Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.35 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:
5 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
4.41 mg/m³
Explanation for the modification of the dose descriptor starting point:

A two-generation reproduction study has been conducted at doses of 5, 15 and 25 mg/kg using

the p-(2,3-epoxypropoxy)- N,N-bis (2,3-epoxypropyl)aniline (MY0500) isomer. The results of this

test indicated that the 5 mg/kg bw/day was the No Observed Effect Level (NOEL) for the repeated

administration of the test item on reproduction, pre-natal development and post-natal

development of the rat when administered over two successive generations. The next highest

dose was 15 mg/kg bw/d and provided the LOEL. As noted during the conduct of the prenatal

developmental study irritation of the GI tract was observed at doses 15 mg/kg bw/day (15 and

25 mg/kg bw/d) and this indicates that there is a clear threshold dose whereby the primary toxicity

response is associated with the effects on the gastrointestinal tract (duodenum and stomach).


During the conduct of the two-generation reproduction study with the p-(2,3-epoxypropoxy)- N,Nbis

(2,3-epoxypropyl)aniline (MY0500) isomer the following effects were identified in animals

treated with 15 mg/kg bw d.


• Degeneration/atrophy of the glandular mucosa (minimal to moderate) of the stomach

• Degeneration/atrophy of the mucosa (minimal to mild) and regenerative hyperplasia of

the mucosa (minimal to mild) of the duodenum

• Regenerative hyperplasia of the mucosa (minimal) of the Jejunum


As a result of the effects described above it is proposed that 15 mg/kg bw d represents a clear

threshold dose for the mature animals and severe effects on the gastrointestinal tract which

subsequently leads to a detrimental health status on the animals. At a dose of 5 mg/kg bw d the

following effects were identified:


• P0 Parental liver weight

• Pituitary weight P0 females

• Prostate gland weight (F1)

• Epididymis weight (F1)

• Kidney weight (F1)

• Testes Weight (F1)

• Seminal vesicle weight (F1)


Only two out of the seven endpoints described above are identified in the parental animals and

the remaining five are relevant to the F1 offspring. It is proposed that the effects on liver weight

and pituitary weight in the P0 generation reflects first pass metabolism becoming saturated due

to the length of the exposure regime to high dose levels tested (350 mg per day based on 70kg

human equivalent, which is completely unfeasible based on the proposed industrial applications/uses). Using this argumentation, there is no surprise that younger F1 animals are

more susceptible and that there is a manifestation of sublethal effects..


It is proposed that the use of either 5 or 15 mg/kg bw d could be considered as the NOEL for risk

assessment purposes. The effects identified at 5 mg/kg bw d in F1 animals are the consequence

of parental animals with compromised health status e.g. pituitary and liver weight changes are

both classic signs of metabolism systems under stress. Whilst 15 mg/kg bw d would be protective

and suitable for industrial applications currently registered it is suggested that a conservative

DNEL is derived using a NOEL of 5 mg/kg bw d.


Hazard identification

The extensive data set for p-(2,3-epoxypropoxy)- N,N-bis (2,3-epoxypropyl)aniline (MY0500) m-

(2,3-epoxypropoxy)- N,N-bis (2,3-epoxypropyl)aniline (MY0600) clearly presents the toxicological

cascade of effects following exposure. At doses greater than 15 mg/kg bw d combined with repeated and reproductive test duration animals are clearly compromised by the effects on saturated metabolism pathways which leads to apical endpoints of irritation, corrosion and ulceration of the of the gastrointestinal epithelia (Annex 1 Read Across). At a reduced dose of 5 mg/kg bw d combined with repeated and reproductive test durations there is insufficient dose and time available to overwhelm and cause damage to the gastrointestinal tract but the lower dose and same timescale are sufficient to identify that first pass metabolic systems are under significant stress which is represented by changes in pituitary and liver weights. An Adverse Outcome Pathway has been proposed in Annex 2 of Read Across).


