Registration Dossier

Administrative data

Key value for chemical safety assessment

Effects on fertility

Description of key information

No adverse effects on fertility at doses of primary alkylamines or TPA below those resulting in generalized (repeated dose) toxicity.

Link to relevant study records

Referenceopen allclose all

Endpoint:
screening for reproductive / developmental toxicity
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Summary of study from EU RAR on Primary alkylamines
Justification for type of information:
The analogue approach is used for the hazard assessment of toxicological, eco-toxicological and environmental fate endpoints for the registration Pentamid™ KH (EC 934-047-1). The hypothesis is that data can be read-across between Pentamid™ KH and its structural analogues, based on structural similarity and common breakdown/metabolic products (Scenario 1 of the Read-Across Assessment Framework (RAAF, ECHA, 2015)).

For mammalian toxicity the “parent” substances show no significant systemic or dermal toxicity in mammals and vertebrates. One of the metabolic products of Pentamid™ KH, the well-studied terephthalic acid, has no significant systemic toxicity. The amine metabolite, however, shows diffuse mammalian systemic toxicity at moderate concentrations. This metabolite is employed in the risk assessment, in agreement with the European Union draft Risk Assessment Report of 2008.

The sole classification for Pentamid™ KH is the precautionary aquatic chronic 4 category, based on low water solubility and a log Kow higher than 4.

Read-across data, all evaluated as reliable according to Klimisch scores of 1 or 2, to estimate the toxicity of the registered substance is used for fulfilling the data requirements of the REACH registration and classifying potential hazards. This read-across approach is adequate for the purposes of risk assessment and classification and labeling.
Reason / purpose:
read-across source
Qualifier:
according to
Guideline:
OECD Guideline 421 (Reproduction / Developmental Toxicity Screening Test)
GLP compliance:
yes
Limit test:
no
Species:
rat
Vehicle:
other: sesame oil
Details on mating procedure:
cohabitate 1:1 (male: female) for up to 7 days.
Duration of treatment / exposure:
Males: 28 days (14 days prior to mating until the end of the mating period and up to a maximum of 28 days).
Females: 56 days (14 days before start of the mating period, mating for up to 7 days), during pregnancy (20 days), parturition and until day 3 of lactation)
Frequency of treatment:
once daily by gavage
Dose / conc.:
12.5 mg/kg bw/day (nominal)
Dose / conc.:
50 mg/kg bw/day (nominal)
Dose / conc.:
125 mg/kg bw/day (nominal)
No. of animals per sex per dose:
10
Control animals:
yes, concurrent vehicle
Details on study design:
Males were treated daily from 14 days prior to mating until the end of the mating period for a maximum of 28 days. Females were treated daily for 14 days before start of the mating period, throughout the same, during pregnancy and until day 3 of lactation. The animals were mated one male with one female.
Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
Mild signs of toxicity occurred in the high dose group (salivation after treatment, hunched posture and in some cases soft stools and piloerection). Only salivation occurred in the mid dose group.
Mortality:
mortality observed, treatment-related
Description (incidence):
6/10 males and 5/10 females in the high dose group died between day 9 and day 25 of treatment (during the premating and mating period). In the mid dose group, 1/10
males and 1/10 females each died before day 25. No animals died in the low dose group and in the control group, 1 female died by accident.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
In the high dose group, body weight loss was observed (about 22 g in males, 17 g in females). In mid dose group males and females, body weight gain and mean food consumption were statistically significantly lower during the premating period than in controls.
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
In the high dose group, body weight loss was observed (about 22 g in males, 17 g in females). In mid dose group males and females, body weight gain and mean food consumption were statistically significantly lower during the premating period than in controls.
Organ weight findings including organ / body weight ratios:
effects observed, non-treatment-related
Reproductive performance:
effects observed, treatment-related
Description (incidence and severity):
Fewer pregnancies were observed in high dose females.
Only 3 females out of 7 mated females had positive vaginal smears and of these only one was pregnant, but with only implantation sites and no live pups. At the high dose level the mean pre-coital interval was longer (13.4 days) than that of the control group (2.3 days).
Comparing of the control, low and mid dose groups:
Mating index: 9/9 (100%), 9/10 (90%) and 9/9 (100%) of mated females were sperm positive. Fertility index: 9/9 (100%), 8/10 (80%) and 7/9 (78%) of the mated females became pregnant Mean pre-coital time and parturition: unaffected.
Conception rate: 9/9 (100%), 8/9 (89%) and 7/9 (78%) of sperm positive females became pregnant and delivered live pups.
Corpora lutea: not determined.
Pre-implantation loss: not evaluated.
Staining for the presence of implantation sites was only performed with the uteri of apparently non-pregnant females. The mean number of visible implantation sites per were 17.6, 13.9 and 15.0.
Stillborns or litters with only implantations: none.
Mean number of total pups born per litter : 16.9, 12.3 and 14.
Mean litter index for post-implantation loss: 3.4, 9.9 and 4.5%.
At daily doses of 150 mg/kg bw 6/10 males and 5/10 females died between day 9 and day 25 of treatment (during the premating and mating period). At daily doses of 50 mg/kg bw 1/10 males and 1/10 females died on day 13 respectively on day 24 of treatment. No animals died at 12.5 mg/kg bw/day, and in the control group 1 female died by accident. Clinical observations at 150 mg/kg bw/day revealed salivation after treatment, hunched posture and in some cases soft stools and piloerection. The only clinical sign present at 50 mg/kg bw/day was salivation. No changes were seen at 12.5 mg/kg bw/day.

