Registration Dossier

Reference

Endpoint:

screening for reproductive / developmental toxicity

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Justification for type of information:

The rationale to read across the data is attached in Section 13.

Reason / purpose for cross-reference:

read-across source

Clinical signs:

effects observed, treatment-related

Description (incidence and severity):

Salivation. Decrease in locomotor activity, incomplete eyelid opening or eyelid closure, and loss of hair .

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

significant decrease in body weight females after parturition.

Food consumption and compound intake (if feeding study):

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 specified

Reproductive function: sperm measures:

not specified

Reproductive performance:

no effects observed

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 in male and female rats 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 Day 3 in male animals and on gestation day (GD) 20 in female animals.
REPRODUCTIVE PERFORMANCE (PARENTAL ANIMALS)
No effects on days required for successful copulation, copulation index, fertility indices of males and females, implantation index, gestation length and delivery index.

Dose descriptor:

NOAEL

Effect level:

5 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: Effects seen at 20 mg/kg bw: death (2 females), significant decrease in food consumption, a decrease in locomotor activity, incomplete eyelid opening or eyelid closure, loss of hair and a significant decrease in body weight after parturition.

Dose descriptor:

NOAEL

Effect level:

>= 20 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: no fertility effects observed

Clinical signs:

no effects observed

Mortality / viability:

mortality observed, treatment-related

Description (incidence and severity):

At 20 mg/kg, 18% of newborns were dead.

Body weight and weight changes:

no effects observed

Sexual maturation:

not specified

Organ weight findings including organ / body weight ratios:

not specified

Gross pathological findings:

not specified

Histopathological findings:

not specified

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.

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.

Reproductive effects observed:

not specified

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
============================================================

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. Since no effects were seen on fertility and development, the NOAELs for these endpoint were found to be >= 20 mg/kg bw. The result is read across to TEAH.

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.

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. The result is read across to TEAH.

Endpoint conclusion:

no adverse effect observed

Study duration:

subacute

Species:

rat

Quality of whole database:

Study conducted following OECD guideline 421 and GLP principles. Study is reliable (Klimisch score 2). However, as it was conducted with a substance analogue, the maximum Klimisch score is 2.

Endpoint conclusion:

no study available

Endpoint conclusion:

no study available

A reproductive/developmental toxicity screening test with substance analogue TMAH 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.

Based on these observations, the NOAEL for parental toxicity was found to be 5 mg TMAH/kg bw/day and for reproduction/developmental toxicity >= 20 mg TMAH/kg bw/day in rats. According to the rationale attached in section 13, these data can be read across to TEAH.

Short description of key information:
In a reproductive/developmental toxicity screening test with substance analogue TMAH in rats performed according to OECD guideline 421 and GLP principles, the NOAEL for parental toxicity was found to be 5 mg TMAH/kg bw. Since no effects were seen on fertility and development, the NOAELs for these endpoint were found to be >= 20 mg TMAH /kg bw. According to the rationale attached in section 13, these data can be read across to TEAH.

Justification for selection of Effect on fertility via oral route:
One study performed with substance analogue TMAH is available.

In a reproductive/developmental toxicity screening test in rats with substance analogue TMAH, the NOAEL for parental toxicity was found to be 5 mg/kg bw/d and for developmental toxicity >=20 mg/kg bw/d. According to the rationale attached in section 13, these data can be read across to TEAH.

Reference

Endpoint:

developmental toxicity

Remarks:

Screening study

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Justification for type of information:

The rationale to read across the data is attached in Section 13.

Reason / purpose for cross-reference:

read-across source

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.
.

Dose descriptor:

NOAEL

Effect level:

5 mg/kg bw/day (actual dose received)

Based on:

test mat.

Basis for effect level:

other: maternal toxicity

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.

Dose descriptor:

NOAEL

Effect level:

>= 20 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: developmental toxicity

Abnormalities:

not specified

Developmental effects observed:

not specified

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 TMAH/kg bw and the developmental NOAEL was found to be >= 20mg TMAH/kg bw. The result is read across to TEAH.

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 TMAH/kg bw/day in rats. No effects on development were seen at the highest test concentration, therefore the developmental NOAEL for TMAH was considered to be >= 20mg/kg bw. The result is read across to TEAH.

Endpoint conclusion:

no adverse effect observed

Study duration:

subacute

Species:

rat

Quality of whole database:

Study conducted following OECD guideline 421 and GLP principles. However, as it was conducted with a substance analogue, the maximum Klimisch score is 2.

A reproductive/developmental toxicity screening test with substance analogue TMAH 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 and for developmental toxicity was >=20 mg/kg bw/d in rats. According to the rationale attached in section 13, these data can be read across to TEAH.

Justification for selection of Effect on developmental toxicity: via oral route:
One study available, performed with substance analogue TMAH.

Based on the available data, TEAH (or a 35% aqueous solution of TEAH) is not classified for reproduction toxicity according to CLP Regulation (EC) No. 1272/2008.