Allylamine

Developmental toxicity / teratogenicity

Administrative data

Endpoint:

developmental toxicity

Type of information:

experimental study

Adequacy of study:

key study

Study period:

11 March 2013 to 09 September 2013

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Remarks:

The study was conducted in accordance with intertnational guidelines (OECD 421) and in compliance with the UK Good Laboratory Practive Regulations. All relevant validity criteria were met.

Cross-reference

Reason / purpose for cross-reference:

reference to same study

Reference

Endpoint:

screening for reproductive / developmental toxicity

Remarks:

based on test type (migrated information)

Type of information:

experimental study

Adequacy of study:

key study

Study period:

11 March 2013 to 09 September 2013

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Remarks:

The study was conducted in accordance with intertnational guidelines (OECD 421) and in compliance with the UK Good Laboratory Practive Regulations. All relevant validity criteria were met.

Reason / purpose for cross-reference:

reference to same study

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 421 (Reproduction / Developmental Toxicity Screening Test)

Deviations:

yes

Remarks:

Dosing of females was until Day 19 of gestation only, due to inhalation dosing

GLP compliance:

yes

Limit test:

no

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River UK
- Age at study initiation: Nominall 10 weeks
- Weight at study initiation: Males: 374 to 453 g; Females: 235 to 287 g
- Fasting period before study: No
- Housing:5/cage prior to pairing, then 1M:1F. After mating, males re-housed as previously and females housed singly
- Diet (e.g. ad libitum): Ad lib
- Water (e.g. ad libitum): Ad lib
- Acclimation period: 2 weeks

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19-23
- Humidity (%): 40-70
- Air changes (per hr): not stated
- Photoperiod (hrs dark / hrs light):12/12

IN-LIFE DATES: From: March 2013 To: May 2013

Route of administration:

inhalation: vapour

Type of inhalation exposure (if applicable):

whole body

Vehicle:

air

Details on exposure:

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
Directed Flow Whole Body Exposure Chamber:
0.75 m3 chamber of stainless-steel and glass construction.
Animal Restraint:
Wire mesh modular caging.
Vapour Generator:
Medium sintered glass vaporiser for Groups 2 to 4. Feed rate used to alter concentration.
Test groups 18 L/min.
Diluent Airflow:
From in-house compressed air system – breathing quality. Group 1: 150 L/min.
Groups 2-4: 130 L/min.
Extract Airflow:
Drawn by a fan extract system.
Drawn from base of exposure system.
Controlled by a gate clamp situated at the rear of the chamber.
Airflow Monitoring:
In-line flowmeters monitored continuously for generation and diluent airflows.
Chamber pressure differential monitored by Magnelhelic set at -1 to -5m/H2O to ensure a slight negative pressure within the chamber
~ 150 L/min.

TEST ATMOSPHERE
- Brief description of analytical method used: samples in trapping solvent, followed by HPLC analysis. minimum of 3 samples/group/exposure, plus one from control chamber
- Samples taken from breathing zone: yes

Details on mating procedure:

- M/F ratio per cage: 1M : 1F
- Length of cohabitation: Up to 2 weeks
- Proof of pregnancy: Ejected copulation plugs, sperm in vaginal smear: referred to as Day 0 of pregnancy

- After successful mating each pregnant female was caged (how): singly
- Any other deviations from standard protocol: No

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Vapour samples collected as follows:
Sample frequency – minimum of 1 sample/ exposure for Group 1 and minimum of 3 samples/exposure for Groups 2 to 4.
Sample location – representative animal level.
Sample position remained constant.
Sample analysis:
HPLC.
Vapour samples were analysed as μg/L and subsequently converted to ppm.

Duration of treatment / exposure:

6 hours per day

Frequency of treatment:

Daily for 2 weeks prior to mating, then for a total of 4 weeks for males, and for females until Day 19 of gestation.

Details on study schedule:

Males were treated for 2 weeks prior to pairing, and then for a total of 4 weeks.
Females were treated for 2 weeks prior to pairing, then throughout mating and until Day 19 of gestation. Females were then retained and allowed to litter and raise their pups until at least Day 4 post partum.

Dose / conc.:

3.57 ppm (analytical)

Dose / conc.:

7.53 ppm (analytical)

Dose / conc.:

14.4 ppm (analytical)

No. of animals per sex per dose:

10M / 10F per dose group

Control animals:

yes, concurrent vehicle

Positive control:

None

Parental animals: Observations and examinations:

CLINICAL OBSERVATIONS: Yes
- Time schedule: Before dosing, during dosing if visible, on return to home cage, at end of working day
- Cage side observations were included.

