Amines, N-(C16-18 and C18-unsatd. alkyl)trimethylenedi-, N-(hydroxyethyl) derivs.

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Effect on fertility: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

25 mg/kg bw/day

Study duration:

subacute

Species:

rat

Quality of whole database:

Based on read-across to substance with same structure but slightly varying chain length. The study is GLP compliant and has Klimisch score 1. Information is supported by cross-reading from non-ethoxylated alkyl-diamines.

Effect on fertility: via inhalation route

Endpoint conclusion:

no study available

Effect on fertility: via dermal route

Endpoint conclusion:

no study available

Additional information

Evaluation of repeated dose toxicity of Tris (2-hydroxyethyl) tallow diaminopropane, CAS 90367-27-4 (recently redefined as Amines, N-(C16-18 (even numbered) and C18-unsatd. alkyl) trimethylenedi-, ethoxylated (NLP), CAS 1290049-56-7), also referred to as Tallow-diamine3EO:

For this endpoint partial read-across is applied to Tris (2-hydroxyethyl) oleyl diaminopropane(CAS 90367-27-4, referred to further as Oleyl-diamine3EO).

Data from Oleyl-diamine3EO is also considered applicable for Tallow-diamine3EO, as both substances have the same molecular structure, thus showing the exact same basic chemical reactivity. Both substances onlyslightly differ in chain length:Oleyl alkyl chains are mainly C18 and have a higher level of unsaturation than tallow, whereas tallow also contains some saturated C16 chains.

 

Available data from OECD 422 study show no impact to reproduction parameters at all up to highest tested dose of 25 mg/kg bw/day.

 

Oleyl-diamine3EO has been evaluated ina reproduction/developmental toxicity screening test according to OECD 422 guidelines andin compliance to GLP.

Four groups of ten male and ten female rats were exposed by oral gavage toOleyl-diamine3EOat 0, 1, 5 and 25 mg/kg/day. Males were exposed for 29 days, females were exposed for 43-52 days, i.e. during 2 weeks prior to mating, during mating, during post-coitum, and during at least 4 days of lactation.

Reproduction/developmental parameters were evaluated, consisting of mating, fertility and conception indices, precoital time, number of corpora lutea and implantation sites, gestation index and duration, parturition, maternal care, sex ratio and early postnatal pup development (mortality, clinical signs, body weights and macroscopy).

No reproduction or developmental toxicity was observed up to the highest dose level tested (25 mg/kg). No treatment-related changes were noted in any of the reproductive parameters investigated in this study (i.e. mating, fertility and conception indices, precoital time, and numbers of corpora lutea and implantation sites), or in any of the developmental parameters (i.e. gestation index and duration, parturition, maternal care and early postnatal pup development consisting of mortality, clinical signs, body weight and macroscopy).

The study therefore concluded to a reproduction NOAEL of at least 25 mg/kg/day.

In contrast, the parental NOAEL for repeated dose toxicity was found to be 1 mg/kg/day

 

Also cross-reading from non-ethoxylated diamines indicate no concerns for reproduction toxicity as noadverse effects on reproductive organs were identified in the 90 day study in rats on C12-14-diamine. A developmental toxicity study performed on Oleyl-diamine also included endpoints relevant to assessing an effect on fertility. No effects on pre/post implantation rate, late/early resorptions, corpora lutea or number of live fetuses were seen in this study. Similarly, a developmental toxicity study on Tallow-diamine3EO itself in rabbits also indicate no great concerns.

Although the available data does not include information on sperm parameters and oestrus cycle, there are currently no indications of an effect of alkyl-diamines or alkyl-diamine3EO on fertility. In addition, there is no consumer exposure to Tallow-diamine3EO, and manufacture and use are highly controlled, limiting the possibility of exposures.

Short description of key information:

There are no indications for reproduction toxicity indicated by results form an available reproduction screening study. Possible exposures are very limited due to the characteristics of the substance.

