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Description of key information

A 28-day oral toxicity study with the methyl ester of 3-mercaptopropionic acid (MMP) in rats showed only minor effects on organ weights as well as forestomach hyperplasia at the highest dose level (100 mg/kg/day). These effects are not adverse or relevant for human risk assessment. The NOAEL of MMP is equivalent to a NOAEL of 135 mg/kg/d for BuMP.

Key value for chemical safety assessment

Toxic effect type:
dose-dependent

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records
Reference
Endpoint:
short-term repeated dose toxicity: oral
Type of information:
read-across based on grouping of substances (category approach)
Adequacy of study:
key study
Justification for type of information:
This scenario covers the category approach for which the read-across hypothesis is based on biotransformation to common compounds. For the REACH information requirement under consideration, the property investigated in studies conducted with different source substances is used to predict the property that would be observed in a study with the target substance if it were to be conducted. Similar properties are observed for the different source substances; this may include absence of effects for every member of the category.
There are differences in strength of the effect(s) forming a regular pattern. The prediction is based either on this regular pattern within the category, when the members are ordered by a variable related to the structural differences in the category or is based on a worst-case approach.
The read-across is a category approach based on the hypothesis that the substances in this category are transformed to a common compound. This approach serves to use existing data on acute toxicity, repeated-dose toxicity, and reproductive toxicity endpoints for substances in this category.
There are differences in strength of the effects forming a regular pattern. This corresponds to Scenario 3 of the RAAF. The substances MMP, BuMP, EHMP, iOMP, iC13MP, and ODMP are esters of a common acid, 3-mercaptopropionic acid (3-MPA). They are likely to be rapidly hydrolysed to 3-mercaptopropionic acid and the respective alcohol (i.e. methanol, butanol, ethylhexanol, iso-octanol, iso-tridecanol, and octadecanol). In vitro studies on hydrolysis/metabolism are planned to strengthen the hypothesis.
The observed differences in effect levels (higher effect levels with increasing carbon chain length were observed in the available acute oral toxicity studies) are assumed to be mainly due to differences in molecular weight (corrections will be made for these differences) and decreasing bioavailability with increasing carbon chain length (no corrections are made for this effect; a worst-case approach is applied here, since based on the available data no exact quantification for bioavailability differences is possible at the moment).
It can be predicted with high confidence that the substances within this category will lead to the same type of effects. The main driver for toxicity is the common compound 3-mercaptopropionic acid, whereas the alcohols do not contribute to a relevant extent to overall toxicity.

Beside structural similarities and the common toxophore, the MPA moiety, category members are also likely to have similar metabolites. As explained in the Toxicokinetics section, substances are predicted to be rapidly hydrolysed into 3-MPA and the respective alcohol after absorption. According to low toxicity of the corresponding alcohols (Table 8), this would support the role of the MPA moiety as toxophore, as well as propose scenario 3 of the RAAF as applicable for this category approach. 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. Based on the results of these studies, scenario selection will be revaluated.

For details, please refer to the category document attached to Iuclid section 13.
Reason / purpose for cross-reference:
read-across: supporting information
Reason / purpose for cross-reference:
read-across source
Qualifier:
according to guideline
Guideline:
OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
Deviations:
no
Species:
rat
Strain:
Wistar
Sex:
male/female
Route of administration:
oral: gavage
Clinical signs:
effects observed, treatment-related
Mortality:
mortality observed, treatment-related
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
no effects observed
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not specified
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
not specified
Behaviour (functional findings):
no effects observed
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
no effects observed
Dose descriptor:
NOAEL
Effect level:
135 mg/kg bw/day (actual dose received)
Sex:
male/female
Basis for effect level:
other: Neither the slight forestomach hyperplasia not the liver weight increase are adverse or relevant effects.
Remarks on result:
other: correction for difference in molecular weight
Critical effects observed:
not specified
Conclusions:
A NOAEL (No Observed Effect Level) of 100 mg/kg/day was determined for MMP in a study according to OECD 422. Based on the category approach, BuMP is considered to show similar effects. Therefor, the reproduction/developmental toxicity NOEL of BuMP, corrected for differences in molecular weight, was determined to be 135 mg/kg bw/day.

As Toxikokinetic literature data indicate that after absorption rapid ester hydrolysis accurs to all category members, toxicokinetic in vitro studies are planned to gain better insight on toxicokinetic properties of the substances. Depending on the results of metabolism and simulated gastric acid hydrolysis studies, scenario selection will be revaluated.
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
135 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
The available key studies are reliable or reliable with restrictions (Klimisch 1 – 2) and were conducted according to or similar to guidelines.

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

No experimental data are available for the target substance BuMP. A Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test was conducted with MMP. A justification for read-across is attached to Iuclid section 13.


The test item was administered in corn oil as vehicle at dosages of 25, 50, and 100 mg/kg body weight/day, and controls received the vehicle only. The test item was administered to male rats for at least 28 days and to female rats for 14 days prior to pairing, through the pairing and gestation periods until the F1 generation reached day 4 post partum. Administration of 50 and 100 mg/kg/day resulted in dose-dependently increased liver weights relative to body weights and brain weights in males. In the absence of a histopathological correlation these higher weights were considered to be of no adverse character. Furthermore at 100 mg/kg/day, a minimal to slight hyperplasia of the forestomach squamous epithelium was noted in males and females. Based on these results a general NOAEL (No Observed Adverse Effect Level) was established at 50 mg/kg body weight/day. The NOEL (No Observed Effect Level) for reproduction/developmental toxicity was considered to be 100 mg/kg/day.


After correcting for differences in molecular weight, the NOAEL for BuMP was calculated as 135 mg/kg bw/d.

Justification for classification or non-classification

Based on teh available data, no classification for specific organ toxicity after repeated exposure is required.