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Weekly

BODY WEIGHT: Yes
- Time schedule for examinations: Weekly for males and for females prior to pairing. Females on Days 0, 3, 7, 10, 14, 17 and 20 of gestation, and Days 1 and 4 of lactation.

FOOD CONSUMPTION : Yes. Weekly prior to pairing, then at approximately 3 day intervals for females during gestation and lactation.


WATER CONSUMPTION : No

OTHER:

Oestrous cyclicity (parental animals):

Vaginal lavages were taken daily from pairing until mating.

Sperm parameters (parental animals):

Parameters examined in all males: testis weight, epididymis weight, histopathology of male reproductive organs, including PAS stain of the testes. Sperm counts were estimated from vaginal smears at mating.

Litter observations:

Time elapsed between mating and commencement of parturition recorded, including any difficulty with parturition.
Number of live and dead offspring recorded at birth
Litter size recordecdaily from Day 1-4
Sex ratio and individual offspring body weights recorded on Day 1 and 4 of age

Postmortem examinations (parental animals):

SACRIFICE
Scheduled kill - males: During week 5 of treatment.
Females failing to produce viable litter: Day 25 after mating.
Scheduled kill - females: Day 4 of lactation

GROSS NECROPSY
All adult animals were subject to a complete macroscopic examination. For all females, the following was recorded:
Uterus: Number of implantation sites.

HISTOPATHOLOGY / ORGAN WEIGHTS
The tissues indicated in Table 1 were prepared for microscopic examination and weighed, respectively.

Postmortem examinations (offspring):

SACRIFICE
Scheduled kill - Day 4 of age

GROSS NECROPSY
- Gross necropsy consisted of external and internal examinations including the cervical, thoracic, and abdominal viscera.

Premature deaths: Missing offspring and any grossly autolysed or grossly cannibalised could not be examined. All other remaining offspring dying were examined as detailed above; the examination also included an assessment for the presence of milk in the stomach, where this was possible.
Scheduled kill (Day 4 of age): Only offspring that were externally abnormal were examined. Offspring considered to be externally normal were discarded without examination.

HISTOPATHOLOGY / ORGAN WEIGHTS
For all offspring, samples of any abnormal tissues were retained, but since no treatment- related findings were detected, these tissues were not processed for examination.

Statistics:

All statistical analyses were carried out separately for males and females. Data relating to food consumption before pairing were analysed on a cage basis. For all other parameters, the analyses were carried out using the individual animal as the basic experimental unit.
The following data types were analysed at each timepoint separately:
Bodyweight, using absolute weights and gains over appropriate study periods Food consumption, over appropriate study periods
Gestation length
Litter size and survival indices
Organ weights, either absolute or adjusted for teminal bodyweight where appropriate.

Clinical signs:

effects observed, treatment-related

Description (incidence and severity):

At 7.53 and 14.4 ppm, animals were underactive, unresponsive, with hunched posture and piloerection. At 3.57 ppm the signs were generally limited to underactivity and piloerection

Dermal irritation (if dermal study):

not examined

Mortality:

no mortality observed

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

Dose related decrease in weight gain in pre-mating period (92, 70 and 59% of Control, males; 73, 71 and 55% of Control , females) at 3.42, 7.53 and 14.4 ppm. Similar effect over Day 0-3 of gestation ,but gains similar for remainder of gestation.

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Description (incidence and severity):

Dose related decrease in weight gain in pre-mating period (92, 70 and 59% of Control, males; 73, 71 and 55% of Control , females) at 3.42, 7.53 and 14.4 ppm. Similar effect over Day 0-3 of gestation ,but gains similar for remainder of gestation.

Food efficiency:

not examined

Water consumption and compound intake (if drinking water study):

not examined

Ophthalmological findings:

not examined

Haematological findings:

no effects observed

Clinical biochemistry findings:

no effects observed

Urinalysis findings:

no effects observed

Behaviour (functional findings):

no effects observed

Immunological findings:

no effects observed

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Histopathological findings: non-neoplastic:

no effects observed

Description (incidence and severity):

No treatment related changes were observed in the limited tissues examined.

Histopathological findings: neoplastic:

not examined

Other effects:

not examined

Reproductive function: oestrous cycle:

no effects observed

Reproductive function: sperm measures:

no effects observed

Description (incidence and severity):

Sperm parameters at mating were similar in all groups.

