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Key value for chemical safety assessment

Effects on fertility

Description of key information

Results for toxicity to reproduction of the substance (CAS no. 29340-81-6), were based on results of one of the two dissociation products of CAS no. 29340-81-6, namely triethanolamine (TEA, CAS no. 102-71-6), and its structural analogue monoethanolamine (MEA, CAS no. 141 -43 -5).

 

In a OECD 421 study with TEA (CAS no. 102-71-6) no adverse effects were found for reproductive performance, fertility or systemic toxicity at any dose level. Adverse developmental effects (decreased numbers of implants and delivered pups, and an increased post-implantation loss) were observed at the highest dose tested, i.e. 1000mg/kg bw/day. Therefore, the NOAEL for systemic toxicity and reproductive performance/fertility was determined to be 1000 mg/kg bw/day and the NOAEL for developmental toxicity was determined to be 300 mg/kg bw/day.

A two-generation reproduction toxicity study (OECD 416) is available for the source substance MEA (CAS No. 141-43-5) . Under the conditions of a two-generation reproduction toxicity study with CAS No. 2002-24-6 (which represents CAS No. 141-43-5 with HCl), the NOAEL for systemic toxicity and fertility, reproductive performance in parental F0 and F1 Wistar rats is 300 mg/kg bw/day. The NOAEL for pre-and postnatal developmental toxicity in their offspring is 1000 mg/kg bw/day.

Link to relevant study records
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:
See read-across record in section 13.
Reason / purpose for cross-reference:
read-across source
Reason / purpose for cross-reference:
read-across source
Key result
Dose descriptor:
NOAEL
Remarks:
Systemic toxicity
Effect level:
1 000 mg/kg bw/day (actual dose received)
Sex:
male/female
Basis for effect level:
other: No adverse systemic effects were observed up to the highest dose tested
Remarks on result:
other: Result read-across source CAS No. 102-71-6
Remarks:
Correction for molecular weight is not necessary.
Dose descriptor:
NOAEL
Remarks:
Reproductive performance and fertility
Effect level:
1 000 mg/kg bw/day (actual dose received)
Sex:
male/female
Basis for effect level:
other: No adverse effects were observed up to the highest dose tested
Remarks on result:
other: Result read-across source CAS No. 102-71-6
Remarks:
Correction for molecular weight is not necessary.
Key result
Dose descriptor:
NOAEL
Remarks:
reproductive performance and fertility
Effect level:
300 mg/kg bw/day (actual dose received)
Sex:
female
Basis for effect level:
reproductive performance
Remarks on result:
other: Result read-across source CAS No. 102-71-6
Remarks:
Correction for molecular weight is not necessary.
Dose descriptor:
NOAEL
Remarks:
systemic toxicity
Effect level:
300 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
body weight and weight gain
food consumption and compound intake
organ weights and organ / body weight ratios
Remarks on result:
other: Result read-across source CAS No. 2002-24-6
Remarks:
Correction for molecular weight is not necessary.
Dose descriptor:
NOAEL
Remarks:
reproductive toxicity
Effect level:
300 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
female
Basis for effect level:
reproductive performance
Remarks on result:
other: Result read-across source CAS No. 2002-24-6
Remarks:
Correction for molecur weight is not necessary.
Dose descriptor:
NOAEL
Remarks:
reproductive toxicity
Effect level:
1 000 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male
Basis for effect level:
reproductive function (sperm measures)
Remarks on result:
other: Result read-across source CAS No. 2002-24-6
Remarks:
Correction for molecur weight is not necessary.
Key result
Critical effects observed:
no
Dose descriptor:
NOAEL
Remarks:
systemic toxicity
Effect level:
300 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
body weight and weight gain
food consumption and compound intake
organ weights and organ / body weight ratios
Remarks on result:
other: Result read-across source CAS No. 2002-24-6
Remarks:
Correction for molecular weight is not necessary.
Key result
Dose descriptor:
NOAEL
Remarks:
reproductive toxicity
Effect level:
300 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
female
Basis for effect level:
reproductive performance
Remarks on result:
other: Result read-across source CAS No. 2002-24-6
Remarks:
Correction for molecur weight is not necessary.
Key result
Dose descriptor:
NOAEL
Remarks:
reproductive toxicity
Effect level:
1 000 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male
Basis for effect level:
reproductive performance
Remarks on result:
other: Result read-across source CAS No. 2002-24-6
Remarks:
Correction for molecur weight is not necessary.
Key result
Critical effects observed:
no
Key result
Dose descriptor:
NOAEL
Generation:
F1
Effect level:
300 mg/kg bw/day
Sex:
male/female
Basis for effect level:
other: Decreased numbers of delivered pups.
Remarks on result:
other: Result read-across source CAS No. 102-71-6
Dose descriptor:
NOAEL
Generation:
F1
Effect level:
1 000 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: pre-and postnatal developmental toxicity
Remarks on result:
other: Result read-across source CAS No. 2002-24-6
Remarks:
Correction for molecular weight not necessary.
Key result
Critical effects observed:
no
Key result
Dose descriptor:
NOAEL
Generation:
F2
Effect level:
1 000 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: pre-and postnatal developmental toxicity
Remarks on result:
other: Result read-across source CAS No. 2002-24-6
Remarks:
Correction for molecular weight not necessary.
Key result
Critical effects observed:
no
Key result
Reproductive effects observed:
yes
Lowest effective dose / conc.:
1 000 mg/kg bw/day (actual dose received)
Treatment related:
yes
Relation to other toxic effects:
reproductive effects in the absence of other toxic effects
Dose response relationship:
no
Relevant for humans:
not specified
Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
1 000 mg/kg bw/day
Study duration:
chronic
Species:
rat
Quality of whole database:
GLP compliant OECD 416 study
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

