Butyl 3-mercaptopropionate

Endpoint summary

Description of key information

Based on the available data in the category, the oral LD50 of BuMP is predicted to be 262 mg/kg bw, the dermal LD50 is predicted to be >2000 mg/kg bw, the inhalation LC50 is predicted to be 2.85 mg/L air.

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Reference

Endpoint:

acute toxicity: oral

Type of information:

read-across based on grouping of substances (category approach)

Adequacy of study:

key study

Justification for type of information:

There are no relevant variations in qualitative properties among source substances and the same potency is predicted for all target substances. This is Scenario 4 of the RAAF1. Substances MMP, BuMP, EHMP, iOMP, iC13MP, and ODMP are different alkyl esters of a common acid, 3-mercaptopropionic acid (3-MPA).

This scenario covers the category approach for which the read-across hypothesis is based on the assumption, that toxicity of compounds in this category are driven by a common toxophore. This approach serves to use existing data on genotoxicity, acute toxicity, repeated-dose toxicity and reproductive toxicity endpoints for substances in this category. 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 effects forming a regular pattern. This corresponds to Scenario 4 of the RAAF. The substances MMP, BuMP, EHMP, iOMP, iC13MP, and ODMP are esters of a common acid, 3-mercaptopropionic acid (3-MPA). All category members share the same mercaptopropionic acid moiety with one free SH group per MPA unit. The MPA unit with free SH is a prerequisite for this category.
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 free SH group of the MPA moiety.
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 detailed information please refer to section 13.2.

Reason / purpose for cross-reference:

read-across: supporting information

Reason / purpose for cross-reference:

read-across source

Species:

rat

Route of administration:

oral: gavage

Key result

Dose descriptor:

LD50

Effect level:

262 mg/kg bw

Based on:

test mat.

Remarks on result:

other: read across MMP

Interpretation of results:

Category 3 based on GHS criteria

Conclusions:

Based on read-across from MMP, the LD50 of BuMP is 262 mg/kg bw.

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:

adverse effect observed

Dose descriptor:

LD50

Value:

262 mg/kg bw

Acute toxicity: via inhalation route

Link to relevant study records

Reference

Endpoint:

acute toxicity: inhalation

Type of information:

read-across based on grouping of substances (category approach)

Adequacy of study:

key study

Justification for type of information:

There are no relevant variations in qualitative properties among source substances and the same potency is predicted for all target substances. This is Scenario 4 of the RAAF1. Substances MMP, BuMP, EHMP, iOMP, iC13MP, and ODMP are different alkyl esters of a common acid, 3-mercaptopropionic acid (3-MPA).

This scenario covers the category approach for which the read-across hypothesis is based on the assumption, that toxicity of compounds in this category are driven by a common toxophore. This approach serves to use existing data on genotoxicity, acute toxicity, repeated-dose toxicity and reproductive toxicity endpoints for substances in this category. 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 effects forming a regular pattern. This corresponds to Scenario 4 of the RAAF. The substances MMP, BuMP, EHMP, iOMP, iC13MP, and ODMP are esters of a common acid, 3-mercaptopropionic acid (3-MPA). All category members share the same mercaptopropionic acid moiety with one free SH group per MPA unit. The MPA unit with free SH is a prerequisite for this category.
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 free SH group of the MPA moiety.
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 detailed information please refer to section 13.2.

Reason / purpose for cross-reference:

read-across: supporting information

Reason / purpose for cross-reference:

read-across source

Species:

rat

Route of administration:

inhalation: vapour

Key result

Sex:

male/female

Dose descriptor:

LC50

Effect level:

2.85 mg/L air

Based on:

test mat.

Exp. duration:

4 h

Interpretation of results:

Category 3 based on GHS criteria

Conclusions:

Based on read-across from MMP, the 4-h Inhalation LC50 of BuMP as vapour is 2.85 mg/L. This read across is conservative due to the lower vapour pressure of BuMP.

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:

adverse effect observed

Dose descriptor:

LC50

Value:

2.85 mg/m³ air

Acute toxicity: via dermal route

Link to relevant study records

Reference

Endpoint:

acute toxicity: dermal

Type of information:

read-across based on grouping of substances (category approach)

Adequacy of study:

key study

Justification for type of information:

There are no relevant variations in qualitative properties among source substances and the same potency is predicted for all target substances. This is Scenario 4 of the RAAF1. Substances MMP, BuMP, EHMP, iOMP, iC13MP, and ODMP are different alkyl esters of a common acid, 3-mercaptopropionic acid (3-MPA).