Body weight loss of about 22 g at the 150 mg/kg bw dose group and statistically significant (p > 0.01) lower body weight gain at the 50 mg/kg bw dose group during the premating period together with a lower mean food consumption was observed in the males. Also in the females body weight loss of about 17 g at the 150 mg/kg bw dose group and statistically significant lower body weight gain at the 50 mg/kg bw dose group together with a lower mean food consumption during the premating period was observed.

Only 3 females out of 7 mated females had positive vaginal smears and of these only one was pregnant, but with only implantation sites and no live pups. At the high dose level the mean pre-coital interval was longer (13.4 days) than that of the control group (2.3 days). There were no other significant changes is reproductive indices.


Key result
Dose descriptor:
NOAEL
Effect level:
12.5 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
body weight and weight gain
reproductive performance
Key result
Critical effects observed:
yes
Lowest effective dose / conc.:
50 mg/kg bw/day (nominal)
System:
female reproductive system
Organ:
not specified
Treatment related:
yes
Dose response relationship:
yes
Relevant for humans:
not specified
Clinical signs:
no effects observed
Concerning reproductive indices, fewer high dose females mated, conceived, and delivered litters. Only 3 females out of 7 mated high dose females had positive vaginal smears and of these only one was pregnant, but with only implantation sites and no live pups. At the high dose level the mean pre-coital interval was longer (13.4 days) than that of the control group (2.3 days).
Comparing of the control, low and mid dose groups:
Mating index: 9/9 (100%), 9/10 (90%) and 9/9 (100%) of mated females were sperm positive. Fertility index: 9/9 (100%), 8/10 (80%) and 7/9 (78%) of the mated females became pregnant Mean pre-coital time and parturition: unaffected.
Conception rate: 9/9 (100%), 8/9 (89%) and 7/9 (78%) of sperm positive females became pregnant and delivered live pups.
Corpora lutea: not determined.
Pre-implantation loss: not evaluated.
Staining for the presence of implantation sites was only performed with the uteri of apparently non-pregnant females. The mean number of visible implantation sites per were 17.6, 13.9 and 15.0.
Stillborns or litters with only implantations: none.
Mean number of total pups born per litter : 16.9, 12.3 and 14.
Mean litter index for post-implantation loss: 3.4, 9.9 and 4.5%.
Pup sex ratio: no change.

No abnormalities were observed in any pup either at birth or at autopsy on day 4 of lactation neither in the 12.5 nor in the 50 mg/kg bw/day treated groups. A lower mean value of live born pups per litter and of pups per litter alive at day 4 were found for the intermediate dose group. These findings on survival were considered unlikely to be related to the compound. A slightly lower pup body weight was observed in the mid dose group in comparison with the control group at birth and at day 4 of lactation but not for the pups of the low dose group.

Based on findings of general toxicity (death, clinical signs, reduced body weight gain) at the high and mid dose levels, a NOEL/systemic toxicity of 12.5 mg/kg bw/d can be derived from
the study. Based on the findings of a lower fertility index and a lower conception in the mid dose group, a NOEL/fertility of 12.5 mg/kg bw/d can be derived from the results of this screening study.
Key result
Dose descriptor:
NOEL
Generation:
F1
Effect level:
12.5 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
female
Basis for effect level:
other: no effects seen
Key result
Critical effects observed:
no
Key result
Reproductive effects observed:
yes
Lowest effective dose / conc.:
50 mg/kg bw/day (nominal)
Treatment related:
yes
Relation to other toxic effects:
reproductive effects as a secondary non-specific consequence of other toxic effects
Dose response relationship:
yes
Relevant for humans:
not specified
Conclusions:
A guideline OECD 421 study was performed on analogue substances, tallow alkylamines, in rats by oral gavage, at doses of 12.5, 50 and 150 mg/kg bw day. Animals were exposed for 14 days prior to mating, during mating and through PD Day 4. Based on findings of general toxicity (death, clinical signs, reduced body weight gain) at daily dosages of 50 mg/kg bw/d, a NOEL/maternal toxicity of 12.5 mg/kg bw/d can be derived from the study. Based on the findings of a lower fertility index and a lower conception rate at daily dosages of 50 mg/kg bw/d, a NOEL/fertility of 12.5 mg/kg bw/d can be derived from the results of this screening study. The EU Risk Assessment Report on Primary Alkylamines recommends that there be no specific classification and labelling for tallow alkylamines and analogues/category members as reproductive toxicants.
Endpoint:
one-generation reproductive toxicity
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
guideline study with acceptable restrictions
Justification for type of information:
The analogue approach is used for the hazard assessment of toxicological, eco-toxicological and environmental fate endpoints for the registration Pentamid™ KH (EC 934-047-1). The hypothesis is that data can be read-across between Pentamid™ KH and its structural analogues, based on structural similarity and common breakdown/metabolic products (Scenario 1 of the Read-Across Assessment Framework (RAAF, ECHA, 2015)).