Justification for selection of Effect on fertility via oral route:

Only available study

Justification for selection of Effect on fertility via inhalation route:

Tallow-diamine3EO is a viscous fluid with a bp > 300°C and has a vapour pressure < 0.0015 Pa at 20°C. Its use is limited to industrial and professional users and does not involve the forming of aerosols, particles or droplets of an inhalable size. So exposure to humans via the inhalation route will be unlikely to occur.

Justification for selection of Effect on fertility via dermal route:

Manufacture and use are highly controlled. Its use is limited to industrial and professional users where its severe corrosive properties will ensure sufficient protection measures to prevent dermal exposure. Furthermore, the substance is not expected to easily pass the skin, and in view of their severe corrosive properties, testing via dermal route for developmental toxicity is not a first choice.

Effects on developmental toxicity

Description of key information

Available data from OECD 422 study show no impact to reproduction parameters at all up to highest tested dose of 25 mg/kg bw/day. Parental NOAEL =1 mg/kg bw

Prenatal developmental toxicity (OECD 414, GLP) based on read-across from Oleyl-diamine: Developmental NOAEL: 20 mg/kg bw, Maternal toxicity NOAEL = 5 mg/kg bw.

Link to relevant study records

Reference

Endpoint:

developmental toxicity

Type of information:

migrated information: read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Study period:

2008-05-14 - 2010-04-27

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: GLP - Guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 414 (Prenatal Developmental Toxicity Study)

Deviations:

no

Qualifier:

according to guideline

Guideline:

EU Method B.31 (Prenatal Developmental Toxicity Study)

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Limit test:

no

Species:

rat

Strain:

Wistar

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Janvier S.A.S, Route des Chênes secs-B.P.4105-53941 LE GENEST-ST-ISLE-France
- Age at study initiation: 11 - 12 weeks
- Weight at study initiation: within ± 20% of the mean weight (no more information given)
- Housing: The animals were housed individually in IVC cages (except during mating
period where 2 females were paired with one male), type III H, polysulphone cages on Altromin saw fiber bedding
- Diet: Free access to Altromin 1324 maintenance diet for rats and mice
- Water: Free access to tap water, sulphur acidified to a pH of approximately 2.8 (drinking water, municipal residue control, microbiol. controlled periodically)
- Acclimation period: 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 3 °C
- Humidity (%): 55 ± 10%
- Air changes (per hr): 10 x / hour
- Photoperiod (hrs dark / hrs light): Artificial light, sequence being 12 hours light, 12 hours dark

Route of administration:

oral: gavage

Vehicle:

corn oil

Details on exposure:

PREPARATION OF DOSING SOLUTIONS:
The test item was dissolved or suspended corn oil. The vehicle was chosen as suggested by sponsor and the test item’s solubility. The test item formulation was prepared freshly on each administration day before the administration procedure.

VEHICLE
- Lot/batch no. (if required): 058K0070 and 128K0040 (Sigma)

- Administered dose volume: 4 mL/kg bw

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

The assessment of homogeneity as well as a determination of the nominal concentration of the test item in the vehicle was performed at specified intervals. Analysis of the dose formulations of the test item in the vehicle (nominal concentration) was performed in the first and last week of the study for all doses. Samples for homogeneity were taken from the top, middle and bottom of the high dose and low dose preparation. The determination was performed in the first and last week of the study. The dose formulation analysis was performed at BSL BIOSERVICE Scientific Laboratories GmbH under the BSL study Nr. 081567.

Details on mating procedure:

- Impregnation procedure: cohoused
- if cohoused:
- M/F ratio per cage: 1/2
- Length of cohabitation: overnight
- Proof of pregnancy: vaginal plug / sperm in vaginal smear referred to as day 0 of pregnancy

Duration of treatment / exposure:

The test item was administered to sperm positive females (presumed pregnant) from respective GD 0 to GD 19.

