2-tert-butylaminoethyl methacrylate

Endpoint summary

Description of key information

The only repeat dose study available on 2-tert-butylaminethyl methacrylate is an OECD 422 repeated dose toxicity oral study, via the drinking water.  The NOAEL from this study can also be used to calculate DNELs for the dermal and inhalation routes.   Testing is not scientifically justified for these routes due to the corrosive properties of 2-tert-butylaminethyl methacrylate and the limited possibility of exposure by these routes in the workplace.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Reference

Endpoint:

short-term repeated dose toxicity: oral

Remarks:

combined repeated dose and reproduction / developmental screening

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Guideline study without detailed documentation. Peer-reviewed database.

Qualifier:

according to guideline

Guideline:

OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)

GLP compliance:

yes

Specific details on test material used for the study:

Test substance 99.9% purity, Sanyo-Kasei. Co

Species:

rat

Strain:

Crj: CD(SD)

Details on species / strain selection:

Rats supplied by Charles River Japan

Sex:

male/female

Details on test animals or test system and environmental conditions:

Rats were purchased at 7 weeks of age. After quarantine and acclimatisation for 7 days

Route of administration:

oral: gavage

Vehicle:

corn oil

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

Males: 43 days
Females: from 14 days before mating to day 3 of lactation (41 -52 days)

Frequency of treatment:

once daily

Remarks:

Doses / Concentrations:
0 (Vehicle), 40, 200, 1000 mg/kg/day
Basis:
actual ingested

No. of animals per sex per dose:

12

Control animals:

yes, concurrent vehicle

Details on study design:

- Dose selection rationale: As the LD50 value of > 2000 mg/kg was known, a preliminary test to decide the highest dose level at 30, 100, 300, and 1000 mg/kg/day for 14 days was conducted. At 1000 mg/kg/day, decrease of body weight in males and suppression of body weight increase in females were observed. Then the highest dose level for the test was set at 1000 mg/kg/day.
- Post-exposure period: 1 day

Details on results:

MALES:
At 1000 mg/kg/day, no deaths occured. Clinical observations revealed late onset of twitching, chronic convulsion and suppression of body weight gain. The histopathological examinations revealed a degeneration of nerve fibers in the brain and spinal cord, hyperplasia of the mucosa, edema and inflammatory cell infiltration in the forestomach and increased kidney and liver weights without histopathological correlates. Hematological and blood chemical examinations revealed a slight increase in BUN and slight anemic changes such as decreases in erythrocyte counts, hemoglobin concentration and hematocrit value, associated with a significant increase in reticulocyte ratio.

At 200 mg/kg/day, no adverse effects except for slight anemic changes such as decrease in hemoglobin concentration and hematocrit value with
increase in reticulocyte ratio were observed. However, the severities of these slight anemic changes were considered toxicologically insignificant.

At 40 mg/kg/day, no effects were observed.

FEMALES:
At 1000 mg/kg/day, 3 females out of 12 died. By clinical observations, late onset of twitching, chronic convulsion, suppression of body weight gain and a decrease in food consumption during lactation period were observed. Histopathological examinations revealed a degeneration of nerve fibers in
the brain and the spinal cord, a hyperplasia of the mucosa in the gastric tract, edema and inflammatory cell infiltrations in the forestomach, and an atrophy of the thymus. Also the increases in the weight of the kidney and the adrenals without histopathological changes were observed.

At 200 mg/kg/day no effects were observed.

At 40 mg/kg/day no effects were observed.

