Registration Dossier
Registration Dossier
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EC number: - | CAS number: -
- Life Cycle description
- Uses advised against
- Endpoint summary
- Appearance / physical state / colour
- Melting point / freezing point
- Boiling point
- Density
- Particle size distribution (Granulometry)
- Vapour pressure
- Partition coefficient
- Water solubility
- Solubility in organic solvents / fat solubility
- Surface tension
- Flash point
- Auto flammability
- Flammability
- Explosiveness
- Oxidising properties
- Oxidation reduction potential
- Stability in organic solvents and identity of relevant degradation products
- Storage stability and reactivity towards container material
- Stability: thermal, sunlight, metals
- pH
- Dissociation constant
- Viscosity
- Additional physico-chemical information
- Additional physico-chemical properties of nanomaterials
- Nanomaterial agglomeration / aggregation
- Nanomaterial crystalline phase
- Nanomaterial crystallite and grain size
- Nanomaterial aspect ratio / shape
- Nanomaterial specific surface area
- Nanomaterial Zeta potential
- Nanomaterial surface chemistry
- Nanomaterial dustiness
- Nanomaterial porosity
- Nanomaterial pour density
- Nanomaterial photocatalytic activity
- Nanomaterial radical formation potential
- Nanomaterial catalytic activity
- Endpoint summary
- Stability
- Biodegradation
- Bioaccumulation
- Transport and distribution
- Environmental data
- Additional information on environmental fate and behaviour
- Ecotoxicological Summary
- Aquatic toxicity
- Endpoint summary
- Short-term toxicity to fish
- Long-term toxicity to fish
- Short-term toxicity to aquatic invertebrates
- Long-term toxicity to aquatic invertebrates
- Toxicity to aquatic algae and cyanobacteria
- Toxicity to aquatic plants other than algae
- Toxicity to microorganisms
- Endocrine disrupter testing in aquatic vertebrates – in vivo
- Toxicity to other aquatic organisms
- Sediment toxicity
- Terrestrial toxicity
- Biological effects monitoring
- Biotransformation and kinetics
- Additional ecotoxological information
- Toxicological Summary
- Toxicokinetics, metabolism and distribution
- Acute Toxicity
- Irritation / corrosion
- Sensitisation
- Repeated dose toxicity
- Genetic toxicity
- Carcinogenicity
- Toxicity to reproduction
- Specific investigations
- Exposure related observations in humans
- Toxic effects on livestock and pets
- Additional toxicological data
Endpoint summary
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
- 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 for cross-reference:
- read-across source
- Qualifier:
- according to guideline
- 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%. - 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
- 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 for cross-reference:
- read-across source
- Qualifier:
- equivalent or similar to guideline
- 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
- 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)
- 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
- 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.
Referenceopen allclose all
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.
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.
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).
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
- 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 for cross-reference:
- read-across source
- Qualifier:
- according to guideline
- 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 for cross-reference:
- read-across source
- Qualifier:
- according to guideline
- 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 for cross-reference:
- read-across source
- Qualifier:
- according to guideline
- 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
Referenceopen allclose all
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.
Additional information
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