Frequency of treatment:

daily

Duration of test:

Duration of test: 20 days (animals were killed on day 20)

Remarks:

Doses / Concentrations:
1.25, 5.0, 20.0 mg/kg bw
Basis:
actual ingested

No. of animals per sex per dose:

20

Control animals:

yes, concurrent vehicle

Maternal examinations:

CAGE SIDE OBSERVATIONS: No data

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Each animal was observed twice daily during entire gestation period except during weekends and holidays where clinical observation was made only once. Mortality, morbidity, pertinent behavioural changes and all signs of overt toxicity were recorded.

BODY WEIGHT: Yes
- Time schedule for examinations: The sperm positive females were weighed during GD 0, 3, 5, 8, 11, 14, 17 and 20. Males were not weighed in this study.

FOOD CONSUMPTION: Yes
- Food consumption of sperm positive females was measured on respective GD 3, 5, 8, 11, 14, 17 and 20.

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 20
- Organs examined: uterus, ovaries

OTHER:
- Inflammatory Markers:
Serum samples were collected at terminal sacrifice from all females and stored at ≤ -20 °C for the possible analysis of inflammatory markers by ELISA technique.

Ovaries and uterine content:

The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: Yes
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes

Fetal examinations:

- External examinations: Yes: all per litter
- Soft tissue examinations: Yes: half per litter
- Skeletal examinations: Yes: half per litter
- Head examinations: Yes

Statistics:

For statistical analysis one-way analysis of variance (ANOVA) followed by Dunnett’s multiple comparison test was carried out to reveal any differences between control and test groups. Statistical significance for fetal anamolies were determined by Chi Square analysis. Statistical analysis was performed with GraphPad Prism (Version V) software (p < 0.05 was considered as statistical significant).

Details on maternal toxic effects:

Maternal toxic effects:yes

Details on maternal toxic effects:
Test item related clinical signs were observed in high dose females during the entire treatment period. 4 decedents were found (1 in the MD and 3 in the HD group). But the death of only 2 animals might be considered due to toxicity. Statistically significant decrease for the body weight and for the food consumption in the HD group was observed. Also statistical anlysis of parental data revealed significance in the parental parameters gravid uterus weight and adjusted maternal weight in HD group compared to corresponding controls. Decrease in pregnancy rate was observed in HD group (69.56% compared to LD (96%), MD (96.8%) and, control (95.8%)).
The terminally sacrificed animals belonging to the HD group revealed incidences of few lesions at necropsy, which were as gas filled stomach and intestine, whitish spots on adrenals, discoloured liver, small spleen and thymus, enlarged adrenals, bloody lung, discoloured heart, bloody lung.

Dose descriptor:

NOAEL

Effect level:

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

Based on:

test mat.

Basis for effect level:

other: maternal toxicity

Details on embryotoxic / teratogenic effects:

Embryotoxic / teratogenic effects:yes

Details on embryotoxic / teratogenic effects:
Few gross abnormalities were seen in fetuses among the control and the treatment groups. Typical external finding noted were protruding tongue,
malrotated limbs, micrognathia, edematous neck, small neck and hematoma (localised). But no statistical deviation was observed for these above findings except for hematoma which were localised and did not show dose related pattern.
Internal observation of the viscera by free hand micro discussion technique revealed range of visceral abnormalities in all groups including control.
However, the statistical analysis revealed differences for findings viz., hemorrhagic kidney-bilateral (HD group), convoluted ureter-bilateral (HD
group), dilated renal pelvis-left side (MD group), split thymus (MD), small spleen (MD group). Most of the above findings (except for hemorrhagic kidney and convoluted ureter in HD group) were not attributed to toxicity due to lack of dose dependent effect.
Skeletal examination of the Alizarin red stained fetuses revealed a range of abnormalities which were of a type or which occurred at an incidence in both treatment and control groups. The statistical difference observed for supernumerary 14th rib-right side –bilaterally (MD group) and right (HD group), large naso-frontal suture (MD group), incomplete ossification of 4th sternebrum (LD group), split interparietal (HD group) and small hyoid (HD group) were attributed to toxicity, but the statistical difference observed for other anamalies were not considered of toxicological relevance due to lack of dose related pattern.

Dose descriptor:

NOAEL

Effect level:

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

Based on:

test mat.

