reaction mass of dipentarythritol and 3-mercaptopropionic acid

Endpoint summary

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:

Currently, do data on toxicokinetics/metabolism is available for this category. Based on structural features (e.g. sterical hindrance) it is however assumed, that ester cleavage would not be fast and complete, especially since the substances contain up to 6 ester functions, which are in addition sterically shielded. Therefore, it seems more reasonable to base the category hypothesis on structural similarity.
In addition, it is not clear yet, whether the strength of the effects vary in a predictable manner, or if no relevant variations occur. However, there are variations in structure (number of ester bonds and consequently number of free -SH groups) and physicochemical properties (especially water solubility and log Kow). It is assumed that these variations will also be reflected by variations in effect levels. Therefore, scenario 4 is the working hypothesis for the time being.
More data points within the category are needed to further strengthen the category hypothesis. The scenario selection will be re-evaluated after the studies are finished.
This currently selected scenario covers the category approach for which the read-across hypothesis is based on structural similarity. 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 expected to be differences in strength of the effects forming a regular pattern. The prediction will be based on a worst-case approach. The read-across is a category approach based on the hypothesis that the substances in this category share structural similarities with common functional groups. This approach serves to use existing data on acute toxicity, repeated-dose toxicity, and reproductive toxicity endpoints for substances in this category.
The hypothesis corresponds to Scenario 4 of the RAAF. The substances GDMP, TMPMP, PETMP, and Di-PETMP are esters of a common acid, 3-mercaptopropionic acid (3-MPA). The key functionality of the substances within this category is the presence of free SH-groups. It is hypothesised that the strength of effects correlates with the number of SH-groups. In addition, differences in bioavailability are expected to influence the strength of effects.
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

Sex:

female

Dose descriptor:

LD50

Effect level:

> 1 600 - < 3 200 mg/kg bw

Based on:

test mat.

Interpretation of results:

Category 4 based on GHS criteria

Conclusions:

Based on read-across from PETMP and GDMP, the LD50 for Di-PETMP is estimated to be 1600 - 3200 mg/kg bw

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LD50

Value:

> 1 600 - < 3 200 mg/kg bw

Acute toxicity: via inhalation route

Endpoint conclusion

Endpoint conclusion:

no study available

Acute toxicity: via dermal route

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

No experimental data on acute toxicity are available for Di-PETMP. Studies are available for PETMP for the oral and inhalation route, and for GDMP for the oral route. A justification for read-across is attached to Iuclid section 13.

 

Acute oral toxicity

GDMP

A single dose oral treatment (gavage) was performed with GDMP according to the acute toxic class method (OECD 423 and Commission Regulation (EC) No 440/2008 of 30 May 2008, B.1.tris) in Han:WIST rats.
Three groups of three female rats each were treated with the test item at a dose level of 300 (Groups 1 and Group 2) or 2000 (Groups 3) mg/kg body weight (bw).

At the dose level of 2000 mg/kg bw, 2/3 animals were found dead on Day 0 and 1/3 on Day 1.
At the dose level of 300 mg/kg bw, one animal (out of 6) was found dead on Day 6, five animals survived.

Clinical symptoms such as slight decreased activity, hunched back and on the day of treatment were noted in the 300 mg/kg bw group. Tonic convulsions with vocalization were observed twenty minutes after the treatment followed by moderate decreased activity and prone position at thirty minutes after the treatment in two out of three animals at the dose level of 2000 mg/kg bw. The animals were found dead at 1 hour after treatment. In one animal moderate decreased activity, hunched back, piloerection and continuous tremors were observed on the day of treatment. The animal was found dead on Day 1.

Under the conditions of this study, the acute oral LD50 value of the test item was found to be 300 < LD50 ≤ 2000 mg/kg bw in female Han:WIST rats. The LD50 cut-off value is 500 mg/kg bw.

 

PETMP

A study was performed to assess the acute oral toxicity of PETMP following a single oral administration in the Sprague-Dawley CD strain rat in accordance with OECD TG 423. A group of three fasted females was treated with the test material at a dose level of 300 mg/kg bodyweight. Based on the results from this dose level further groups of fasted females were treated at dose levels of 2000 and 300 mg/kg bodyweight.
Two animals treated with 2000 mg/kg were found dead four hours or two days after dosing. One animal treated with 2000 mg/kg was killed in extremis one day after dosing. There were no deaths noted in animals treated with 300 mg/kg.
Signs of systemic toxicity noted in animals treated with 2000 mg/kg were hunched posture, increased lachrymation, clonic and/or tonic convulsions, pilo-erection, ptosis, decreased respiratory rate, laboured respiration, loss of righting reflex, ataxia and hypothermia.
One animal treated with 2000 mg/mg was found comatose. Signs of systemic toxicity noted in animals treated with 300 mg/kg were hunched posture, increased lachrymation, clonic and/or tonic convulsions and pilo-erection. Abnormalities noted at necropsy of animals that died or were killed in extremis during the study were abnormally red lungs, dark liver, slight haemorrhage or sloughing of the gastric mucosa and slight haemorrhage of the non-glandular epithelium of the stomach. No abnormalities were noted at necropsy of animals that were killed at the end of the study. The acute oral median lethal dose (LD50) of the test material was estimated to be in the range of 1000 - 2000 mg/kg bw.

 

Acute inhalation toxicity

A study on the acute inhalation toxicity of PETMP on rats was conducted in accordance with OECD TG 403. Two groups of rats were nose-only exposed to actual liquid aerosol at concentrations of 1505 and 3363 mg/m³ air. Mortality did not occur up to the maximum technically attainable concentration.

Clinical signs suggestive of respiratory tract irritation (laboured and irregular breathing patterns, bradypnea, muzzle area with red encrustations) occurred concentration-dependent and were essentially reversible within the first post-exposure week. The 4 h LC50 was >3363 mg/m³

 

Acute toxicity data of 3-MPA esters

	Acute oral toxicity	Acute dermal toxicity	Acute inhalation toxicity
GDMP	LD50 cut-off = 500 mg/kg bw   (2.1 mmol/kg bw)	No data	No data
TMPMP	No data	No data	No data
PETMP	LD50 = 1000 – 2000 mg/kg bw   (2.05-4.1 mmol/kg bw)	No data
Di-PETMP	No data	No data	No data

 

The LD50 cut-off of GDMP is similar to the lower end of the LD50 range of PETMP; however, the actual LD50 of PETMP is probably >1000 mg/kg bw. This increase in oral LD50 values - also when calculated in mmol/ kg bw from GDMP to PETMP could be explained by decreasing bioavailability, which can be expected based on increasing molecular weight and log Kow with in parallel decreasing water solubility.

 

Calculated LD50 and LC50 values

Substance	Estimated oral LD50 [mg/kg bw] (based on PETMP data, including molecular weight correction)	Estimated oral LD50 [mg/kg bw] (based on GDMP data, including molecular weight correction)
GDMP	487	n.a.
TMPMP	815	865
PETMP	n.a.	1025
Di-PETMP	1600	1640
Substance	Estimated inhalation LC50 [mg/m³]	---
GDMP	>1640	---
TMPMP	>2700	---

 

 

After correction for molecular weight differences, the LD50 for Di-PETMP is estimated to be approx.1600 mg/kg bw.

 

 

Justification for classification or non-classification

Based on read across from PETMP, Di-PETMP is assumed to be harmful if swallowed (LD50 >600 <3200 mg/kg bw, Acute Tox 4, H302) and non-toxic if inhaled (no mortality at highest attainable concentration).