Risk Characterisation

It should not be ignored that sensitizing properties were identified following exposure to both, p-

(2,3-epoxypropoxy)- N,N-bis (2,3-epoxypropyl)aniline (MY0500) m-(2,3-epoxypropoxy)- N,N-bis

(2,3-epoxypropyl)aniline (MY0600), both substances are classified as category 1A sensitizers

and fall within the “High hazard band” of ECHAs Part E guidance: Risk Characterisation Guidance

(Table E. 3.1). The prescribed protection for tackling sensitization creates an overarching “hazard

umbrella” i.e. potential for exposure needs to be eliminated. This “hazard umbrella”, the relevant

risk management measures and personal protective equipment requirements effectively

eliminates the need for quantitative risk assessment and the relevance of any NOEL/DNEL values

derived via the repeat dose or reproduction studies.


Parental seminal vesicle, testes and epididymis and spleen weights most sensitive endpoints at 15 mg/kg bw d although it should be noted that the following effects were also present at 15 mg/kg bw d Degeneration/atrophy of the mucosa (minimal to mild) duodenum Regenerative hyperplasia of the mucosa (minimal to mild) duodenum and therefore at doses equal to or greater than 15 mg/kg bw d irritation/corrosion to the gastrointestinal tract is the primary toxicological response and all other effects are due to the health status of the exposed animals.


A conservative approach has been used and the NOAEL of 5 mg/kg bw d used for risk characterisaion.

The oral endpoint of 5 mg/kg bw d has been converted to an NOAEC as follows:


5/2 / 0.38 = Inhalation NOAEL of 6.57 mg/m3 (8h) NOAEC = 6.57 x 0.67 = 4.40 mg/m 3


The REACH Guidance on information requirements and chemical safety assessment (R.8.4.2) prescribes a default factor of 2 in case of oral to inhalation extrapolation. Standard respiratory volume of a rat, corrected for 8 h exposure, as proposed in the REACH Guidance on information requirements and chemical safety assessment (R.8.4.2)

Justification:
Oral endpoint is derived from a chronic oral 2-generation reproductive study and therefore an assessment factoer for
AF for other interspecies differences:
2.5
Justification:
Remaining difference
AF for intraspecies differences:
5
Justification:
Worker population
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
hazard unknown (no further information necessary)
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown (no further information necessary)
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.1 mg/kg bw/day
Most sensitive endpoint:
effect on fertility
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
50
Modified dose descriptor starting point:
NOAEL
Value:
5 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
On the assumption that, in general, dermal absorption will not be higher than oral absorption, no default factor is introduced for the oral to dermal extrapolation. The REACH Guidance on information requirements and chemical safety assessment (R.8.4.2) prescribes a default factor of 1 in case of oral to dermal extrapolation.
Justification:
Assessment factor is not required, the NOAEL is derived using a chronic 2-generation reproduction study.
AF for interspecies differences (allometric scaling):
4
Justification:
Rats to humans
AF for other interspecies differences:
2.5
Justification:
Remaining differences
AF for intraspecies differences:
5
Justification:
Worker population
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
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:
no hazard identified

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - workers

According to the REACH Guidance on information requirements and chemical safety assessment, a leading DN(M)EL needs to be derived for every relevant human population and every relevant route, duration and frequency of exposure, if feasible. 

Short-term toxicity:

According to the REACH guideline (R8, Appendix R 8-8), 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 risk for high peak exposures. Since the substance is not classified for acute dermal and inhalation, no short-term DNELs needs to be derived for these routes of exposure.

Additionally long-term DNELs are normally sufficient to ensure that effects do not occur and to protect workers, if long term DNELs are maintained.

Skin sensitisation:

The substance is considered to a skin sensitizer and classified Skin sens. Cat 1B.

Long-term toxicity:

A chronic oral 2 -generation reproduction study in the rat is available, A NOAEL of 25 mg/kg bw was determined for systemic toxicity.

Since only a chronic oral toxicity study is available a route-to-route extrapolation is needed to derive the DNELs for dermal and inhalation route.According to Chapter R.8 of REACH Guidance on information requirements and chemical safety assessment, it is proposed in the absence of route-specific information on the starting route, to include a default factor of 2 in the case of oral-to-inhalation extrapolation. On the assumption that, in general, dermal absorption will not be higher than oral absorption, no default factor is introduced for the oral to dermal extrapolation. The REACH Guidance on information requirements and chemical safety assessment (R.8.4.2) prescribes a default factor of 1 in case of oral to dermal extrapolation. This approach will be taken forward to DNEL derivation.

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
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