Basis for effect level:

other: fetotoxicity

Abnormalities:

not specified

Developmental effects observed:

not specified

Summary of clinical observations

Clinical Finding	Group
	C (0 mg/kg)	LD (1.25 mg/kg)	MD (5 mg/kg)	HD (20 mg/kg)
Total number of animals examined	24	25	25	26
Regurgitation	0	1	1	0
Dyspnoea	0	1	0	1
Moving the bedding	0	0	2	1
Salivation	0	0	3	15
Vocalization	0	0	4	9
Sneezing	0	0	0	4
Bloody nasal discharge	0	0	0	1
Weight loss	0	0	0	5
Piloerection	0	0	0	3
Half eye lid closure	0	0	0	1
Apnoea	0	0	0	2
Swollen abdomen	0	0	0	1
Swollen snout	0	0	0	1
Cyanosis	0	0	0	1
Diarrhea	0	0	0	1

Summary of prenatal data

Parameters		C (0 mg/kg)	LD (1.25 mg/kg)	MD (5 mg/kg)	HD (20 mg/kg)
Terminal Body weight (g)	Mean ± SD N	420.17 24.94 23	412.33 38.72 24	408.83 24.85 23	369.13* 53.44 16
Uterus weight (g)	Mean ± SD N	73.16 13.83 23	68.79 26.44 24	74.52 16.57 23	67.5* 24.25 16
Adjusted maternal weight (g)	Mean ± SD N	347.04 20.66 23	343.54 19.42 24	334.3 18.97 23	301.63* 34.13 16
Corpora lutea	Mean ± SD N	14.26 1.48 23	14.88 2.76 24	15.0 2.58 23	15.19 1.42 16
Implantation	Mean ± SD N	12.74 2.14 23	12.63 4.22 24	12.74 3.15 23	13.5 3.2 16
Live Fetuses	Mean ± SD N	12.22 2.26 23	11.75 4.70 24	12.74 3.15 23	11.88 4.5 16
Early resorptions	Mean ± SD N	0.48 0.79 23	0.88 1.03 24	0.52 0.9 23	0.75 1.44 16
Late resorptions	Mean ± SD N	0.04 0.21 23	0.0 0.0 24	0.0 0.0 23	0.88 3.5 16
Total resorptions	Mean ± SD N	0.52 0.79 23	0.88 1.03 24	0.52 0.9 23	1.63 3.59 16
Dead Fetuses	Mean ± SD N	0.0 0.0 23	0.04 0.2 24	0.09 0.29 23	0.0 0.0 16
Sex Ratio (M/F)	Mean ± SD N	2.27 2.37 23	0.96* 0.61 23	1.02* 0.66 22	12.67 3.31 15
Pre-implantation loss	Mean ± SD N	10.86 10.55 23	16.96 22.51 24	15.17 15.3 23	11.07 19.09 16
Post-implantation loss	Mean ± SD N	4.24 6.04 23	11.88 22.48 24	0.0 0.0 23	11.38 25.65 16

Summary of Fetal Visceral Examination

Observations	Group	Control		Low Dose		Mid Dose		High Dose
	Dose	0 mg/kg bw		1.25 mg/kg bw		5 mg/kg bw		20 mg/kg bw
	No. Of litters evaluated	23		24		23		16
	No. Of pups evaluated	147		147		152		99
		A	B	A	B	A	B	A	B
Hemorrhagic Kidney (B)		0	0.0	1*	0.75	3	2.11	5	5.49
Convoluted Ureter (B)		7	5.19	11	8.21	16	11.27	15*	16.48
Dilated Renal Pelvis (L)		0	0.0	3	2.24	5*	3.52	0	0.0
Thymus		0	0.0	2	1.49	4*	2.82	1	1.1
Small Spleen		2	1.48	2	1.49	9*	6.34	2	2.2