Key result

Dose descriptor:

NOAEL

Effect level:

200 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

body weight and weight gain

food consumption and compound intake

haematology

histopathology: non-neoplastic

mortality

neuropathology

Dose descriptor:

NOEL

Effect level:

40 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male

Basis for effect level:

body weight and weight gain

food consumption and compound intake

haematology

neuropathology

Dose descriptor:

NOEL

Effect level:

200 mg/kg bw/day (actual dose received)

Sex:

female

Basis for effect level:

body weight and weight gain

food consumption and compound intake

mortality

neuropathology

Critical effects observed:

not specified

Hematological examination results in male rats (mean ± SD):

 

Dose mg/kg)	0	200	1000
No. of males	12	12	11
RBC (10000/µl)	881.7 ± 43.6	859.8 ± 36.7	821.6 ± 34.1**
Hematocrit (%)	46.73 ± 2.45	44.84 ± 1.26*	41.72 ± 1.97**
Hemoglobin (g/dL)	15.91 ± 0.69	15.28 ± 0.40*	14.24 ± 0.74**
Reticulocytes (‰)	17.81 ± 2.61	21.56 ± 3.57*	24.84 ± 3.75**

 

* = p<0.05, ** = p<0.01

_

Major histopathological findings in male rats:

 

Dose (mg/kg)	0	200	1000
No. of males	12	12	11
Findings in stomach:
Slight dilatation, gastric gland	0	0	0
Slight edema	0	0	7**
Slight hyperplasia, squamous, forestomach diffuse	0	0	11**
Slight inflammatory cell infiltration, forestomach	0	0	10**
Slight ulcer, forestomach	0	0	0
Slight ulcer, glandular stomach	0	0	0
Findings in brain:
Slight degeneration, nerve fiber	0	0	3
Findings in spinal cord:
Slight degeneration, nerve fiber	0	0	8**

 

** = p<0.01

_

Major histopathological findings in female rats:

 

Dose (mg/kg)	0		200	1000
	Surviving	Dead^a)		Surviving	Dead^b)
No. of females	11	1	12	9	3
Findings in stomach:
Slight dilatation, gastric gland	0	0	0	0	0/2
Slight edema	0	0	0	2	1/2
Slight hyperplasia, squamous, forestomach diffuse	0	0	0	9**	2/2
Slight inflammatory cell infiltration, forestomach	0	0	0	5**	1/2
Slight ulcer, forestomach	0	0	0	1	0/2
Slight ulcer, glandular stomach	0	0	0	0	1/2
Findings in brain:
Slight degeneration, nerve fiber	0	0	0	4	0
Findings in spinal cord:
Slight degeneration, nerve fiber	0	0	0	6**	0

a)     One female died of dystocia at gestation day 23

b)     Dead animals were observed at days 26 and 38 after administration

** = p<0.01

Conclusions:

According to this study, the NOAEL for oral (gavage) repeated dose toxicity in rats is considered to be 200 mg/kg/day for both sexes. The NOELs for repeated dose toxicity are considered to be 40 mg/kg/day for males and 200 mg/kg/day for females.

Executive summary:

The test substance was studied for oral (gavage) toxicity in rats in an OECD combined repeated dose and reproductive/developmental toxicity screening test at doses of 0, 40, 200 and 1000 mg/kg/day. The study was conducted in compliance with GLP.

Three females died in the 1000 mg/kg group. Soiled tail, twitching, chronic convulsion and suppression of body weight gain in both sexes, and a decrease in food consumption in females were also observed in the late period of administration in this group. Histopathological examination revealed degeneration of nerve fibers in the brain and spinal cord, and hyperplasia of the mucosa, edema and inflammatory cell infiltration in the forestomach in both sexes, and atrophy of the thymus in females in the 1000 mg/kg group. Increases in organ weights without histopathological changes were observed for the kidneys of both sexes, the livers of males, and the

adrenals of females in this group. BUN was slightly increased in males in the same group. Slight anemic changes were observed in males of the 200 and 1000 mg/kg groups.

Conclusion: According to this study, the NOAEL for oral (gavage) repeated dose toxicity in rats is considered to be 200 mg/kg/day for both sexes. The NOELs for repeated dose toxicity are considered to be 40 mg/kg/day for males and 200 mg/kg/day for females.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEL

200 mg/kg bw/day

Study duration:

subacute

Species:

rat

Quality of whole database:

There is no repeat dose oral dosing study for 2-tert-butylaminoethyl methacrylate but there is Klimisch 2 OECD422 repeat dose, gavage oral dosing study in rats on a read across substance 2-(dimethylamino)ethyl methacrylate CAS No 2867-47-2. A NOAEL of 200 mg/kg bodyweight/day was established, it is considered acceptable to use this value for read across to establish DNELs.

