctane. Based on results, the maternal systemic No Observed Adverse Effect Level (NOAEL) was considered to be 100 mg/kg/day due to the microscopic findings of inflammation and hyperplasia in the kidney and/or urinary bladder at ≥300 mg/kg/day, and body weight loss and decreased food consumption at 1000 mg/kg/day. The maternal reproductive and embryo-fetal NOAELs were both determined to be 1000 mg/kg/day (the highest dose administered).
Executive summary:

Prenatal Developmental Toxicity Study via Oral Gavage in Rats was performed with 1,4-diazabicyclooctane. Dose levels used were 100, 300 and 1 000

mg/kg/day.

Administration of TEDA at 300 mg/kg/day was associated with minimal to slight acute/subacute inflammation and urothelial hyperplasia in the kidneys and/or urinary bladder. Inflammation and hyperplasia were considered to be adverse because they could potentially compromise organ function or the ability to respond to additional environmental challenge.

Statistically significant, test item-related decreases in absolute body weights, body weight loss/decreased body weight gain, and decreased food consumption were noted in females at 1000 mg/kg/day throughout the dosing and one-day recovery periods. Decreases in food consumption likely contributed to the test item-related, non-adverse increases in alkaline phosphatase and decreases in total protein, albumin, and globulins at 1000 mg/kg/day.

Based on these data, the maternal systemic No Observed Adverse Effect Level (NOAEL) was considered to be 100 mg/kg/day due to the microscopic findings of inflammation and hyperplasia in the kidney and/or urinary bladder at 300 mg/kg/day, and body weight loss and decreased food consumption at 1000 mg/kg/day. The maternal reproductive and embryo-fetal NOAELs were both determined to be 1000 mg/kg/day (the highest dose administered).