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Please be aware that this old REACH registration data factsheet is no longer maintained; it remains frozen as of 19th May 2023.

The new ECHA CHEM database has been released by ECHA, and it now contains all REACH registration data. There are more details on the transition of ECHA's published data to ECHA CHEM here.

Diss Factsheets

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.86 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
12.5
Dose descriptor starting point:
NOAEL
Value:
8.8 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
10.9 mg/m³
Explanation for the modification of the dose descriptor starting point:

Please refer to additional information.

AF for dose response relationship:
1
Justification:
The dose response relationship is considered unremarkable, therefore no additional factor is used.
AF for differences in duration of exposure:
1
Justification:
No time extrapolation factor is needed since a chronic toxicity study is available.

AF for interspecies differences (allometric scaling):
1
Justification:
Respiratory interspecies differences are fully covered by the factors used for route to route extrapolation.
AF for other interspecies differences:
2.5
Justification:
Default AF for remaining differences.
AF for intraspecies differences:
5
Justification:
The default value for the relatively homogenous group "worker" is used.
AF for the quality of the whole database:
1
Justification:
The quality of the whole data base is considered to be sufficient and uncritical.
AF for remaining uncertainties:
1
Justification:
The approach used for DNEL derivation is conservative. No further assessment factors are required.
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
8.4 mg/m³
Most sensitive endpoint:
acute toxicity
Route of original study:
By inhalation
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
100
Explanation for the modification of the dose descriptor starting point:

Please refer to additional information.

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
skin irritation/corrosion
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
skin irritation/corrosion
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
4.2 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Dermal
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
180
Dose descriptor starting point:
NOAEL
Value:
1 000 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
750 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

Please refer to additional information.

AF for dose response relationship:
1
Justification:
The dose response relationship is considered unremarkable, therefore no additional factor is used.
AF for differences in duration of exposure:
6
Justification:
The default extrapolation factor for exposure duration is used: subacute (starting point) to chronic (end point).
AF for interspecies differences (allometric scaling):
2.4
Justification:
The default allometric scaling factor for the differences between rabbits and humans is used.
AF for other interspecies differences:
2.5
Justification:
Default AF for other interspecies differences.
AF for intraspecies differences:
5
Justification:
The default value for the relatively homogenous group "worker" is used.
AF for the quality of the whole database:
1
Justification:
The quality of the whole data base is considered to be sufficient and uncritical.
AF for remaining uncertainties:
1
Justification:
The approach used for DNEL derivation is conservative. No further assessment factors are required.
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
acute toxicity
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)
Most sensitive endpoint:
sensitisation (skin)
Acute/short term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)
Most sensitive endpoint:
sensitisation (skin)

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - workers

General


DNEL derivation for the test item is performed under consideration of the recommendations of ECHA, Guidance on information requirements and chemical safety assessment, Chapter R.8: Characterization of dose-response for human health (Version: 2.1, November 2012).


Inhalation


Long term, systemic DNEL – exposure via inhalation (workers)


No repeated dose inhalation toxicity study with the target substance is available. Therefore, it will be necessary to obtain a long-term DNEL by route-to-route extrapolation:


A study according EPA OPP 83-5 (GLP) and similar to OECD TG 453 performed in rats is available and a 1-year oral administration study in dogs. The study according OECD TG 453 performed in rats was used as key study because of the chronic exposure duration compared to the 1-year dog study.


In males and females rats at dose levels of 1200 or 6000 ppm treatment-related effects were seen which included body weight depression, anemia, accelerated nephropathy, adrenal cortical lipidosis, hepatocellular hypertrophy with an associated increase in serum cholesterol and total protein, decreased T3/T4, increased TSH, and thyroid follicular hyperplasia. A treatment-related increase in organ weights of liver, thyroid and kidneys also occurred. Based upon body weight depression and mortality, the MTD was determined to be 1200 ppm for both sexes. At 6000 ppm, approximately 5 times the MTD, an increase in thyroid follicular cell adenomas was observed in the males. These adenomas were considered to be a secondary effect, related to the treatment-related changes in hormonal homeostasis of the pituitary-thyroid axis. The NOAEL was 200 ppm (8.8 and 10.2 mg/kg bw/day in male and female rats, respectively).


The substance is harmonized classified for Muta. 2 (H341) and is harmonized classified for carcinogenicity Cat.2 (H351). The experimental results suggest that for the mutagenicity of the test item an aneugenic mechanism is prevalent while clastogenicity is not demonstrated. The available in vivo studies in germ cells did not demonstrate any genotoxic effect.


According to the new Draft guidance on aneugenicity assessment (EFSA Scientific Committee (SC), 2020) TPM is a purely aneugenic substance and threshold setting is justified based on the underlying mode of action (please refer to attached statement).


If a substance is demonstrated to be an aneugen, it is assumed that its genotoxicity is thresholded, in contrast to non-thresholded genotoxicity. Both types of genotoxicity mechanisms trigger different ways to perform risk assessment (ECHA Endpoint specific guidance 7a, 2017). Therefore, a DNEL was derived and the NOAEL of 8.8 mg/kg bw/day was as PoD.