For mammalian toxicity the “parent” substances show no significant systemic or dermal toxicity in mammals and vertebrates. One of the metabolic products of Pentamid™ KH, the well-studied terephthalic acid, has no significant systemic toxicity. The amine metabolite, however, shows diffuse mammalian systemic toxicity at moderate concentrations. This metabolite is employed in the risk assessment, in agreement with the European Union draft Risk Assessment Report of 2008.

The sole classification for Pentamid™ KH is the precautionary aquatic chronic 4 category, based on low water solubility and a log Kow higher than 4.

Read-across data, all evaluated as reliable according to Klimisch scores of 1 or 2, to estimate the toxicity of the registered substance is used for fulfilling the data requirements of the REACH registration and classifying potential hazards. This read-across approach is adequate for the purposes of risk assessment and classification and labeling.
Reason / purpose:
read-across source
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 415 [One-Generation Reproduction Toxicity Study (before 9 October 2017)]
GLP compliance:
yes
Limit test:
no
Species:
rat
Strain:
other: CD and Wistar
Sex:
male/female
Route of administration:
oral: feed
Vehicle:
other: feed
Duration of treatment / exposure:
paternal: 90 days prior to and throughout mating
maternal: 90 days prior to mating, throughout mating, gestation, and lactation
offspring: 51 days; from birth through lactation and 30 days post weaning
Frequency of treatment:
daily in feed
Dose / conc.:
14 mg/kg bw/day (nominal)
Remarks:
corresponds to 0.03%. Actual in CD strain: 14 and 17 mg/kg bw/d in males, females, respectively. Actual: 14 and 19 mg/kg bw/d in Wistar males, females respectively
Dose / conc.:
59 mg/kg bw/day (nominal)
Remarks:
corresponds to 0.125%. Actual: 59 and 67 mg/kg bw/d in CD males, females respectively. Actual: 61 and 78 mg/kg bw/d in Wistar males, females respectively.
Dose / conc.:
240 mg/kg bw/day (nominal)
Remarks:
corresponds to 0.5%. Actual: 240 and 282 mg/kg bw/d in CD males, females respectively. Actual: 249 and 307 mg/kg bw/d in Wistar males, females respectively
Dose / conc.:
960 mg/kg bw/day (nominal)
Remarks:
corresponds to 0.2.0%. Actual: 960 and 1107 mg/kg bw/d in CD males, females respectively. Actual: 960 and 1219 mg/kg bw/d in Wistar males, females respectively
Dose / conc.:
2 480 mg/kg bw/day (nominal)
Remarks:
corresponds to 5.0%. Actual: 2480 and 2780 mg/kg bw/d in CD males, females respectively. Actual: 2480 and 3018 mg/kg bw/d in Wistar males, females respectively.
No. of animals per sex per dose:
30
Control animals:
yes, plain diet
Details on study design:
Experimental conditions were identical for the two different strains of rats. Rats 15-17 weeks of age (n=30) were grouped housed 3/cage for the first 90 days of exposure. Body weight and feed intake were determined weekly during this time period. On Day 91, breeding pairs (n=10/sex) were housed together for 2 weeks prior to being separated. On Day 0 (delivery) the number and viability of offspring were evaluated and grossly examined. Offspring were recounted, sexed, and weighed on Day 1. These measurements were repeated at weaning on Day 21. After weaning, the litters were reduced to 2/sex/dose from each of 5 litters (20 pups/dose/strain) and maintained on test diets for 30 more days (Day 51) prior to sacrifice.
Statistics:
Body weight gain and standard reproductive indices were assessed and statistically compared using ANOVA and Dunnett’s-t-test using SAS statistical programs.
Reproductive indices:
Parameters evaluated consisted of: fertility index, number of offspring born per dam; number and proportion of each sex born; number (Day 0, 1, and 21) and proportion (Day 1 and 21) of each sex alive; average weight at Day 1 and 21 of all offspring and of each sex.
Mortality:
mortality observed, treatment-related
Description (incidence):
Prior to mating, there were 5 deaths (3 CD females, and a Wistar male and female) reported during weeks 4-13 among those given 5% TPA in the diet. After mating, 3 CD (1 male at 2.0%, and one male and one female at 5.0%) and 4 Wistar female (2 at 5.0% and 2 at 0.03%) rats died.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Body weights were statistically decreased after 13 weeks in both sexes of CD rats on 2% and 5% TPA diets, and in males exposed to 0.03%. This effect occurred in Wistars (both sexes) only at the 5% level.
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
decreased food consumption in CD females treated with 2% and 5% test material, and in both sexes of high dose Wistars
Reproductive performance:
no effects observed
The NOAEL for parental toxicity and the F1 generation was 0.5% TPA in the diet (approximately 240-307 mg/kg/day). During the one-generation component of the study 3 CD (1 male at 2.0%, 1/sex at 5.0%) and 4 Wistar female (2 at 5.0% and 2 at 0.03%) rats died. There was no effect of treatment on fertility index and litter size.
Key result
Dose descriptor:
NOAEL
Effect level:
240 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
mortality
gross pathology
reproductive performance
Remarks on result:
other: in CD rats
Remarks:
in Wistar, NOAEL = 960 mg/kg bw/d
Key result
Critical effects observed:
yes
Lowest effective dose / conc.:
960 mg/kg bw/day (nominal)
In the highest two doses, there was evidence that generalized toxicity affected dams, resulting in a failure of the dams to allow the offspring to nurse. These dams were consuming dietary levels of TPA known to cause reduced feed consumption and diarrhea, and to induce the formation of renal and bladder calculi. Unscheduled deaths during the postweaning period (Day 21-51) were confined to the 5% TPA group (18 Wistar and 16 CD) and were associated with a very high incidence of renal and bladder calculi. Renal and bladder calculi were noted in all animals exposed to 5% that were necropsied at Day 21. Day 51 necropsy findings also reported a very high incidence of renal and bladder calculi and the histological sequelae of the presence of the calculi.
Key result
Dose descriptor:
NOAEL
Generation:
F1
Effect level:
> 2 480 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Remarks on result:
not determinable due to absence of adverse toxic effects
Key result
Critical effects observed:
no
Key result
Reproductive effects observed:
no