Reproductive performance:

no effects observed

Description (incidence and severity):

There was no effect on pre-coital interval. All animals showed evidence of mating, and all allylamine-treated females were pregnant. There was no treatment-related effect on gestation length or gestation index.

Key result

Dose descriptor:

LOAEC

Effect level:

3.57 ppm (analytical)

Based on:

test mat.

Sex:

female

Basis for effect level:

other: Reduced body weight gain

Key result

Dose descriptor:

NOAEC

Effect level:

3.57 ppm (analytical)

Based on:

test mat.

Sex:

male

Basis for effect level:

other: Slight body weight effects not considered as adverse

Key result

Critical effects observed:

no

Key result

Dose descriptor:

NOAEC

Effect level:

14.4 ppm (analytical)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

reproductive performance

Remarks on result:

not determinable due to adverse toxic effects at highest dose / concentration tested

Key result

Critical effects observed:

no

Clinical signs:

no effects observed

Description (incidence and severity):

There were no treatment-related clinical observations noted for the offspring in life.

Dermal irritation (if dermal study):

not examined

Mortality / viability:

no mortality observed

Body weight and weight changes:

no effects observed

Description (incidence and severity):

There were no treatment-related effects on the bodyweight of male or female offspring to Day 4 post partum.

Food consumption and compound intake (if feeding study):

not examined

Food efficiency:

not examined

Water consumption and compound intake (if drinking water study):

not examined

Ophthalmological findings:

not examined

Haematological findings:

no effects observed

Clinical biochemistry findings:

no effects observed

Urinalysis findings:

no effects observed

Sexual maturation:

not examined

Organ weight findings including organ / body weight ratios:

not examined

Gross pathological findings:

no effects observed

Histopathological findings:

not examined

Other effects:

no effects observed

Behaviour (functional findings):

not examined

Developmental immunotoxicity:

not examined

Key result

Dose descriptor:

NOAEC

Generation:

F1

Effect level:

14.4 ppm (analytical)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: Litter size, offspring survival and body weights

Key result

Critical effects observed:

no

Key result

Reproductive effects observed:

no

Conclusions:

Exposure of rats to Allylamine in this screening study to assess the general systemic toxic potential, including reproductive/developmental effects, following administration by whole body inhalation at concentrations of 3.57, 7.53 or 14.4 ppm was associated with systemic effects (clinical signs during exposure, and lower bodyweight gain and food consumption), but had no effect on reproductive or developmental endpoints.
Within this screening study, a no observed adverse effect level (NOAEL) for systemic toxicity was not established; whilst the no observed adverse effect level (NOAEL) for reproductive and developmental toxicity was considered to be 14.4 ppm.

Executive summary:

The objective of this study was the assessment of Allylamine (a raw material in polymer manufacture) on the general systemic toxic potential in rats, including reproductive/developmental effects, with administration of the test substance by inhalation administration for at least 4 weeks.

Three groups of 10 male and 10 female rats received Allylamine by whole body inhalation at target exposure levels of 4, 7.5 or 15 ppm, 7 days per week, 6 hours per day. The adults were treated daily for fifteen days before pairing until Week 5 for males and, for females, until Day 19 of gestation. Females were untreated from Day 20 post coitum to necropsy on Day 4 after birth of F1 generation. A similarly constituted Control group received air only for the same duration.

The F1 generation received no direct administration of the test substance; any exposure was in utero or via the milk.

During the study, data was recorded on clinical condition, bodyweight, food consumption, mating performance and fertility, gestation length, parturition observations and reproductive performance. Organ weight, macroscopic and limited microscopic pathology investigations were undertaken on the F0 generation adults. The clinical condition of offspring, litter size and survival, sex ratio and bodyweight was assessed on the F1 generation offspring to Day 4 post partum.

The achieved chamber concentrations of Allylamine were 3.57, 7.53 and 14.4 ppm (89, 100 and 96% of the target concentration) for Groups 2, 3 and 4 respectively.

Signs during exposure included underactivity, unresponsiveness, hunched posture and piloerection at 7.53 and 14.4 ppm, with partially closed eyelids also noted at 14.4 ppm and, to a lesser extent, 7.53 ppm. At 3.57 ppm, signs during exposure were limited to underactivity and piloerection, with hunched posture and partially closed eyelids being noted infrequently.

