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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.
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 421OECD 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 / concentrations
Remarks:
Doses / Concentrations:
0, 1, 5 and 20 mg/kg bw
Basis:
actual ingested
No. of animals per sex per dose:
10
Control animals:
yes

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.

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:
Maternal toxic effects:yes. Remark: Two females died, clinical effects were seen and decrease in weight gain.

Details on maternal toxic effects:
One female rat at 20 mg/kg bw/day died on GD 22 and another one on GD 23 during parturition.

CLINICAL SIGNS AND MORTALITY (PARENTAL ANIMALS)
Salivation was observed on the 4th day of administration and later at 5 mg/kg bw/day and higher. 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
BODY WEIGHT AND FOOD CONSUMPTION (PARENTAL ANIMALS)
Significant decrease in food consumption was observed at 20 mg/kg bw/day on gestation day (GD) 20 in female animals.
.

Effect levels (maternal animals)

open allclose all
Dose descriptor:
NOAEL
Effect level:
5 mg/kg bw/day (actual dose received)
Based on:
test mat.
Basis for effect level:
other: maternal toxicity
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)

Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:yes. Remark: Lowered number of live newborns at birth

Details on embryotoxic / teratogenic effects:
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.
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 respectively. The number of offspring per dam was 13.2, 14, 13.5 and 12.3 for 0, 1, 5 and 20 mg/kg bw respectively.

Fetal abnormalities

Abnormalities:
not specified

Overall developmental toxicity

Developmental effects observed:
not specified

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 and the developmental NOAEL was found to be >= 20mg/kg bw.
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.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 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 >= 20mg/kg bw.