The NOAEL for reproductive toxicity was > 5% in the diet (approximately 2480-3018 mg/kg/day).

The NOAEL for parental toxicity and the F1 generation was 0.5% TPA in the diet (approximately 240-307 mg/kg/day).

Conclusions:
A one-generation reproductive toxicity study of dietary terephthalic acid to both CD and Wistar rats at five doses ranging from 14 mg/kg bw/d (0.03% in the diet) to 2480 mg/kg bw/d (5% in the diet). Parental toxicity was displayed at doses of 960 and 2480 mg/kg bw/d in both strains of rat: bladder calculi and renal toxicity was observed in offspring of these doses which were continued on the diet throughout the F1 post-weaning periods, and maternal post-natal behaviour was adversely affected. The NOAEL for parental toxicity was 240 mg/kg bw/d (0.5%). There were no teratologic effects or other adverse reproductive effects of the test substance. The NOAEL for reproduction was 2450 mg/kg bw/d (5%) in both strains.
Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
12.5 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
adequate
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available

Effects on developmental toxicity

Description of key information

No adverse effects on developmental toxicity from exposure to primary alkylamines or TPA.

Link to relevant study records

Referenceopen allclose all

Endpoint:
developmental toxicity
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Summary in the EU Risk Assessment Report on Primary Alkylamines
Justification for type of information:
The analogue approach is used for the hazard assessment of toxicological, eco-toxicological and environmental fate endpoints for the registration Pentamid™ KH (EC 934-047-1). The hypothesis is that data can be read-across between Pentamid™ KH and its structural analogues, based on structural similarity and common breakdown/metabolic products (Scenario 1 of the Read-Across Assessment Framework (RAAF, ECHA, 2015)).

For mammalian toxicity the “parent” substances show no significant systemic or dermal toxicity in mammals and vertebrates. One of the metabolic products of Pentamid™ KH, the well-studied terephthalic acid, has no significant systemic toxicity. The amine metabolite, however, shows diffuse mammalian systemic toxicity at moderate concentrations. This metabolite is employed in the risk assessment, in agreement with the European Union draft Risk Assessment Report of 2008.

The sole classification for Pentamid™ KH is the precautionary aquatic chronic 4 category, based on low water solubility and a log Kow higher than 4.

Read-across data, all evaluated as reliable according to Klimisch scores of 1 or 2, to estimate the toxicity of the registered substance is used for fulfilling the data requirements of the REACH registration and classifying potential hazards. This read-across approach is adequate for the purposes of risk assessment and classification and labeling.
Reason / purpose:
read-across source
Qualifier:
according to
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
GLP compliance:
yes
Limit test:
no
Species:
rat
Strain:
Sprague-Dawley
Route of administration:
oral: gavage
Duration of treatment / exposure:
days 6-15 of gestation
Frequency of treatment:
once daily
Dose / conc.:
10 mg/kg bw/day (nominal)
Dose / conc.:
40 mg/kg bw/day (nominal)
Dose / conc.:
80 mg/kg bw/day (nominal)
No. of animals per sex per dose:
7 females
Control animals:
yes, concurrent vehicle
Maternal examinations:
Clinical signs, body weight and weight on days 6, 9, 12, 16 and 20
Ovaries and uterine content:
in 2 sacrificed animals per dose group on day 16
Fetal examinations:
on day 20
Indices:
viable fetuses, early and late resorptions as well as the number of corpora lutea. Fetuses were examined for external, visceral and skeletal abnormalities.
Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
In mid and high dose, generalised irritative effects of the test substance as characterised by rales, salivation, unkempt appearance and changes in the amount, colour and consistency of the feces. In high dose females, additonal body weight loss, rough coat and dark red material around the eyes, nose and/or mouth. Primarily occurring during dosing but occasionally noted in post-treatment time frame.