Bodyweight gain of treated males and females were reduced in the first 2 weeks of treatment, in a dose related manner. Thereafter bodyweight gain was similar to the controls. Food consumption at 7.53 ppm for males and 14.4 ppm for males and females was slightly lower in the first 2 weeks of treatment and the first 2 days of gestation for females at 14.4 ppm.

There was no effect of Allylamine on mating performance, maintenance of pregnancy or gestation length, or growth and survival of the offspring to Day 4 of lactation.

There were no pathological changes in the reproductive organs investigated.

Exposure of rats to Allylamine in this screening study to assess the general systemic toxic potential, including reproductive/developmental effects, following administration by whole body inhalation at concentrations of 3.57, 7.53 or 14.4 ppm was associated with systemic effects (clinical signs during exposure, and lower bodyweight gain and food consumption), but had no effect on reproductive or developmental endpoints.

Within this screening study, a no observed adverse effect level (NOAEL) for systemic toxicity was not established; whilst the no observed adverse effect level (NOAEL) for reproductive and developmental toxicity was considered to be 14.4 ppm.

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2013

Materials and methods

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

other: OECD Guideline 421

Deviations:

yes

Remarks:

Dosing of females was until Day 19 of gestation only, due to inhalation dosing

GLP compliance:

yes

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Allylamine

EC Number:

203-463-9

EC Name:

Allylamine

Cas Number:

107-11-9

Molecular formula:

C3H7N

IUPAC Name:

prop-2-en-1-amine

Test material form:

other: liquid

Details on test material:

Identification: Allylamine

Test animals

Species:

rat

Strain:

Sprague-Dawley

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River UK
- Age at study initiation: Nominall 10 weeks
- Weight at study initiation: Males: 374 to 453 g; Females: 235 to 287 g
- Fasting period before study: No
- Housing:5/cage prior to pairing, then 1M:1F. After mating, males re-housed as previously and females housed singly
- Diet (e.g. ad libitum): Ad lib
- Water (e.g. ad libitum): Ad lib
- Acclimation period: 2 weeks

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19-23
- Humidity (%): 40-70
- Air changes (per hr): not stated
- Photoperiod (hrs dark / hrs light):12/12

IN-LIFE DATES: From: March 2013 To: May 2013

Administration / exposure

Route of administration:

inhalation: vapour

Type of inhalation exposure (if applicable):

whole body

Vehicle:

air

Details on exposure:

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
Directed Flow Whole Body Exposure Chamber:
0.75 m3 chamber of stainless-steel and glass construction.
Animal Restraint:
Wire mesh modular caging.
Vapour Generator:
Medium sintered glass vaporiser for Groups 2 to 4. Feed rate used to alter concentration.
Test groups 18 L/min.
Diluent Airflow:
From in-house compressed air system – breathing quality. Group 1: 150 L/min.
Groups 2-4: 130 L/min.
Extract Airflow:
Drawn by a fan extract system.
Drawn from base of exposure system.
Controlled by a gate clamp situated at the rear of the chamber.
Airflow Monitoring:
In-line flowmeters monitored continuously for generation and diluent airflows.
Chamber pressure differential monitored by Magnelhelic set at -1 to -5m/H2O to ensure a slight negative pressure within the chamber
~ 150 L/min.

TEST ATMOSPHERE
- Brief description of analytical method used: samples in trapping solvent, followed by HPLC analysis. minimum of 3 samples/group/exposure, plus one from control chamber
- Samples taken from breathing zone: yes

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Vapour samples collected as follows:
Sample frequency – minimum of 1 sample/ exposure for Group 1 and minimum of 3 samples/exposure for Groups 2 to 4.
Sample location – representative animal level.
Sample position remained constant.
Sample analysis:
HPLC.
Vapour samples were analysed as μg/L and subsequently converted to ppm.

Details on mating procedure:

- M/F ratio per cage: 1M : 1F
- Length of cohabitation: Up to 2 weeks
- Proof of pregnancy: Ejected copulation plugs, sperm in vaginal smear: referred to as Day 0 of pregnancy

- After successful mating each pregnant female was caged (how): singly
- Any other deviations from standard protocol: No

Duration of treatment / exposure:

6 hours per day

Frequency of treatment:

Daily for 2 weeks prior to mating, then for a total of 4 weeks for males, and for females until Day 19 of gestation.