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Quality of whole database:

The requirement for a repeat dose inhalation study is waived due to the availability of a Klimisch 2 OECD422 study by the oral route and the technical difficulties of carry out an inhalation study with a corrosive substance. The oral NOAEL with the additional assessment factor of 2 can provide an adequate systemic DNEL.

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Quality of whole database:

There is no inhalation study available for 2-tert-butylaminethyl methacrylate. Due to the limited potential for inhalation exposure and the ethical considerations in performing an inhalation study with a test substance that is corrosive to skin and eyes indicates, it is not scientifically justified to perform additional animal tests to establish a NOAEL for local effects in the respiratory tract.

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Quality of whole database:

No repeat dose dermal study is available for 2-tert-butylaminethyl methacrylate or the read across substance 2-(dimethylamino)ethyl methacrylate but the use of the oral NOAEL will allow the calculation of systemic dermal DNELs. It is not considered scientifically justified to carry out test. The data base is adequate for the calculation of the DNELs

Repeated dose toxicity: dermal - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Quality of whole database:

There is not study available on 2-tert-butylaminethyl methacrylate or the read across substance 2-(dimethylamino)ethyl methacrylate, to determine a NOAEL for local dermal effects, as the corrosive and skin sensitizing properties of 2-tert-butylaminethyl methacrylate require the use of gloves and protective clothing, the potential for skin contact will be minimized. The available information is sufficient for the safe use of 2-tert-butylaminethyl methacrylate.

Additional information

There is no repeat dose oral dosing study for 2-tert-butylaminoethyl methacrylate but there is Klimisch 2 OECD422 repeat dose, gavage oral dosing study in rats on a read across substance 2-(dimethylamino)ethyl methacrylate CAS No 2867-47-2. Justification for the read across is attached in Section 13. In this OECD422 study 2-(dimethylamino)ethyl methacrylate produced a variety of effects at the 1000 mg/kg bodyweight/day highest dose including the deaths of 3/12 of the females. The middle dose of 200mg/kg bodyweight/day was a NOAEL for both males and females, with the males showing some very minor differences in haemoglobin concentration and haematocrit but these were considered toxicologically insignificant, i.e. not an adverse effect.  This NOAEL of 200 mg/kg bodyweight/day is for the parental animals after 43 days dosing in males and at 41-52 days dosing in females (to day 5post partum) which will allow the calculation of DNELs.

There are no studies for2-tert-butylaminethyl methacrylate or the read across substance2-(dimethylamino)ethyl methacrylate by the inhalation or dermal routes of exposure. The requirement for a repeat dose inhalation study is waived due to the availability of a Klimisch 2 OECD422 study by the oral route and the technical difficulties of carry out an inhalation study with a corrosive substance. The oral NOAEL with the additional assessment factor of 2 can provide an adequate systemic DNEL. Also there is no repeat dose dermal study available but the use of the oral NOAEL will allow the calculation of systemic dermal and inhalation DNELs with the appropriate assessment factors. It is not considered scientifically justified to carry out test by these routs due to the corrosive properties of the 2-tert-butylaminethyl methacrylate. The data base is adequate for the calculation of the DNELs.

Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:

There is no repeat dose oral dosing study for 2-tert-butylaminoethyl methacrylate but there  is Klimisch 2 OECD422 repeat dose,  gavage oral dosing study in rats on a read across substance 2-(dimethylamino)ethyl methacrylate CAS No 2867-47-2. Justification for the read across is attached in Section 13.  In this OECD422 study 2-(dimethylamino)ethyl methacrylate produced a variety of effects at the 1000 mg/kg bodyweight/day highest dose including the deaths of 3/12 of the females.  The middle dose of 200mg/kg bodyweight/day was a NOAEL for both males and females, with the males showing some very minor differences in haemoglobin concentration and haematocrit but these were considered toxicologically insignificant, i.e. not an adverse effect.   This NOAEL of 200 mg/kg bodyweight/day is for the parental animals after 43 days dosing in males and at 41-52 days dosing in females (to day 5 post partum) which will allow the calculation of DNELs.