Mortality:
no mortality observed
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Dose-dependent body weight loss In mid and high dose (during gestation days 6-9) or reduced weight gain (during gestation days 12-16), along with a corresponding reduction in food consumption occurred during the treatment period. Net body weight gain (adjusted for gravid uterine weight) was observed in mid and high doses after treatment ceased, during days 16-20, along with increased food consumption.
Ophthalmological findings:
no effects observed
Gross pathological findings:
no effects observed
Details on results:
Outward clinical signs of toxicity were observed at the 40 and 80 mg/kg bw/d dose levels. The observations indicated a generalised irritative effect of the test substance as characterised by rales, salivation, unkempt appearance and changes in the amount, colour and consistency of the feces. However, no other signs of treatment-related gastrointestinal irritation or other internal changes were observed at the gestation day 15 and 20 necropsies. More pronounced signs of toxicity were apparent only in the 80 mg/kg bw/d dose group and included emaciation, rough coat and dark red material around the eyes, nose and/or mouth. Similar clinical signs were infrequently noted during the post-dose observations. Dose-dependent body weight loss (during gestation days 6-9) or reduced weight gain (during gestation days 12-16), along with a corresponding reduction in food consumption occurred during the treatment period in the 40 and 80 mg/kg bw/d dose groups. Net body weight gain (adjusted for gravid uterine weight) was also lower at these levels. Following cessation of treatment (days 16-20), increase in weight gain and food consumption were noted at both dose levels.
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:
not examined
Changes in number of pregnant:
no effects observed
Key result
Dose descriptor:
NOAEL
Effect level:
10 mg/kg bw/day (nominal)
Based on:
test mat.
Basis for effect level:
body weight and weight gain
Key result
Abnormalities:
no effects observed
Description (incidence and severity):
No specific effects other than generalized toxicity and absence of body weight gain
Fetal body weight changes:
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
Key result
Dose descriptor:
NOAEL
Effect level:
> 80 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
not specified
Remarks on result:
not determinable due to absence of adverse toxic effects
Key result
Abnormalities:
no effects observed
Key result
Developmental effects observed:
no
Conclusions:
In a teratology study in rats, the amine test material was administered by gavage at doses of 10, 40 and 80 mg/kg bw/d on days 6-15 of gestation. The high and mid dose groups showed evidence of generalised toxicity as a decrease in grooming behaviour and decreased body weight gain. There were no teratologic or fetotoxic effects. The NOAEL for maternal toxicity was 10 mg/kg bw/d, and the NOAEL for reproductive effects was > 80 mg/kg bw/d. These values are read across to the target substance.
Endpoint:
developmental toxicity
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Summary in the EU Risk Assessment Report on Primary Alkylamines
Justification for type of information:
The analogue approach is used for the hazard assessment of toxicological, eco-toxicological and environmental fate endpoints for the registration Pentamid™ KH (EC 934-047-1). The hypothesis is that data can be read-across between Pentamid™ KH and its structural analogues, based on structural similarity and common breakdown/metabolic products (Scenario 1 of the Read-Across Assessment Framework (RAAF, ECHA, 2015)).

For mammalian toxicity the “parent” substances show no significant systemic or dermal toxicity in mammals and vertebrates. One of the metabolic products of Pentamid™ KH, the well-studied terephthalic acid, has no significant systemic toxicity. The amine metabolite, however, shows diffuse mammalian systemic toxicity at moderate concentrations. This metabolite is employed in the risk assessment, in agreement with the European Union draft Risk Assessment Report of 2008.

The sole classification for Pentamid™ KH is the precautionary aquatic chronic 4 category, based on low water solubility and a log Kow higher than 4.