This scenario covers the category approach for which the read-across hypothesis is based on the assumption, that toxicity of compounds in this category are driven by a common toxophore. This approach serves to use existing data on genotoxicity, acute toxicity, repeated-dose toxicity and reproductive toxicity endpoints for substances in this category. 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 effects forming a regular pattern. This corresponds to Scenario 4 of the RAAF. The substances MMP, BuMP, EHMP, iOMP, iC13MP, and ODMP are esters of a common acid, 3-mercaptopropionic acid (3-MPA). All category members share the same mercaptopropionic acid moiety with one free SH group per MPA unit. The MPA unit with free SH is a prerequisite for this category.
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 free SH group of the MPA moiety.
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 detailed information please refer to section 13.2.

Reason / purpose for cross-reference:

read-across: supporting information

Reason / purpose for cross-reference:

read-across source

Remarks:

Source MMP (CAS No. 2935-90-2)

Key result

Sex:

male/female

Dose descriptor:

LD50

Effect level:

2 572 mg/kg bw

Based on:

test mat.

Remarks on result:

other: corrected for molecular weight differences

Interpretation of results:

GHS criteria not met

Conclusions:

Based on read-across from MMP, the dermal LD50 of BuMP is 2572 mg/kg bw.

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:

LD50

Value:

> 2 000 mg/kg bw

Additional information

No acute toxicity study is available for BuMP. However, experimental data on acute toxicity are available for 3-MPA, MMP, iOMP, and iC13 MP for the oral route. Acute dermal toxicity studies are available for MMP and iOMP. Acute inhalation toxicity studies are available for 3-MPA and MMP. A justification for read-across is attached to Iuclid section 13.

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.

Acute oral toxicity

MMP

In a study similar to OECD TG 401, male and female Sprague-Dawley rats (5/sex/dose) were administered a single dose of MMP by gavage at dose levels of 50, 100, 150, 250, 500 and 5000 mg/kg bw. The animals were observed for 14 days.

All female and male animals died within 4 hours of treatment with 250, 500, 5000 mg/kg bw with the exception of one male animal that completely recovered by Day 5.

LD50 Male: 206.4 mg/kg bw (149.0 to 285.9)
LD 50 Female: 181.7 mg/kg bw (132.6 to 248.9)
LD50 Combined: 193.6 mg/kg bw (154.2 to 243.2)

 

iOMP

In a study according to OECD TG 401, male and female Sprague-Dawley rats (5/sex/dose) were administered a single dose of iOMP at dose levels of 354, 500 and 707 mg/kg bw (males) or 354 mg/kg bw (females). The animals were observed for 14 days.

Deaths were noted at dose levels of 707 (3 males found dead approximately 3 hours after dosing) and 500 mg/kg (1 male 2 hours after dosing) bw during the day of dosing.

Common signs of systemic toxicity noted in all dose groups were hunched posture, lethargy, decreased respiratory rate and labored respiration. Ataxia was commonly noted in animals treated with 707 and 500 mg/kg bw. Common signs of systemic toxicity noted in animals treated with 707 mg/kg bw were prostration, clonic and tonic convulsions. Occasional body tremors were commonly noted in females treated with 354 mg/kg bw with incidents of occasional body tremors noted in animals treated with 707 and 500 mg/kg bw. Incidents of vocalization and chromodacryorrhoea were noted in animals treated with 707 mg/kg bw with incidents of prostration, increased salivation and ptosis and an isolated incident of pilo-erection noted in animals treated with 500 mg/kg bw. Incidents of splayed gait were noted in animals treated with 500 and 354 mg/kg bw with incidents of ataxia noted in males treated with 354 mg/kg.

Surviving animals recovered four to eight days after dosing.

The LD50 (males) was 674 mg/kg bw.

 

iC13MP

A study was performed to assess the acute oral toxicity of iC13MP following a single oral administration to the Sprague Dawley CD strain rat. The method used was according to the "Acute toxic Class Method”.
200 mg/kg bodyweight was selected as the starting dose. A group of three females was treated with the starting dose of 200 mg/kg. This was followed by a group of three males at the same dose level. Based on the results from this dose level a further group of females was treated at a dose level of 2000 mg/kg bodyweight and a further group of males and females was treated at a dose level of 500 mg/kg bw. Dosing was performed sequentially. The test material was administered orally as a solution in arachis oil. Animals were observed for 14 days.

Two females treated with 2000mg/kg were found dead during the day of dosing and the remaining female treated with 2000mg/kg was found dead one day after dosing. Clinical signs of toxicity noted, prior to death, in animals treated with 2000mg/kg were hunched posture, lethargy, decreased respiratory rate, laboured respiration, prostration, ataxia, increased salivation, tonic convulsions and pallor of the extremities. Clinical signs of toxicity noted in animals treated with 500 mg/kg were hunched posture, up to one day after dosing. No clinical signs of toxicity were noted in animals treated with 200 mg/kg. The surviving animals showed expected gains in bodyweight over the study period.

