Registration Dossier

Administrative data

Key value for chemical safety assessment

Effects on fertility

Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no adverse effect observed
Additional information

OECD 421 Study (BASF SE, 2015):

Tris(2-hydroxyethyl)methylammonium methyl sulphate was administered orally via the drinking water to groups of 10 male and 10 female Wistar rats (F0 animals) at concentrations of 0 ppm (test group 0), 1200 ppm (test group 1), 4000 ppm (test group 2) and 12000 ppm (test group 3).

The duration of treatment covered a 2-week premating period and mating in both sexes (mating pairs were from the same test group) as well as entire gestation and 4 days of lactation period in females up to one day prior to the day of scheduled sacrifice of the

animals.

OBSERVATIONS

The parents' and the pups' state of health was checked each day, and parental animals were examined for their mating and reproductive performances.

F0 animals were mated 13 days after the beginning of treatment to produce a litter (F1 generation pups). As soon as sperm was detected in the vaginal smear, mating was discontinued. F0 animals were examined for their reproductive performance including determinations of the number of implantations and the calculation of the postimplantation loss in all F0 females.

A detailed clinical observation (DCO) was performed in all animals before initial test substance administration and, as a rule, thereafter at weekly intervals.

Food consumption of the F0 parents was determined regularly once weekly before and after the mating period, as well as in dams during gestation (days 0-7, 7-14, 14-20) and lactation (days 1-4).

Water consumption of the F0 parents was determined once weekly during premating. In dams water consumption was determined for gestation days 6-7, 13-14, 19-20 and lactation days 3-4.

In general, the body weights of F0 animals were determined once a week. However, during gestation and lactation, F0 females were weighed on gestation days (GD) 0, 7, 14 and 20, and on postnatal days (PND) 0 and 4.

The pups were sexed and examined for macroscopically evident changes on PND 0. They were weighed on PND 1 and on PND 4 and their viability was recorded. At necropsy on PND 4, all pups were sacrificed under isoflurane anesthesia with CO2 and examined macroscopically for external and visceral findings at necropsy.

Towards the end of the administration period a functional observational battery (FOB) was performed and motor activity (MA) was measured in 5 animals per sex and test group.

All F0 parental animals were sacrificed by decapitation, under isoflurane anesthesia, and were assessed by gross pathology. Weights of selected organs were recorded and a histopathological examination was performed.

RESULTS

Analyses

The various analyses confirmed

• the stability of the test substance in drinking water over a period of 4 days at room

temperature,

• the overall accuracy of the prepared concentrations.

Effects

The following test substance-related effects/findings were noted:

Test group 3: 12000 ppm

(774 mg/kg bw/d in parental males, 1564 mg/kg bw/d in parental females)

F0 PARENTAL ANIMALS

Clinical Examinations, Reproductive Performance, Clinical Pathology and Pathology

• No test substance-related, adverse findings were noted.

F1 PUPS

Clinical Examinations/ Gross Findings

• No test substance-related, adverse findings were noted.

Test group 2: 4000 ppm

(253 mg/kg bw/d in parental males, 439 mg/kg bw/d in parental females)

F0 PARENTAL ANIMALS

Clinical Examinations, Reproductive Performance, Clinical Pathology and Pathology

• No test substance-related, adverse findings were noted.

F1 PUPS

Clinical Examinations/Gross Findings

• No test substance-related, adverse findings were noted.

Test group 1: 1200 ppm

(75 mg/kg bw/d in parental males, 118 mg/kg bw/d in parental females)

F0 PARENTAL ANIMALS

Clinical Examinations, Reproductive Performance, Clinical Pathology and Pathology

• No test substance-related, adverse findings were noted.

F1 PUPS

Clinical Examinations/Gross Findings

• No test substance-related, adverse findings were noted.

CONCLUSION

Under the conditions of the present Reproduction/Developmental Toxicity Screening Test the oral administration of Tris(2-hydroxyethyl)methylammonium methyl sulphate to male and female Wistar rats did not result in signs of systemic toxicity up to a concentration of 12000 ppm. Thus, the no observed adverse effect level (NOAEL) for general systemic toxicity was 12000 ppm for male (774 mg/kg bw/d) and female Wistar rats (1564 mg/kg bw/d).

In addition, signs of neurotoxicity were not observed. The NOAEL for neurotoxicity was set to 12000 ppm for male and female animals.

The NOAEL for reproductive performance and fertility was also set to 12000 ppm for male and female Wistar rats.

The NOAEL for developmental toxicity was 12000 ppm.

Dose range finding study

The objective of the study was to assess if the animals tolerate the test substance at the offered concentrations in drinking water in order to select concentrations for subsequent studies. The test substance was administered via drinking water to groups of each 3 male and 3 female Wistar rats at concentrations of 4000 and 12000 ppm.

Body weight was determined on study days 0, 3, 7 and 14. Food and drinking water consumption was determined on study days 3, 7 and 14. The animals were checked daily for any abnormal clinically signs. Abnormalities and changes were documented for each rat. At the end of the administration period the animals were sacrificed and assessed by gross pathology. The following results were obtained:

Test group 2: 12000 ppm

(873 mg/kg bw/d in males and 1337 mg/kg bw/d in females)

Clinical Examinations: Increased water consumption in male animals between study days 3-7 (+22 %) and in female animals during the entire study period (+49 % on study day 14)

Pathology: No treatment-related, adverse effects were observed.

Test group 1: 4000 ppm

(265 mg/kg bw/d in males and 337 mg/kg bw/d in females)

Clinical Examinations and Pathology: No treatment-related, adverse effects were observed.

For the subsequent OECD 421 study the concentrations in drinking water were set to 0, 1200, 4000 and 12000 ppm.