Read-across data, all evaluated as reliable according to Klimisch scores of 1 or 2, to estimate the toxicity of the registered substance is used for fulfilling the data requirements of the REACH registration and classifying potential hazards. This read-across approach is adequate for the purposes of risk assessment and classification and labeling.
Reason / purpose:
read-across source
Qualifier:
according to
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
GLP compliance:
yes
Limit test:
no
Species:
rabbit
Strain:
New Zealand White
Route of administration:
oral: gavage
Duration of treatment / exposure:
days 6-18 of gestation
Frequency of treatment:
once daily
Dose / conc.:
3 mg/kg bw/day (nominal)
Dose / conc.:
10 mg/kg bw/day (nominal)
Dose / conc.:
30 mg/kg bw/day (nominal)
No. of animals per sex per dose:
5 females
Control animals:
yes, concurrent vehicle
Maternal examinations:
Clinical signs, body weight and weight on days 6, 9, 12, 16 and 20
Ovaries and uterine content:
in 2 sacrificed animals per dose group on day 18
Fetal examinations:
on day 29
Indices:
viable fetuses, early and late resorptions as well as the number of corpora lutea. Fetuses were examined for external, visceral and skeletal abnormalities.
Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
Rales and laboured breathing were noted among high dose rabbits. Additional findings in the high dose group included irritation of the mouth, emaciation and decreased formation of feces.
Dermal irritation (if dermal study):
effects observed, treatment-related
Description (incidence and severity):
skin irritation around the mouth in high dose group
Mortality:
mortality observed, treatment-related
Description (incidence):
2 deaths occurred in the high dose group: 1 o day 9 and 1 on day 25
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Dose-dependent body weight loss or reduced weight gain (beginning with dosing on day 6 of gestation) occurred during the treatment period in the mid and high dose groups. Net body weight gain (adjusted for gravid uterine weight) was also lower. Following cessation of treatment, weight gain increased in the high dose group.
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
Dose-dependent reduction in food consumption, occurred during the treatment period in the mid and high dose groups.

Gross pathological findings:
no effects observed
Number of abortions:
effects observed, non-treatment-related
Description (incidence and severity):
1 animal in each dose group spontaneously aborted prior to the scheduled sacrifice
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:
not examined
Changes in number of pregnant:
no effects observed
Details on maternal toxic effects:
As result of the study, treatment-related mortality occurred as two females died in the 30 mg/kg bw/d group, one on gestation day 9 and the other on gestation day 25. In addition, one female each at the 3, 10, and 30 mg/kg bw/d levels aborted prior to scheduled sacrifice. Outward clinical signs of toxicity were observed at the 10 and 30 mg/kg bw/d levels. In the 10 mg/kg bw/d dose group, rales and laboured breathing were noted. Additional findings in the 30 mg/kg bw/d level included few or no feces and emaciation. Irritation of the mouth area also developed in females in this group. The irritation was characterised by swollen raised white areas, scab-like lesions and /or sloughing of the skin of the lips and the chin. No other signs of treatment-related gastrointestinal irritation or internal changes were observed at gross necropsy at gestation days 18 and 29. Dose-dependent body weight loss or reduced weight gain (beginning with dosing on day 6 of gestation), along with a corresponding reduction in food consumption, occurred during the treatment period in the mid and high dose groups. Net body weight gain (adjusted for gravid uterine weight) was also lower. Following cessation of treatment, weight gain increased in the high dose group. No such effects were observed in the dose group treated with 3 mg/kg bw/d. A NOAEL/maternal toxicity of 3 mg/kg bw/d was established.
Key result
Dose descriptor:
NOAEL
Effect level:
3 mg/kg bw/day (nominal)
Based on:
test mat.
Basis for effect level:
body weight and weight gain
Key result
Abnormalities:
no effects observed
Description (incidence and severity):
No specific effects other than generalized toxicity and absence of body weight gain
Fetal body weight changes:
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
Details on embryotoxic / teratogenic effects:
Caesarean section data obtained from the treated groups did not reveal any meaningful differences (concerning number of corpora lutea, implantation sites, viable fetuses, implantation loss, fetal sex and fetal weight) when compared with the controls. Fetal evaluations of type and frequency of malformations and variations did not reveal any indications for a treatment related teratogenic effect. In summary, oral administration of octadecenylamine to pregnant rabbits produced dosedependent maternal toxicity in the 10 and 30 mg/kg bw/d dose groups. No indications of an embryotoxic, fetotoxic or teratogenic effect was observed at any tested level. A NOAEL/developmental toxicity of > 30 mg/kg bw/d can be derived from the study.
Key result
Dose descriptor:
NOAEL
Effect level:
> 30 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
not specified
Remarks on result:
not determinable due to absence of adverse toxic effects
Key result
Abnormalities:
no effects observed
Key result
Developmental effects observed:
no
Conclusions:
In a teratology study in rabbits, the amine test material was administered by gavage at doses of 3, 10 and 30 mg/kg bw/d on days 6-18 of gestation. The high and mid dose groups showed evidence of generalised toxicity as laboured breathing, rales, dermal mouth irritation and decreased body weight gain during the dosing period. There were no teratologic or fetotoxic effects attributed to the administration of test material. The NOAEL for maternal toxicity was 3 mg/kg bw/d, and the NOAEL for reproductive effects was > 30 mg/kg bw/d. This value is read-across to the target substance.
Endpoint:
developmental toxicity
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Justification for type of information:
The analogue approach is used for the hazard assessment of toxicological, eco-toxicological and environmental fate endpoints for the registration Pentamid™ KH (EC 934-047-1). The hypothesis is that data can be read-across between Pentamid™ KH and its structural analogues, based on structural similarity and common breakdown/metabolic products (Scenario 1 of the Read-Across Assessment Framework (RAAF, ECHA, 2015)).