Duration of test:

Males were treated for 2 weeks prior to pairing, and then for a total of 4 weeks.
Females were treated for 2 weeks prior to pairing, then throughout mating and until Day 19 of gestation. Females were then retained and allowed to litter and raise their pups until at least Day 4 post partum.

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

3.57 ppm (analytical)

Doses / concentrations 2

Dose / conc.:

7.53 ppm (analytical)

Doses / concentrations 3

Dose / conc.:

14.4 ppm (analytical)

No. of animals per sex per dose:

10M/ 10F

Control animals:

yes, concurrent vehicle

Examinations

Maternal examinations:

Females were allowed to litter and rear their litters to Day 4 post partum

Ovaries and uterine content:

Uteri examined for number of implantation sites

Fetal examinations:

Females allowed to litter, but pups examined daily from birth until Day 4 post partum, including survival and weights on Days 1 and 4.

Indices:

Post-implantation survival index, live birth index, viability index

Results and discussion

Results: maternal animals

General toxicity (maternal animals)

Clinical signs:

no effects observed

Description (incidence and severity):

There were no treatment-related clinical signs observed during the weekly detailed physical examination.

Dermal irritation (if dermal study):

not examined

Mortality:

mortality observed, non-treatment-related

Description (incidence):

One female in the control group (number 49) was sacrificed due to signs of dystocia on Day 21 after mating, red staining (presumed blood) was noted in the cage and clinical signs included underactivity, reduced body temperature, hunched posture, piloerection and general pallor. At necropsy, one partially cannibalised pup was found in the cage (presumably born between transportation between the animal unit and the necropsy suite) and the uterus contained 2 live pups in the right horn and one live pup and one late resorption in the left horn. The spleen was enlarged. The microscopic correlate for the enlarged spleen was moderate extramedullary haematopoiesis suggestive of suppurative lesions elsewhere in the body. In the absence of microscopic examination of other organs from this animal, the histopathological factor contributory to death is undetermined.

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

Mean bodyweight gain of treated females was also lower than the controls, in a dose dependent manner, during the 2 weeks prior to pairing (73, 71 and 55% of Control for females at 3.57, 7.53 and 14.4 ppm, respectively). The lower bodyweight gain was most apparent between Days 8 and 11, which coincided with the period of higher achieved exposure levels.There were considered to be no effects of treatment on bodyweight gain during gestation (Days 0-20) or from Day 1 to 4 post partum.

Food consumption and compound intake (if feeding study):

not examined

Food efficiency:

not examined

Water consumption and compound intake (if drinking water study):

not examined

Ophthalmological findings:

not examined

Haematological findings:

not examined

Clinical biochemistry findings:

not examined

Urinalysis findings:

not examined

Behaviour (functional findings):

not examined

Immunological findings:

not examined

Organ weight findings including organ / body weight ratios:

no effects observed

Description (incidence and severity):

Mean seminal vesicles weights (adjusted for bodyweight as covariate) were slightly high for males at 14.4 ppm compared with control (114% of Control, respectively). Review of weights for individual animals did not reveal any obvious outlier and as there were no histopathological findings in animals in this group, this finding is considered to be unrelated to treatment.
There were considered to be no treatment related effects on the other organ weights assessed.

Gross pathological findings:

no effects observed

Description (incidence and severity):

The macroscopic examinations performed after the scheduled treatment of F0 animals revealed no intergroup differences of note.
The nature and incidence of all the findings were consistent with the commonly seen background of macroscopic changes in Sprague-Dawley rats at these laboratories.

Neuropathological findings:

not examined

Histopathological findings: non-neoplastic:

no effects observed

Histopathological findings: neoplastic:

no effects observed

Other effects:

no effects observed

Maternal developmental toxicity

Number of abortions:

no effects observed

Pre- and post-implantation loss:

no effects observed

Total litter losses by resorption:

no effects observed

Early or late resorptions:

no effects observed

Dead fetuses:

no effects observed

Changes in pregnancy duration:

no effects observed

Description (incidence and severity):

Migrated Data from removed field(s)
Field "Effects on pregnancy duration" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsMaternalAnimals.MaternalDevelopmentalToxicity.EffectsOnPregnancyDuration): no effects observed

Changes in number of pregnant:

no effects observed

Other effects:

no effects observed

Details on maternal toxic effects:

Maternal toxic effects:yes

Details on maternal toxic effects:
Maternal weight gain was reduced, in dose-dependent manner in 2 weeks prior to pairing and also over Day 0-3 of gestation. Thereafter weight gains similar in all groups. At 7.53 and 14.4 ppm, animals were underactive, unresponsive, with hunched posture and piloerection; at 3.57 ppm, animals were underactive with piloerection.