Summary of Fetal Skeletal Examination

Observations	Group	Control		Low Dose		Mid Dose		High Dose
	Dose	0 mg/kg bw		1.25 mg/kg bw		5 mg/kg bw		20 mg/kg bw
	No. Of litters evaluated	23		24		23		16
	No. Of pups evaluated	147		147		152		99
		A	B	A	B	A	B	A	B
Supernumerary rib-14th T (B)		6	4.08	10	6.8	24*	15.79	4	4.04
Supernumerary rib-14th T (R)		2	1.36	8	5.44	8	5.26	6*	6.06
Large-NasoFrontal Suture		0	0.0	1	0.68	5*	3.29	0	0.0
IO-4th Sternerbum		0	0.0	5*	3.4	1	0.66	0	0.0
Split-Interparietal		15	10.2	13	8.84	18	11.84	19*	19.19
Small-Hyoid		0	0.0	2	1.36	3	1.97	3*	3.03

Conclusions:

Based on the findings, the NOAEL (No observed adverse effect level) for maternal toxicity is believed to be 1.25 mg/ kg body weight based on clinical observations seen in some animals at 5 mg/kg, whereas the NOAEL for embryo-fetal toxicity is believed to be 20 mg/ kg body weight.

Executive summary:

This Prenatal developmental toxicity study of N-Oleyl-1,3-diaminopropane was conducted in pregnant female Wistar rats to detect the possible adverse effect on pregnant females and embryofetal development when administered by oral gavage from respective gestation day 0 to 19.

Nulliparous and non pregnant females were mated with males (2:1 ratio) and divided into four groups based on their body weights on day of positive vaginal smears (GD 0). Four groups of presumed pregnant females were dosed daily by oral gavage with 1.25, 5 and 20 mg/kg body weight per day of N-Oleyl-1,3-diaminopropane at dose volume of 4 mL/kg body weight. Control animals were handled identically as treated groups and received vehicle in similar volume as treated groups. The test item formulation was prepared freshly and dose volumes were adjusted based on the most recent body weight measurement. Animals were examined daily for the clinical signs and mortality. Body weight and food consumption was measured on various gestation days. The treated and control females were sacrificed on respective gestation day 20.

Followed by the gross necropsy evaluation of the females, the uteri and ovaries were removed, weighed and examined for number of implantations, resorptions (early and late) live and dead fetuses. Fetuses were identified by colour strings, sexed and weighed. All fetuses were observed for the external abnormalities, half of the fetuses for the visceral abnormalities, craniofacial examination and remain half of the litter for skeletal abnormalities. Uteri of the non pregnant females were processed with 0.5 % ammonium sulphide solution and checked for the early embryonic deaths if any.

 

Results:

Test item related clinical signs were observed in high dose females during the entire treatment period. Also effects on clinical observations were observed in animals of the MD group.

However, there were four decedents in this study [1 in MD group (Animal 62) and 3 in HD group (Animals 80, 82 and 98)]. Animal no. 82 was euthanised for humane reason. The death of two animals (Animals 62 and 98) were considered due to gavaging error and other two (Animals 80 and 82) might be considered due to toxicity. 

Statistically significant decrease was observed for body weight and body weight change throughout the gestation period in HD group.  Statistically significant decrease in overall food consumption was observed in HD group compared to corresponding control. Statistical analysis of prenatal data revealed significance in prenatal parameters like gravid uterus weight and adjusted maternal weight in HD group compared to corresponding controls. No other prenatal parameters like No. of corpora lutea, implantations percent preimplantation loss, group mean number of live fetuses, early resorptions, late resorptions, total resorptions, group mean number of female fetuses, sex ratio (M/F) and percent post implantation loss showed statistical deviation compared to corresponding controls.

 

Statistically significant difference was observed for group male litter weight (LD group), sex ratio (LD and MD groups) and total number of male fetuses (LD group) compared with controls. These findings were not attributed to toxicity as no dose related pattern was observed. Decrease in pregnancy rate was observed in HD group (69.56%) as compared to LD (96%), MD (95.8%), and control (95.8%).

Few gross external abnormalities were seen in fetuses among the control and treatment groups. Typical external findings noted were protruding tongue, malrotated limbs, micrognathia, edematous neck, small neck and hematoma (localised).But no statistical deviation was observed for these above findings except for hematoma which were localised and did not show dose related pattern.