For mammalian toxicity the “parent” substances show no significant systemic or dermal toxicity in mammals and vertebrates. One of the metabolic products of Pentamid™ KH, the well-studied terephthalic acid, has no significant systemic toxicity. The amine metabolite, however, shows diffuse mammalian systemic toxicity at moderate concentrations. This metabolite is employed in the risk assessment, in agreement with the European Union draft Risk Assessment Report of 2008.

The sole classification for Pentamid™ KH is the precautionary aquatic chronic 4 category, based on low water solubility and a log Kow higher than 4.

Read-across data, all evaluated as reliable according to Klimisch scores of 1 or 2, to estimate the toxicity of the registered substance is used for fulfilling the data requirements of the REACH registration and classifying potential hazards. This read-across approach is adequate for the purposes of risk assessment and classification and labeling.
Reason / purpose:
read-across source
Qualifier:
according to
Guideline:
other: OECD Guideline 415 (One-Generation Reproduction Toxicity Study)
Principles of method if other than guideline:
OECD Guideline 415 (One-Generation Reproduction Toxicity Study)
GLP compliance:
yes
Limit test:
no
Species:
rat
Strain:
other: CD and Wistar
Route of administration:
oral: feed
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
no data
Duration of treatment / exposure:
paternal: 90 days prior to and throughout mating
maternal: 90 days prior to mating, throughout mating, gestation, and lactation
offspring: 51 days; from birth through lactation and 30 days post weaning
Frequency of treatment:
daily ad lib
Duration of test:
at least 151 days
Dose / conc.:
14 mg/kg bw/day (nominal)
Remarks:
corresponds to 0.03%. Actual in CD strain: 14 and 17 mg/kg bw/d in males, females, respectively. Actual: 14 and 19 mg/kg bw/d in Wistar males, females respectively
Dose / conc.:
59 mg/kg bw/day (nominal)
Remarks:
corresponds to 0.125%. Actual: 59 and 67 mg/kg bw/d in CD males, females respectively. Actual: 61 and 78 mg/kg bw/d in Wistar males, females respectively.
Dose / conc.:
240 mg/kg bw/day (nominal)
Remarks:
corresponds to 0.5%. Actual: 240 and 282 mg/kg bw/d in CD males, females respectively. Actual: 249 and 307 mg/kg bw/d in Wistar males, females respectively
Dose / conc.:
960 mg/kg bw/day (nominal)
Remarks:
corresponds to 2.0%. Actual: 960 and 1107 mg/kg bw/d in CD males, females respectively.
Actual: 960 and 1219 mg/kg bw/d in Wistar males, females respectively
Dose / conc.:
2 480 mg/kg bw/day (nominal)
Remarks:
corresponds to 5.0%. Actual: 2480 and 2780 mg/kg bw/d in CD males, females respectively.
Actual: 2480 and 3018 mg/kg bw/d in Wistar males, females respectively.
No. of animals per sex per dose:
30
Control animals:
yes, plain diet
Details on study design:
Experimental conditions were identical for the two different strains of rats. Rats 15-17 weeks of age
(n=30) were grouped housed 3/cage for the first 90 days of exposure. Body weight and feed intake
were determined weekly during this time period. On Day 91, breeding pairs (n=10/sex) were housed
together for 2 weeks prior to being separated. On Day 0 (delivery) the number and viability of offspring
were evaluated and grossly examined. Offspring were recounted, sexed, and weighed on Day 1.
These measurements were repeated at weaning on Day 21. After weaning, the litters were reduced to
2/sex/dose from each of 5 litters (20 pups/dose/strain) and maintained on test diets for 30 more days
(Day 51) prior to sacrifice.
Clinical signs:
no effects observed
Mortality:
mortality observed, treatment-related
Description (incidence):
Prior to mating, there were 5 deaths (3 CD females, and a Wistar male and female) reported during
weeks 4-13 among those given 5% TPA in the diet. After mating, 3 CD (1 male at 2.0%, and one
male and one female at 5.0%) and 4 Wistar female (2 at 5.0% and 2 at 0.03%) rats died.
Details on maternal toxic effects:
At the top two dose levels, several large litters of pups were lost to dams suffering obvious signs of toxicity. Several of these dams did not allow the pups to nurse or attend to the litters. These pups were noted not to have milk in their stomachs and presented clinically as being very weak. These dams were consuming dietary levels of TPA known to cause reduced feed consumption, diarrhea and gastric trichobezoars (hairballs) and induce the formation of renal and bladder calculi. Unscheduled deaths during the postweaning period (Day 21-51) were confined to the 5% TPA group (18 Wistar and 16 CD) and were associated with a very high incidence of renal and bladder calculi.
Key result
Dose descriptor:
NOAEL
Effect level:
240 mg/kg bw/day (nominal)
Based on:
test mat.
Basis for effect level:
other: no data provided in review article
Key result
Abnormalities:
not specified
Fetal body weight changes:
effects observed, treatment-related
Description (incidence and severity):
Average body weights of high dose Wistar offspring were reduced 17-19% on PND 1 (by litter), and by 32-36% on PND 21. Body weights were not initially reduced in CD offspring, but were 57-58% lower in CD's on PND 21.
Reduction in number of live offspring:
effects observed, treatment-related
Description (incidence and severity):
At 2 and 5% doses, there were 12 and 1 Wistar pups found dead at birth respecitvely; there were 7 and 15 CD pups dead at birth, respectively.
Changes in postnatal survival:
effects observed, treatment-related
Description (incidence and severity):
50% decreases in survivability of 5% CD strain maie and female pups on PND 21; no effects on 21-day viability of Wistar strain pups.
Visceral malformations:
effects observed, treatment-related
Description (incidence and severity):
Bladder calculi were observed in 44 and 51% of male and female Wistar offspring. Calculi were seen in 56 and 70% of male and female CD offspring, respectively.
Key result
Dose descriptor:
NOAEL
Effect level:
240 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
reduction in number of live offspring
fetal/pup body weight changes
changes in postnatal survival
visceral malformations
Abnormalities:
effects observed, treatment-related
Localisation:
other: not localized except for bladder calculi
Key result
Developmental effects observed:
yes
Lowest effective dose / conc.:
1 100 mg/kg bw/day (nominal)
Treatment related:
yes
Relation to maternal toxicity:
developmental effects occurring together with maternal toxicity effects, but not as a secondary non-specific consequence of maternal toxicity effects
Dose response relationship:
yes
Relevant for humans:
not specified