Justification for selection of repeated dose toxicity inhalation - systemic effects endpoint:

We do not have any repeat exposure inhalation study for 2-tert-butylaminoethyl  methacrylate, but there  is Klimisch 2 OECD422 repeat dose,  gavage oral dosing study in rats on a read across substance 2-(dimethylamino)ethyl methacrylate CAS No 2867-47-2.  Inhalation is not expected to be a significant route of exposure due to the containment required as any vapour generated would be irritant/corrosive.  Testing of corrosive substances by inhalation would be technically difficult as none corrosive exposure would have to be established.  The additional factor of 2 as recommended by ECHA, when using oral data to calculate an inhalation long term systemic DNEL, assumes 100% absorption by inhalation and 50% by the oral route.  Based on this, using the REACH guidance a DNEL for systemic effects from inhalation can be calculated for the oral NOAEL.  Therefore it is not scientifically justified to carry out an inhalation study; this avoids the use of additional animals.

Justification for selection of repeated dose toxicity inhalation - local effects endpoint:

We have no study for local effects in the respiratory tract on 2-tert-butylaminoethyl methacrylate.  2-tert-butylaminoethyl methacrylate is corrosive to skin and eyes and therefore inhalation would be expected to cause local irritant effects in the upper respiratory tract.  As 2-tert-butylaminoethyl methacrylate is handled as a monomer in contained inhalation exposure. Due to the limited potential for inhalation exposure and the ethical considerations in performing an inhalation study with a test substance that is corrosive to skin and eyes indicates, it is not scientifically justified to perform additional animal tests to establish a NOAEL for local effects in the respiratory tract.

Justification for selection of repeated dose toxicity dermal - systemic effects endpoint:

There is no dermal repeat dose study for 2-tert-butylaminethyl methacrylate, however there is an oral study Repeated dose toxicity  OECD  422 study available on the read across substance 2-(dimethylamino)ethyl methacrylate.  REACH guidance allows for the calculation of dermal DNELS for systemic effects from the Oral NOAEL.  As for 2-tert-butylaminethyl methacrylate is classified as a skin sensitizer and corrosive to skin gloves and protective clothing will be required when handling it so dermal exposure should be minimized.  Therefore as dermal systemic DNELS can be calculated from the oral NOAEL and there are ethical concerns about a repeat dose dermal study for a corrosive chemical, it is not scientifically justified to perform such a test.  Dermal repeat dose testing will be waived.

Justification for selection of repeated dose toxicity dermal - local effects endpoint:

There is no specific test data available to establish a NOAEL for 2-tert-butylaminethyl methacrylate, while some work was done to establish doses within the guinea pig skin sensitisation study where 50% was used as the challenge dose.  This is not considered suitable for defining a NOAEL for local effects in the skin.  2-tert-butylaminethyl methacrylate is classified as a skin sensitizer and as corrosive to skin, local effects on the skin would be expected to be irritancy/corrosion, therefore the use of appropriate gloves and protective clothing will be required, which will minimize the potential for skin contact.  Therefore it is not necessary or scientifically justified to perform an animal study.

Repeated dose toxicity: via oral route - systemic effects (target organ) digestive: stomach; neurologic: central nervous system

Justification for classification or non-classification

Classification for Specific Target Organ Toxicity STOT, by the EU CLP(GHS) guideline requires serious adverse effects on organs at dose levels of less than 100mg/kg bodyweight/day in a 90 day study or <300mg/kg bodyweight/day in a 28 day study. In the OECD 422 study the duration was 43 days for males and 5 day post partum for the females (in excess of 41 days). These values for STOT could therefore be considered to be between the 28 and 90 day i.e. less than 200 mg/kg bodyweight/day. The OECD 422 showed no adverse effects that could be considered to be STOT at the NOAEL dose of 200mg/kg bodyweight/day. Therefore there were no effects that would require classification for STOT