No data on the reproductive toxicity of the test substance (CAS no. 29340-81-6) are available. However, according to Article 13 of the REACH legislation, in case no appropriate animal studies are available for assessment, information should be generated whenever possible by means other than vertebrate animal tests, i.e. applying alternative methods such as in vitro tests, QSARs, grouping and read-across. CAS no. 29340-81-6 is a salt of triethanolamine (TEA, CAS no. 102-71-6) and citric acid (CAS no. 77-92-9) and is expected to dissociated into the respective triethanolammonium cation and dihydrogen citrate anion (which may subsequently undergo (partial) dissociation to monohydrogen citrate and citrate anions) upon uptake by the body. Therefore it is considered to be acceptable to derive lacking information on toxicological properties of CAS no. 29340-81-6 by read-across from its starting materials. Citric acid is an important intermediate of the Krebs cycle (also known as citric acid cycle), and therefore occurs naturally as a metabolite in virtually all living organisms. It is also used as a natural food preservative and a food additive. The average daily intake (ADI) is not limited according to the evaluation of Joint FAO/WHO Expert Committee on Food Additives (1973), which concluded that the substance is non-hazardous to men. Furthermore, although no conventional studies on reproductive toxicity are available for citric acid, a widespread use of the substance and the lack of reports on possible reproductive effects allow to conclude with a high degree of certainty that the substance is not a reproductive toxicant. Therefore the toxicological behaviour of CAS no. 29340-81-6 is expected to be governed primarily by the toxicity of triethanolamine.

The source substance TEA was investigated in a reproduction/developmental toxicity screening study, performed according to OECD guideline 421 and following GLP. Ten Wistar rats/sex/dose were exposed by oral gavage to 0, 100, 300 or 1000 mg/kg bw/day during a premating period of 2 weeks and a mating period (max. 2 weeks) for both sexes, during approximately 1 week post-mating for males, and during the entire gestation period as well as 4 days of lactation for females. Mortality, food consumption, body weight, clinical signs, mating and reproductive performance were examined in parental animals. At necropsy, animals were assessed for gross pathology and selected organs were weighed and examined histopathologically. In pups, bodyweight, viability and macroscopic changes were recorded. At necropsy on PND 4, all pups were examined macroscopically for external and visceral findings. At the high dose of 1000 mg/kg bw/day, a decreased number of implantation sites, increased postimplantation loss and a lower average litter size were observed. No adverse effects were observed regarding reproductive performance, fertility or systemic toxicity at any dose level. No test substance-related adverse findings were observed in pups. Therefore, the NOAEL for systemic toxicity and fertility was determined to be 1000 mg/kg bw/day. The NOAEL for developmental toxicity was determined to be 300 mg/kg bw/day (BASF, 2010).

For the source substance MEA two generation reproduction toxicity study of the hydrochloric acid of the test substance was performed according to OECD Guideline 416 and GLP. The test itemwas orally administered (as a homogeneous addition to the food, continues administration) to groups of 25 male and 25 female healthy young Wistar rats (F0 parental generation) at target dose levels of 0, 100, 300 and 1000 mg/kg body weight/day (mg/kg bw/d) in a GLP-compliant study according to OECD Test Guideline 416 (BASF, 2009). At least 75 days after the beginning of treatment, F0 animals were mated to produce a litter (F1 generation). Mating pairs were taken from the same dose group and F1 animals selected for breeding were continued in the same dose group as their parents. Groups of 25 males and 25 females, selected from F1 pups to become F1 parental generation, were offered diets containing target dosages of 0, 100, 300 and 1000 mg/kg bw/d of the test substance post weaning, and the breeding program was repeated to produce a F2 litter. The study was terminated with the terminal sacrifice of the F2 weanlings and F1 parental animals.

