Diammonium 2,2'-dithiodiacetate

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

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:

supporting study

Reliability:

2 (reliable with restrictions)

Justification for type of information:

This scenario covers the analogue approach for which the read-across hypothesis is based on the assumption, that source and target substance form common metabolites. This approach serves to use existing data on repeated-dose toxicity and reproductive toxicity endpoints of the source substance to predict the property that would be observed in a study with the target substance if it were to be conducted.

It is very likely, that the main metabolite of the source substance sodium thioglycolate is the oxidized form which is structural and chemical similar to the anion of the target substance DADTDG. However, no experimental toxicokinetic data to support this hypothesis are available by now. To proof this hypothesis, simulated gastric acid hydrolysis studies, as well as in-vitro metabolism studies using liver microsomes will be conducted.

Differences regarding molecular weight of source and target substance will most likely lead to lower resorption and distribution of the target substance compared to the source. Therefore, corrections for molecular weight are applied.

For detailed information see section 13.2.

Reason / purpose for cross-reference:

read-across: supporting information

Reason / purpose for cross-reference:

read-across source

Dose descriptor:

LOAEL

Remarks:

reproductive performance

Effect level:

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

Based on:

act. ingr.

Sex:

male/female

Basis for effect level:

other:

Remarks on result:

other: corrected for molecular weight differences

Dose descriptor:

NOEL

Remarks:

reproductive performance

Effect level:

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

Based on:

act. ingr.

Sex:

female

Basis for effect level:

clinical signs

mortality

body weight and weight gain

food consumption and compound intake

Remarks on result:

other: correction for molecular weight differences

Dose descriptor:

NOAEL

Remarks:

reproductive performance

Effect level:

>= 152 mg/kg bw/day (actual dose received)

Based on:

act. ingr.

Sex:

male

Basis for effect level:

clinical signs

mortality

body weight and weight gain

food consumption and compound intake

Remarks on result:

other: corrected for molecular weight differences

Dose descriptor:

LOAEL

Remarks:

parental toxicity

Effect level:

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

Based on:

act. ingr.

Sex:

male/female

Basis for effect level:

mortality

Remarks on result:

other: corrected for molecular weight differences

Dose descriptor:

NOEL

Remarks:

parental toxicity

Effect level:

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

Based on:

act. ingr.

Sex:

male/female

Basis for effect level:

other: no effects observed

Remarks on result:

other: corrected for molecular weight differences

Dose descriptor:

NOEL

Generation:

F1

Effect level:

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

Based on:

act. ingr.

Sex:

male/female

Basis for effect level:

other:

Remarks on result:

other: corrected for molecular weight differences

Dose descriptor:

LOAEL

Remarks:

effects on progeny

Generation:

F1

Effect level:

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

Based on:

act. ingr.

Sex:

male/female

Basis for effect level:

clinical signs

mortality

body weight and weight gain

Remarks on result:

other: corrected for molecular differences

Conclusions:

Based on the read-across hypothesis, effects of the target substanc can be compareble to effects observed with the source substance. Effect levels were corrected for molecular weight differences.
Under the experimental conditions of this study:
. the No Observed Adverse Effect Level (NOAEL) for parental toxicity was considered to be 38 mg/kg/day (based on deaths at 40 and 80 mg/kg/day),
.   male reproductive performance was not affected by treatment with sodium thioglycolate.
No Observed Effect Level (NOEL) for female reproductive performance was therefore set at 38 mg/kg/day,
.   the NOEL for toxic effects on progeny was set at 76 mg/kg/day

Effect on fertility: via oral route

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEL

38 mg/kg bw/day

Study duration:

subchronic

Species:

rat

Effect on fertility: via inhalation route

Endpoint conclusion:

no study available

Effect on fertility: via dermal route

Endpoint conclusion:

no study available

Additional information

The studies with thioglycolic acid and its salts e.g. sodium thioglycolate (NaTG) can be used as a surrogate to investigate reproduction toxicity of the dithiodiglycolic anion, the main metabolite of the thioglycolate. This can be considered as a valid read-across approach based on the metabolism of thioglycolates in vivo as shown in section 7.1 Toxicokinetics.

Reproduction/Developmental Screening Study (OECD 421)

In a reproduction/developmental screening test performed according to the OECD Guideline 421, four groups of 12 male and 12 female Sprague-Dawley rats received sodium thioglycolate (purity 98.9% pure), daily, by oral (gavage) administration, 10 weeks before mating and through mating and, for the females, through gestation until day 5 post-partum at dose-levels of 0, 20, 40 or 80 mg/kg bw/d.

