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EC number: 200-880-8 | CAS number: 75-57-0
Endpoint summary
Administrative data
Key value for chemical safety assessment
Effects on fertility
Link to relevant study records
- Endpoint:
- screening for reproductive / developmental toxicity
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- guideline study without detailed documentation
- Remarks:
- Study conducted following OECD guideline 421 and GLP principles. However, only limited data were available for review (data from SIDS Initial Assessment Report).
- Justification for type of information:
- The rationale to read across the data is attached in section 14.
- Reason / purpose for cross-reference:
- reference to same study
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 421 (Reproduction / Developmental Toxicity Screening Test)
- GLP compliance:
- yes
- Limit test:
- no
- Species:
- rat
- Strain:
- Sprague-Dawley
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: not reported
- Age at study initiation: (P) 9 wks; (F1) 4 days
No further details provided. - Route of administration:
- oral: gavage
- Vehicle:
- water
- Details on exposure:
- No details reported.
- Details on mating procedure:
- No details reported.
- Analytical verification of doses or concentrations:
- not specified
- 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
- Details on study schedule:
- No details reported
- 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
- Details on study design:
- For mating, 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. Day 0 of gestation (GD 0) was defined as the day a vaginal plug or sperm was found.
- Positive control:
- No
- Parental animals: Observations and examinations:
- CAGE SIDE OBSERVATIONS: Yes
DETAILED CLINICAL OBSERVATIONS: Yes, twice daily
BODY WEIGHT: Yes, males were weighed on Day 1 and 3 of dosing, and weekly thereafter. Females were weighed on Day 1, 3 and 7 of dosing, weekly thereafter until delivery, and PND 0 and 4. - Litter observations:
- Clinical signs and body weights of the live pups were recorded.
- Postmortem examinations (parental animals):
- Autopsy at end of experiment.
- Postmortem examinations (offspring):
- Autopsy at end of experiment.
- Statistics:
- Statistical analysis : Bartlett's test, one-way analysis of variance, Dunnett's test, Kruskal-wallis test, chi-square test
- 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. Although the two deaths occurred at highest dose level, no further details are included on cause of death. therefore it is unclear if mortality was substance-related or incidental.
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- Significant decrease in body weight females after parturition.
- Organ weight findings including organ / body weight ratios:
- not specified
- Histopathological findings: non-neoplastic:
- not specified
- Reproductive function: oestrous cycle:
- not examined
- Reproductive function: sperm measures:
- not specified
- Reproductive performance:
- no effects observed
- Description (incidence and severity):
- Tetramethylammonium hydroxide showed no effect on number of days required for successful copulation, copulation index, fertility indices of males and females, implantation index, gestation length and delivery index.
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 5 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- female
- Basis for effect level:
- mortality
- body weight and weight gain
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- >= 20 mg/kg bw/day
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- reproductive performance
- Clinical signs:
- no effects observed
- Mortality / viability:
- mortality observed, treatment-related
- Description (incidence and severity):
- At 20 mg/kg, one stillborn was observed (male). The number of total newborns per dam that delivered newborns was 13.2, 14.0, 13.5 and 12.3 at respectively 0, 1, 5 and 20 mg/kg bw/day.
- Body weight and weight changes:
- not examined
- Sexual maturation:
- not examined
- Organ weight findings including organ / body weight ratios:
- not specified
- Gross pathological findings:
- not specified
- Histopathological findings:
- not examined
- Behaviour (functional findings):
- not examined
- Developmental immunotoxicity:
- not examined
- Key result
- Dose descriptor:
- NOAEL
- Generation:
- F1
- Effect level:
- >= 20 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: No effects seen at highest test concentration.
- Remarks on result:
- other: Mortality of pups during day 1-4 after birth was seen at 20 mg/kg bw/day, but in absence of more detailed information this effect is considered to be related to maternal toxicity and not a direct effect of TMAH.
- Key result
- Reproductive effects observed:
- no
- Conclusions:
- In a reproductive/developmental toxicity screening test in rats according to OECD guideline 421 and GLP principles, the NOAEL for parental toxicity was found to be 5 mg/kg bw/d. Since no effects were seen on fertility and development, the NOAELs for these endpoint were found to be >=20 mg/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.
Based on these observations, the NOAEL for parental toxicity was found to be 5 mg/kg bw/day and for reproduction/developmental toxicity >=20 mg/kg bw/day in rats.
Reference
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.
Table
1. Mating and fertility findings in the reproductive/developmental
toxicity screening test of tetramethylammonium hydroxide.
============================================================
Parameter Dose
(mg/kg bw/day)
--------------------------------
0 1 5 20
-----------------------------------------------------------
[Male]
No. of animals mated 10 10 10 11
No. of animals that copulated
10 10 10 10
No. of animals that produced pregnant female
10 10 10 10
-----------------------------------------------------------
[Female]
No. of animals mated 10 10 10 10
No. of animals that copulated
10 10 10 10
No. of pregnant animals 10 10 10 10
-----------------------------------------------------------
Duration of mating(days required for successful copulation)
Mean 3.0 2.7 3.2 4.7
S.D. 1.49 1.42 1.03 5.44
============================================================
Table
2. Postnatal outcomes in the reproductive/developmental toxicity
screening test of tetramethylammonium hydroxide.