The parents' and the pups' state of health was checked each day, and parental animals were examined for their mating and reproductive performances. Food consumption of F0 and F1 parental animals was determined regularly once weekly (over a period of at least 6 days each) and weekly during gestation (days 0-7, 7-14, 14-20 post coitum; p.c.) and lactation periods (days 1-4, 4-7, 7-14 post partum; p.p.). Body weights of F0 and F1 parents were determined once weekly. During gestation and lactation F0 and F1 females were weighed on days 0, 7, 14 and 20 of gestation, and on days 1, 4, 7, 14 and 21 after birth. Oestrous cycle data were evaluated for F0 and F1 generation females over a three week period prior to mating until evidence of mating occurred. Moreover, the oestrous stage of each female was determined on the day of scheduled sacrifice. The F1 and F2 pups were sexed on the day of birth (day 0 p.p.) and weighed on days 1, 4, 7, 14, and 21 p.p. Their viability was recorded. At necropsy, all pups were examined macroscopically (including weight determinations of brain, spleen and thymus in one pup/sex/litter). For all F1 pups selected to become F1 parental generation the date of sexual maturation was recorded, i.e. day of vaginal opening or preputial separation. Various sperm parameters (motility, sperm head count, morphology) were assessed in F0 and F1 generation males at scheduled sacrifice after appropriate staining. Blood samples were taken from all F0 and F1 parental animals of each sex and test group during week 10 of premating treatment and the plasma was analysed for the concentration of Ethanolamine hydrochloride. All F0 and F1 parental animals were assessed by gross pathology (including weight determinations of several organs) and subjected to an extensive histopathological examination, special attention being paid to the organs of the reproductive system. A quantitative assessment of primordial and growing follicles in the ovaries was performed for all control and high-dose F1 parental females. Liver samples (lobus medialis) were taken from 10 female animals per test group during dissection of the animals. They were analysed for their choline content in a separate study.

At 1000 mg/kg bw/day, (statistically significant) observations in F0 included yellow discoloured urine for male and female parental animals, decreased body weight gain of the dams during gestation (body weight 8% below control on gestation day 20), decreased food consumption in parental females during lactation, decreased sperm head count in the cauda epididymidis of males, decreased absolute and relative weight of epididymides, cauda epididymidis and prostate in males, less implantation sites, increased post-implantation loss and smaller litters. In P1 parental animals statistically significant) observations included yellow discoloured urine for male and female parental animals, decreased body weight gain of the dams during gestation, decreased food consumption in parental females during lactation, decreased absolute and relative weight of epididymides and cauda epididymidis in males, less implantation sites, increased post-implantation loss and smaller litters. No test-substance related adverse effects were noted in F1 and F2 pups in the 1000 mg/kg bw/day group. At 300 and 100 mg/kg bw/day no test-substance related adverse effects were noted in F0 and F1 parental animals or in F1 and F2 pups.

Based on these results, the NOAEL of the source substance MEA for fertility, reproductive performance and systemic toxicity in parental F0 and F1 Wistar rats is 300 mg/kg bw/day. The NOAEL for pre-and postnatal developmental toxicity in their offspring is 1000 mg/kg bw/day.

Effects on developmental toxicity

Description of key information

Results for toxicity to reproduction of the substance (CAS no. 29340-81-6), were based on results of one of the two dissociation products of CAS no. 29340-81-6, namely triethanolamine (TEA, CAS no. 102-71-6).

In an oral screening reproduction/developmental toxicity study (OECD 421) with the source substance (CAS No. 102-71-6) in rats, the NOAEL for systemic toxicity and postnatal toxicity in the offspring was 1000 mg/kg bw/day, whereas the NOAEL for prenatal developmental toxicity was determined to be 300 mg/kg bw/day based on decreased numbers of implants and delivered pups, and an increased postimplantation loss.