Internal observation of the viscera by free hand micro discussion technique revealed range of visceral abnormalities in all groups including control. However, the statistical analysis revealed differences for findings viz., hemorrhagic kidney-bilateral (HD group), convoluted ureter-bilateral (HD group), dilated renal pelvis-left side (MD group), split thymus (MD), small spleen (MD group). Most of the above findings (except for hemorrhagic kidney and convoluted ureter in HD group) were not attributed to toxicity due to lack of dose dependent effect.

Craniofacial examination by razor blade serial sectioning technique revealed no statistical significant difference for any of the findings observed in treatment and control groups. 

Skeletal examination of the Alizarin red stained fetuses revealed a range of abnormalities which were of a type or which occurred at an incidence in both treatment and control groups. The statistical difference observed for supernumerary 14th rib-right side-bilaterally (MD group) and right (HD group), large naso-frontal suture (MD group), incomplete ossification of 4th sternebrum (LD group), split interparietal (HD group) and small hyoid (HD group) were attributed to toxicity, but the statistical difference observed for other anomalies were not considered of toxicological relevance due to lack of dose related pattern.

The terminally sacrificed animals belonging to the HD group revealed incidences of few lesions at necropsy, which were as gas filled stomach and intestine, whitish spots on adrenals, discoloured liver, small spleen and thymus, enlarged adrenals, bloody lung, discoloured heart, bloody lung. The finding like dark coloured food rest in caecum observed in most of the animals of control and treatment groups cannot be considered as toxicity related and in most of the animals this finding observed was not reported.

 

Based on the findings, the NOAEL (No observed adverse effect level) for maternal toxicity is believed to be 1.25 mg/ kg body weight based on clinical observations seen in some animals at 5 mg/kg, whereas the NOAEL for embryo-fetal toxicity is believed to be 20 mg/ kg body weight.

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

20 mg/kg bw/day

Quality of whole database:

Based on cross-reading to Oleyl-diamine. The study is GLP compliant and has Klimisch score 1.

Effect on developmental toxicity: via inhalation route

Endpoint conclusion:

no study available

Effect on developmental toxicity: via dermal route

Endpoint conclusion:

no study available

Additional information

Evaluation of repeated dose toxicity of Tris (2-hydroxyethyl) tallow diaminopropane, CAS 90367-27-4 (recently redefined as Amines, N-(C16-18 (even numbered) and C18-unsatd. alkyl) trimethylenedi-, ethoxylated (NLP), CAS 1290049-56-7), also referred to as Tallow-diamine3EO:

For this endpoint partial read-across is applied to Tris (2-hydroxyethyl) oleyl diaminopropane(CAS 90367-27-4, referred to further as Oleyl-diamine3EO).

Data from Oleyl-diamine3EO is also considered applicable for Tallow-diamine3EO, as both substances have the same molecular structure, thus showing the exact same basic chemical reactivity. Both substances onlyslightly differ in chain length:Oleyl alkyl chains are mainly C18 and have a higher level of unsaturation than tallow, whereas tallow also contains some saturated C16 chains.

 

Oleyl-diamine3EO has been evaluated ina reproduction/developmental toxicity screening test according to OECD 422 guidelines andin compliance to GLP.

Four groups of ten male and ten female rats were exposed by oral gavage toOleyl-diamine3EOat 0, 1, 5 and 25 mg/kg/day. Males were exposed for 29 days, females were exposed for 43-52 days, i.e. during 2 weeks prior to mating, during mating, during post-coitum, and during at least 4 days of lactation.

Reproduction/developmental parameters were evaluated, consisting of mating, fertility and conception indices, precoital time, number of corpora lutea and implantation sites, gestation index and duration, parturition, maternal care, sex ratio and early postnatal pup development (mortality, clinical signs, body weights and macroscopy).