Abnormalities noted at necropsy of animals that died during the study were haemorrhagic lungs, dark liver and dark kidneys. No abnormalities were noted at necropsy of animals that were killed at the end of the study. Mortalities were noted at a dose level of 2000 mg/kg bodyweight. No mortalities were noted in animals treated with 200 or 500 mg/kg bw.

The acute oral LD50 of the test material was determined to be greater than 500 mg/kg bw but less than 2000 mg/kg bw.

 

Acute dermal toxicity

MMP

In an acute dermal toxicity study similar to OECD TG 402, MMP was applied to the trunk of New Zealand White rabbits (3/sex/dose) and maintained in contact for 24 hours at doses of 1000, 1500, 2000 or 2500 mg/kg bw. The animals were observed for 14 days.

All animals survived at the 1000 mg/kg bw dose, 2 m / 1 f died at 1500 mg/ kg bw, 1 m / 2 f died at 2000 mg/kg bw/d, and 2 m / 2 f died at 2500 mg/kg bw.

All animals dosed 1000 mg/kg bw of body weight appeared normal during the study with exception of slight depression in one male at 1 hour and one female at 4 hours.  Effects of toxicity in the remaining animals were noted by 1 hour post dosing and included one or more of the following: depression, slight depression, laboured respiration, cyanotic appearance, anorexia, and tremors.    

The dermal LD50 of MMP in rabbit was 1905 mg/kg bw.

 

iOMP

In an acute dermal toxicity study according to OECD TG 434 5 female Wistar rats were dermally exposed to iOMP at a single dose of 2000 mg/kg bw (24 h, occlusive). The animals were observed for 14 days. No mortality occurred during the study. In the main study 1 out of 4 animals showed a bloody nose on day 9 after the application of the test item. This finding is considered to be incidental and not treatment related. No other clinical signs of toxicity were observed throughout the observation period, neither in the sighting nor in the main study. The dermal LD50 was >2000 mg/kg bw.

 

Acute inhaltion toxicity

3-MPA

In an acute inhalation toxicity study according to OECD TG 403, three groups of Wistar rats were nose-only exposed to 3-MPA as liquid aerosol in concentrations of 860, 1350, and 2053 mg/m³ air. The 4 h LC50 was 1.818 mg/L

Mortality occurred in few rats at 1350 mg/m³ and above. All exposure concentrations caused pronounced irritant effects in the upper respiratory tract (nose) and central nervous effects. The following clinical signs were observed: bradypnea, irregular breathing patterns, tachypnea, labored breathing patterns, dyspnea, vocalization, breathing sounds, high-legged gait, salivation, nasal discharge (serous), nose: reddened, nose: swollen, nostrils/muzzle: red encrustations, nose: necrosis, piloerection, hair-coat ungroomed, behavioral changes (transient), exaggerated

response, fasciculations, convulsions (tonic), jerks, tremor, motility increased, motility reduced, limp, apathy, flaccidity (hindlegs), prostration, exophthalmia, miosis, chromodacryorrhea, cornea: opalescence, lens: opalescence, eyelids: red encrustations, cyanosis, emaciation, abdominal enlargement, hypothermia, decreased reflexes, and decreased body weights.

Internationally recognised recommendations such as of SOT (1992) were fulfilled, in regard to the respirability of the aerosol generated, i.e. the MMAD was <4 µm (MMAD 2.5-2.7 µm, GSD 1.9). NO(A)EC Males & females: <860 mg/m³ air

In summary, the aerosolized test substance (liquid aerosol of undiluted test article) proved to have a moderate to low acute inhalation toxicity in rats.

 

MMP

In an acute inhalation toxicity study similar to OECD TG 403 Crl:CD(SD)BR rats (5/sex/dose) were exposed by inhalation (head-only) over a period of 4 hours to MMP at nominal concentrations of 396, 437, 682, 595, and 815 ppm (276, 350, 456, 493, and 529 ppm (mean measured), equivalent to 1.35, 1.72, 2.24, 2.42, and 2.60 mg/L, respectively). A similar group of 10 rats (5/sex) were exposed to room air as a control. Exposure was followed by an observation period of at least 14 days. The animals were observed for 14 days.

The 4 h LC50 of MMP as vapour is 430 ppm (2.11 mg/L).

 

 

Conclusion for BuMP

Based on the available data in the category, the oral LD50 of BuMP is predicted to be 262 mg/kg bw, the dermal LD50 is predicted to be >2000 mg/kg bw, the inhalation LC50 is predicted to be 2.85 mg/L air.

Justification for classification or non-classification

Based on read across from MMP, BuMP is considered toxic if swallowed (LD50 = 262 mg/kg bw, Acute Tox 3 - H301) and toxic by inhalation (4-h LC50, vapour = 2.85 mg/L, Acute Tox 3 - H331). No classicifcation is required for acute dermal toxicity.