Clinical signs and mortality were checked daily. Body weight and food consumption were recorded weekly until mating and then at designated intervals throughout gestation and lactation. The animals were paired for mating and the dams were allowed to litter and rear their progeny until day 5 post-partum. The total litter sizes and numbers of pups of each sex were recorded after birth, pup clinical signs were recorded daily and pup body weights were recorded on days 1 and 5 post-partum. The males were sacrificed after completion of the mating period and the females on day 5 post-partum (or on day 25 post-coitum for females which did not deliver). The body weight and selected organs (brain, epididymides, heart, kidneys, liver, ovaries, prostate, seminal vesicles and testes and uterus) were weighed and a macroscopic post-mortem examination of the principal thoracic and abdominal organs and a microscopic examination of selected organs (macroscopic lesions, epididymides, heart, kidneys, liver, ovaries, prostate, seminal vesicles, testes, and uterus) were performed. In the females, which were apparently non-pregnant, the presence of implantation scars on the uterus was checked using ammonium sulphide staining technique. Epididymal sperm was sampled for motility, morphology and count and testicular sperm heads resistant to homogenization (i.e. elongated spermatids and mature spermatozoa) were counted. The pups were sacrificed on day 5 post-partum and were carefully examined for gross external abnormalities and a macroscopic post-mortem examination was performed.

Two males and one female given 80 mg/kg bw/d were found dead during the pre-mating or mating periods with no clinical signs observed before death and no relevant post-mortem findings. Four females at 80 mg/kg/d and one at 40 mg/kg bw/d were found dead or were prematurely sacrificed because of difficulties to deliver. Ptyalism was observed at 40 and 80 mg/kg bw/d with a dose-related incidence and may be related to the taste of dosing solution. All male and female groups had body weight gains comparable with the controls throughout the study. There were no adverse effects of treatment on mean food consumption, except a slight lowering of food consumption during the lactation period for females given 80 mg/kg bw/d.

The mean number of estrous cycles in each group was between 4 and 5 during the period measured and the mean cycle length was a normal 4 or 5 days. All pairs mated and the majority of the females were pregnant. There were no effects of treatment on the mean number of days taken to mate.

Females given 80 mg/kg bw/d had a statistically significantly longer gestation period, a non-statistically significantly lower number of corpora lutea and a statistically significantly lower number of implantations and pups. One female had total resorptions and one litter died on day 1 post-partum.

There were no effects of treatment on sperm morphology, motility or counts. The mean absolute seminal vesicle weights were statistically significantly lower for all treated groups compared to the control group, but the mean relative weight was only decreased at 80 mg/kg bw/d. For all treated groups, the absolute weights were in the range of the historical control data. Only at 80 mg/kg bw/d, the relative weight was outside the historical data and was correlated with a slight decrease in secretory content in the seminal vesicles. There were no treatment-related adverse effects in pups based on clinical signs, mean body weight gain and necropsy findings.

The NOAEL for parental toxicity was considered to be 20 mg/kg bw/d (based on deaths at 40 and 80 mg/kg bw/d), the NOAEL for reproductive performance (mating, fertility and delivery) was considered to be 20 mg/kg bw/d (based on deaths at 40 and 80 mg/kg bw/d) and the NOAEL for toxic effects on progeny was 40 mg/kg bw/d (based on the dead litter at 80 mg/kg bw/d which cannot definitively be attributed to maternal condition).

 

Short description of key information:
Thioglycolic acid, its salts and its metabolites are not considered to be reproductive toxicants. The conducted reproduction toxicity studiy with sodium thioglycolate can be bridged to other salts of the thioglycolic acid as well as to the main metabolite the dithiodiglycolic anion.

Justification for selection of Effect on fertility via oral route:
Read-across to thioglycolate anion studies which can be served as a surrogate for DADTDG. A lot of repeat-dose and toxicity to reproduction GLP and OECD TG studies are available for thioglycolic acid and its salts. The main metabolite of the thioglycolate is the oxidized form which is structural and chemical similar to the anion of DADTDG. Therefore, DADTDG can be considered as co-tested in all mentioned studies under section 7.8. Due to the metabolism of thioglycolate and its salts repeat-dose toxicity as well as toxicity to reproduction for DADTDG does not need to be conducted.

Effects on developmental toxicity

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no study available

Effect on developmental toxicity: via inhalation route

Endpoint conclusion:

no study available

Effect on developmental toxicity: via dermal route

Endpoint conclusion:

no study available

Justification for classification or non-classification

Overall, sodium thioglycolateis not considered to be developmental or reproductive toxicants, excepted at dose levels associated with maternal lethality. Therefore, also the main metabolite, the dithiodiglycolic anion, co-tested in all studies, is not considered to be a develpmental or reproductive toxicant and based on this data, no classification for DADTDG is needed in this context.