Effect levels (maternal animals)

Key result

Dose descriptor:

LOAEC

Effect level:

3.57 ppm (analytical)

Based on:

test mat.

Basis for effect level:

body weight and weight gain

Maternal abnormalities

Key result

Abnormalities:

no effects observed

Results (fetuses)

Fetal body weight changes:

no effects observed

Description (incidence and severity):

Migrated Data from removed field(s)
Field "Fetal/pup body weight changes" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.FetalPupBodyWeightChanges): no effects observed

Reduction in number of live offspring:

no effects observed

Changes in sex ratio:

no effects observed

Changes in litter size and weights:

no effects observed

Changes in postnatal survival:

no effects observed

External malformations:

no effects observed

Skeletal malformations:

no effects observed

Visceral malformations:

no effects observed

Other effects:

no effects observed

Details on embryotoxic / teratogenic effects:

Embryotoxic / teratogenic effects:no effects

Details on embryotoxic / teratogenic effects:
No effects on litter size and survival, pup development and weight

Effect levels (fetuses)

Key result

Dose descriptor:

NOAEL

Effect level:

14.4 ppm (analytical)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: No effects observed

Fetal abnormalities

Key result

Abnormalities:

no effects observed

Overall developmental toxicity

Key result

Developmental effects observed:

no

Applicant's summary and conclusion

Conclusions:

Based on the data available at the time of submission, the following NOAEC/LOAEC's are indicated:
LOAEC for parental effects: 3.57 ppm
NOAEC for mating, fertility and offspring effects: 14.4 ppm

Executive summary:

The objective of this study was the assessment of Allylamine (a raw material in polymer manufacture) on the general systemic toxic potential in rats, including reproductive/developmental effects, with administration of the test substance by inhalation administration for at least 4 weeks.

Three groups of 10 male and 10 female rats received Allylamine by whole body inhalation at target exposure levels of 4, 7.5 or 15 ppm, 7 days per week, 6 hours per day. The adults were treated daily for fifteen days before pairing until Week 5 for males and, for females, until Day 19 of gestation. Females were untreated from Day 20 post coitum to necropsy on Day 4 after birth of F1 generation. A similarly constituted Control group received air only for the same duration.

The F1 generation received no direct administration of the test substance; any exposure was in utero or via the milk.

During the study, data was recorded on clinical condition, bodyweight, food consumption, mating performance and fertility, gestation length, parturition observations and reproductive performance. Organ weight, macroscopic and limited microscopic pathology investigations were undertaken on the F0 generation adults. The clinical condition of offspring, litter size and survival, sex ratio and bodyweight was assessed on the F1 generation offspring to Day 4 post partum.

The achieved chamber concentrations of Allylamine were 3.57, 7.53 and 14.4 ppm (89, 100 and 96% of the target concentration) for Groups 2, 3 and 4 respectively.

Signs during exposure included underactivity, unresponsiveness, hunched posture and piloerection at 7.53 and 14.4 ppm, with partially closed eyelids also noted at 14.4 ppm and, to a lesser extent, 7.53 ppm. At 3.57 ppm, signs during exposure were limited to underactivity and piloerection, with hunched posture and partially closed eyelids being noted infrequently.

Bodyweight gain of treated males and females were reduced in the first 2 weeks of treatment, in a dose related manner. Thereafter bodyweight gain was similar to the controls. Food consumption at 7.53 ppm for males and 14.4 ppm for males and females was slightly lower in the first 2 weeks of treatment and the first 2 days of gestation for females at 14.4 ppm.

There was no effect of Allylamine on mating performance, maintenance of pregnancy or gestation length, or growth and survival of the offspring to Day 4 of lactation.

There were no pathological changes in the reproductive organs investigated.

Exposure of rats to Allylamine in this screening study to assess the general systemic toxic potential, including reproductive/developmental effects, following administration by whole body inhalation at concentrations of 3.57, 7.53 or 14.4 ppm was associated with systemic effects (clinical signs during exposure, and lower bodyweight gain and food consumption), but had no effect on reproductive or developmental endpoints.

Within this screening study, a no observed adverse effect level (NOAEL) for systemic toxicity was not established; whilst the no observed adverse effect level (NOAEL) for reproductive and developmental toxicity was considered to be 14.4 ppm.