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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:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Study conducted following OECD guideline 421 and GLP principles. However, only limited data are available for review (based on SIDS).
Cross-reference
Reason / purpose:
reference to same study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2005
Report Date:
2005

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
other: OECD Guideline 421 (Reproduction / Developmental Toxicity Screening Test)
GLP compliance:
yes
Limit test:
yes

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): TMAH
- Analytical purity: >99.9%
- Lot No.: 40914

Test animals

Species:
rat
Strain:
Sprague-Dawley
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: not reported
- Age at study initiation: (P) 9 wks; (F1) 4 days
No further details provided.

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
water
Details on mating procedure:
One male to one female mating was used. A female rat was placed together with a male rat until copulation occurred. When no copulation was observed, the female animal was mated with another male animal of the same dose group for additional 14 days.
Duration of treatment / exposure:
Male: 14 days before mating to the day before scheduled death through mating (total 32 days).
Female: 14 days before mating to 3 days after delivery through mating and gestation periods.
Frequency of treatment:
Daily
Duration of test:
Females and pups were sacrificed at 4 days after birth.
Doses / concentrationsopen allclose all
Dose / conc.:
1 mg/kg bw/day
Dose / conc.:
5 mg/kg bw/day
Dose / conc.:
20 mg/kg bw/day
No. of animals per sex per dose:
10
Control animals:
yes, concurrent vehicle

Examinations

Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes

DETAILED CLINICAL OBSERVATIONS: Yes, twice daily

BODY WEIGHT: Yes, females were weighed on Day 1, 3 and 7 of dosing, weekly thereafter until delivery, and post natal day 0 and 4.
Ovaries and uterine content:
The ovaries and uterine content was examined after termination: No
Fetal examinations:
External examinations and gross pathology: Yes, all per litter
Statistics:
Statistical analysis : Bartlett's test, one-way analysis of variance, Dunnett's test, Kruskal-wallis test, chi-square test.
Indices:
Copulation index, fertility indices of males and females, implantation index, gestation length and delivery index were calculated.

Results and discussion

Results: maternal animals

General toxicity (maternal animals)

Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
Salivation was observed on the 4th day of administration and later in male and female rats at 5 mg/kg bw/day and higher. Salivation was considered to be due to strong alkaline property of TMAH, but not due to toxic effects of TMAH. In the female animals at 20 mg/kg bw/day, a decrease in locomotor activity, incomplete eyelid opening or eyelid closure, and loss of hair were observed on GD 21 and thereafter.
Mortality:
mortality observed, treatment-related
Description (incidence):
One female rat at 20 mg/kg bw/day died on GD 22 and another one on GD 23 during parturition.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Significant decrease in body weight on days 0 and 4 after parturition (PND 0 and 4) were observed in females at 20 mg/kg bw/day.
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
A significant decrease in food consumption was observed at 20 mg/kg bw/day on day 3 in male animals and on gestation day (GD) 20 in female animals.
Organ weight findings including organ / body weight ratios:
not specified
Gross pathological findings:
not specified
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
not specified
Histopathological findings: neoplastic:
not specified

Maternal developmental toxicity

Number of abortions:
not examined
Pre- and post-implantation loss:
no effects observed
Total litter losses by resorption:
no effects observed
Early or late resorptions:
not examined
Dead fetuses:
effects observed, non-treatment-related
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

Effect levels (maternal animals)

open allclose all
Key result
Dose descriptor:
NOAEL
Effect level:
5 mg/kg bw/day (actual dose received)
Based on:
test mat.
Basis for effect level:
mortality
body weight and weight gain
Key result
Dose descriptor:
NOAEL
Effect level:
>= 20 mg/kg bw/day (actual dose received)
Based on:
test mat.
Basis for effect level:
other: developmental toxicity

Results (fetuses)

Fetal body weight changes:
not specified
Description (incidence and severity):
Migrated Data from removed field(s)
Field "Fetal/pup body weight changes" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.FetalPupBodyWeightChanges): not specified
Reduction in number of live offspring:
effects observed, treatment-related
Description (incidence and severity):
The number of offspring per dam at birth was 13.2, 14, 13.5 and 12.3 for 0, 1, 5 and 20 mg/kg bw respectively.
Changes in sex ratio:
no effects observed
Changes in litter size and weights:
no effects observed
Changes in postnatal survival:
effects observed, treatment-related
Description (incidence and severity):
The percentage of live newborns at day 4 after birth was 97.7%, 98.4%, 100% and 85.4% for 0, 1, 5 and 20 mg/kg bw respectively.
Details on embryotoxic / teratogenic effects:
Details on embryotoxic / teratogenic effects:
At 20 mg/kg bw, a reduced number of offspring per dam at birth and increased post-natal mortality was observed. This can be related to the mortality of one mother during parturition and on reduced body weight of mothers in the high dose group after birth.

Effect levels (fetuses)

Key result
Dose descriptor:
NOAEL
Effect level:
20 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No effect seen on fetuses seen at highest dose tested.
Remarks on result:
other: Effects seen at 20 mg/kg bw/ day were considered to be related to maternal toxicity.

Overall developmental toxicity

Key result
Developmental effects observed:
no

Applicant's summary and conclusion

Conclusions:
In a reproductive/developmental toxicity screening test in rats according to OECD guideline 421 and GLP principles, the NOAEL for parents was found to be 5 mg/kg bw/d and the developmental NOAEL was found to be >= 20mg/kg bw/d.
Executive summary:

A reproductive/developmental toxicity screening test was performed with rats according to OECD guideline 421 and GLP principles. TMAH was dosed by oral gavage at 0, 1, 5 and 20 mg/kg bw/d. A significant decrease in food consumption was observed at 20 mg/kg bw/day on Day 3 in male animals and on gestation day (GD) 20 in female animals. In the female animals at 20 mg/kg bw/day, a decrease in locomotor activity, incomplete eyelid opening or eyelid closure, and loss of hair were observed on GD 21 and thereafter, and a significant decrease in body weight on days 0 and 4 after parturition (PND 0 and 4). One female rat at 20 mg/kg bw/day died on GD 22 and another one on GD 23 during parturition.Tetramethylammonium hydroxide showed no effect on any of the following parental reproductive parameters; days required for successful copulation, copulation index, fertility indices of males and females, implantation index, gestation length and delivery index.There was no effect of tetramethylammonium hydroxide on either the numbers of total newborns, sex ratio. No compound-related abnormality was observed either in external features. However, the percentage of live newborns at birth was 97.7%, 98.4%, 100% and 85.4% for 0, 1, 5 and 20 mg/kg bw/d respectively.

Based on these observations, the NOAEL for parental toxicity was found to be 5 mg/kg bw/day in rats. No effects on development were seen at the highest test concentration, therefore the developmental NOAEL was considered to be >= 20 mg/kg bw/d.