At 2 and 5% doses, there were 12 and 1 Wistar pups found dead at birth respecitvely; there were 7 and 15 CD pups dead at birth, respectively. Average body weights of high dose Wistar offspring were reduced 17-19% on PND 1 (by litter), and by 32-36% on PND 21 in this strain.  Body weights were not initially reduced in CD offspring, but were 57-58% lower on PND 21. There were 50% decreases in survivability of CD strain pups on PND 21, but no effects on survivability of Wistar strain pups. Bladder calculi were observed in 44 and 51% of male and female Wistar offspring.  Calculi were seen in 56 and 70% of male and female CD offspring, respectively.

Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
Study duration:
subacute
Species:
other: rat and rabbit
Quality of whole database:
adequate
Effect on developmental toxicity: via inhalation route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEC
10 mg/m³
Study duration:
subacute
Species:
rat
Quality of whole database:
adequate
Effect on developmental toxicity: via dermal route
Endpoint conclusion:
no study available

Mode of Action Analysis / Human Relevance Framework

Discussion:

There are no adverse reproductive effects known for terephthalic acid as a metabolic analogue using oral or inhalation routes of exposure, except for high doses above the maternal maximally tolerated dose.

A guideline OECD 421 study was performed to assess fertility effects from tallow alkylamines in rats by oral gavage, at doses of 12.5, 50 and 150 mg/kg bw day. Findings of general toxicity (death, clinical signs, reduced body weight gain, lower fertility index and a lower conception rate) at doses of 50 mg/kg bw/d resulted in a NOEL/maternal toxicity and NOEL/fertility of 12.5 mg/kg bw/d. The EU Risk Assessment Report on Primary Alkylamines recommends that there be no specific classification and labelling for tallow alkylamines and analogue/category members as reproductive toxicants.

Regarding developmental toxicity, a teratology study in rabbits on an analogue substance, N-octadecenylamine, by oral gavage at doses of 3, 10 and 30 mg/kg bw/d on days 6-18 of gestation showed generalised toxicity including laboured breathing, rales, mouth irritation and decreased body weight gain at the two highest doses.  There were no teratologic or fetotoxic effects attributed to the administration of test material at any of these doses.  The NOAEL for maternal toxicity was 3 mg/kg bw/d, and the NOAEL for reproductive effects was > 30 mg/kg bw/d in rabbits. In another teratology study performed in rats, the N-octadecenylamine test material was administered by gavage at doses of 10, 40 and 80 mg/kg bw/d on days 6-15 of gestation. The high and mid dose groups showed evidence of generalised toxicity as a decrease in grooming behaviour and decreased body weight gain; there were no teratologic or fetotoxic effects.  The NOAEL for maternal toxicity was 10 mg/kg bw/d, and the NOAEL for reproductive effects was > 80 mg/kg bw/d. These values are read across to the target substance.

Justification for classification or non-classification

There are no adverse reproductive effects known for terephthalic acid as a metabolic analogue. In experimental studies of metabolites (amine analogues) of the target substance, there was a decrease in selected fertility measures in rats only at doses associated with maternal (adult) toxicity. There were no adverse effects in developmental toxicity studies in rats or rabbits. In accordance with the EU Draft RAR on Primary Alkylamines, the substances (source and target) are not classified as reproductive toxicants.