No reproduction or developmental toxicity was observed up to the highest dose level tested (25 mg/kg). No treatment-related changes were noted in any of the reproductive parameters investigated in this study (i.e. mating, fertility and conception indices, precoital time, and numbers of corpora lutea and implantation sites), or in any of the developmental parameters (i.e. gestation index and duration, parturition, maternal care and early postnatal pup development consisting of mortality, clinical signs, body weight and macroscopy).

The study therefore concluded to a reproduction NOAEL of at least 25 mg/kg/day.

In contrast, the parental NOAEL for repeated dose toxicity was found to be 1 mg/kg/day

 

Additional information is on developmental toxicity of Oleyl-diamine3EO can be derived by cross-reading from the non-ethoxylated diamine Oleyl-diamine. For this substance afull developmental toxicity study is available according to OECD 414 guidelinesin compliance to GLP.

Cross-reading from this substance is acceptable on the basis of similarities of structure and properties leading to common biological activity.

This study was performed by dosing pregnant rats from day 0-19 of gestation with either 0, 1.25, 5 or 20 mg/kg bw of Oleyl-diamine. The animals were then sacrificed and the fetuses subject to external, visceral and skeletal examination. There was a slight increase in visceral and skeletal variations. No malformations were observed. Neither of the variations are considered to be of toxicological relevance as there were no dose-response pattern. Maternal toxicity including deaths in the high dose group, reduced bodyweight gain and reduced pregnancy rate were observed. The NOAEL (No observed adverse effect level) for maternal toxicity is believed to be 1.25 mg/ kg body weight based on clinical observations seen in some animals at 5 mg/kg, whereas the NOAEL for embryo-fetal toxicity is believed to be 20 mg/ kg body weight.

The conclusion that Tallow-diamine3EO is not teratogenic is supported by information that was submitted for TSCA 8(e) involving an illegible copy of an old study report. Adequate assessment of the data is not possible leading to a low validity.

This study concluded that treatment of pregnant NZW rabbits during gd 6-18 withTallow-diamine3EOat dose levels of 0, 1, 5 and 25 mg ai/kgbw/d did not cause any increase in major malformations, minor anomalies or skeletal variants. Based on the findings above, the test material is embryotoxic at maternally toxic doses, but is not teratogenic.

 

Justification for selection of Effect on developmental toxicity: via oral route:

The study is GLP compliant and has Klimisch score 1

Justification for selection of Effect on developmental toxicity: via inhalation route:

Tallow-diamine3EO is a viscous fluid with a bp > 300°C and has a vapour pressure < 0.0015 Pa at 20°C. Its use is limited to industrial and professional users and does not involve the forming of aerosols, particles or droplets of an inhalable size. So exposure to humans via the inhalation route will be unlikely to occur.

Justification for selection of Effect on developmental toxicity: via dermal route:

Manufacture and use are highly controlled. Its use is limited to industrial and professional users where its severe corrosive properties will ensure sufficient protection measures to prevent dermal exposure. Furthermore, the substance is not expected to easily pass the skin, and in view of their severe corrosive properties, testing via dermal route for developmental toxicity is not a first choice

Justification for classification or non-classification

Available data from a reproduction screening study (OECD 422) with Oleyl-diamine3EO showed no effects on reproduction parameters. Also cross-reading from adevelopmental toxicity(OECD 414) with Oleyl-diamine indicate no concerns for developmental toxicity. In both studies the lack of developmental effects at the highest dose levels tested of 25 resp. 20 mg/kg bw/day is in large contrast with the NOAELs obtained for parental toxicity of 1 resp. 5 mg/kg bw.

Also information from a developmental study of Tallow-diamine3EO in rabbits showed no concerns for reproduction toxicity.

In conclusion, the available data do not indicate a concern for reproductive health.

 

For fertility a firm conclusion regarding classification cannot be made, as a full 2-generation reproduction study is lacking. But based on limited exposures by dermal route (substance is severely irritating/ corrosive) or by inhalation (very low vapour pressure), as well as lack of indication for concerns regarding reproductive toxicity from repeated dose studies and a developmental toxicity study there are no concerns and further testing is not indicated.