============================================================
Parameter Dose
(mg/kg bw/day)
----------------------------------
0 1 5 20
-----------------------------------------------------------
[Dam]
No. of dams 10 10 10 9
No. of
dams delivered live newborns
10 9 10 8
Duration of pregnancy(day)
Mean 22.0 22.0 21.8 22.3
S.D. 0.00 0.50 0.42 0.46
No. of implantation sites 1)
141(14.1) 147(14.7) 148(14.8) 123(13.7)
-----------------------------------------------------------
[Newborns]
No. of newborns
Total
2) 132(13.2) 126(14.0) 135(13.5) 98(12.3)
Male 61 65 71 45
Female 71 61 64 52
No. of stillborns 0 0 0 1(Male)
Sex ratio of live newborns at birth (male/female)
61/71 65/61 71/64 44/52
No. of deads 3 2 0 14
No. of live newborns on PND 4
Total
3) 129(97.7) 124(98.4) 135(100) 82(85.4)
Male
3) 58(95.1) 64(98.5) 71(100) 37(84.1)
Female
3) 71(100) 60(98.4) 64(100) 45(86.5)
============================================================
1)
The value in parentheses is the number of implantation sites per dam.
2) The value in parentheses is the number of total newborns per dam
delivered live newborns.
3) The value in parentheses is percentage of live newborns at birth.
Table
3. External findings on newborns in the reproductive/developmental
toxicity screening test of tetramethylammonium hydroxide.
============================================================
Parameter Dose(mg/kg
bw/day)
------------------------------------
0 1 5 20
-----------------------------------------------------------
No. of dams 10 9 10 8
-----------------------------------------------------------
[PND 0]
No. of newborns examined 132 126 135 82
No. of newborns with abnormalities
0 0 0 0
-----------------------------------------------------------
[PND 4]
No. of newborns examined 129 124 135 82
No. of newborns with abnormalities
0 0 0 0
============================================================
Effect on fertility: via oral route
- Endpoint conclusion:
- no adverse effect observed
- Dose descriptor:
- NOAEL
- 20 mg/kg bw/day
- Study duration:
- subacute
- Species:
- rat
- Quality of whole database:
- Study conducted following OECD guideline 421 and GLP principles. Study is reliable (klimisch score = 1).
Effect on fertility: via inhalation route
- Endpoint conclusion:
- no study available
Effect on fertility: via dermal route
- Endpoint conclusion:
- no study available
Additional information
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 the number of total newborns or on the sex ratio. No compound-related abnormality was observed in external features.
Based on these observations, the NOAEL for parental toxicity was found to be 5 mg/kg bw/day and for reproduction/developmental toxicity >= 20 mg/kg bw/day in rats.
Justification for using the study performed with TMAH for determination of the toxicity of TMAC is given in the attached Read Across document.
Short description of key information:
In a reproductive/developmental toxicity screening test in rats performed with TMAH according to OECD guideline 421 and GLP principles, the NOAEL for parental toxicity was found to be 5 mg/kg bw. Since no effects were seen on fertility and development, the NOAELs for these endpoint were found to be >= 20 mg/kg bw.
Justification for selection of Effect on fertility via oral route:
One study available, performed with the Read Across substance TMAH.
Effects on developmental toxicity
Description of key information
In a reproductive/developmental toxicity screening test in rats with TMAH, the NOAEL for parental toxicity was found to be 5 mg/kg bw/day and for developmental toxicity >=20 mg/kg bw/day.
Link to relevant study records
- 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).
- Reason / purpose for cross-reference:
- reference to same study
- Qualifier:
- according to guideline
- Guideline:
- other: OECD Guideline 421 (Reproduction / Developmental Toxicity Screening Test)
- GLP compliance:
- yes
- Limit test:
- yes
- Species:
- rat
- Strain:
- Sprague-Dawley
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: not reported
- Age at study initiation: (P) 9 wks; (F1) 4 days
No further details provided. - 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.
- 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
- 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.
- 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
- 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
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 5 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Basis for effect level:
- body weight and weight gain
- mortality
- 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
- 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. - 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.
- Key result
- Developmental effects observed:
- no
- 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.
Reference
Effect on developmental toxicity: via oral route
- Endpoint conclusion:
- no adverse effect observed
- Dose descriptor:
- NOAEL
- 20 mg/kg bw/day
- Study duration:
- subacute
- Species:
- rat
- Quality of whole database:
- Study conducted following OECD guideline 421 and GLP principles. Study is reliable (klimisch score = 1).
Additional information
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 of TMAH was found to be 5 mg/kg bw/day and for developmental toxicity >=20 mg/kg bw/day in rats.
Justification for using the study performed with TMAH for determination of the toxicity of TMAC is given in the attached Read Across document.
Justification for selection of Effect on developmental toxicity: via oral route:
One study available, performed with Read Across substance TMAH.
Justification for classification or non-classification
Based on the available data, TMAC is not classified for reproduction toxicity according to CLP Regulation (EC) No. 1272/2008.
Additional information
Information on Registered Substances comes from registration dossiers which have been assigned a registration number. The assignment of a registration number does however not guarantee that the information in the dossier is correct or that the dossier is compliant with Regulation (EC) No 1907/2006 (the REACH Regulation). This information has not been reviewed or verified by the Agency or any other authority. The content is subject to change without prior notice.
Reproduction or further distribution of this information may be subject to copyright protection. Use of the information without obtaining the permission from the owner(s) of the respective information might violate the rights of the owner.