 


Step 1: PoD: NOAEL = 8.8 mg/kg bw/day


Step 2: Modification of PoD:


Standard respiratory volume, human (sRVhuman) for 8 hours: 6.7 m3


Standard respiratory volume of the rat (sRVrat) for 8 hours: 0.38 m3/kg bw


Worker respiratory volume (wRV) for 8 hours with light physical activity: 10 m3


Oral absorption of the rat/ inhalation absorption of humans (ABS oral-rat / ABS inh-human): 50%/100 % (default)


Correction for difference between human and experimental exposure conditions: 7 d rat/5 d worker


Corrected NOAEC (inhalation) for workers:


= 8.8 mg/kg bw/day x 0.5 x 1/0.38 m3/kg bw/day x (6.7 m3/10 m3) x 1.4


= 10.9 mg/m3


Step 3: Overall AF= 12.5


Intraspecies AF (worker): 5


Interspecies AF, remaining differences: 2.5


Dose response relationship AF: 1


Exposure duration AF: 1 (chronic study)


Whole database AF: 1


The toxicity study was conducted according to regulatory standards and was adequately reported. On this basis the quality of the database is not considered to contribute uncertainty and it is therefore not necessary to apply an additional factor.


In conclusion,long term systemic inhalation DNEL, workers = 0.86 mg/m3


Acute, systemic DNEL- exposure via inhalation (workers)


Due to the acute inhalation toxicity observed for the test item (LC50=1700 mg/m3), the substance is considered to be classified for acute inhalation toxicity Cat.4 under Regulation (EC) No 1272/2008. In the ECHA Guidance it is stated that “[...] a DNEL for acute toxicity should be derived if an acute toxicity hazard (leading to C&L) has been identified and there is a potential for high peak exposures.”


From an acute toxicity study a LC50 of 1700 mg/m3 was obtained. In this study sub-lethal effects have been reported for male and female animals at 500 mg/m3 (0.5 mg/L) after 4 h exposure (=240 min). This dose is used as PoD.


Time extrapolation using the modified Haber´s law: Cnx t = k; n=3 for extrapolation from long to short exposure times, C=0.5 mg/L, t=240 min


Cnx t = Cn’ x t’


0.53x 240 min = Cn‘ x 15 min


C‘ =


³√[(0.125*240)/15]


For a 15 min exposure time: C’=1.26 mg/L


Correction for differences in respiratory volumes between animals (usually at rest) and humans (light activity for worker): 0.67


1.26 mg/L x 0.67 = 0.84 mg/L


AF: 100 (default)


0.84/100


DNEL, short-term systemic inhalation = 8.4 mg/m3


Long term & acute, local DNEL- exposure via inhalation (workers)


The substance is not classified for skin/eye irritation and in conclusion local mucosal membrane damage of the respiratory membranes is not expected. Therefore, no DNEL was derived.


Dermal


Long term, systemic DNEL- exposure via dermal route (workers)


A subacute repeated dose dermal toxicity study with the target substance is available.


A study according to EPA 82-2 and similar to OECD TG 410 was conducted. New-Zealand White rabbits were treated with the substance at doses of 100, 300 and 1000 mg/kg bw/day. The NOAEL is considered to be 1000 mg/kg bw/day under the conditions of this study.


Step 1:PoD: NOAEL = 1000 mg/kg bw/day


Step 2:Modification into a correct starting point:


Correction for difference between human and experimental exposure conditions: 6 h per day/5 days vs. 8 h per day/5 days (=0.75)


Corrected NOAEL (dermal) for workers:


= 1000 mg/kg bw/day x 0.75


= 750 mg/kg bw/day


Step 3:Overall AF= 180


Interspecies AF, allometric scaling (rabbit to human): 2.4


Interspecies AF, remaining differences: 2.5


Intraspecies AF (worker): 5


Dose-response relationship AF: 1


Exposureduration AF: 6 (subacute to chronic)


In conclusion,long term systemic dermal DNEL, workers = 4.2 mg/kg bw/day


Acute, systemic DNEL- dermal exposure (workers)


According to ECHA Guidance on information requirements and chemical safety, Chapter R.8, Appendix R. 8-8, „a DNEL for acute toxicity should be derived if an acute toxicity hazard (leading to C&L) has been identified. The substance has low acute dermal toxicity with the LD50 of >2000 mg/kg. Therefore, the DNEL is not required.


Long term & acute, local DNEL- dermal exposure (workers)


According to the REACH guidance on information requirements and chemical safety assessment, Part E: Risk Characterization, a qualitative risk characterization should be performed for this endpoint. This qualitative approach has to be implemented to deal with the skin sensitizing properties of the substance. As a result, a medium hazard is derived. In order to guarantee "adequately control of risks", it is necessary to stipulate risk management measures that prevent skin, eye and mucous membrane exposure.


Hazard to the eye-local effects (worker)


The test item is not classified for eye damage according to Regulation (EC) No 1272/2008 (CLP).


 


References


ECHA (2012). Guidance on information requirements and chemical safety assessment. Chapter R.8:


Characterisation of dose [concentration]-response for human health. Version 2.1, November 2012


ECHA (2016). Guidance on information requirements and chemical safety assessment. Part E: Risk Characterisation, Version 3.0, May 2016


ECHA (2017).Guidance on Information Requirements and Chemical Safety Assessment, Chapter R.7a: Endpoint specific guidance, Version 6.0


SCC GmbH; 2020. Evaluation of the genotoxicity hazard of Thiophanate-methyl (TPM, CAS 23564-05-8) based on the Draft guidance on aneugenicity assessment (EFSA Scientific Committee (SC), 2020)

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
acute toxicity
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - General Population

No hazard to the general population is expected since the substance is only formulated in plant protection products in EU and afterwards exported.