Short description of key information:
The no observed adverse effect level (NOAEL) for general systemic toxicity was 12000 ppm for male (774 mg/kg bw/d) and female Wistar rats (1564 mg/kg bw/d) in an OECD 421 study, the highest dose level tested. In addition, signs of neurotoxicity were not observed. The NOAEL for neurotoxicity was set to 12000 ppm for male and female animals. The NOAEL for reproductive performance and fertility was also set to 12000 ppm for male and female Wistar rats.

Effects on developmental toxicity

Description of key information
The NOAEL for developmental toxicity was 12000 ppm in an OECD 421 study, the highest dose level tested.
Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Effect on developmental toxicity: via inhalation route
Endpoint conclusion:
no study available
Effect on developmental toxicity: via dermal route
Endpoint conclusion:
no study available
Additional information

OECD 421 Study (BASF SE, 2015):

Tris(2-hydroxyethyl)methylammonium methyl sulphate was administered orally via the drinking water to groups of 10 male and 10 female Wistar rats (F0 animals) at concentrations of 0 ppm (test group 0), 1200 ppm (test group 1), 4000 ppm (test group 2) and 12000 ppm (test group 3).

The duration of treatment covered a 2-week premating period and mating in both sexes (mating pairs were from the same test group) as well as entire gestation and 4 days of lactation period in females up to one day prior to the day of scheduled sacrifice of the

animals.

OBSERVATIONS

The parents' and the pups' state of health was checked each day, and parental animals were examined for their mating and reproductive performances.

F0 animals were mated 13 days after the beginning of treatment to produce a litter (F1 generation pups). As soon as sperm was detected in the vaginal smear, mating was discontinued. F0 animals were examined for their reproductive performance including determinations of the number of implantations and the calculation of the postimplantation loss in all F0 females.

A detailed clinical observation (DCO) was performed in all animals before initial test substance administration and, as a rule, thereafter at weekly intervals.

Food consumption of the F0 parents was determined regularly once weekly before and after the mating period, as well as in dams during gestation (days 0-7, 7-14, 14-20) and lactation (days 1-4).

Water consumption of the F0 parents was determined once weekly during premating. In dams water consumption was determined for gestation days 6-7, 13-14, 19-20 and lactation days 3-4.

In general, the body weights of F0 animals were determined once a week. However, during gestation and lactation, F0 females were weighed on gestation days (GD) 0, 7, 14 and 20, and on postnatal days (PND) 0 and 4.

The pups were sexed and examined for macroscopically evident changes on PND 0. They were weighed on PND 1 and on PND 4 and their viability was recorded. At necropsy on PND 4, all pups were sacrificed under isoflurane anesthesia with CO2 and examined macroscopically for external and visceral findings at necropsy.

Towards the end of the administration period a functional observational battery (FOB) was performed and motor activity (MA) was measured in 5 animals per sex and test group.

All F0 parental animals were sacrificed by decapitation, under isoflurane anesthesia, and were assessed by gross pathology. Weights of selected organs were recorded and a histopathological examination was performed.

RESULTS

Analyses

The various analyses confirmed

• the stability of the test substance in drinking water over a period of 4 days at room

temperature,

• the overall accuracy of the prepared concentrations.

Effects

The following test substance-related effects/findings were noted:

Test group 3: 12000 ppm

(774 mg/kg bw/d in parental males, 1564 mg/kg bw/d in parental females)

F0 PARENTAL ANIMALS

Clinical Examinations, Reproductive Performance, Clinical Pathology and Pathology

• No test substance-related, adverse findings were noted.

F1 PUPS

Clinical Examinations/ Gross Findings

• No test substance-related, adverse findings were noted.

Test group 2: 4000 ppm

(253 mg/kg bw/d in parental males, 439 mg/kg bw/d in parental females)

F0 PARENTAL ANIMALS

Clinical Examinations, Reproductive Performance, Clinical Pathology and Pathology

• No test substance-related, adverse findings were noted.

F1 PUPS

Clinical Examinations/Gross Findings

• No test substance-related, adverse findings were noted.

Test group 1: 1200 ppm

(75 mg/kg bw/d in parental males, 118 mg/kg bw/d in parental females)

F0 PARENTAL ANIMALS

Clinical Examinations, Reproductive Performance, Clinical Pathology and Pathology

• No test substance-related, adverse findings were noted.

F1 PUPS

Clinical Examinations/Gross Findings

• No test substance-related, adverse findings were noted.

CONCLUSION

Under the conditions of the present Reproduction/Developmental Toxicity Screening Test the oral administration of Tris(2-hydroxyethyl)methylammonium methyl sulphate to male and female Wistar rats did not result in signs of systemic toxicity up to a concentration of 12000 ppm. Thus, the no observed adverse effect level (NOAEL) for general systemic toxicity was 12000 ppm for male (774 mg/kg bw/d) and female Wistar rats (1564 mg/kg bw/d).

In addition, signs of neurotoxicity were not observed. The NOAEL for neurotoxicity was set to 12000 ppm for male and female animals.

The NOAEL for reproductive performance and fertility was also set to 12000 ppm for male and female Wistar rats.

The NOAEL for developmental toxicity was 12000 ppm.

Justification for classification or non-classification

Dangerous Substance Directive (67/548/EEC)

The available study is considered reliable and suitable for classification purposes under 67/548/EEC. As a result, the substance does not need to be classified and labelled for toxicity to reproduction under Directive 67/548/EEC, as amended for the 31st time in Directive 2009/2/EC.

 

Classification, Labelling, and Packaging Regulation (EC) No 1272/2008

The available experimental test data is reliable and suitable for classification purposes under Regulation 1272/2008. As a result the substance does not need to be classified and labelled for toxicity to reproduction under Regulation (EC) No 1272/2008, as amended for the sixth time in Regulation (EC) No 605/2014.