Link to relevant study records
Reference
Endpoint:
developmental toxicity
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Justification for type of information:
See read-across record in section 13.
Reason / purpose for cross-reference:
read-across source
Key result
Dose descriptor:
NOAEL
Remarks:
Only at 1000 mg/kg bw/day: - Lower mean number of implantation sites (about 20% below control) - Increased postimplantation loss (19.4%* [*=pā‰¤0.05] vs. 3.7% in control)
Effect level:
1 000 mg/kg bw/day (actual dose received)
Based on:
test mat.
Basis for effect level:
other: No adverse systemic effects were observed up to the highest dose tested.
Remarks on result:
other: Result read-across source CAS No. 102-71-6
Remarks:
Correction for molecular weight is not necessary.
Key result
Dose descriptor:
NOAEL
Remarks:
Developmental
Effect level:
300 mg/kg bw/day (actual dose received)
Based on:
test mat.
Basis for effect level:
pre and post implantation loss
Remarks on result:
other: Result read-across source CAS No. 102-71-6
Remarks:
Correction for molecular weight is not necessary.
Key result
Abnormalities:
no effects observed
Key result
Dose descriptor:
NOAEL
Effect level:
300 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
changes in litter size and weights
Remarks on result:
other: Result read-across source CAS No. 102-71-6
Remarks:
Correction for molecular weight is not necessary.
Key result
Abnormalities:
no effects observed
Developmental effects observed:
yes
Lowest effective dose / conc.:
300 mg/kg bw/day (actual dose received)
Treatment related:
yes
Relation to maternal toxicity:
developmental effects in the absence of maternal toxicity effects
Dose response relationship:
not specified
Relevant for humans:
not specified
Effect on developmental toxicity: via oral route
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
300 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
GLP compliant OECD 421 study
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

No data on the reproductive toxicity of the test substance (CAS no. 29340-81-6) are available. However, according to Article 13 of the REACH legislation, in case no appropriate animal studies are available for assessment, information should be generated whenever possible by means other than vertebrate animal tests, i.e. applying alternative methods such as in vitro tests, QSARs, grouping and read-across. CAS no. 29340-81-6 is a salt of triethanolamine (TEA, CAS no. 102-71-6) and citric acid (CAS no. 77-92-9) and is expected to dissociated into the respective triethanolammonium cation and dihydrogen citrate anion (which may subsequently undergo (partial) dissociation to monohydrogen citrate and citrate anions) upon uptake by the body. Therefore it is considered to be acceptable to derive lacking information on toxicological properties of CAS no. 29340-81-6 by read-across from its starting materials. Citric acid is an important intermediate of the Krebs cycle (also known as citric acid cycle), and therefore occurs naturally as a metabolite in virtually all living organisms. It is also used as a natural food preservative and a food additive. The average daily intake (ADI) is not limited according to the evaluation of Joint FAO/WHO Expert Committee on Food Additives (1973), which concluded that the substance is non-hazardous to men. Furthermore, although no conventional studies on reproductive toxicity are available for citric acid, a widespread use of the substance and the lack of reports on possible reproductive effects allow to conclude with a high degree of certainty that the substance is not a reproductive toxicant. Therefore the toxicological behaviour of CAS no. 29340-81-6 is expected to be governed primarily by the toxicity of triethanolamine.

CAS No. 102-71-6

In a reproduction/developmental toxicity screening study with the test substance (CAS No. 102-71-6), performed according to OECD guideline 421, Wistar rats (10/sex/dose) were exposed by gavage to 0, 100, 300 or 1000 mg/kg bw/day during a premating period of 2 weeks and a mating period (max. 2 weeks) for both sexes, during approximately 1 week post-mating for males, and during the entire gestation period as well as 4 days of lactation for females. Food consumption, body weight, clinical signs, mating and reproductive performance (including determinations of the number of implantations and the calculation of the postimplantation loss in females) were examined in parental animals. At necropsy, animals were assessed for gross pathology and selected organs were weighed and examined histopathologically. In pups, bodyweight, viability and macroscopic changes were recorded. At necropsy on PND 4, all pups were examined macroscopically for external and visceral findings. At the high dose of 1000 mg/kg bw/day, a decreased number of implantation sites, increased postimplantation loss and a lower average litter size were observed. No adverse effects were observed regarding reproductive performance, fertility or systemic toxicity at any dose level. Thus, the NOAEL for systemic toxicity as well as for reproductive performance and fertility in parental animals was established at 1000 mg/kg bw/day, the NOAEL for postnatal toxicity in the offspring was 1000 mg/kg bw/day, and the NOAEL for prenatal developmental toxicity was determined to be 300 mg/kg bw/day (BASF AG, 2010).

 

Justification for classification or non-classification

Based on the results of the available studies, classification for toxicity to reproduction is not warranted in accordance with EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulation No. (EC) 1272/2008.

Additional information